HK40117012A - Combination treatment of an anti-cd20/anti-cd3 bispecific antibody and chemotherapy - Google Patents

Description

Combination therapy of anti-CD20/anti-CD3 bispecific antibodies and chemotherapy

Technical Field

This invention relates to a method for treating B-cell proliferative disorders (e.g., primary refractory or relapsed diffuse large B-cell lymphoma (DLBCL)) by administering an anti-CD20/anti-CD3 bispecific antibody in combination with an anti-CD20 antibody (e.g., olibutuzumab or rituximab) and one or more chemotherapeutic agents selected from ifosfamide, carboplatin and/or etoposide.

Background Technology

Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy worldwide (Bray et al. 2018). The most common B-cell-derived NHL subtype (Sun et al. Am. J. Clin. Pathol. 138:429-434, 2012; Al-Hamadani et al. Am. J. Hematol. 24:4785-4797, 2015), DLBCL is an aggressive NHL in which the median survival in untreated patients is <1 year (Rovira et al. Ann. Hematol. 94:803-812, 2015). Despite its invasive disease course, approximately 50% to 70% of patients can be cured with the current standard of care, which consists of a combination of rituximab (a monoclonal antibody targeting CD20) and chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) (Flowers et al. CA Cancer J. Clin. 60:393-408 2010; Tilly et al. Ann. Oncol. 26(Suppl 5):v116-125 2015; NCCN Clinical Practice Guidelines in Oncology, 2020).

Nevertheless, due to primary refractory nature, R-CHOP has been found to be ineffective in 30% to 50% of patients. Primary refractory nature is defined as failure to achieve complete remission (CR) after first-line therapy with rituximab plus anthracycline (Vardhana et al., Br. J. Haematol. 176:591-599, 2017) or relapse after achieving CR. For patients who are not cured by first-line therapy and are medically tolerant of intensive therapy, ASCT following high-dose salvage chemoimmunotherapy provides a second chance for long-term remission. Approximately half of patients with relapsed DLBCL are refractory to salvage chemoimmunotherapy (Gisselbrecht et al., J. Clin. Oncol. 28:4184-4190, 2010) and are therefore ineligible for ASCT. Furthermore, CAR-T therapy is a viable treatment option for subgroups of patients with DLBCL, particularly those with primary refractory disease or those who have relapsed within 12 months of initial immunotherapy (Kamdar et al. 2022, Lancet 399, 2294-2308; Locke et al. 2022, N Engl J Med 386, 640-54). Given that the median EFS observed in both studies was less than 1 year, there remains an opportunity to optimize treatment regimens involving CAR-T therapy. Therefore, there is a significant clinical need to improve salvage immunochemotherapy regimens for patients with relapsed or refractory (R/R) DLBCL.

Combining anti-CD20/anti-CD3 bispecific antibodies with anti-CD20 antibodies (e.g., olibutuzumab or rituximab) and one or more chemotherapeutic agents selected from ifosfamide, carboplatin, and/or etoposide can provide improved response rates to salvage chemoimmunotherapy, which may ultimately translate into a higher proportion of patients receiving ASCT or CAR-T therapy as a final treatment and improved survival in that therapeutic setting.

Invasive mature B-NHL accounts for approximately 60% of all pediatric non-Hodgkin lymphoma (NHL) cases. The major histological subtypes are Burkitt lymphoma (BL), Burkitt leukemia (BAL; similar to mature B-cell leukemia FAB L3), diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), and aggressive mature B-NHL that cannot be further classified. While first-line therapy with intensive chemotherapy plus rituximab is highly effective in children, with a 3-year event-free survival rate of 94% (Minard-Colin et al., N.Eng.J.Med.382:2207-2219, 2020), developing effective salvage regimens for patients with relapsed/relapsed disease remains an urgent and highly unmet need (Pearson et al., Eur.J.Cancer.110:74-85, 2019). Survival rates for R/R B-NHL are extremely low in children, adolescents, and young adults, with a 1-year overall survival (OS) rate of less than 30% (Cairo et al. Br. J. Haematol. 182:859-869, 2018; Woessmann et al. Blood. 135:1124-1132, 2020; Burkhardt et al. Cancers. 13:2075, 2021; Crombie and LaCasce Blood. 137:743-750, 2021).

Summary of the Invention

In one aspect, the invention is characterized by a method of treating a subject with a CD20-positive proliferative disorder, the method comprising administering an effective amount to the subject in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle:

(a) Bispecific antibodies that bind to CD20 and CD3;

(b) Anti-CD20 antibody; and

(c) One or more chemotherapeutic agents selected from ifosfamide, carboplatin and/or etoposide.

In one embodiment, the subject is 18 years of age or older (e.g., 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, or 110 years of age or older). In another embodiment, the subject is 31 years of age or older.

In one embodiment, the first dosing cycle includes a first dose (C1D1) of a bispecific antibody binding to CD20 and CD3 and a second dose (C1D2) of the bispecific antibody, wherein the C1D1 of the bispecific antibody is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of the bispecific antibody is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); and the second dosing cycle includes the bispecific antibody... A single dose (C2D1) of the bispecific antibody, wherein the C2D1 of the bispecific antibody is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg or ± 1 mg), about 16 mg (e.g., 16 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg or ± 1.6 mg), or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg). In one embodiment, the C2D1 of the bispecific antibody is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

In one embodiment, a first dose (C1D1) of the bispecific antibody binding to CD20 and CD3 and a second dose (C1D2) of the bispecific antibody binding to CD20 and CD3 are administered to the subject on days 8 and 15 of the first dosing cycle, respectively. In another embodiment, C2D1 of the bispecific antibody binding to CD20 and CD3 is administered to the subject on day 8 of the second dosing cycle.

In one embodiment, the anti-CD20 antibody is olibutuzumab and/or rituximab. In one embodiment, the first dosing cycle comprises a single dose of olibutuzumab (C1D1); and the second dosing cycle comprises a single dose of rituximab (C2D1). In one embodiment, the single dose of olibutuzumab C1D1 is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg), and the single dose of rituximab is about 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ). In one embodiment, the anti-CD20 antibody is administered with a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein the first dosing cycle comprises a single dose of olibutuzumab on day 1 (C1D1); and the second dosing cycle comprises a single dose of rituximab on day 1 (C2D1).

In one embodiment, step c) includes all three chemotherapeutic agents. In one embodiment, the first dosing cycle includes a single dose of ifosfamide (C1D1), a single dose of carboplatin (C1D1), and a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of etoposide; and the second cycle each includes a single dose of ifosfamide (C2D1), a single dose of carboplatin (C2D1), and a first dose (C2D1), a second dose (C2D2), and a third dose (C2D3) of etoposide. In one embodiment, the concentration is approximately 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ), approximately 4000 mg/ ^m² (e.g., 4000 mg/ ^m² ± 40 mg/ ^m² , ± 50 mg/ ^m² , ± 100 mg/m², ± 200 mg/ ^m² , ± 300 mg/ ^m² , or ± 400 mg/ ^{m² )} , or approximately 1666 mg/ ^m² (e.g., 1666 mg/ ^m² ± 25 mg/ ^m² , ± 50 mg/ ^m² , ± 100 mg/ ^m² , or ± 166.6 mg/m² ^). Ifosfamide is administered at a dose of approximately 5 mg/mL/min (e.g., 5 mg/mL/min ± 0.05 mg/mL/min, ± 0.1 mg/mL/min, ± 0.25 mg/mL/min, or ± 0.5 mg/mL/min), with the maximum dose being approximately 750 mg (e.g., 750 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 75 mg), and carboplatin is administered at a dose of approximately 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/ ^m² ) or 75 mg/ ^m² (e.g., 0.5 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 7.5 mg/m² ^). Etoposide is administered at the following doses. In one embodiment, ifosfamide is administered at a dose of 5000 mg/ ^m² , 4000 mg/ ^m² , or 1666 mg/ ^m² , carboplatin is administered at a dose of 750 mg (calculated as mg) up to the target area under the curve (AUC) of 5 mg/mL/min, and etoposide is administered at a dose of 100 mg/ ^m² or 75 mg/ ^m² . In another embodiment, ifosfamide is administered at a dose of 5000 mg/ ^m² , carboplatin is administered at a dose of 750 mg (calculated as mg) up to the target area under the curve (AUC) of 5 mg/mL/min, and etoposide is administered at a dose of 100 mg/ ^m² . In one embodiment, ifosfamide and carboplatin are administered on day 2 of the first and second dosing cycles, and etoposide is administered on each of days 1, 2, and 3 of the first and second dosing cycles.

In one embodiment, the first and second dosing cycles are 21-day dosing cycles.

In one embodiment, the dosing regimen includes one or more additional dosing cycles. In one embodiment, the additional dosing cycle is a 21-day dosing cycle. In one embodiment, the dosing regimen includes a total of three dosing cycles.

In one embodiment, one or more additional dosing cycles include:

(a) An additional single dose of a bispecific antibody that binds to both CD20 and CD3.

(b) An additional single dose of anti-CD20 antibody, and

(c) Additional single doses of ifosfamide, additional single doses of carboplatin, and additional first, second, and third doses of etoposide. In one embodiment, the additional single dose of the bispecific antibody is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

In one embodiment, the anti-CD20 antibody for one or more additional dosing cycles is rituximab. In one embodiment, the additional single dose of rituximab is about 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ). In one embodiment, this additional single dose of rituximab is administered on day 1 of the additional dosing cycle.

In one embodiment, the additional single dose of ifosfamide is about 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ), about 4000 mg/ ^m² (e.g., 4000 mg/ ^m² ± 40 mg/ ^m² , ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , or ± 400 mg/ ^m² ), or about 1666 mg/ ^m² (e.g., 1666 mg/ ^m² ± 25 mg/ ^m² , ± 50 mg/ ^m² , ± 100 mg/ ^m² , or ± 166.6 mg/m² ^). The additional single dose of carboplatin is approximately 5 mg/mL/min (e.g., 5 mg/mL/min ± 0.05 mg/mL/min, ± 0.1 mg/mL/min, ± 0.25 mg/mL/min, or ± 0.5 mg/mL/min), with the maximum dose being approximately 750 mg (e.g., 750 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 75 mg), and the additional first, second, and third doses of etoposide are 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/ ^m² ) or 75 mg/ ^m² (e.g., 0.5 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 7.5 mg/ ^m² ). In one embodiment, the additional single dose of ifosfamide is 5000 mg/ ^m² , 4000 mg/ ^m² , or 1666 mg/ ^m² , the additional single dose of carboplatin is 750 mg, up to a target area under the curve (AUC) of 5 mg/mL/min, and the additional first, second, and third doses of etoposide are 100 mg/ ^m² or 75 mg/ ^m² . In one embodiment, ifosfamide is administered at a dose of 5000 mg/ ^m² , carboplatin is administered at a dose of 750 mg, up to a target area under the curve (AUC) of 5 mg/mL/min, and etoposide is administered at a dose of 100 mg/ ^m² .

In one embodiment, ifosfamide and carboplatin are administered on day 2 of the additional dosing cycle, and etoposide is administered on each of days 1, 2, and 3 of the additional dosing cycle.

In one embodiment, the method further includes administering one or more additional therapeutic agents to the subject. In one embodiment, the one or more additional therapeutic agents are tocilizumab. In one embodiment, the subject weighs more than or equal to about 30 kg and is administered tocilizumab at a dose of about 8 mg/kg (e.g., 8 mg/kg ± 0.05 mg/kg, ± 0.1 mg/kg, ± 0.25 mg/kg, ± 0.5 mg/kg, or ± 0.8 mg/kg). In one embodiment, the subject weighs less than 30 kg and is administered tocilizumab at a dose of about 12 mg/kg (e.g., 12 mg/kg ± 0.05 mg/kg, ± 0.1 mg/kg, ± 0.25 mg/kg, ± 0.5 mg/kg, ± 0.75 mg/kg, ± 1 mg/kg, or ± 1.2 mg/kg). In some embodiments, the maximum dose of tocilizumab is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg).

In one embodiment, one or more additional therapeutic agents are corticosteroids. In one embodiment, the corticosteroids include prednisone, prednisolone, methylprednisolone, or dexamethasone. In one embodiment, dexamethasone is administered intravenously at a dose of about 20 mg (e.g., 20 mg ± 0.1 mg, ± 0.25 mg, ± 0.5 mg, ± 1 mg, ± 1.5 mg, or ± 2 mg) at least one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before the administration of any dose of the bispecific antibody. In one embodiment, dexamethasone is administered intravenously at a dose of about 20 mg (e.g., 20 mg ± 0.1 mg, ± 0.25 mg, ± 0.5 mg, ± 1 mg, ± 1 mg, ± 1.5 mg, or ± 2 mg) at least about one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before any dose of olibutuzumab is administered. In one embodiment, methylprednisolone is administered intravenously at a dose of about 80 mg (e.g., 80 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, or ± 8 mg) at least about one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before any dose of the bispecific antibody is administered. In one embodiment, methylprednisolone is administered intravenously at a dose of about 80 mg (e.g., 80 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, or ± 8 mg) at least one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before any dose of olibutuzumab is administered. In one embodiment, prednisone is administered orally at a dose of about 100 mg (e.g., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) at least one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before any dose of the bispecific antibody is administered. In one embodiment, prednisolone is administered intravenously at a dose of about 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 8 mg, or ± 10 mg) at least about one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before any dose of the bispecific antibody is administered.

In one embodiment, one or more additional therapeutic agents are antihistamines. In one embodiment, the antihistamine is diphenhydramine. In one embodiment, diphenhydramine is administered orally or intravenously at a dose of about 50 mg (e.g., 50 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, or ± 5 mg) at least about 30 minutes (i.e., at least 30 minutes ± 3 minutes; for example, at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before the administration of any dose of the bispecific antibody.

In one embodiment, one or more additional therapeutic agents include granulocyte colony-stimulating factor (G-CSF). In one embodiment, G-CSF is administered approximately one to approximately two days (e.g., 24, 26, 28, 30, 32, 36, 38, 40, 42, 44, 46, or 48 hours) following administration of any dose of rituximab, ifosfamide, carboplatin, and/or etoposide.

In one embodiment, one or more additional therapeutic agents are antipyretics. In one embodiment, the antipyretic is acetaminophen or paracetamol. In one embodiment, acetaminophen or paracetamol is administered orally at a dose between about 500 mg and about 1000 mg (e.g., at least 30 minutes ± 3 minutes; for example, at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before administration of any dose of the bispecific antibody. In one embodiment, acetaminophen or paracetamol is administered orally at a dose between about 500 mg and about 1000 mg (e.g., at least 30 minutes ± 3 minutes; for example, at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before administration of any dose of olibutuzumab.

In one embodiment, one or more additional therapeutic agents are mesna. In one embodiment, the concentration is approximately 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ), approximately 4000 mg/ ^m² (e.g., 4000 mg/ ^m² ± 40 mg/ ^m² , ± 50 mg/ ^m² , ± 100 mg/m², ± 200 mg/ ^m² , ± 300 mg/ ^m² , or ± 400 mg/ ^{m² )} , or approximately 1666 mg/ ^m² (e.g., 1666 mg/ ^m² ± 25 mg/ ^m² , ± 50 mg/ ^m² , ± 100 mg/ ^m² , or ± 166.6 mg/m² ^). Mesna was administered intravenously at a dose of 100 mg/dL.

In one aspect, the invention is characterized by a method for treating a subject aged between 6 months and 17 years with CD20-positive proliferative disorders, the method comprising administering an effective amount to the subject in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle:

(a) Bispecific antibodies that bind to CD20 and CD3;

(b) Anti-CD20 antibody; and

(c) One or more chemotherapeutic agents selected from ifosfamide, carboplatin and/or etoposide.

In one embodiment, the first dosing cycle includes a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody, wherein the C1D1 of the bispecific antibody is about 0.03 mg/kg (e.g., 0.03 mg/kg ± 0.0005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg, or ± 0.003 mg/kg), about 0.04 mg/kg (e.g., 0.04 mg/kg ± 0.0005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg, ± 0.003 mg/kg, or ± 0.004 mg/kg), or about 2.5 mg/kg. mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of the bispecific antibody is about 0.15 mg/kg (e.g., 0.15 mg/kg ± 0.001 mg/kg, ± 0.0025 mg/kg, ± 0.005 mg/kg, ± 0.01 mg/kg, or ± 0.015 mg/kg) or about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); and

The second dosing cycle includes a single dose (C2D1) of the bispecific antibody, wherein the C2D1 of the bispecific antibody is about 0.4 mg/kg (e.g., 0.4 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg or ± 0.04 mg/kg), about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, ± 0.04 mg/kg or ± 0.05 mg/kg), or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg).

In one embodiment, (a) the subject's weight is greater than or equal to about 7.5 kg and less than about 13 kg, and the C1D1 of the bispecific antibody is about 0.04 mg/kg (e.g., 0.04 mg/kg ± 0.0005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg, ± 0.003 mg/kg, or ± 0.004 mg/kg), and the C1D2 of the bispecific antibody is about 0.15 mg/kg (e.g., 0.15 mg/kg). The C2D1 of the bispecific antibody is approximately 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.001 mg/kg, ± 0.0025 mg/kg, ± 0.005 mg/kg, ± 0.01 mg/kg, or ± 0.015 mg/kg), and the C2D1 of the bispecific antibody is approximately 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, ± 0.04 mg/kg, or ± 0.05 mg/kg).

(b) The subject's weight is greater than or equal to about 13 kg and less than about 45 kg, and the C1D1 of the bispecific antibody is about 0.03 mg/kg (e.g., 0.03 mg/kg ± 0.0005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg, or ± 0.003 mg/kg), the C1D2 of the bispecific antibody is about 0.15 mg/kg (e.g., 0.15 mg/kg ± 0.001 mg/kg, ± 0.0025 mg/kg, ± 0.005 mg/kg, ± 0.01 mg/kg, or ± 0.015 mg/kg), and the C2D1 of the bispecific antibody is about 0.4 mg/kg (e.g., 0.4 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, or ± 0.04 mg/kg); or

(c) The subject weighs 45 kg or more and has a C1D1 dose of about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg or ± 0.25 mg), a C1D2 dose of about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg or ± 1 mg), and a C2D1 dose of about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg).

In one embodiment, the bispecific antibody C1D1 and bispecific antibody C1D2 are administered to the subject on days 8 and 15 of the first dosing cycle, respectively. In another embodiment, the bispecific antibody C2D1 is administered to the subject on day 1 of the second dosing cycle.

In one embodiment, the anti-CD20 antibody is olibutuzumab and/or rituximab.

In one embodiment, the first dosing cycle includes a first dose (C1D1) of oxetuzumab and a second dose (C1D2) of oxetuzumab. In one embodiment, (a) the subject's weight is greater than or equal to about 7.5 kg and less than about 13 kg, and the sum of C1D1 and C1D2 of olibutuzumab is about 38 mg/kg (e.g., 38 mg/kg ± 0.25 mg/kg, ± 0.5 mg/kg, ± 1 mg/kg, ± 2 mg/kg, ± 3 mg/kg, or ± 3.8 mg/kg); (b) the subject's weight is greater than or equal to about 13 kg and less than about 20 kg, and the sum of the C1D1 and C1D2 of olibutuzumab is about 28 mg/kg (e.g., 28 mg/kg ± 0.25 mg/kg, ± 0.5 mg/kg, ± 1 mg/kg, ± 2 mg/kg, or ± 2.8 mg/kg); (c) the subject's weight is greater than or equal to about 20 kg and less than about 32 kg, and the sum of the C1D1 and C1D2 of olibutuzumab is about 38 mg/kg (e.g., 28 mg/kg ± 0.25 mg/kg, ± 0.5 mg/kg, ± 1 mg/kg, ± 2 mg/kg, or ± 2.8 mg/kg); The sum of C1D1 and C1D2 is about 23 mg/kg (e.g., 23 mg/kg ± 0.25 mg/kg, ± 0.5 mg/kg, ± 1 mg/kg, ± 2 mg/kg, or ± 2.3 mg/kg); (d) the subject weighs more than or equal to about 32 kg and less than about 45 kg, and the sum of C1D1 and C1D2 of olibutuzumab is about 20 mg/kg (e.g., 23 mg/kg ± 0.25 mg/kg, ± 0.5 mg/kg, ± 1 mg/kg, or ± 2 mg/kg); or (e) the subject weighs more than or equal to about 45 kg, and the sum of C1D1 and C1D2 of olibutuzumab is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg).

In one embodiment, the C1D1 of oxytocinumab is about one-tenth the sum of the C1D1 and C1D2 of oxytocinumab, and the C1D2 of oxytocinumab is about nine-tenths the sum of the C1D1 and C1D2 of oxytocinumab. In one embodiment, (a) the subject's weight is greater than or equal to about 7.5 kg and less than about 13 kg, and the C1D1 of olibutuzumab is about 3.8 mg/kg (e.g., 3.8 mg/kg ± 0.05 mg/kg, 0.1 mg/kg, ± 0.2 mg/kg, ± 0.3 mg/kg, or ± 0.38 mg/kg) and the C1D2 of olibutuzumab is about 34.2 mg/kg (e.g., 34.2 mg/kg ± 0.5 mg/kg, 1 mg/kg, ± 2 mg/kg, ± 3 mg/kg, or ± 3.42 mg/kg); (b) the subject's weight is greater than or equal to about 13 kg and less than about 20 kg, and the C1D2 of olibutuzumab is about 3.8 mg/kg (e.g., 3.8 mg/kg ± 0.05 mg/kg, 0.1 mg/kg, ± 0.2 mg/kg, ± 0.3 mg/kg, or ± 0.38 mg/kg) and the C1D2 of olibutuzumab is about 34.2 mg/kg (e.g., 34.2 mg/kg ± 0.5 mg/kg, 1 mg/kg, ± 2 mg/kg, ± 3 mg/kg, or ± 3.42 mg/kg); The C1D1 of olibutuzumab is about 2.8 mg/kg (e.g., 2.8 mg/kg ± 0.05 mg/kg, 0.1 mg/kg, ± 0.2 mg/kg, or ± 0.28 mg/kg), and the C1D2 of olibutuzumab is about 35.2 mg/kg (e.g., 35.2 mg/kg ± 0.5 mg/kg, 1 mg/kg, ± 2 mg/kg, ± 3 mg/kg, or ± 3.52 mg/kg); (c) the subject's weight is greater than or equal to about 20 kg and less than about 32 kg, and the C1D1 of olibutuzumab is about 2.3 mg/kg (e.g., 2.3 mg/kg ± 0.05 mg/kg, 0.1 mg/kg, ± 0.2 mg/kg, or ± 0.28 mg/kg). (d) The subject's weight is greater than or equal to about 32 kg and less than about 45 kg, and the C1D1 of olibutuzumab is about 2.0 mg/kg (e.g., 2.0 mg/kg ± 0.05 mg/kg, 0.1 mg/kg or ± 0.2 mg/kg), and the C1D2 of olibutuzumab is about 36.0 mg/kg (e.g., 36 mg/kg ± 0.2 mg/kg, ± 0.23 ... (e) The subject's weight is greater than or equal to about 45 kg, and the C1D1 of olibutuzumab is about 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 8 mg or ± 10 mg) and the C1D2 of olibutuzumab is about 900 mg (e.g., 900 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 40 mg, ± 50 mg, ± 60 mg, ± 70 mg, ± 80 mg or ± 90 mg).

In one embodiment, the subject is given C1D1 of bisacodyltocilizumab on day 1 of the first dosing cycle and C1D2 of bisacodyltocilizumab on day 2 of the first dosing cycle.

In one embodiment, the second dosing cycle comprises a single dose (C2D1) of rituximab. In one embodiment, the C2D1 of rituximab is approximately 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ). In one embodiment, rituximab is administered to the subject on day 5 of the second dosing cycle.

In one embodiment, the method includes administering ifosfamide, carboplatin, and etoposide to a subject.

In one embodiment, the first dosing cycle includes:

(a) The first dose of ifosfamide (C1D1), the second dose of ifosfamide (C1D2), and the third dose of ifosfamide (C1D3);

(b) A single dose of carboplatin (C1D1); and

(c) The first dose of etoposide (C1D1), the second dose of etoposide (C1D2), and the third dose of etoposide (C1D3);

And the second cycle includes:

(a) The first dose of ifosfamide (C2D1), the second dose of ifosfamide (C2D2), and the third dose of ifosfamide (C2D3);

(b) A single dose of carboplatin (C2D1); and

(c) The first dose of etoposide (C2D1), the second dose of etoposide (C2D2), and the third dose of etoposide (C2D3).

In one embodiment, ifosfamide is administered at a dose of approximately 3000 mg/ ^m² (e.g., 3000 mg/ ^m² ± 40 mg/ ^m² , ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , or ± 300 mg/ ^m² ). For each dose of ifosfamide, carboplatin is administered at a dose of approximately 635 mg/ ^m² (e.g., 635 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , ± 50 mg/ ^m² , ± 60 mg/ ^m² , or ± 63.5 mg/ ^m² ), and carboplatin is administered at a dose of approximately 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/m² ^). Etoposide is administered at each dose of etoposide. In one embodiment, (a) ifosfamide C1D1, C1D2, and C1D3 are administered on days 3, 4, and 5 of the first dosing cycle, respectively; (b) carboplatin C1D1 is administered on day 3 of the first dosing cycle; (c) etoposide C1D1, C1D2, and C1D3 are administered on days 3, 4, and 5 of the first dosing cycle, respectively; (d) ifosfamide C2D1, C2D2, and C2D3 are administered on days 6, 7, and 8 of the second dosing cycle, respectively; (e) carboplatin C2D1 is administered on day 6 of the second dosing cycle; and (f) etoposide C2D1, C2D2, and C2D3 are administered on days 6, 7, and 8 of the second dosing cycle, respectively.

In one embodiment, the first and second dosing cycles are each 21-day dosing cycles. In one embodiment, the dosing regimen includes one or more additional dosing cycles. In one embodiment, the one or more additional dosing cycles are each 21-day dosing cycles. In one embodiment, the dosing regimen includes a total of three dosing cycles.

In one embodiment, one or more additional dosing cycles each include:

(a) An additional single dose of a bispecific antibody that binds to both CD20 and CD3.

(b) An additional single dose of anti-CD20 antibody, and

(c) Additional first, second, and third doses of ifosfamide; an additional single dose of carboplatin; and additional first, second, and third doses of etoposide. In one embodiment, (a) the subject weighs more than or equal to about 7.5 kg and less than about 13 kg, and the additional single dose of the bispecific antibody is about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, ± 0.04 mg/kg, or ± 0.05 mg/kg); (b) the subject weighs more than or equal to about 13 kg and less than about 45 kg, and the additional single dose of the bispecific antibody is... (c) The subject weighs more than or equal to about 45 kg, and the additional single dose of the bispecific antibody is about 30 mg (e.g., 0.4 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg or ± 0.04 mg/kg); or (d) the subject weighs more than or equal to about 45 kg, and the additional single dose of the bispecific antibody is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg).

In one embodiment, an additional single dose of the bispecific antibody is administered to the subject on day 1 of each of one or more additional dosing cycles.

In one embodiment, the anti-CD20 antibody is rituximab. In one embodiment, the additional single dose of rituximab is about 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ). In one embodiment, the additional single dose of rituximab is administered on day 5 of each of one or more additional dosing cycles.

In one embodiment, the additional first, second, and third doses of ifosfamide are each about 3000 mg/ ^m² (e.g., 3000 mg/ ^m² ± 40 mg/ ^m² , ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , or ± 300 mg/ ^m² ), the additional single dose of carboplatin is about 635 mg/ ^m² (e.g., 635 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , ± 50 mg/ ^m² , ± 60 mg/ ^m² , or ± 63.5 mg/ ^m² ), and the additional first, second, and third doses of etoposide are each about 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/m²). ² or ±10 mg/ ^m² ). In one embodiment, (a) the subject is given an additional first dose, an additional second dose, and an additional third dose of ifosfamide on days 6, 7, and 8 of each of the one or more additional dosing cycles; (b) an additional single dose of carboplatin is given on day 6 of each of the one or more additional dosing cycles; and (c) an additional first dose, an additional second dose, and an additional third dose of etoposide are given to the subject on days 6, 7, and 8 of each of the one or more additional dosing cycles.

In one embodiment, the method further includes administering one or more additional therapeutic agents to the subject.

In one embodiment, one or more additional therapeutic agents are tocilizumab. In one embodiment, the subject weighs more than or equal to about 30 kg and is administered tocilizumab at a dose of about 8 mg/kg (e.g., 8 mg/kg ± 0.05 mg/kg, ± 0.1 mg/kg, ± 0.25 mg/kg, ± 0.5 mg/kg, or ± 0.8 mg/kg), or the subject weighs less than 30 kg and is administered tocilizumab at a dose of about 12 mg/kg (e.g., 12 mg/kg ± 0.05 mg/kg, ± 0.1 mg/kg, ± 0.25 mg/kg, ± 0.5 mg/kg, ± 0.75 mg/kg, ± 1 mg/kg, or ± 1.2 mg/kg), wherein the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg).

In one embodiment, one or more additional therapeutic agents are corticosteroids. In one embodiment, corticosteroids include prednisone, prednisolone, methylprednisolone, or dexamethasone.

In one embodiment, the corticosteroid is dexamethasone. In one embodiment, dexamethasone is administered intravenously at a dose between about 0.15 mg/kg (e.g., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) and about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.001 mg/kg, ± 0.0025 mg/kg, ± 0.005 mg/kg, ± 0.01 mg/kg, or ± 0.015 mg/kg) before any dose of the bispecific antibody, and wherein the maximum daily dose is 10 mg. In one embodiment, dexamethasone is administered intravenously at a dose between about 0.15 mg/kg (e.g., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) and about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.001 mg/kg, ± 0.0025 mg/kg, ± 0.005 mg/kg, ± 0.01 mg/kg or ± 0.015 mg/kg) and about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, ± 0.04 mg/kg or ± 0.05 mg/kg) before administration of any dose of olibutuzumab, and wherein the maximum daily dose is 10 mg.

In one embodiment, the corticosteroid is methylprednisolone. In one embodiment, methylprednisolone is administered intravenously at a dose between about 1 mg/kg and about 2 mg/kg (e.g., 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.9 or 2.0 mg/kg) at least one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) prior to the administration of any dose of the bispecific antibody. In one embodiment, methylprednisolone is administered intravenously at a dose between about 1 mg/kg and about 2 mg/kg (e.g., 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.9 or 2.0 mg/kg) for at least about one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) prior to the administration of any dose of olibutuzumab.

In one embodiment, the corticosteroid is prednisone or prednisolone. In one embodiment, prednisone or prednisolone is administered intravenously at a dose of about 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 8 mg, or ± 10 mg) or about 2 mg/kg at least one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) or about 2 mg/kg before administration of any dose of the bispecific antibody. In one embodiment, prednisone or prednisolone is administered intravenously at a dose of about 100 mg (e.g., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) or about 2 mg/kg, at least one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before any dose of olibutuzumab.

In one embodiment, one or more additional therapeutic agents are antihistamines. In one embodiment, the antihistamine is diphenhydramine. In one embodiment, the subject is between 2 and 17 years of age, and diphenhydramine is administered intravenously at a dose of about 10 mg to 20 mg (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg), wherein the maximum single dose is about 1.25 mg/kg. In one embodiment, the subject is less than two years of age, and diphenhydramine is administered rectally at a dose of about 20 mg (e.g., 20 mg ± 0.1 mg, ± 0.25 mg, ± 0.5 mg, ± 1 mg, ± 1.5 mg, or ± 2 mg). In one embodiment, diphenhydramine is administered at least about 30 minutes (i.e., at least 30 minutes ± 3 minutes; for example, at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) prior to the administration of any dose of the bispecific antibody and/or anti-CD20 antibody.

In one embodiment, one or more additional therapeutic agents include granulocyte colony-stimulating factor (G-CSF). In one embodiment, G-CSF is administered approximately one to approximately two days (e.g., 24, 26, 28, 30, 32, 36, 38, 40, 42, 44, 46, or 48 hours) following administration of any dose of rituximab, ifosfamide, carboplatin, and/or etoposide. In one embodiment, G-CSF is administered intravenously or subcutaneously at a dose of about 5 μg/kg/day (e.g., 5 μg/kg/day ± 0.05 μg/kg/day, ± 0.1 μg/kg/day, ± 0.2 μg/kg/day, ± 0.3 μg/kg/day, ± 0.4 μg/kg/day, ± 0.5 μg/kg/day) or about 10 μg/kg/day (e.g., 10 μg/kg/day ± 0.1 μg/kg/day, ± 0.2 μg/kg/day, ± 0.4 μg/kg/day, ± 0.6 μg/kg/day, ± 0.8 μg/kg/day, ± 1 μg/kg/day). In one embodiment, G-CSF is administered at a dose of about 5 μg/kg/day in the first dosing cycle (e.g., 5 μg/kg/day ± 0.05 μg/kg/day, ± 0.1 μg/kg/day, ± 0.2 μg/kg/day, ± 0.3 μg/kg/day, ± 0.4 μg/kg/day, ± 0.5 μg/kg/day) in the second dosing cycle and/or each additional dosing cycle at a dose of about 10 μg/kg/day (e.g., 10 μg/kg/day ± 0.1 μg/kg/day, ± 0.2 μg/kg/day, ± 0.4 μg/kg/day, ± 0.6 μg/kg/day, ± 0.8 μg/kg/day, ± 1 μg/kg/day).

In one embodiment, one or more additional therapeutic agents are antipyretics. In one embodiment, the antipyretic is acetaminophen or paracetamol. In one embodiment, acetaminophen or paracetamol is administered orally or intravenously at a dose between about 500 and about 1000 mg (e.g., 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg). In one embodiment, acetaminophen or paracetamol is administered at least about 30 minutes (i.e., at least 30 minutes ± 3 minutes; e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before the administration of any dose of the bispecific antibody and/or anti-CD20 antibody.

In one embodiment, one or more additional therapeutic agents are mesna. In one embodiment, mesna is administered intravenously daily in five doses totaling 3000 mg/ ^m² . In one embodiment, mesna is administered intravenously at a first dose of about 600 mg/ ^m² and four repeated doses of about 600 mg/ ^m² prior to any dose of ifosfamide, each repeated dose approximately three hours, six hours, and 12 hours after the first dose of ifosfamide, respectively. In one embodiment, mesna is administered to the subject daily on days 3, 4, and 5 of the first dosing cycle, days 6, 7, and 8 of the second dosing cycle, and/or on days 6, 7, and 8 of each additional dosing cycle.

In one aspect, the invention is characterized by a method for treating a subject aged 18 to 30 years with a CD20-positive proliferative disorder, the method comprising administering an effective amount to the subject in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle:

(a) Bispecific antibodies that bind to CD20 and CD3;

(b) Anti-CD20 antibody; and

(c) One or more chemotherapeutic agents selected from ifosfamide, carboplatin and/or etoposide.

In one embodiment, the first dosing cycle includes a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody, wherein the C1D1 of the bispecific antibody is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of the bispecific antibody is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); and

The second dosing cycle includes a single dose (C2D1) of the bispecific antibody, wherein the C2D1 of the bispecific antibody is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

In one embodiment, the bispecific antibody C1D1 and bispecific antibody C1D2 were administered to the subject on day 8 and day 15 of the first dosing cycle, respectively.

In one embodiment, the subject is given the bispecific antibody C2D1 on day 1 of the second dosing cycle.

In one embodiment, the anti-CD20 antibody is olibutuzumab and/or rituximab.

In one embodiment, the first dosing cycle comprises a first dose (C1D1) of olibutuzumab and a second dose (C1D2) of olibutuzumab. In one embodiment, the sum of olibutuzumab C1D1 and C1D2 is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg). In one embodiment, the olibutuzumab C1D1 is about one-tenth the amount of the sum of olibutuzumab C1D1 and C1D2, and the olibutuzumab C1D2 is about nine-tenths the amount of the sum of olibutuzumab C1D1 and C1D2. In one embodiment, the C1D1 of olibutuzumab is about 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 8 mg, or ± 10 mg) and the C1D2 of olibutuzumab is about 900 mg (e.g., 900 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 40 mg, ± 50 mg, ± 60 mg, ± 70 mg, ± 80 mg, or ± 90 mg). In one embodiment, the C1D1 of olibutuzumab is administered to the subject on day 1 of the first dosing cycle, and the C1D2 of olibutuzumab is administered to the subject on day 2 of the first dosing cycle.

In one embodiment, the second dosing cycle comprises a single dose (C2D1) of rituximab. In one embodiment, the C2D1 of rituximab is approximately 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ). In one embodiment, the C2D1 of rituximab is administered to the subject on day 5 of the second dosing cycle.

In one embodiment, the method includes administering ifosfamide, carboplatin, and etoposide to a subject. In one embodiment, the first dosing cycle includes:

(a) A single dose of ifosfamide (C1D1);

(b) A single dose of carboplatin (C1D1); and

(c) The first dose of etoposide (C1D1), the second dose of etoposide (C1D2), and the third dose of etoposide (C1D3);

And the second cycle includes:

(a) A single dose of ifosfamide (C2D1);

(b) A single dose of carboplatin (C2D1); and

(c) The first dose of etoposide (C2D1), the second dose of etoposide (C2D2), and the third dose of etoposide (C2D3).

In one embodiment, ifosfamide is administered at a dose of about 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 ^mg / ^m² , ± 100 mg/m², ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ), carboplatin is administered at a dose of about 5 × (25 + creatinine clearance (CrCl)) mg, with the largest dose being about 750 mg (e.g., 750 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 75 mg), and etoposide is administered at a dose of about 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/ ^m² ) for each dose of etoposide.

In one embodiment, (a) the subject is male, and CrCl is calculated using the formula CrCl = ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]); or (b) the subject is female, and CrCl is calculated using the formula CrCl = 0.85 × ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]).

In one embodiment, (a) the subject has < about 60 mL/min of CrCl, and each single dose of ifosfamide is reduced to 4000 mg/ ^m² ; and/or (b) the subject has < about 50 mL/min of CrCl, and each dose of etoposide is reduced to 75 mg/ ^m² .

In one embodiment, (a) C1D1 ifosfamide is administered on day 3 of the first dosing cycle;

(b) Administer carboplatin C1D1 on day 3 of the first dosing cycle;

(c) Etoposide C1D1, C1D2 and C1D3 were administered on days 3, 4 and 5 of the first dosing cycle, respectively;

(d) Administer C2D1 of ifosfamide on day 6 of the second dosing cycle;

(e) Administer carboplatin C2D1 on day 6 of the second dosing cycle; and

(f) Etoposide C2D1, C2D2 and C2D3 were administered on days 6, 7 and 8 of the second dosing cycle, respectively.

In one embodiment, the first and second dosing cycles are each 21-day dosing cycles. In one embodiment, the dosing regimen includes one or more additional dosing cycles. In one embodiment, the one or more additional dosing cycles are each 21-day dosing cycles. In one embodiment, the dosing regimen includes a total of three dosing cycles.

In one embodiment, one or more additional dosing cycles each include:

(a) An additional single dose of a bispecific antibody that binds to both CD20 and CD3.

(b) An additional single dose of anti-CD20 antibody, and

(c) Additional single doses of ifosfamide; additional single doses of carboplatin; and additional first, second and third doses of etoposide.

In one embodiment, an additional single dose of the bispecific antibody is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg). In one embodiment, an additional single dose of the bispecific antibody is administered to the subject on day 1 of each of one or more additional dosing cycles.

In one embodiment, the anti-CD20 antibody is rituximab. In one embodiment, the additional single dose of rituximab is about 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ). In one embodiment, the additional single dose of rituximab is administered on day 5 of each of one or more additional dosing cycles.

In one embodiment, the additional single dose of ifosfamide is about 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ), the additional single dose of carboplatin is about 5 × (25 + creatinine clearance (CrCl)) mg, with the maximum dose being about 750 mg (e.g., 750 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 75 mg), and the additional first, second, and third doses of etoposide are each about 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/ ^m² ).

In one embodiment, (a) the subject is male, and CrCl is calculated using the formula CrCl = ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]); or (b) the subject is female, and CrCl is calculated using the formula CrCl = 0.85 × ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]).

In one embodiment, (a) the subject has < about 60 mL/min of CrCl, and the additional single dose of ifosfamide is reduced to 4000 mg/ ^m² ; and/or (b) the subject has < about 50 mL/min of CrCl, and each additional dose of etoposide is reduced to 75 mg/ ^m² .

In one embodiment, (a) an additional single dose of ifosfamide is administered on day 6 of each of one or more additional dosing cycles;

(b) Administer an additional single dose of carboplatin on day 6 of each of these one or more additional dosing cycles; and

(c) The subject is given an additional first dose, an additional second dose, and an additional third dose of etoposide on days 6, 7, and 8 of each of the one or more additional dosing cycles.

In one embodiment, the method further includes administering one or more additional therapeutic agents to the subject.

In one embodiment, one or more additional therapeutic agents are tocilizumab. In one embodiment, the subject weighs more than or equal to about 30 kg and is administered tocilizumab at a dose of about 8 mg/kg (e.g., 8 mg/kg ± 0.05 mg/kg, ± 0.1 mg/kg, ± 0.25 mg/kg, ± 0.5 mg/kg, or ± 0.8 mg/kg), or the subject weighs less than 30 kg and is administered tocilizumab at a dose of about 12 mg/kg (e.g., 12 mg/kg ± 0.05 mg/kg, ± 0.1 mg/kg, ± 0.25 mg/kg, ± 0.5 mg/kg, ± 0.75 mg/kg, ± 1 mg/kg, or ± 1.2 mg/kg), wherein the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg).

In one embodiment, one or more additional therapeutic agents are corticosteroids.

In one embodiment, the corticosteroid includes prednisone, prednisolone, methylprednisolone, or dexamethasone.

In one embodiment, the corticosteroid is dexamethasone. In one embodiment, dexamethasone is administered intravenously at a dose between about 0.15 mg/kg (e.g., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) and about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.001 mg/kg, ± 0.0025 mg/kg, ± 0.005 mg/kg, ± 0.01 mg/kg, or ± 0.015 mg/kg) before any dose of the bispecific antibody, and wherein the maximum daily dose is 10 mg. In one embodiment, dexamethasone is administered intravenously at a dose between about 0.15 mg/kg (e.g., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) and about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.001 mg/kg, ± 0.0025 mg/kg, ± 0.005 mg/kg, ± 0.01 mg/kg or ± 0.015 mg/kg) and about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, ± 0.04 mg/kg or ± 0.05 mg/kg) before administration of any dose of olibutuzumab, and wherein the maximum daily dose is 10 mg.

In one embodiment, the corticosteroid is methylprednisolone. In one embodiment, methylprednisolone is administered intravenously at a dose between about 1 mg/kg and about 2 mg/kg (e.g., 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.9 or 2.0 mg/kg) at least one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) prior to the administration of any dose of the bispecific antibody. In one embodiment, methylprednisolone is administered intravenously at a dose between about 1 mg/kg and about 2 mg/kg (e.g., 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.9 or 2.0 mg/kg) for at least about one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) prior to the administration of any dose of olibutuzumab.

In one embodiment, the corticosteroid is prednisone or prednisolone. In one embodiment, prednisone or prednisolone is administered intravenously at a dose of about 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 8 mg, or ± 10 mg) or about 2 mg/kg at least one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) or about 2 mg/kg before administration of any dose of the bispecific antibody. In one embodiment, prednisone or prednisolone is administered intravenously at a dose of about 100 mg (e.g., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) or about 2 mg/kg, at least one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before any dose of olibutuzumab.

In one embodiment, one or more additional therapeutic agents are antihistamines. In one embodiment, the antihistamine is diphenhydramine. In one embodiment, diphenhydramine is administered orally or intravenously at a dose of about 50 mg (e.g., 50 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, or ± 5 mg). In one embodiment, diphenhydramine is administered at least about 30 minutes (i.e., at least 30 minutes ± 3 minutes; e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before the administration of any dose of the bispecific antibody and/or anti-CD20 antibody.

In one embodiment, one or more additional therapeutic agents include granulocyte colony-stimulating factor (G-CSF). In one embodiment, G-CSF is administered approximately one to approximately two days (e.g., 24, 26, 28, 30, 32, 36, 38, 40, 42, 44, 46, or 48 hours) following administration of any dose of rituximab, ifosfamide, carboplatin, and/or etoposide. In one embodiment, G-CSF is administered intravenously or subcutaneously at a dose of about 5 μg/kg/day (e.g., 5 μg/kg/day ± 0.05 μg/kg/day, ± 0.1 μg/kg/day, ± 0.2 μg/kg/day, ± 0.3 μg/kg/day, ± 0.4 μg/kg/day, ± 0.5 μg/kg/day) or about 10 μg/kg/day (e.g., 10 μg/kg/day ± 0.1 μg/kg/day, ± 0.2 μg/kg/day, ± 0.4 μg/kg/day, ± 0.6 μg/kg/day, ± 0.8 μg/kg/day, ± 1 μg/kg/day). In one embodiment, G-CSF is administered at a dose of about 5 μg/kg/day in the first dosing cycle (e.g., 5 μg/kg/day ± 0.05 μg/kg/day, ± 0.1 μg/kg/day, ± 0.2 μg/kg/day, ± 0.3 μg/kg/day, ± 0.4 μg/kg/day, ± 0.5 μg/kg/day) in the second dosing cycle and/or each additional dosing cycle at a dose of about 10 μg/kg/day (e.g., 10 μg/kg/day ± 0.1 μg/kg/day, ± 0.2 μg/kg/day, ± 0.4 μg/kg/day, ± 0.6 μg/kg/day, ± 0.8 μg/kg/day, ± 1 μg/kg/day).

In one embodiment, one or more additional therapeutic agents are antipyretics. In one embodiment, the antipyretic is acetaminophen or paracetamol. In one embodiment, acetaminophen or paracetamol is administered orally or intravenously at a dose between about 500 and about 1000 mg (e.g., 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg). In one embodiment, acetaminophen or paracetamol is administered at least about 30 minutes (i.e., at least 30 minutes ± 3 minutes; e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before the administration of any dose of the bispecific antibody and/or anti-CD20 antibody.

In one embodiment, one or more additional therapeutic agents are mesna. In one embodiment, mesna is administered intravenously at a dose of about 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± ¹⁰⁰ mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/m², ± 400 mg/ ^m² , or ± 500 mg/ ^m² ). In one embodiment, mesna is administered via continuous infusion over about 24 hours on day 3 of the first dosing cycle, day 6 of the second dosing cycle, and/or day 6 of each additional dosing cycle. In one embodiment, mesna is administered concurrently with any dose of ifosfamide.

In one aspect, the invention is characterized by a method of treating a subject with a CD20-positive proliferative disorder, the method comprising administering to the subject effective amounts of glibenclamide, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein

(a) The first dosing cycle comprises administering a first dose (C1D1) of glimetuzumab on day 8 and a second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of glimetuzumab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); and

(b) The second dosing cycle consists of a single dose (C2D1) of glimetuzumab administered on day 8, wherein the C2D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

In one aspect, the invention is characterized by a method of treating a subject with CD20-positive proliferative disorder, the method comprising administering to the subject effective amounts of glibenclamide, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle, wherein...

(a) The first dosing cycle consists of administering the first dose (C1D1) of glimetuzumab on day 8 and the second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg or ± 0.25 mg), and the C1D2 of glimetuzumab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg or ± 1 mg);

(b) The second dosing cycle comprises a single dose (C2D1) of glimetuzumab administered on day 8, wherein the C2D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg); and

(c) The third dosing cycle includes a single dose (C3D1) of glimetuzumab administered on day 8, wherein the C3D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

In one aspect, the invention is characterized by a method of treating a subject with a CD20-positive proliferative disorder, the method comprising administering to the subject effective amounts of glibenclamide, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein

(a) The first dosing cycle includes:

(i) Administer the first dose (C1D1) of glimetuzumab on day 8 and the second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg or ± 0.25 mg), and the C1D2 of glimetuzumab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg or ± 1 mg);

(ii) Administer the first dose (C1D1) of olibutuzumab on day 1, wherein the C1D1 of olibutuzumab is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg or ± 100 mg);

(iii) A single dose (C1D1) of ifosfamide is administered on day 2, wherein the C1D1 of ifosfamide is about 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/ ^m2 , ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), and the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg or ± 80 mg);

(iv) A single dose (C1D1) of carboplatin was administered on day 2, wherein the C1D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C1D1) on day 1, the second dose of etoposide (C1D2) on day 2, and the third dose of etoposide (C1D3) on day 3, wherein the C1D1, C1D2, and C1D3 of etoposide are each approximately 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/ ^m² ); and

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab is administered on day 8, wherein the C2D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg);

(ii) Administer the first dose of rituximab (C2D1) on day 1, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 );

(iii) A single dose (C2D1) of ifosfamide is administered on day 2, wherein the C2D1 of ifosfamide is about 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/ ^m2 , ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), and the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg or ± 80 mg);

(iv) A single dose (C2D1) of carboplatin was administered on day 2, wherein the C2D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C2D1) on day 1, the second dose of etoposide (C2D2) on day 2, and the third dose of etoposide (C2D3) on day 3, wherein the C2D1, C2D2, and C2D3 of etoposide are each approximately 100 mg/ ^m2 (e.g., 100 mg/ ^m2 ± 1 mg/ ^m2 , ± 2.5 mg/ ^m2 , ± 5 mg/ ^m2 , or ± 10 mg/ ^m2 ).

In one aspect, the invention is characterized by a method of treating a subject with CD20-positive proliferative disorder, the method comprising administering to the subject effective amounts of glibenclamide, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle, wherein...

(a) The first dosing cycle includes:

(i) Administer the first dose (C1D1) of glimetuzumab on day 8 and the second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg or ± 0.25 mg), and the C1D2 of glimetuzumab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg or ± 1 mg);

(ii) Administer the first dose (C1D1) of olibutuzumab on day 1, wherein the C1D1 of olibutuzumab is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg or ± 100 mg);

(iii) A single dose (C1D1) of ifosfamide is administered on day 2, wherein the C1D1 of ifosfamide is about 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/ ^m2 , ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), and the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg or ± 80 mg);

(iv) A single dose (C1D1) of carboplatin was administered on day 2, wherein the C1D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C1D1) on day 1, the second dose of etoposide (C1D2) on day 2, and the third dose of etoposide (C1D3) on day 3, wherein the C1D1, C1D2, and C1D3 of etoposide are each approximately 100 mg/ ^m2 (e.g., 100 mg/ ^m2 ± 1 mg/ ^m2 , ± 2.5 mg/ ^m2 , ± 5 mg/ ^m2 , or ± 10 mg/ ^m2 );

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab is administered on day 8, wherein the C2D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg);

(ii) Administer the first dose of rituximab (C2D1) on day 1, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 );

(iii) A single dose (C2D1) of ifosfamide is administered on day 2, wherein the C2D1 of ifosfamide is about 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/ ^m2 , ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), and the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg or ± 80 mg);

(iv) A single dose (C2D1) of carboplatin was administered on day 2, wherein the C2D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C2D1) on day 1, the second dose of etoposide (C2D2) on day 2, and the third dose of etoposide (C2D3) on day 3, wherein the C2D1, C2D2, and C2D3 of etoposide are each approximately 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/ ^m² ); and

(c) The third dosing cycle includes:

(i) A single dose (C3D1) of glimetuzumab is administered on day 8, wherein the C3D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg);

(ii) Administer the first dose of rituximab (C3D1) on day 1, wherein the C3D1 of rituximab is approximately 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 );

(iii) A single dose (C3D1) of ifosfamide is administered on day 2, wherein the C3D1 of ifosfamide is about 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/ ^m2 , ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), and the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg or ± 80 mg);

(iv) A single dose of carboplatin (C3D1) was administered on day 2, wherein the C3D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C3D1) on day 1, the second dose of etoposide (C3D2) on day 2, and the third dose of etoposide (C3D3) on day 3, wherein the C3D1, C3D2, and C3D3 of etoposide are each approximately 100 mg/ ^m2 (e.g., 100 mg/ ^m2 ± 1 mg/ ^m2 , ± 2.5 mg/ ^m2 , ± 5 mg/ ^m2 , or ± 10 mg/ ^m2 ).

In one embodiment, mesna is administered concurrently with any dose of ifosfamide. In one embodiment, mesna is administered intravenously at a dose of about 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ). In one embodiment, mesna is administered via continuous infusion over about 24 hours on day 2 of each dosing cycle.

In one aspect, the invention is characterized by a method of treating a subject aged 6 months to 17 years with CD20-positive proliferative disorder, the method comprising administering to the subject effective amounts of glimepiride, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein

(a) The first dosing cycle comprises administering the first dose (C1D1) of glimetuzumab on day 8 and the second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is approximately 0.03 mg/kg (e.g., 0.03 mg/kg ± 0.0005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg, or ± 0.003 mg/kg), approximately 0.04 mg/kg (e.g., 0.04 mg/kg ± 0.0005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg, ± 0.003 mg/kg, or ± 0.004 mg/kg), or approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of glimepiride is about 0.15 mg/kg (e.g., 0.15 mg/kg ± 0.001 mg/kg, ± 0.0025 mg/kg, ± 0.005 mg/kg, ± 0.01 mg/kg, or ± 0.015 mg/kg) or about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); and

(b) The second dosing cycle consists of a single dose (C2D1) of glimetuzumab administered on day 8, wherein the C2D1 of glimetuzumab is about 0.4 mg/kg (e.g., 0.4 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg or ± 0.04 mg/kg), about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, ± 0.04 mg/kg or ± 0.05 mg/kg), or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg).

In one aspect, the invention is characterized by a method of treating a subject aged 6 months to 17 years with CD20-positive proliferative disorder, the method comprising administering to the subject effective amounts of glimepiride, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle, wherein...

(a) The first dosing cycle comprises administering a first dose (C1D1) of glimetuzumab on day 8 and a second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is approximately 0.03 mg/kg (e.g., 0.03 mg/kg ± 0.0005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg, or ± 0.003 mg/kg), approximately 0.04 mg/kg (e.g., 0.04 mg/kg ± 0.0005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg, ± 0.003 mg/kg, or ± 0.004 mg/kg), or Approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of glimepiride is approximately 0.15 mg/kg (e.g., 0.15 mg/kg ± 0.001 mg/kg, ± 0.0025 mg/kg, ± 0.005 mg/kg, ± 0.01 mg/kg, or ± 0.015 mg/kg) or approximately 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg);

(b) The second dosing cycle comprises a single dose (C2D1) of glimetuzumab administered on day 8, wherein the C2D1 of glimetuzumab is approximately 0.4 mg/kg (e.g., 0.4 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, or ± 0.04 mg/kg), approximately 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, ± 0.04 mg/kg, or ± 0.05 mg/kg), or approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg); and

(c) The third dosing cycle consists of a single dose (C3D1) of glimetuzumab administered on day 8, wherein the C3D1 of glimetuzumab is about 0.4 mg/kg (e.g., 0.4 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg or ± 0.04 mg/kg), about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, ± 0.04 mg/kg or ± 0.05 mg/kg), or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg).

In one aspect, the invention is characterized by a method of treating a subject aged 6 months to 17 years with CD20-positive proliferative disorder, the method comprising administering to the subject effective amounts of glimepiride, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein

(a) The first dosing cycle includes:

(i) Administer the first dose (C1D1) of glimetuzumab on day 8 and the second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 dose of glimetuzumab is approximately 0.03 mg/kg (e.g., 0.03 mg/kg ± 0.0005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg, or ± 0.003 mg/kg), approximately 0.04 mg/kg (e.g., 0.04 mg/kg ± 0.0005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg, ± 0.003 mg/kg, or ± 0.004 mg/kg), or approximately 2.5 mg/kg. mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of glimepiride is about 0.15 mg/kg (e.g., 0.15 mg/kg ± 0.001 mg/kg, ± 0.0025 mg/kg, ± 0.005 mg/kg, ± 0.01 mg/kg, or ± 0.015 mg/kg) or about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg);

(ii) Administer the first dose (C1D1) of olibutuzumab on day 1 and the second dose (C1D2) of olibutuzumab on day 2, wherein the C1D1 of olibutuzumab is approximately one-tenth the sum of the C1D1 and C1D2 of olibutuzumab, and the C1D2 of olibutuzumab is approximately nine-tenths the sum of the C1D1 and C1D2 of olibutuzumab, and wherein the sum of the C1D1 and C1D2 of olibutuzumab is approximately 38 mg/kg (e.g., 38 mg/kg ± 0.25 mg/kg, ± 0.5 mg/kg, ± 1 mg/kg, ± 2 mg/kg). ±3 mg/kg or ±3.8 mg/kg), approximately 28 mg/kg (e.g., 28 mg/kg ±0.25 mg/kg, ±0.5 mg/kg, ±1 mg/kg, ±2 mg/kg or ±2.8 mg/kg), approximately 23 mg/kg (e.g., 23 mg/kg ±0.25 mg/kg, ±0.5 mg/kg, ±1 mg/kg, ±2 mg/kg or ±2.3 mg/kg), approximately 20 mg/kg or approximately 1000 mg (e.g., 1000 mg ±5 mg, ±10 mg, ±20 mg, ±30 mg, ±50 mg, ±75 mg or ±100 mg);

(iii) Administer the first dose of ifosfamide (C1D1) on day 3, the second dose of ifosfamide (C1D2) on day 4, and the third dose of ifosfamide (C1D3) on day 5, wherein the C1D1, C1D2 and C1D3 of ifosfamide are each about 3000 mg/ ^m2 (e.g., 3000 mg/ ^m2 ± 40 mg/ ^m2 , ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 or ± 300 mg/ ^m2 );

(iv) A single dose (C1D1) of carboplatin is administered on day 3, wherein the C1D1 of carboplatin is approximately 635 mg/ ^m² (e.g., 635 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , ± 50 mg/ ^m² , ± 60 mg/ ^m² , or ± 63.5 mg/ ^m² ); and

(v) Administer the first dose of etoposide (C1D1) on day 3, the second dose of etoposide (C1D2) on day 4, and the third dose of etoposide (C1D3) on day 5, wherein the C1D1, C1D2, and C1D3 of etoposide are each approximately 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/ ^m² ); and

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab is administered on day 1, wherein the C2D1 of glimetuzumab is about 0.4 mg/kg (e.g., 0.4 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg or ± 0.04 mg/kg), about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, ± 0.04 mg/kg or ± 0.05 mg/kg) or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg);

(ii) Administer the first dose (C2D1) of rituximab on day 5, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 );

(iii) Administer the first dose of ifosfamide (C2D1) on day 6, the second dose of ifosfamide (C2D2) on day 7, and the third dose of ifosfamide (C2D3) on day 8, wherein the C2D1, C2D2 and C2D3 of ifosfamide are each about 3000 mg/ ^m2 (e.g., 3000 mg/ ^m2 ± 40 mg/ ^m2 , ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 or ± 300 mg/ ^m2 );

(iv) A single dose (C2D1) of carboplatin was administered on day 6, wherein the C2D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C2D1) on day 6, the second dose of etoposide (C2D2) on day 7, and the third dose of etoposide (C2D3) on day 8, wherein the C2D1, C2D2 and C2D3 of etoposide are each about 100 mg/ ^m2 (e.g., 100 mg/ ^m2 ± 1 mg/ ^m2 , ± 2.5 mg/ ^m2 , ± 5 mg/ ^m2 or ± 10 mg/ ^m2 ).

In one aspect, the invention is characterized by a method of treating a subject aged 6 months to 17 years with CD20-positive proliferative disorder, the method comprising administering to the subject effective amounts of glimepiride, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle, wherein...

(a) The first dosing cycle includes:

(i) Administer the first dose (C1D1) of glimetuzumab on day 8 and the second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is about 0.03 mg/kg, about 0.04 mg/kg (e.g., 0.04 mg/kg ± 0.0005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg, ± 0.003 mg/kg, or ± 0.004 mg/kg) or about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.004 mg/kg). 3 mg, ±0.05 mg, ±0.1 mg, ±0.2 mg or ±0.25 mg), and the C1D2 of glimepiride is about 0.15 mg/kg (e.g., 0.15 mg/kg ±0.001 mg/kg, ±0.0025 mg/kg, ±0.005 mg/kg, ±0.01 mg/kg or ±0.015 mg/kg) or about 10 mg (e.g., 10 mg ±0.05 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.5 mg, ±0.75 mg or ±1 mg);

(ii) Administer the first dose (C1D1) of olibutuzumab on day 1 and the second dose (C1D2) of olibutuzumab on day 2, wherein the C1D1 of olibutuzumab is approximately one-tenth the sum of the C1D1 and C1D2 of olibutuzumab, and the C1D2 of olibutuzumab is approximately nine-tenths the sum of the C1D1 and C1D2 of olibutuzumab, wherein the sum of the C1D1 and C1D2 of olibutuzumab is approximately 38 mg/kg (e.g., 38 mg/kg ± 0.25 mg/kg, ± 0.5 mg/kg, ± 1 mg/kg, ± 2 mg/kg, ± 3 mg/kg, or ± 3.8 mg/kg), approximately 28 mg/kg. g/kg (e.g., 28 mg/kg ± 0.25 mg/kg, ± 0.5 mg/kg, ± 1 mg/kg, ± 2 mg/kg or ± 2.8 mg/kg), about 23 mg/kg (e.g., 23 mg/kg ± 0.25 mg/kg, ± 0.5 mg/kg, ± 1 mg/kg, ± 2 mg/kg or ± 2.3 mg/kg), about 20 mg/kg (e.g., 23 mg/kg ± 0.25 mg/kg, ± 0.5 mg/kg, ± 1 mg/kg or ± 2 mg/kg) or about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg or ± 100 mg);

(iii) Administer the first dose of ifosfamide (C1D1) on day 3, the second dose of ifosfamide (C1D2) on day 4, and the third dose of ifosfamide (C1D3) on day 5, wherein the C1D1, C1D2 and C1D3 of ifosfamide are each about 3000 mg/ ^m2 (e.g., 3000 mg/ ^m2 ± 40 mg/ ^m2 , ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 or ± 300 mg/ ^m2 );

(iv) A single dose (C1D1) of carboplatin is administered on day 3, wherein the C1D1 of carboplatin is approximately 635 mg/ ^m² (e.g., 635 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , ± 50 mg/ ^m² , ± 60 mg/ ^m² , or ± 63.5 mg/ ^m² ); and

(v) Administer the first dose of etoposide (C1D1) on day 3, the second dose of etoposide (C1D2) on day 4, and the third dose of etoposide (C1D3) on day 5, wherein the C1D1, C1D2, and C1D3 of etoposide are each approximately 100 mg/ ^m2 (e.g., 100 mg/ ^m2 ± 1 mg/ ^m2 , ± 2.5 mg/ ^m2 , ± 5 mg/ ^m2 , or ± 10 mg/ ^m2 );

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab is administered on day 1, wherein the C2D1 of glimetuzumab is about 0.4 mg/kg (e.g., 0.4 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg or ± 0.04 mg/kg), about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, ± 0.04 mg/kg or ± 0.05 mg/kg) or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg);

(ii) Administer the first dose (C2D1) of rituximab on day 5, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 );

(iii) Administer the first dose of ifosfamide (C2D1) on day 6, the second dose of ifosfamide (C2D2) on day 7, and the third dose of ifosfamide (C2D3) on day 8, wherein the C2D1, C2D2 and C2D3 of ifosfamide are each about 3000 mg/ ^m2 (e.g., 3000 mg/ ^m2 ± 40 mg/ ^m2 , ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 or ± 300 mg/ ^m2 );

(iv) A single dose (C2D1) of carboplatin was administered on day 6, wherein the C2D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C2D1) on day 6, the second dose of etoposide (C2D2) on day 7, and the third dose of etoposide (C2D3) on day 8, wherein the C2D1, C2D2, and C2D3 of etoposide are each approximately 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/ ^m² ); and

(c) The third dosing cycle includes:

(i) A single dose (C3D1) of glimetuzumab is administered on day 1, wherein the C3D1 of glimetuzumab is about 0.4 mg/kg (e.g., 0.4 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg or ± 0.04 mg/kg), about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, ± 0.04 mg/kg or ± 0.05 mg/kg) or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg);

(ii) Administer the first dose of rituximab (C3D1) on day 5, wherein the C3D1 of rituximab is approximately 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 );

(iii) Administer the first dose of ifosfamide (C3D1) on day 6, the second dose of ifosfamide (C3D2) on day 7, and the third dose of ifosfamide (C3D3) on day 8, wherein the C3D1, C3D2 and C3D3 of ifosfamide are each about 3000 mg/ ^m2 (e.g., 3000 mg/ ^m2 ± 40 mg/ ^m2 , ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 or ± 300 mg/ ^m2 );

(iv) A single dose of carboplatin (C3D1) was administered on day 6, wherein the C3D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C3D1) on day 6, the second dose of etoposide (C3D2) on day 7, and the third dose of etoposide (C3D3) on day 8, wherein the C3D1, C3D2, and C3D3 of etoposide are each approximately 100 mg/ ^m2 (e.g., 100 mg/ ^m2 ± 1 mg/ ^m2 , ± 2.5 mg/ ^m2 , ± 5 mg/ ^m2 , or ± 10 mg/ ^m2 ).

In one embodiment, mesna is administered to the subject on days 3, 4, and 5 of the first dosing cycle, days 6, 7, and 8 of the second dosing cycle, and/or days 6, 7, and 8 of each additional dosing cycle. In one embodiment, mesna is administered intravenously daily at five doses totaling 3000 mg/ ^m² . In one embodiment, mesna is administered intravenously at a first dose of approximately 600 mg/ ^m² and four repeated doses of approximately 600 mg/ ^m² prior to any dose of ifosfamide, each repeated dose approximately three hours, approximately six hours, and approximately 12 hours after the first dose of ifosfamide.

In one aspect, the invention is characterized by a method of treating a subject aged 18 to 30 years with CD20-positive proliferative disorders, the method comprising administering to the subject effective amounts of glimepiride, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein

(a) The first dosing cycle comprises administering a first dose (C1D1) of glimetuzumab on day 8 and a second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of glimetuzumab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); and

(b) The second dosing cycle consists of a single dose (C2D1) of glimetuzumab administered on day 1, wherein the C2D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

In one aspect, the invention is characterized by a method of treating a subject aged 18 to 30 years with CD20-positive proliferative disorders, the method comprising administering to the subject effective amounts of glimepiride, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle, wherein...

(a) The first dosing cycle consists of administering the first dose (C1D1) of glimetuzumab on day 8 and the second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg or ± 0.25 mg), and the C1D2 of glimetuzumab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg or ± 1 mg);

(b) The second dosing cycle comprises a single dose (C2D1) of glimetuzumab administered on day 1, wherein the C2D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg); and

(c) The third dosing cycle consists of a single dose (C3D1) of glimetuzumab administered on day 1, wherein the C3D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

In one aspect, the invention is characterized by a method of treating a subject aged 18 to 30 years with CD20-positive proliferative disorders, the method comprising administering to the subject effective amounts of glimepiride, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein

(a) The first dosing cycle includes:

(i) Administer the first dose (C1D1) of glimetuzumab on day 8 and the second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg or ± 0.25 mg), and the C1D2 of glimetuzumab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg or ± 1 mg);

(ii) Administer a first dose (C1D1) of olibutuzumab on day 1 and a second dose (C1D2) of olibutuzumab on day 2, wherein the C1D1 of olibutuzumab is approximately one-tenth of the sum of the C1D1 and C1D2 of olibutuzumab, and the C1D2 of olibutuzumab is approximately nine-tenths of the sum of the C1D1 and C1D2 of olibutuzumab, and wherein the sum of the C1D1 and C1D2 of olibutuzumab is approximately 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg or ± 100 mg);

(iii) A single dose (C1D1) of ifosfamide is administered on day 3, wherein the C1D1 of ifosfamide is about 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/ ^m2 , ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), and the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg or ± 80 mg);

(iv) A single dose of carboplatin (C1D1) was administered on day 3, wherein the C1D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C1D1) on day 3, the second dose of etoposide (C1D2) on day 4, and the third dose of etoposide (C1D3) on day 5, wherein the C1D1, C1D2, and C1D3 of etoposide are each approximately 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/ ^m² ); and

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab is administered on day 1, wherein the C2D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg);

(ii) Administer the first dose (C2D1) of rituximab on day 5, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 );

(iii) A single dose (C2D1) of ifosfamide is administered on day 6, wherein the C2D1 of ifosfamide is about 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/ ^m2 , ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), and the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg or ± 80 mg);

(iv) A single dose (C2D1) of carboplatin was administered on day 6, wherein the C2D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C2D1) on day 6, the second dose of etoposide (C2D2) on day 7, and the third dose of etoposide (C2D3) on day 8, wherein the C2D1, C2D2 and C2D3 of etoposide are each about 100 mg/ ^m2 (e.g., 100 mg/ ^m2 ± 1 mg/ ^m2 , ± 2.5 mg/ ^m2 , ± 5 mg/ ^m2 or ± 10 mg/ ^m2 ).

In one aspect, the invention is characterized by a method of treating a subject aged 18 to 30 years with CD20-positive proliferative disorders, the method comprising administering to the subject effective amounts of glimepiride, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle, wherein...

(a) The first dosing cycle includes:

(i) Administer the first dose (C1D1) of glimetuzumab on day 8 and the second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg or ± 0.25 mg), and the C1D2 of glimetuzumab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg or ± 1 mg);

(ii) Administer a first dose (C1D1) of olibutuzumab on day 1 and a second dose (C1D2) of olibutuzumab on day 2, wherein the C1D1 of olibutuzumab is approximately one-tenth of the sum of the C1D1 and C1D2 of olibutuzumab, and the C1D2 of olibutuzumab is approximately nine-tenths of the sum of the C1D1 and C1D2 of olibutuzumab, and wherein the sum of the C1D1 and C1D2 of olibutuzumab is approximately 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg or ± 100 mg);

(iii) A single dose (C1D1) of ifosfamide is administered on day 3, wherein the C1D1 of ifosfamide is about 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/ ^m2 , ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), and the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg or ± 80 mg);

(iv) A single dose of carboplatin (C1D1) was administered on day 3, wherein the C1D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C1D1) on day 3, the second dose of etoposide (C1D2) on day 4, and the third dose of etoposide (C1D3) on day 5, wherein the C1D1, C1D2, and C1D3 of etoposide are each approximately 100 mg/ ^m2 (e.g., 100 mg/ ^m2 ± 1 mg/ ^m2 , ± 2.5 mg/ ^m2 , ± 5 mg/ ^m2 , or ± 10 mg/ ^m2 );

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab is administered on day 1, wherein the C2D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg);

(ii) Administer the first dose (C2D1) of rituximab on day 5, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 );

(iii) A single dose (C2D1) of ifosfamide is administered on day 6, wherein the C2D1 of ifosfamide is about 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/ ^m2 , ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), and the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg or ± 80 mg);

(iv) A single dose (C2D1) of carboplatin was administered on day 6, wherein the C2D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C2D1) on day 6, the second dose of etoposide (C2D2) on day 7, and the third dose of etoposide (C2D3) on day 8, wherein the C2D1, C2D2, and C2D3 of etoposide are each approximately 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/ ^m² ); and

(c) The third dosing cycle includes:

(i) A single dose (C3D1) of glimetuzumab is administered on day 1, wherein the C3D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg);

(ii) Administer the first dose of rituximab (C3D1) on day 5, wherein the C3D1 of rituximab is approximately 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 );

(iii) A single dose (C3D1) of ifosfamide is administered on day 6, wherein the C3D1 of ifosfamide is about 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/ ^m2 , ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), and the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg or ± 80 mg);

(iv) A single dose of carboplatin (C3D1) was administered on day 6, wherein the C3D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C3D1) on day 6, the second dose of etoposide (C3D2) on day 7, and the third dose of etoposide (C3D3) on day 8, wherein the C3D1, C3D2, and C3D3 of etoposide are each approximately 100 mg/ ^m2 (e.g., 100 mg/ ^m2 ± 1 mg/ ^m2 , ± 2.5 mg/ ^m2 , ± 5 mg/ ^m2 , or ± 10 mg/ ^m2 ).

In one embodiment, mesna is administered concurrently with any dose of ifosfamide. In one embodiment, mesna is administered intravenously at a dose of about 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ). In one embodiment, mesna is administered via continuous infusion over about 24 hours on day 3 of the first dosing cycle, day 6 of the second dosing cycle, and/or day 6 of each additional dosing cycle. In one embodiment, the CD20-positive proliferative disorder is relapsed and/or refractory DLBCL. In one embodiment, the CD20-positive proliferative disorder is relapsed and/or refractory mature B-cell NHL.

In one embodiment, the bispecific antibody binding to CD20 and CD3 comprises at least one Fab molecule that specifically binds to CD20, the Fab molecule containing the following six hypervariable regions (HVRs):

(i)HVR-H1, which contains the amino acid sequence of YSWIN (SEQ ID NO:1);

(ii) HVR-H2, which contains the amino acid sequence RIFPGDGDTDYNGKFKG (SEQ ID NO:2);

(iii) HVR-H3, which contains the amino acid sequence NVFDGYWLVY (SEQ ID NO:3);

(iv) HVR-L1, which contains the amino acid sequence RSSKSLLHSNGITYLY (SEQ ID NO:4);

(v)HVR-L2, which contains the amino acid sequence of QMSNLVS (SEQ ID NO:5); and

(vi)HVR-L3, which contains the amino acid sequence of AQNLELPYT (SEQ ID NO:6).

In one embodiment, the bispecific antibody binding to CD20 and CD3 comprises at least one Fab molecule that specifically binds to CD20, the Fab molecule comprising: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:7; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:8; or (c) the VH domain as in (a) and the VL domain as in (b).

In one embodiment, the Fab molecule that specifically binds to CD20 comprises: (a) a VH domain containing the amino acid sequence of SEQ ID NO:7; and (b) a VL domain containing the amino acid sequence of SEQ ID NO:8.

In one embodiment, the bispecific antibody binding to CD20 and CD3 comprises at least one Fab molecule that specifically binds to CD3, the Fab molecule containing the following six HVRs:

(i)HVR-H1, which contains the amino acid sequence of TYAMN (SEQ ID NO:9);

(ii) HVR-H2, which contains the amino acid sequence RIRSKYNNYATYYADSVKG (SEQ ID NO:10);

(iii) HVR-H3, which contains the amino acid sequence HGNFGNSYVSWFAY (SEQ ID NO:11);

(iv) HVR-L1, which contains the amino acid sequence GSSTGAVTTSNYAN (SEQ ID NO:12);

(v)HVR-L2, which contains the amino acid sequence of GTNKRAP (SEQ ID NO: 13); and

(vi)HVR-L3, which contains the amino acid sequence of ALWYSNLWV (SEQ ID NO:14).

In one embodiment, the bispecific antibody binding to CD20 and CD3 comprises at least one Fab molecule that specifically binds to CD3, the Fab molecule comprising: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:15; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:16; or (c) the VH domain as in (a) and the VL domain as in (b).

In one embodiment, the Fab molecule that specifically binds to CD3 comprises: (a) a VH domain containing the amino acid sequence of SEQ ID NO:15; and (b) a VL domain containing the amino acid sequence of SEQ ID NO:16.

In one embodiment, the bispecific antibody binding to CD20 and CD3 is bivalent to CD20 and monovalent to CD3. In one embodiment, the bispecific antibody binding to CD20 and CD3 comprises two Fab molecules that specifically bind to CD20 and one Fab molecule that specifically binds to CD3. In one embodiment, the bispecific antibody binding to CD20 and CD3 is a humanized antibody. In one embodiment, the bispecific antibody binding to CD20 and CD3 is glimepiride.

In one embodiment, a bispecific antibody that binds to CD20 and CD3 is administered intravenously.

In one embodiment, anti-CD20 antibody is administered intravenously.

In one embodiment, the CD20-positive proliferative disorder is a B-cell proliferative disorder. In one embodiment, the B-cell proliferative disorder is non-Hodgkin's lymphoma (NHL) or central nervous system lymphoma (CNSL). In one embodiment, the NHL is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), high-grade B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma (PMLBCL), diffuse B-cell lymphoma, or small lymphocytic lymphoma. In one embodiment, the NHL is Burkitt lymphoma (BL) or Burkitt leukemia (BAL). In one embodiment, the NHL is aggressive and/or mature. In one embodiment, the NHL is relapsed and/or refractory. In one embodiment, the B-cell proliferative disorder is relapsed and/or refractory mature B-cell NHL. In one embodiment, the subject has received one prior systemic therapy. In one embodiment, the subject has received no more than one prior systemic therapy. In one embodiment, the prior systemic therapy included an anti-CD20 antibody and anthracycline.

In one embodiment, the subject is a human being. In another embodiment, the subject is eligible for transplantation or CAR-T cell therapy.

In one embodiment, the subject receives an autologous stem cell transplant (ASCT) after completing the dosing regimen described above. In one embodiment, the ASCT is an autologous hematopoietic stem cell transplant. In one embodiment, the subject receives an allogeneic hematopoietic stem cell transplant after completing the dosing regimen described above. In one embodiment, the subject receives CAR-T cell therapy after completing the dosing regimen described above.

In one aspect, the invention is characterized by a bispecific antibody that binds to CD20 and CD3 for use in a method of treating a subject with a CD20-positive proliferative disorder, wherein the bispecific antibody that binds to CD20 and CD3 is administered in combination with an anti-CD20 antibody and one or more chemotherapeutic agents selected from ifosfamide, carboplatin, and/or etoposide, in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

In one embodiment, the first dosing cycle includes a first dose (C1D1) of a bispecific antibody binding to CD20 and CD3 and a second dose (C1D2) of the bispecific antibody, wherein the C1D1 of the bispecific antibody is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of the bispecific antibody is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); and

The second dosing cycle includes a single dose (C2D1) of the bispecific antibody, wherein the C2D1 of the bispecific antibody is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg or ± 1 mg), about 16 mg (e.g., 16 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg or ± 1.6 mg), or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg). In one embodiment, the C2D1 of the bispecific antibody is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg). In one embodiment, the C2D1 of the bispecific antibody is administered to the subject on day 8 of the second dosing cycle.

In one embodiment, the anti-CD20 antibody is olibutuzumab and/or rituximab. In one embodiment, the first dosing cycle comprises a single dose of olibutuzumab (C1D1); and the second dosing cycle comprises a single dose of rituximab (C2D1). In one embodiment, the single dose of olibutuzumab C1D1 is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg), and the single dose of rituximab is about 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ).

In one embodiment, the anti-CD20 antibody is administered with a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein the first dosing cycle comprises a single dose of olibutuzumab on day 1 (C1D1); and the second dosing cycle comprises a single dose of rituximab on day 1 (C2D1).

In one aspect, the invention is characterized by a bispecific antibody that binds to CD20 and CD3 for use in a method of treating a subject with a CD20-positive proliferative disorder, wherein the bispecific antibody that binds to CD20 and CD3 is administered in combination with an anti-CD20 antibody, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

In one embodiment, the first dosing cycle includes a single dose of ifosfamide (C1D1), a single dose of carboplatin (C1D1), and a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of etoposide; and the second cycle each includes a single dose of ifosfamide (C2D1), a single dose of carboplatin (C2D1), and a first dose (C2D1), a second dose (C2D2), and a third dose (C2D3) of etoposide. In one embodiment, the concentration is approximately 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ), approximately 4000 mg/ ^m² (e.g., 4000 mg/ ^m² ± 40 mg/ ^m² , ± 50 mg/ ^m² , ± 100 mg/m², ± 200 mg/ ^m² , ± 300 mg/ ^m² , or ± 400 mg/ ^{m² )} , or approximately 1666 mg/ ^m² (e.g., 1666 mg/ ^m² ± 25 mg/ ^m² , ± 50 mg/ ^m² , ± 100 mg/ ^m² , or ± 166.6 mg/m² ^). Ifosfamide is administered at a dose of approximately 5 mg/mL/min (e.g., 5 mg/mL/min ± 0.05 mg/mL/min, ± 0.1 mg/mL/min, ± 0.25 mg/mL/min, or ± 0.5 mg/mL/min), with the maximum dose being approximately 750 mg (e.g., 750 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 75 mg), and carboplatin is administered at a dose of approximately 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/ ^m² ) or 75 mg/ ^m² (e.g., 0.5 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 7.5 mg/m² ^). Etoposide is administered at the following doses. In one embodiment, ifosfamide is administered at a dose of 5000 mg/ ^m² , 4000 mg/ ^m² , or 1666 mg/ ^m² , carboplatin is administered at a dose of 750 mg (calculated as mg) up to the target area under the curve (AUC) of 5 mg/mL/min, and etoposide is administered at a dose of 100 mg/ ^m² or 75 mg/ ^m² . In another embodiment, ifosfamide is administered at a dose of 5000 mg/ ^m² , carboplatin is administered at a dose of 750 mg (calculated as mg) up to the target area under the curve (AUC) of 5 mg/mL/min, and etoposide is administered at a dose of 100 mg/ ^m² . In one embodiment, ifosfamide and carboplatin are administered on day 2 of the first and second dosing cycles, and etoposide is administered on each of days 1, 2, and 3 of the first and second dosing cycles.

In one embodiment, the first and second dosing cycles are 21-day dosing cycles.

In one embodiment, the dosing regimen includes one or more additional dosing cycles. In one embodiment, the additional dosing cycle is a 21-day dosing cycle.

In one embodiment, the dosing regimen comprises a total of three dosing cycles.

In one embodiment, one or more additional dosing cycles include:

(a) An additional single dose of a bispecific antibody that binds to both CD20 and CD3.

(b) An additional single dose of anti-CD20 antibody

(c) Additional single doses of ifosfamide, additional single doses of carboplatin, and additional first, second, and third doses of etoposide.

In one embodiment, an additional single dose of the bispecific antibody binding to CD20 and CD3 is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

In one embodiment, the anti-CD20 antibody is rituximab. In one embodiment, the additional single dose of rituximab is about 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ). In one embodiment, this additional single dose of rituximab is administered on day 1 of the additional dosing cycle.

In one embodiment, the additional single dose of ifosfamide is about 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ), about 4000 mg/ ^m² (e.g., 4000 mg/ ^m² ± 40 mg/ ^m² , ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , or ± 400 mg/ ^m² ), or about 1666 mg/ ^m² (e.g., 1666 mg/ ^m² ± 25 mg/ ^m² , ± 50 mg/ ^m² , ± 100 mg/ ^m² , or ± 166.6 mg/m² ^). The additional single dose of carboplatin is approximately 5 mg/mL/min (e.g., 5 mg/mL/min ± 0.05 mg/mL/min, ± 0.1 mg/mL/min, ± 0.25 mg/mL/min, or ± 0.5 mg/mL/min), with the maximum dose being approximately 750 mg (e.g., 750 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 75 mg), and the additional first, second, and third doses of etoposide are 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/ ^m² ) or 75 mg/ ^m² (e.g., 0.5 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 7.5 mg/ ^m² ). In one embodiment, the additional single dose of ifosfamide is 5000 mg/ ^m² , 4000 mg/ ^m² , or 1666 mg/ ^m² , the additional single dose of carboplatin is the largest of the target area under the curve (AUC) up to 5 mg/mL/min, and the additional first, second, and third doses of etoposide are 100 mg/ ^m² or 75 mg/ ^m² .

In one embodiment, ifosfamide is administered at a dose of 5000 mg/ ^m² , carboplatin is administered at a dose of 750 mg up to a target area under the curve (AUC) of 5 mg/mL/min, and etoposide is administered at a dose of 100 mg/ ^m² .

In one embodiment, ifosfamide and carboplatin are administered on day 2 of the additional dosing cycle, and etoposide is administered on each of days 1, 2, and 3 of the additional dosing cycle.

In one embodiment, the method further includes administering one or more additional therapeutic agents to the subject. In one embodiment, the bispecific antibody is used in combination with one or more additional therapeutic agents. In one embodiment, the one or more additional therapeutic agents are tocilizumab. In one embodiment, the subject weighs more than or equal to about 30 kg and is administered tocilizumab at a dose of about 8 mg/kg (e.g., 8 mg/kg ± 0.05 mg/kg, ± 0.1 mg/kg, ± 0.25 mg/kg, ± 0.5 mg/kg, or ± 0.8 mg/kg). In one embodiment, the subject weighs less than 30 kg and is administered tocilizumab at a dose of about 12 mg/kg (e.g., 12 mg/kg ± 0.05 mg/kg, ± 0.1 mg/kg, ± 0.25 mg/kg, ± 0.5 mg/kg, ± 0.75 mg/kg, ± 1 mg/kg, or ± 1.2 mg/kg). In some embodiments, the maximum dose of tocilizumab is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg).

In one embodiment, one or more additional therapeutic agents are corticosteroids.

In one embodiment, the corticosteroid includes prednisone, prednisolone, methylprednisolone, or dexamethasone. In one embodiment, dexamethasone is administered intravenously at a dose of about 20 mg (e.g., 20 mg ± 0.1 mg, ± 0.25 mg, ± 0.5 mg, ± 1 mg, ± 1.5 mg, or ± 2 mg) at least one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before the administration of any dose of the bispecific antibody. In one embodiment, dexamethasone is administered intravenously at a dose of about 20 mg (e.g., 20 mg ± 0.1 mg, ± 0.25 mg, ± 0.5 mg, ± 1 mg, ± 1 mg, ± 1.5 mg, or ± 2 mg) at least about one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before any dose of olibutuzumab is administered. In one embodiment, methylprednisolone is administered intravenously at a dose of about 80 mg (e.g., 80 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, or ± 8 mg) at least about one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before any dose of the bispecific antibody is administered. In one embodiment, methylprednisolone is administered intravenously at a dose of about 80 mg (e.g., 80 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, or ± 8 mg) at least one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before any dose of olibutuzumab is administered. In one embodiment, prednisone is administered orally at a dose of about 100 mg (e.g., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) at least one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before any dose of the bispecific antibody is administered. In one embodiment, prednisolone is administered intravenously at a dose of about 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 6 mg, ± 8 mg, or ± 10 mg) at least one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before any dose of the bispecific antibody is administered.

In one embodiment, one or more additional therapeutic agents are antihistamines.

In one embodiment, the antihistamine is diphenhydramine. In one embodiment, diphenhydramine is administered orally or intravenously at a dose of about 50 mg (e.g., 50 mg ± 3 minutes; for example, at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) at least 30 minutes prior to the administration of any dose of the bispecific antibody (i.e., at least 30 minutes ± 3 minutes; for example, at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more).

In some embodiments, one or more additional therapeutic agents include G-CSF. In one embodiment, G-CSF is administered approximately one to approximately two days after administration of any dose of rituximab, ifosfamide, carboplatin, and/or etoposide (e.g., 24, 26, 28, 30, 32, 36, 38, 40, 42, 44, 46, or 48 hours).

In one embodiment, one or more additional therapeutic agents are antipyretics. In one embodiment, the antipyretic is acetaminophen or paracetamol. In one embodiment, acetaminophen or paracetamol is administered orally at a dose between about 500 mg and about 1000 mg at least about 30 minutes (i.e., at least 30 minutes ± 3 minutes; for example, at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before administration of any dose of the bispecific antibody. In one embodiment, acetaminophen or paracetamol is administered orally at a dose between about 500 mg and about 1000 mg at least about 30 minutes (i.e., at least 30 minutes ± 3 minutes; for example, at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before administration of any dose of olibutuzumab.

In one embodiment, one or more additional therapeutic agents are mesna. In one embodiment, mesna is administered intravenously at a dose of about 5000 mg/ ^m² , about 4000 mg/ ^m² , or about 1666 mg/ ^m² . In one embodiment, mesna is administered via continuous infusion over about 24 hours on day 2 of each dosing cycle. In one embodiment, mesna is administered concurrently with any dose of ifosfamide.

In one aspect, the invention is characterized by a bispecific antibody that binds to CD20 and CD3, which is used in a method of treating a subject with CD20-positive proliferative disorders aged between 6 months and 17 years, wherein the bispecific antibody that binds to CD20 and CD3 is administered in combination with an anti-CD20 antibody and one or more chemotherapeutic agents selected from ifosfamide, carboplatin, and/or etoposide, using a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

In one embodiment, the first dosing cycle includes a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody, wherein the C1D1 of the bispecific antibody is about 0.03 mg/kg (e.g., 0.03 mg/kg ± 0.0005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg, or ± 0.003 mg/kg), about 0.04 mg/kg (e.g., 0.04 mg/kg ± 0.0005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg, ± 0.003 mg/kg, or ± 0.004 mg/kg), or about 2.5 mg/kg. mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of the bispecific antibody is about 0.15 mg/kg (e.g., 0.15 mg/kg ± 0.001 mg/kg, ± 0.0025 mg/kg, ± 0.005 mg/kg, ± 0.01 mg/kg, or ± 0.015 mg/kg) or about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); and

The second dosing cycle includes a single dose (C2D1) of the bispecific antibody, wherein the C2D1 of the bispecific antibody is about 0.4 mg/kg (e.g., 0.4 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg or ± 0.04 mg/kg), about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, ± 0.04 mg/kg or ± 0.05 mg/kg), or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg).

In one embodiment, (a) the subject's weight is greater than or equal to about 7.5 kg and less than about 13 kg, and the C1D1 of the bispecific antibody is about 0.04 mg/kg (e.g., 0.04 mg/kg ± 0.0005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg, ± 0.003 mg/kg, or ± 0.004 mg/kg), and the C1D2 of the bispecific antibody is about 0.15 mg/kg (e.g., 0.15 mg/kg). The C2D1 of the bispecific antibody is approximately 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.001 mg/kg, ± 0.0025 mg/kg, ± 0.005 mg/kg, ± 0.01 mg/kg, or ± 0.015 mg/kg), and the C2D1 of the bispecific antibody is approximately 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, ± 0.04 mg/kg, or ± 0.05 mg/kg).

(b) The subject's weight is greater than or equal to about 13 kg and less than about 45 kg, and the C1D1 of the bispecific antibody is about 0.03 mg/kg (e.g., 0.03 mg/kg ± 0.0005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg, or ± 0.003 mg/kg), the C1D2 of the bispecific antibody is about 0.15 mg/kg (e.g., 0.15 mg/kg ± 0.001 mg/kg, ± 0.0025 mg/kg, ± 0.005 mg/kg, ± 0.01 mg/kg, or ± 0.015 mg/kg), and the C2D1 of the bispecific antibody is about 0.4 mg/kg (e.g., 0.4 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, or ± 0.04 mg/kg); or

(c) The subject weighs 45 kg or more and has a C1D1 dose of about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg or ± 0.25 mg), a C1D2 dose of about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg or ± 1 mg), and a C2D1 dose of about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg).

In one embodiment, the bispecific antibody C1D1 and bispecific antibody C1D2 are administered to the subject on day 8 and day 15 of the first dosing cycle, respectively. In another embodiment, the bispecific antibody C2D1 is administered to the subject on day 1 of the second dosing cycle.

In one embodiment, the anti-CD20 antibody is olibutuzumab and/or rituximab.

In one embodiment, the first dosing cycle includes a first dose (C1D1) of olibutuzumab and a second dose (C1D2) of olibutuzumab. In one embodiment, (a) the subject's weight is greater than or equal to about 7.5 kg and less than about 13 kg, and the sum of C1D1 and C1D2 of olibutuzumab is about 38 mg/kg (e.g., 38 mg/kg ± 0.25 mg/kg, ± 0.5 mg/kg, ± 1 mg/kg, ± 2 mg/kg, ± 3 mg/kg, or ± 3.8 mg/kg); (b) the subject's weight is greater than or equal to about 13 kg and less than about 20 kg, and the sum of the C1D1 and C1D2 of olibutuzumab is about 28 mg/kg (e.g., 28 mg/kg ± 0.25 mg/kg, ± 0.5 mg/kg, ± 1 mg/kg, ± 2 mg/kg, or ± 2.8 mg/kg); (c) the subject's weight is greater than or equal to about 20 kg and less than about 32 kg, and the sum of the C1D1 and C1D2 of olibutuzumab is about 38 mg/kg (e.g., 28 mg/kg ± 0.25 mg/kg, ± 0.5 mg/kg, ± 1 mg/kg, ± 2 mg/kg, or ± 2.8 mg/kg); The sum of C1D1 and C1D2 is about 23 mg/kg (e.g., 23 mg/kg ± 0.25 mg/kg, ± 0.5 mg/kg, ± 1 mg/kg, ± 2 mg/kg, or ± 2.3 mg/kg); (d) the subject weighs more than or equal to about 32 kg and less than about 45 kg, and the sum of C1D1 and C1D2 of olibutuzumab is about 20 mg/kg (e.g., 23 mg/kg ± 0.25 mg/kg, ± 0.5 mg/kg, ± 1 mg/kg, or ± 2 mg/kg); or (e) the subject weighs more than or equal to about 45 kg, and the sum of C1D1 and C1D2 of olibutuzumab is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg).

In one embodiment, the C1D1 of oxytocinumab is about one-tenth the sum of the C1D1 and C1D2 of oxytocinumab, and the C1D2 of oxytocinumab is about nine-tenths the sum of the C1D1 and C1D2 of oxytocinumab. In one embodiment, (a) the subject's weight is greater than or equal to about 7.5 kg and less than about 13 kg, and the C1D1 of olibutuzumab is about 3.8 mg/kg (e.g., 3.8 mg/kg ± 0.05 mg/kg, 0.1 mg/kg, ± 0.2 mg/kg, ± 0.3 mg/kg, or ± 0.38 mg/kg) and the C1D2 of olibutuzumab is about 34.2 mg/kg (e.g., 34.2 mg/kg ± 0.5 mg/kg, 1 mg/kg, ± 2 mg/kg, ± 3 mg/kg, or ± 3.42 mg/kg); (b) the subject's weight is greater than or equal to about 13 kg and less than about 20 kg, and the C1D2 of olibutuzumab is about 3.8 mg/kg (e.g., 3.8 mg/kg ± 0.05 mg/kg, 0.1 mg/kg, ± 0.2 mg/kg, ± 0.3 mg/kg, or ± 0.38 mg/kg) and the C1D2 of olibutuzumab is about 34.2 mg/kg (e.g., 34.2 mg/kg ± 0.5 mg/kg, 1 mg/kg, ± 2 mg/kg, ± 3 mg/kg, or ± 3.42 mg/kg); The C1D1 of olibutuzumab is about 2.8 mg/kg (e.g., 2.8 mg/kg ± 0.05 mg/kg, 0.1 mg/kg, ± 0.2 mg/kg, or ± 0.28 mg/kg), and the C1D2 of olibutuzumab is about 35.2 mg/kg (e.g., 35.2 mg/kg ± 0.5 mg/kg, 1 mg/kg, ± 2 mg/kg, ± 3 mg/kg, or ± 3.52 mg/kg); (c) the subject's weight is greater than or equal to about 20 kg and less than about 32 kg, and the C1D1 of olibutuzumab is about 2.3 mg/kg (e.g., 2.3 mg/kg ± 0.05 mg/kg, 0.1 mg/kg, ± 0.2 mg/kg, or ± 0.28 mg/kg). (d) The subject's weight is greater than or equal to about 32 kg and less than about 45 kg, and the C1D1 of olibutuzumab is about 2.0 mg/kg (e.g., 2.0 mg/kg ± 0.05 mg/kg, 0.1 mg/kg or ± 0.2 mg/kg), and the C1D2 of olibutuzumab is about 36.0 mg/kg (e.g., 36 mg/kg ± 0.2 mg/kg, ± 0.23 ... (e) The subject's weight is greater than or equal to about 45 kg, and the C1D1 of olibutuzumab is about 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 8 mg or ± 10 mg) and the C1D2 of olibutuzumab is about 900 mg (e.g., 900 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 40 mg, ± 50 mg, ± 60 mg, ± 70 mg, ± 80 mg or ± 90 mg).

In one embodiment, the subject is given C1D1 of oxetuzumab on day 1 of the first dosing cycle, and C1D2 of oxetuzumab on day 2 of the first dosing cycle.

In one embodiment, the second dosing cycle comprises a single dose (C2D1) of rituximab. In one embodiment, the C2D1 of rituximab is approximately 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ). In one embodiment, rituximab is administered to the subject on day 5 of the second dosing cycle.

In one embodiment, the method includes administering ifosfamide, carboplatin, and etoposide to a subject.

In one embodiment, the first dosing cycle includes:

(a) The first dose of ifosfamide (C1D1), the second dose of ifosfamide (C1D2), and the third dose of ifosfamide (C1D3);

(b) A single dose of carboplatin (C1D1); and

(c) The first dose of etoposide (C1D1), the second dose of etoposide (C1D2), and the third dose of etoposide (C1D3);

And the second cycle includes:

(a) The first dose of ifosfamide (C2D1), the second dose of ifosfamide (C2D2), and the third dose of ifosfamide (C2D3);

(b) A single dose of carboplatin (C2D1); and

(c) The first dose of etoposide (C2D1), the second dose of etoposide (C2D2), and the third dose of etoposide (C2D3).

In one embodiment, ifosfamide is to be administered at a dose of approximately 3000 mg/ ^m² (e.g., 3000 mg/ ^m² ± 40 mg/ ^m² , ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , or ± 300 mg/ ^m² ). For each dose of ifosfamide, carboplatin is to be administered at a dose of approximately 635 mg/ ^m² (e.g., 635 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , ± 50 mg/ ^m² , ± 60 mg/ ^m² , or ± 63.5 mg/ ^m² ), and carboplatin is to be administered at a dose of approximately 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/m² ^). Etoposide is administered at each dose of etoposide. In one embodiment, (a) ifosfamide C1D1, C1D2, and C1D3 are administered on days 3, 4, and 5 of the first dosing cycle, respectively; (b) carboplatin C1D1 is administered on day 3 of the first dosing cycle; (c) etoposide C1D1, C1D2, and C1D3 are administered on days 3, 4, and 5 of the first dosing cycle, respectively; (d) ifosfamide C2D1, C2D2, and C2D3 are administered on days 6, 7, and 8 of the second dosing cycle, respectively; (e) carboplatin C2D1 is administered on day 6 of the second dosing cycle; and (f) etoposide C2D1, C2D2, and C2D3 are administered on days 6, 7, and 8 of the second dosing cycle, respectively.

In one embodiment, the first and second dosing cycles are each 21-day dosing cycles. In one embodiment, the dosing regimen includes one or more additional dosing cycles. In one embodiment, the one or more additional dosing cycles are each 21-day dosing cycles. In one embodiment, the dosing regimen includes a total of three dosing cycles.

In one embodiment, one or more additional dosing cycles each include:

(a) An additional single dose of a bispecific antibody that binds to both CD20 and CD3.

(b) An additional single dose of anti-CD20 antibody, and

(c) Additional first, second, and third doses of ifosfamide; an additional single dose of carboplatin; and additional first, second, and third doses of etoposide. In one embodiment, (a) the subject weighs more than or equal to about 7.5 kg and less than about 13 kg, and the additional single dose of the bispecific antibody is about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, ± 0.04 mg/kg, or ± 0.05 mg/kg); (b) the subject weighs more than or equal to about 13 kg and less than about 45 kg, and the additional single dose of the bispecific antibody is... (c) The subject weighs more than or equal to about 45 kg, and the additional single dose of the bispecific antibody is about 30 mg (e.g., 0.4 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg or ± 0.04 mg/kg); or (d) the subject weighs more than or equal to about 45 kg, and the additional single dose of the bispecific antibody is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg).

In one embodiment, an additional single dose of the bispecific antibody is administered to the subject on day 1 of each of the one or more additional dosing cycles.

In one embodiment, the anti-CD20 antibody is rituximab. In one embodiment, the additional single dose of rituximab is about 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ). In one embodiment, the additional single dose of rituximab is administered on day 5 of each of the one or more additional dosing cycles.

In one embodiment, the additional first, second, and third doses of ifosfamide are each about 3000 mg/ ^m² (e.g., 3000 mg/ ^m² ± 40 mg/ ^m² , ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , or ± 300 mg/ ^m² ), the additional single dose of carboplatin is about 635 mg/ ^m² (e.g., 635 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , ± 50 mg/ ^m² , ± 60 mg/ ^m² , or ± 63.5 mg/ ^m² ), and the additional first, second, and third doses of etoposide are each about 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/m²). ² or ±10 mg/ ^m² ). In one embodiment, (a) an additional first dose, an additional second dose, and an additional third dose of ifosfamide shall be administered to the subject on days 6, 7, and 8 of each of the one or more additional dosing cycles; (b) an additional single dose of carboplatin shall be administered on day 6 of each of the one or more additional dosing cycles; and (c) an additional first dose, an additional second dose, and an additional third dose of etoposide shall be administered to the subject on days 6, 7, and 8 of each of the one or more additional dosing cycles.

In one embodiment, the method further includes administering one or more additional therapeutic agents to the subject.

In one embodiment, one or more additional therapeutic agents are tocilizumab. In one embodiment, a subject weighing 30 kg or more is to be administered tocilizumab at a dose of about 8 mg/kg (e.g., 8 mg/kg ± 0.05 mg/kg, ± 0.1 mg/kg, ± 0.25 mg/kg, ± 0.5 mg/kg, or ± 0.8 mg/kg), or a subject weighing less than 30 kg is to be administered tocilizumab at a dose of about 12 mg/kg (e.g., 12 mg/kg ± 0.05 mg/kg, ± 0.1 mg/kg, ± 0.25 mg/kg, ± 0.5 mg/kg, ± 0.75 mg/kg, ± 1 mg/kg, or ± 1.2 mg/kg), wherein the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg).

In one embodiment, one or more additional therapeutic agents are corticosteroids. In one embodiment, corticosteroids include prednisone, prednisolone, methylprednisolone, or dexamethasone.

In one embodiment, the corticosteroid is dexamethasone. In one embodiment, dexamethasone is administered intravenously at a dose between about 0.15 mg/kg (e.g., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) and about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.001 mg/kg, ± 0.0025 mg/kg, ± 0.005 mg/kg, ± 0.01 mg/kg, or ± 0.015 mg/kg) before any dose of the bispecific antibody is administered, and wherein the maximum daily dose is 10 mg. In one embodiment, dexamethasone is administered intravenously at a dose between about 0.15 mg/kg (e.g., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) and about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.001 mg/kg, ± 0.0025 mg/kg, ± 0.005 mg/kg, ± 0.01 mg/kg or ± 0.015 mg/kg) and about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, ± 0.04 mg/kg or ± 0.05 mg/kg) before administration of any dose of olibutuzumab, and wherein the maximum daily dose is 10 mg.

In one embodiment, the corticosteroid is methylprednisolone. In one embodiment, methylprednisolone is administered intravenously at a dose between about 1 mg/kg and about 2 mg/kg (e.g., 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.9 or 2.0 mg/kg) at least one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before any dose of the bispecific antibody is administered. In one embodiment, methylprednisolone is administered intravenously at a dose between about 1 mg/kg and about 2 mg/kg (e.g., 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.9 or 2.0 mg/kg) at least one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before any dose of olibutuzumab is administered.

In one embodiment, the corticosteroid is prednisone or prednisolone. In one embodiment, prednisone or prednisolone is administered intravenously at a dose of about 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 8 mg, or ± 10 mg) or about 2 mg/kg at least one hour after administration of any dose of the bispecific antibody (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more). In one embodiment, prednisone or prednisolone is administered intravenously at a dose of about 100 mg (e.g., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) or about 2 mg/kg, at a dose of about 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 8 mg or ± 10 mg) or about 2 mg/kg, at a dose prior to administration of any dose of olibutuzumab.

In one embodiment, one or more additional therapeutic agents are antihistamines. In one embodiment, the antihistamine is diphenhydramine. In one embodiment, the subject is between 2 and 17 years of age, and diphenhydramine is administered intravenously at a dose of about 10 mg to 20 mg (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg), wherein the maximum single dose is about 1.25 mg/kg. In one embodiment, the subject is less than two years of age, and diphenhydramine is administered rectally at a dose of about 20 mg (e.g., 20 mg ± 0.1 mg, ± 0.25 mg, ± 0.5 mg, ± 1 mg, ± 1.5 mg, or ± 2 mg). In one embodiment, diphenhydramine is administered at least about 30 minutes (i.e., at least 30 minutes ± 3 minutes; for example, at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before any dose of the bispecific antibody and/or anti-CD20 antibody is administered.

In one embodiment, one or more additional therapeutic agents include granulocyte colony-stimulating factor (G-CSF). In one embodiment, G-CSF is administered approximately one to approximately two days after administration of any dose of rituximab, ifosfamide, carboplatin, and/or etoposide (e.g., 24, 26, 28, 30, 32, 36, 38, 40, 42, 44, 46, or 48 hours). In one embodiment, G-CSF is administered intravenously or subcutaneously at a dose of about 5 μg/kg/day (e.g., 5 μg/kg/day ± 0.05 μg/kg/day, ± 0.1 μg/kg/day, ± 0.2 μg/kg/day, ± 0.3 μg/kg/day, ± 0.4 μg/kg/day, ± 0.5 μg/kg/day) or about 10 μg/kg/day (e.g., 10 μg/kg/day ± 0.1 μg/kg/day, ± 0.2 μg/kg/day, ± 0.4 μg/kg/day, ± 0.6 μg/kg/day, ± 0.8 μg/kg/day, ± 1 μg/kg/day). In one embodiment, G-CSF is administered at a dose of about 5 μg/kg/day in the first dosing cycle (e.g., 5 μg/kg/day ± 0.05 μg/kg/day, ± 0.1 μg/kg/day, ± 0.2 μg/kg/day, ± 0.3 μg/kg/day, ± 0.4 μg/kg/day, ± 0.5 μg/kg/day) in the second dosing cycle and/or each additional dosing cycle at a dose of about 10 μg/kg/day (e.g., 10 μg/kg/day ± 0.1 μg/kg/day, ± 0.2 μg/kg/day, ± 0.4 μg/kg/day, ± 0.6 μg/kg/day, ± 0.8 μg/kg/day, ± 1 μg/kg/day).

In one embodiment, one or more additional therapeutic agents are antipyretics. In one embodiment, the antipyretic is acetaminophen or paracetamol. In one embodiment, acetaminophen or paracetamol is administered orally or intravenously at a dose between about 500 and about 1000 mg (e.g., 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg). In one embodiment, acetaminophen or paracetamol is administered at least about 30 minutes (i.e., at least 30 minutes ± 3 minutes; e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before the administration of any dose of the bispecific antibody and/or anti-CD20 antibody.

In one embodiment, one or more additional therapeutic agents are mesna. In one embodiment, mesna is administered intravenously daily at five doses totaling 3000 mg/ ^m² . In one embodiment, mesna is administered intravenously at a first dose of about 600 mg/ ^m² and four repeated doses of about 600 mg/ ^m² prior to any dose of ifosfamide, each repeated dose approximately three hours, six hours, and 12 hours after the first dose of ifosfamide, respectively. In one embodiment, mesna is administered to the subject daily on days 3, 4, and 5 of the first dosing cycle, days 6, 7, and 8 of the second dosing cycle, and/or on days 6, 7, and 8 of each additional dosing cycle.

In one aspect, the invention is characterized by a bispecific antibody that binds to CD20 and CD3, which is used in a method of treating a subject aged 18 to 30 years with a CD20-positive proliferative disorder, wherein the bispecific antibody that binds to CD20 and CD3 is administered in combination with an anti-CD20 antibody and one or more chemotherapeutic agents selected from ifosfamide, carboplatin and/or etoposide, in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

In one embodiment, the first dosing cycle includes a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody, wherein the C1D1 of the bispecific antibody is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of the bispecific antibody is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); and

The second dosing cycle includes a single dose (C2D1) of the bispecific antibody, wherein the C2D1 of the bispecific antibody is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

In one embodiment, the bispecific antibody C1D1 and bispecific antibody C1D2 are administered to the subject on day 8 and day 15 of the first dosing cycle, respectively.

In one embodiment, the bispecific antibody C2D1 is administered to the subject on day 1 of the second dosing cycle.

In one embodiment, the anti-CD20 antibody is olibutuzumab and/or rituximab.

In one embodiment, the first dosing cycle comprises a first dose (C1D1) of olibutuzumab and a second dose (C1D2) of olibutuzumab. In one embodiment, the sum of olibutuzumab C1D1 and C1D2 is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg). In one embodiment, the olibutuzumab C1D1 is about one-tenth the amount of the sum of olibutuzumab C1D1 and C1D2, and the olibutuzumab C1D2 is about nine-tenths the amount of the sum of olibutuzumab C1D1 and C1D2. In one embodiment, the C1D1 of olibutuzumab is about 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 8 mg, or ± 10 mg) and the C1D2 of olibutuzumab is about 900 mg (e.g., 900 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 40 mg, ± 50 mg, ± 60 mg, ± 70 mg, ± 80 mg, or ± 90 mg). In one embodiment, the C1D1 of olibutuzumab is administered to the subject on day 1 of the first dosing cycle, and the C1D2 of olibutuzumab is administered to the subject on day 2 of the first dosing cycle.

In one embodiment, the second dosing cycle comprises a single dose (C2D1) of rituximab. In one embodiment, the C2D1 of rituximab is approximately 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ). In one embodiment, the C2D1 of rituximab is administered to the subject on day 5 of the second dosing cycle.

In one embodiment, the method includes administering ifosfamide, carboplatin, and etoposide to a subject. In one embodiment, the first dosing cycle includes:

(a) A single dose of ifosfamide (C1D1);

(b) A single dose of carboplatin (C1D1); and

(c) The first dose of etoposide (C1D1), the second dose of etoposide (C1D2), and the third dose of etoposide (C1D3);

And the second cycle includes:

(a) A single dose of ifosfamide (C2D1);

(b) A single dose of carboplatin (C2D1); and

(c) The first dose of etoposide (C2D1), the second dose of etoposide (C2D2), and the third dose of etoposide (C2D3).

In one embodiment, ifosfamide is administered at a dose of about 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ), carboplatin is administered at a dose of about 5 × (25 + creatinine clearance (CrCl)) mg, with the largest dose being about 750 mg (e.g., 750 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 75 mg), and etoposide is administered at a dose of about 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/ ^m² ) for each dose of etoposide.

In one embodiment, (a) the subject is male, and CrCl is calculated using the formula CrCl = ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]); or (b) the subject is female, and CrCl is calculated using the formula CrCl = 0.85 × ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]).

In one embodiment, (a) the subject has < about 60 mL/min of CrCl, and each single dose of ifosfamide is reduced to 4000 mg/ ^m² ; and/or (b) the subject has < about 50 mL/min of CrCl, and each dose of etoposide is reduced to 75 mg/ ^m² .

In one embodiment, (a) C1D1 ifosfamide is administered on day 3 of the first dosing cycle;

(b) Administer carboplatin C1D1 on day 3 of the first dosing cycle;

(c) Etoposide C1D1, C1D2 and C1D3 were administered on days 3, 4 and 5 of the first dosing cycle, respectively;

(d) Administer C2D1 of ifosfamide on day 6 of the second dosing cycle;

(e) Administer carboplatin C2D1 on day 6 of the second dosing cycle; and

(f) Etoposide C2D1, C2D2 and C2D3 will be administered on days 6, 7 and 8 of the second dosing cycle, respectively.

In one embodiment, the first and second dosing cycles are each 21-day dosing cycles. In one embodiment, the dosing regimen includes one or more additional dosing cycles. In one embodiment, the one or more additional dosing cycles are each 21-day dosing cycles. In one embodiment, the dosing regimen includes a total of three dosing cycles.

In one embodiment, one or more additional dosing cycles each include:

(a) An additional single dose of a bispecific antibody that binds to both CD20 and CD3.

(b) An additional single dose of anti-CD20 antibody, and

(c) Additional single doses of ifosfamide; additional single doses of carboplatin; and additional first, second and third doses of etoposide.

In one embodiment, an additional single dose of the bispecific antibody is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg). In one embodiment, the additional single dose of the bispecific antibody is administered to the subject on day 1 of each of the one or more additional dosing cycles.

In one embodiment, the anti-CD20 antibody is rituximab. In one embodiment, the additional single dose of rituximab is about 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ). In one embodiment, the additional single dose of rituximab is administered on day 5 of each of the one or more additional dosing cycles.

In one embodiment, the additional single dose of ifosfamide is about 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ), the additional single dose of carboplatin is about 5 × (25 + creatinine clearance (CrCl)) mg, with the maximum dose being about 750 mg (e.g., 750 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 75 mg), and the additional first, second, and third doses of etoposide are each about 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/ ^m² ).

In one embodiment, (a) the subject is male, and CrCl is calculated using the formula CrCl = ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]); or (b) the subject is female, and CrCl is calculated using the formula CrCl = 0.85 × ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]).

In one embodiment, (a) the subject has < about 60 mL/min of CrCl, and the additional single dose of ifosfamide is reduced to 4000 mg/ ^m² ; and/or (b) the subject has < about 50 mL/min of CrCl, and each additional dose of etoposide is reduced to 75 mg/ ^m² .

In one embodiment, (a) an additional single dose of ifosfamide is administered on day 6 of each of the one or more additional dosing cycles;

(b) Administer an additional single dose of carboplatin on day 6 of each of the one or more additional dosing cycles; and

(c) The subject shall be given an additional first dose, an additional second dose, and an additional third dose of etoposide on days 6, 7, and 8 of each of the one or more additional dosing cycles.

In one embodiment, the method further includes administering one or more additional therapeutic agents to the subject.

In one embodiment, one or more additional therapeutic agents are tocilizumab. In one embodiment, a subject weighing 30 kg or more is to be administered tocilizumab at a dose of about 8 mg/kg (e.g., 8 mg/kg ± 0.05 mg/kg, ± 0.1 mg/kg, ± 0.25 mg/kg, ± 0.5 mg/kg, or ± 0.8 mg/kg), or a subject weighing less than 30 kg is to be administered tocilizumab at a dose of about 12 mg/kg (e.g., 12 mg/kg ± 0.05 mg/kg, ± 0.1 mg/kg, ± 0.25 mg/kg, ± 0.5 mg/kg, ± 0.75 mg/kg, ± 1 mg/kg, or ± 1.2 mg/kg), wherein the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg).

In one embodiment, one or more additional therapeutic agents are corticosteroids.

In one embodiment, the corticosteroid includes prednisone, prednisolone, methylprednisolone, or dexamethasone.

In one embodiment, the corticosteroid is dexamethasone. In one embodiment, dexamethasone is administered intravenously at a dose between about 0.15 mg/kg (e.g., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) and about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.001 mg/kg, ± 0.0025 mg/kg, ± 0.005 mg/kg, ± 0.01 mg/kg, or ± 0.015 mg/kg) before any dose of the bispecific antibody is administered, and wherein the maximum daily dose is 10 mg. In one embodiment, dexamethasone is administered intravenously at a dose between about 0.15 mg/kg (e.g., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) and about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.001 mg/kg, ± 0.0025 mg/kg, ± 0.005 mg/kg, ± 0.01 mg/kg or ± 0.015 mg/kg) and about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, ± 0.04 mg/kg or ± 0.05 mg/kg) before administration of any dose of olibutuzumab, and wherein the maximum daily dose is 10 mg.

In one embodiment, the corticosteroid is methylprednisolone. In one embodiment, methylprednisolone is administered intravenously at a dose between about 1 mg/kg and about 2 mg/kg (e.g., 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.9 or 2.0 mg/kg) at least one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before any dose of the bispecific antibody is administered. In one embodiment, methylprednisolone is administered intravenously at a dose between about 1 mg/kg and about 2 mg/kg (e.g., 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.9 or 2.0 mg/kg) at least one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before any dose of olibutuzumab is administered.

In one embodiment, the corticosteroid is prednisone or prednisolone. In one embodiment, prednisone or prednisolone is administered intravenously at a dose of about 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 6 mg, ± 8 mg, or ± 10 mg) or about 2 mg/kg at least one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) or about 2 mg/kg before any dose of the bispecific antibody is administered. In one embodiment, prednisone or prednisolone is administered intravenously at a dose of about 100 mg (e.g., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) or about 2 mg/kg, at a dose of about 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 8 mg or ± 10 mg) or about 2 mg/kg, at a dose prior to administration of any dose of olibutuzumab.

In one embodiment, one or more additional therapeutic agents are antihistamines. In one embodiment, the antihistamine is diphenhydramine. In one embodiment, diphenhydramine is administered orally or intravenously at a dose of about 50 mg (e.g., 50 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, or ± 5 mg). In one embodiment, diphenhydramine is administered at least about 30 minutes (i.e., at least 30 minutes ± 3 minutes; e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before the administration of any dose of the bispecific antibody and/or anti-CD20 antibody.

In one embodiment, one or more additional therapeutic agents include granulocyte colony-stimulating factor (G-CSF). In one embodiment, G-CSF is administered approximately one to approximately two days after administration of any dose of rituximab, ifosfamide, carboplatin, and/or etoposide (e.g., 24, 26, 28, 30, 32, 36, 38, 40, 42, 44, 46, or 48 hours). In one embodiment, G-CSF is administered intravenously or subcutaneously at a dose of about 5 μg/kg/day (e.g., 5 μg/kg/day ± 0.05 μg/kg/day, ± 0.1 μg/kg/day, ± 0.2 μg/kg/day, ± 0.3 μg/kg/day, ± 0.4 μg/kg/day, ± 0.5 μg/kg/day) or about 10 μg/kg/day (e.g., 10 μg/kg/day ± 0.1 μg/kg/day, ± 0.2 μg/kg/day, ± 0.4 μg/kg/day, ± 0.6 μg/kg/day, ± 0.8 μg/kg/day, ± 1 μg/kg/day). In one embodiment, G-CSF is administered at a dose of about 5 μg/kg/day in the first dosing cycle (e.g., 5 μg/kg/day ± 0.05 μg/kg/day, ± 0.1 μg/kg/day, ± 0.2 μg/kg/day, ± 0.3 μg/kg/day, ± 0.4 μg/kg/day, ± 0.5 μg/kg/day) in the second dosing cycle and/or each additional dosing cycle at a dose of about 10 μg/kg/day (e.g., 10 μg/kg/day ± 0.1 μg/kg/day, ± 0.2 μg/kg/day, ± 0.4 μg/kg/day, ± 0.6 μg/kg/day, ± 0.8 μg/kg/day, ± 1 μg/kg/day).

In one embodiment, one or more additional therapeutic agents are antipyretics. In one embodiment, the antipyretic is acetaminophen or paracetamol. In one embodiment, acetaminophen or paracetamol is administered orally or intravenously at a dose between about 500 and about 1000 mg (e.g., 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg). In one embodiment, acetaminophen or paracetamol is administered at least about 30 minutes (i.e., at least 30 minutes ± 3 minutes; e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before the administration of any dose of the bispecific antibody and/or anti-CD20 antibody.

In one embodiment, one or more additional therapeutic agents are mesna. In one embodiment, mesna is administered intravenously at a dose of about 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ). In one embodiment, mesna is administered via continuous infusion over about 24 hours on day 3 of the first dosing cycle, day 6 of the second dosing cycle, and/or day 6 of each additional dosing cycle. In one embodiment, mesna is administered concurrently with any dose of ifosfamide.

In one aspect, the invention is characterized by the use of glimetuzumab in a method of treating a subject with CD20-positive proliferative disorders, wherein glimetuzumab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

(a) The first dosing cycle comprises administering a first dose (C1D1) of glimetuzumab on day 8 and a second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of glimetuzumab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); and

(b) The second dosing cycle consists of a single dose (C2D1) of glimetuzumab administered on day 8, wherein the C2D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

In one aspect, the invention is characterized by the use of glimetuzumab in a method of treating a subject with CD20-positive proliferative disorders, wherein glimetuzumab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle.

(a) The first dosing cycle consists of administering the first dose (C1D1) of glimetuzumab on day 8 and the second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg or ± 0.25 mg), and the C1D2 of glimetuzumab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg or ± 1 mg);

(b) The second dosing cycle comprises a single dose (C2D1) of glimetuzumab administered on day 8, wherein the C2D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg); and

(c) The third dosing cycle includes a single dose (C3D1) of glimetuzumab administered on day 8, wherein the C3D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

In one aspect, the invention is characterized by the use of glimetuzumab in a method of treating a subject with CD20-positive proliferative disorders, wherein glimetuzumab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

(a) The first dosing cycle includes:

(i) Administer the first dose (C1D1) of glimetuzumab on day 8 and the second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg or ± 0.25 mg), and the C1D2 of glimetuzumab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg or ± 1 mg);

(ii) Administer the first dose (C1D1) of olibutuzumab on day 1, wherein the C1D1 of olibutuzumab is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg or ± 100 mg);

(iii) A single dose (C1D1) of ifosfamide is administered on day 2, wherein the C1D1 of ifosfamide is about 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/ ^m2 , ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), and the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg or ± 80 mg);

(iv) A single dose (C1D1) of carboplatin was administered on day 2, wherein the C1D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C1D1) on day 1, the second dose of etoposide (C1D2) on day 2, and the third dose of etoposide (C1D3) on day 3, wherein the C1D1, C1D2, and C1D3 of etoposide are each approximately 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/ ^m² ); and

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab is administered on day 8, wherein the C2D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg);

(ii) Administer the first dose of rituximab (C2D1) on day 1, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 );

(iii) A single dose (C2D1) of ifosfamide is administered on day 2, wherein the C2D1 of ifosfamide is about 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/ ^m2 , ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), and the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg or ± 80 mg);

(iv) A single dose (C2D1) of carboplatin was administered on day 2, wherein the C2D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C2D1) on day 1, the second dose of etoposide (C2D2) on day 2, and the third dose of etoposide (C2D3) on day 3, wherein the C2D1, C2D2, and C2D3 of etoposide are each approximately 100 mg/ ^m2 (e.g., 100 mg/ ^m2 ± 1 mg/ ^m2 , ± 2.5 mg/ ^m2 , ± 5 mg/ ^m2 , or ± 10 mg/ ^m2 ).

In one aspect, the invention is characterized by the use of glimetuzumab in a method of treating a subject with CD20-positive proliferative disorders, wherein glimetuzumab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle.

(a) The first dosing cycle includes:

(i) Administer the first dose (C1D1) of glimetuzumab on day 8 and the second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg or ± 0.25 mg), and the C1D2 of glimetuzumab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg or ± 1 mg);

(ii) Administer the first dose (C1D1) of olibutuzumab on day 1, wherein the C1D1 of olibutuzumab is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg or ± 100 mg);

(iii) A single dose (C1D1) of ifosfamide is administered on day 2, wherein the C1D1 of ifosfamide is about 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/ ^m2 , ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), and the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg or ± 80 mg);

(iv) A single dose (C1D1) of carboplatin was administered on day 2, wherein the C1D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C1D1) on day 1, the second dose of etoposide (C1D2) on day 2, and the third dose of etoposide (C1D3) on day 3, wherein the C1D1, C1D2, and C1D3 of etoposide are each approximately 100 mg/ ^m2 (e.g., 100 mg/ ^m2 ± 1 mg/ ^m2 , ± 2.5 mg/ ^m2 , ± 5 mg/ ^m2 , or ± 10 mg/ ^m2 );

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab is administered on day 8, wherein the C2D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg);

(ii) Administer the first dose of rituximab (C2D1) on day 1, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 );

(iii) A single dose (C2D1) of ifosfamide is administered on day 2, wherein the C2D1 of ifosfamide is about 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/ ^m2 , ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), and the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg or ± 80 mg);

(iv) A single dose (C2D1) of carboplatin was administered on day 2, wherein the C2D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C2D1) on day 1, the second dose of etoposide (C2D2) on day 2, and the third dose of etoposide (C2D3) on day 3, wherein the C2D1, C2D2, and C2D3 of etoposide are each approximately 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/ ^m² ); and

(c) The third dosing cycle includes:

(i) A single dose (C3D1) of glimetuzumab is administered on day 8, wherein the C3D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg);

(ii) Administer the first dose of rituximab (C3D1) on day 1, wherein the C3D1 of rituximab is approximately 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 );

(iii) A single dose (C3D1) of ifosfamide is administered on day 2, wherein the C3D1 of ifosfamide is about 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/ ^m2 , ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), and the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg or ± 80 mg);

(iv) A single dose (C3D1) of carboplatin was administered on day 2, wherein the C3D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C3D1) on day 1, the second dose of etoposide (C3D2) on day 2, and the third dose of etoposide (C3D3) on day 3, wherein the C3D1, C3D2, and C3D3 of etoposide are each approximately 100 mg/ ^m2 (e.g., 100 mg/ ^m2 ± 1 mg/ ^m2 , ± 2.5 mg/ ^m2 , ± 5 mg/ ^m2 , or ± 10 mg/ ^m2 ).

In one embodiment, mesna is administered concurrently with any dose of ifosfamide. In one embodiment, mesna is administered intravenously at a dose of about 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ). In one embodiment, mesna is administered via continuous infusion over about 24 hours on day 2 of each dosing cycle.

In one aspect, the invention is characterized by a method of treating a subject aged 6 months to 17 years with CD20-positive proliferative disorder, the method comprising administering to the subject effective amounts of glimepiride, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein

(a) The first dosing cycle comprises administering the first dose (C1D1) of glimetuzumab on day 8 and the second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is approximately 0.03 mg/kg (e.g., 0.03 mg/kg ± 0.0005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg, or ± 0.003 mg/kg), approximately 0.04 mg/kg (e.g., 0.04 mg/kg ± 0.0005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg, ± 0.003 mg/kg, or ± 0.004 mg/kg), or approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of glimepiride is about 0.15 mg/kg (e.g., 0.15 mg/kg ± 0.001 mg/kg, ± 0.0025 mg/kg, ± 0.005 mg/kg, ± 0.01 mg/kg, or ± 0.015 mg/kg) or about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); and

(b) The second dosing cycle consists of a single dose (C2D1) of glimetuzumab administered on day 8, wherein the C2D1 of glimetuzumab is about 0.4 mg/kg (e.g., 0.4 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg or ± 0.04 mg/kg), about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, ± 0.04 mg/kg or ± 0.05 mg/kg), or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg).

In one aspect, the invention is characterized by a method of treating a subject aged 6 months to 17 years with CD20-positive proliferative disorder, the method comprising administering to the subject effective amounts of glimepiride, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle, wherein...

(a) The first dosing cycle comprises administering a first dose (C1D1) of glimetuzumab on day 8 and a second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is approximately 0.03 mg/kg (e.g., 0.03 mg/kg ± 0.0005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg, or ± 0.003 mg/kg), approximately 0.04 mg/kg (e.g., 0.04 mg/kg ± 0.0005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg, ± 0.003 mg/kg, or ± 0.004 mg/kg), or Approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of glimepiride is approximately 0.15 mg/kg (e.g., 0.15 mg/kg ± 0.001 mg/kg, ± 0.0025 mg/kg, ± 0.005 mg/kg, ± 0.01 mg/kg, or ± 0.015 mg/kg) or approximately 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg);

(b) The second dosing cycle comprises a single dose (C2D1) of glimetuzumab administered on day 8, wherein the C2D1 of glimetuzumab is approximately 0.4 mg/kg (e.g., 0.4 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, or ± 0.04 mg/kg), approximately 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, ± 0.04 mg/kg, or ± 0.05 mg/kg), or approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg); and

(c) The third dosing cycle consists of a single dose (C3D1) of glimetuzumab administered on day 8, wherein the C3D1 of glimetuzumab is about 0.4 mg/kg (e.g., 0.4 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg or ± 0.04 mg/kg), about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, ± 0.04 mg/kg or ± 0.05 mg/kg), or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg).

In one aspect, the invention is characterized by a method of treating a subject aged 6 months to 17 years with CD20-positive proliferative disorder, the method comprising administering to the subject effective amounts of glimepiride, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein

(a) The first dosing cycle includes:

(i) Administer the first dose (C1D1) of glimetuzumab on day 8 and the second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 dose of glimetuzumab is approximately 0.03 mg/kg (e.g., 0.03 mg/kg ± 0.0005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg, or ± 0.003 mg/kg), approximately 0.04 mg/kg (e.g., 0.04 mg/kg ± 0.0005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg, ± 0.003 mg/kg, or ± 0.004 mg/kg), or approximately 2.5 mg/kg. mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of glimepiride is about 0.15 mg/kg (e.g., 0.15 mg/kg ± 0.001 mg/kg, ± 0.0025 mg/kg, ± 0.005 mg/kg, ± 0.01 mg/kg, or ± 0.015 mg/kg) or about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg);

(ii) Administer the first dose (C1D1) of olibutuzumab on day 1 and the second dose (C1D2) of olibutuzumab on day 2, wherein the C1D1 of olibutuzumab is approximately one-tenth the sum of the C1D1 and C1D2 of olibutuzumab, and the C1D2 of olibutuzumab is approximately nine-tenths the sum of the C1D1 and C1D2 of olibutuzumab, and wherein the sum of the C1D1 and C1D2 of olibutuzumab is approximately 38 mg/kg (e.g., 38 mg/kg ± 0.25 mg/kg, ± 0.5 mg/kg, ± 1 mg/kg, ± 2 mg/kg). ±3 mg/kg or ±3.8 mg/kg), approximately 28 mg/kg (e.g., 28 mg/kg ±0.25 mg/kg, ±0.5 mg/kg, ±1 mg/kg, ±2 mg/kg or ±2.8 mg/kg), approximately 23 mg/kg (e.g., 23 mg/kg ±0.25 mg/kg, ±0.5 mg/kg, ±1 mg/kg, ±2 mg/kg or ±2.3 mg/kg), approximately 20 mg/kg or approximately 1000 mg (e.g., 1000 mg ±5 mg, ±10 mg, ±20 mg, ±30 mg, ±50 mg, ±75 mg or ±100 mg);

(iii) Administer the first dose of ifosfamide (C1D1) on day 3, the second dose of ifosfamide (C1D2) on day 4, and the third dose of ifosfamide (C1D3) on day 5, wherein the C1D1, C1D2 and C1D3 of ifosfamide are each about 3000 mg/ ^m2 (e.g., 3000 mg/ ^m2 ± 40 mg/ ^m2 , ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 or ± 300 mg/ ^m2 );

(iv) A single dose (C1D1) of carboplatin is administered on day 3, wherein the C1D1 of carboplatin is approximately 635 mg/ ^m² (e.g., 635 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , ± 50 mg/ ^m² , ± 60 mg/ ^m² , or ± 63.5 mg/ ^m² ); and

(v) Administer the first dose of etoposide (C1D1) on day 3, the second dose of etoposide (C1D2) on day 4, and the third dose of etoposide (C1D3) on day 5, wherein the C1D1, C1D2, and C1D3 of etoposide are each approximately 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/ ^m² ); and

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab is administered on day 1, wherein the C2D1 of glimetuzumab is about 0.4 mg/kg (e.g., 0.4 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg or ± 0.04 mg/kg), about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, ± 0.04 mg/kg or ± 0.05 mg/kg) or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg);

(ii) Administer the first dose (C2D1) of rituximab on day 5, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 );

(iii) Administer the first dose of ifosfamide (C2D1) on day 6, the second dose of ifosfamide (C2D2) on day 7, and the third dose of ifosfamide (C2D3) on day 8, wherein the C2D1, C2D2 and C2D3 of ifosfamide are each about 3000 mg/ ^m2 (e.g., 3000 mg/ ^m2 ± 40 mg/ ^m2 , ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 or ± 300 mg/ ^m2 );

(iv) A single dose (C2D1) of carboplatin was administered on day 6, wherein the C2D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C2D1) on day 6, the second dose of etoposide (C2D2) on day 7, and the third dose of etoposide (C2D3) on day 8, wherein the C2D1, C2D2 and C2D3 of etoposide are each about 100 mg/ ^m2 (e.g., 100 mg/ ^m2 ± 1 mg/ ^m2 , ± 2.5 mg/ ^m2 , ± 5 mg/ ^m2 or ± 10 mg/ ^m2 ).

In one aspect, the invention is characterized by a method of treating a subject aged 6 months to 17 years with CD20-positive proliferative disorder, the method comprising administering to the subject effective amounts of glimepiride, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle, wherein...

(a) The first dosing cycle includes:

(i) Administer the first dose (C1D1) of glimetuzumab on day 8 and the second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is about 0.03 mg/kg, about 0.04 mg/kg (e.g., 0.04 mg/kg ± 0.0005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg, ± 0.003 mg/kg, or ± 0.004 mg/kg) or about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.004 mg/kg). 3 mg, ±0.05 mg, ±0.1 mg, ±0.2 mg or ±0.25 mg), and the C1D2 of glimepiride is about 0.15 mg/kg (e.g., 0.15 mg/kg ±0.001 mg/kg, ±0.0025 mg/kg, ±0.005 mg/kg, ±0.01 mg/kg or ±0.015 mg/kg) or about 10 mg (e.g., 10 mg ±0.05 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.5 mg, ±0.75 mg or ±1 mg);

(ii) Administer the first dose (C1D1) of olibutuzumab on day 1 and the second dose (C1D2) of olibutuzumab on day 2, wherein the C1D1 of olibutuzumab is approximately one-tenth the sum of the C1D1 and C1D2 of olibutuzumab, and the C1D2 of olibutuzumab is approximately nine-tenths the sum of the C1D1 and C1D2 of olibutuzumab, wherein the sum of the C1D1 and C1D2 of olibutuzumab is approximately 38 mg/kg (e.g., 38 mg/kg ± 0.25 mg/kg, ± 0.5 mg/kg, ± 1 mg/kg, ± 2 mg/kg, ± 3 mg/kg, or ± 3.8 mg/kg), approximately 28 mg/kg. g/kg (e.g., 28 mg/kg ± 0.25 mg/kg, ± 0.5 mg/kg, ± 1 mg/kg, ± 2 mg/kg or ± 2.8 mg/kg), about 23 mg/kg (e.g., 23 mg/kg ± 0.25 mg/kg, ± 0.5 mg/kg, ± 1 mg/kg, ± 2 mg/kg or ± 2.3 mg/kg), about 20 mg/kg (e.g., 23 mg/kg ± 0.25 mg/kg, ± 0.5 mg/kg, ± 1 mg/kg or ± 2 mg/kg) or about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg or ± 100 mg);

(iii) Administer the first dose of ifosfamide (C1D1) on day 3, the second dose of ifosfamide (C1D2) on day 4, and the third dose of ifosfamide (C1D3) on day 5, wherein the C1D1, C1D2 and C1D3 of ifosfamide are each about 3000 mg/ ^m2 (e.g., 3000 mg/ ^m2 ± 40 mg/ ^m2 , ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 or ± 300 mg/ ^m2 );

(iv) A single dose (C1D1) of carboplatin is administered on day 3, wherein the C1D1 of carboplatin is approximately 635 mg/ ^m² (e.g., 635 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , ± 50 mg/ ^m² , ± 60 mg/ ^m² , or ± 63.5 mg/ ^m² ); and

(v) Administer the first dose of etoposide (C1D1) on day 3, the second dose of etoposide (C1D2) on day 4, and the third dose of etoposide (C1D3) on day 5, wherein the C1D1, C1D2, and C1D3 of etoposide are each approximately 100 mg/ ^m2 (e.g., 100 mg/ ^m2 ± 1 mg/ ^m2 , ± 2.5 mg/ ^m2 , ± 5 mg/ ^m2 , or ± 10 mg/ ^m2 );

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab is administered on day 1, wherein the C2D1 of glimetuzumab is about 0.4 mg/kg (e.g., 0.4 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg or ± 0.04 mg/kg), about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, ± 0.04 mg/kg or ± 0.05 mg/kg) or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg);

(ii) Administer the first dose (C2D1) of rituximab on day 5, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 );

(iii) Administer the first dose of ifosfamide (C2D1) on day 6, the second dose of ifosfamide (C2D2) on day 7, and the third dose of ifosfamide (C2D3) on day 8, wherein the C2D1, C2D2 and C2D3 of ifosfamide are each about 3000 mg/ ^m2 (e.g., 3000 mg/ ^m2 ± 40 mg/ ^m2 , ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 or ± 300 mg/ ^m2 );

(iv) A single dose (C2D1) of carboplatin was administered on day 6, wherein the C2D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C2D1) on day 6, the second dose of etoposide (C2D2) on day 7, and the third dose of etoposide (C2D3) on day 8, wherein the C2D1, C2D2, and C2D3 of etoposide are each approximately 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/ ^m² ); and

(c) The third dosing cycle includes:

(i) A single dose (C3D1) of glimetuzumab is administered on day 1, wherein the C3D1 of glimetuzumab is about 0.4 mg/kg (e.g., 0.4 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg or ± 0.04 mg/kg), about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, ± 0.04 mg/kg or ± 0.05 mg/kg) or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg);

(ii) Administer the first dose of rituximab (C3D1) on day 5, wherein the C3D1 of rituximab is approximately 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 );

(iii) Administer the first dose of ifosfamide (C3D1) on day 6, the second dose of ifosfamide (C3D2) on day 7, and the third dose of ifosfamide (C3D3) on day 8, wherein the C3D1, C3D2 and C3D3 of ifosfamide are each about 3000 mg/ ^m2 (e.g., 3000 mg/ ^m2 ± 40 mg/ ^m2 , ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 or ± 300 mg/ ^m2 );

(iv) A single dose of carboplatin (C3D1) was administered on day 6, wherein the C3D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C3D1) on day 6, the second dose of etoposide (C3D2) on day 7, and the third dose of etoposide (C3D3) on day 8, wherein the C3D1, C3D2, and C3D3 of etoposide are each approximately 100 mg/ ^m2 (e.g., 100 mg/ ^m2 ± 1 mg/ ^m2 , ± 2.5 mg/ ^m2 , ± 5 mg/ ^m2 , or ± 10 mg/ ^m2 ).

In one embodiment, mesna is administered to the subject on days 3, 4, and 5 of the first dosing cycle, days 6, 7, and 8 of the second dosing cycle, and/or days 6, 7, and 8 of each additional dosing cycle. In one embodiment, mesna is administered intravenously daily at five doses totaling 3000 mg/ ^m² . In one embodiment, mesna is administered intravenously at a first dose of approximately 600 mg/ ^m² and four repeated doses of approximately 600 mg/ ^m² prior to any dose of ifosfamide, each repeated dose approximately three hours, approximately six hours, and approximately 12 hours after the first dose of ifosfamide.

In one aspect, the invention is characterized by a method of treating a subject aged 18 to 30 years with CD20-positive proliferative disorders, the method comprising administering to the subject effective amounts of glimepiride, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein

(a) The first dosing cycle comprises administering a first dose (C1D1) of glimetuzumab on day 8 and a second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of glimetuzumab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); and

(b) The second dosing cycle consists of a single dose (C2D1) of glimetuzumab administered on day 1, wherein the C2D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

In one aspect, the invention is characterized by a method of treating a subject aged 18 to 30 years with CD20-positive proliferative disorders, the method comprising administering to the subject effective amounts of glimepiride, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle, wherein...

(a) The first dosing cycle consists of administering the first dose (C1D1) of glimetuzumab on day 8 and the second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg or ± 0.25 mg), and the C1D2 of glimetuzumab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg or ± 1 mg);

(b) The second dosing cycle comprises a single dose (C2D1) of glimetuzumab administered on day 1, wherein the C2D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg); and

(c) The third dosing cycle consists of a single dose (C3D1) of glimetuzumab administered on day 1, wherein the C3D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

In one aspect, the invention is characterized by a method of treating a subject aged 18 to 30 years with CD20-positive proliferative disorders, the method comprising administering to the subject effective amounts of glimepiride, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein

(a) The first dosing cycle includes:

(i) Administer the first dose (C1D1) of glimetuzumab on day 8 and the second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg or ± 0.25 mg), and the C1D2 of glimetuzumab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg or ± 1 mg);

(ii) Administer a first dose (C1D1) of olibutuzumab on day 1 and a second dose (C1D2) of olibutuzumab on day 2, wherein the C1D1 of olibutuzumab is approximately one-tenth of the sum of the C1D1 and C1D2 of olibutuzumab, and the C1D2 of olibutuzumab is approximately nine-tenths of the sum of the C1D1 and C1D2 of olibutuzumab, and wherein the sum of the C1D1 and C1D2 of olibutuzumab is approximately 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg or ± 100 mg);

(iii) A single dose (C1D1) of ifosfamide is administered on day 3, wherein the C1D1 of ifosfamide is about 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/ ^m2 , ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), and the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg or ± 80 mg);

(iv) A single dose of carboplatin (C1D1) was administered on day 3, wherein the C1D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C1D1) on day 3, the second dose of etoposide (C1D2) on day 4, and the third dose of etoposide (C1D3) on day 5, wherein the C1D1, C1D2, and C1D3 of etoposide are each approximately 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/ ^m² ); and

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab is administered on day 1, wherein the C2D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg);

(ii) Administer the first dose (C2D1) of rituximab on day 5, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 );

(iii) A single dose (C2D1) of ifosfamide is administered on day 6, wherein the C2D1 of ifosfamide is about 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/ ^m2 , ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), and the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg or ± 80 mg);

(iv) A single dose (C2D1) of carboplatin was administered on day 6, wherein the C2D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C2D1) on day 6, the second dose of etoposide (C2D2) on day 7, and the third dose of etoposide (C2D3) on day 8, wherein the C2D1, C2D2 and C2D3 of etoposide are each about 100 mg/ ^m2 (e.g., 100 mg/ ^m2 ± 1 mg/ ^m2 , ± 2.5 mg/ ^m2 , ± 5 mg/ ^m2 or ± 10 mg/ ^m2 ).

In one aspect, the invention is characterized by a method of treating a subject aged 18 to 30 years with CD20-positive proliferative disorders, the method comprising administering to the subject effective amounts of glimepiride, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle, wherein...

(a) The first dosing cycle includes:

(i) Administer the first dose (C1D1) of glimetuzumab on day 8 and the second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg or ± 0.25 mg), and the C1D2 of glimetuzumab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg or ± 1 mg);

(ii) Administer a first dose (C1D1) of olibutuzumab on day 1 and a second dose (C1D2) of olibutuzumab on day 2, wherein the C1D1 of olibutuzumab is approximately one-tenth of the sum of the C1D1 and C1D2 of olibutuzumab, and the C1D2 of olibutuzumab is approximately nine-tenths of the sum of the C1D1 and C1D2 of olibutuzumab, and wherein the sum of the C1D1 and C1D2 of olibutuzumab is approximately 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg or ± 100 mg);

(iii) A single dose (C1D1) of ifosfamide is administered on day 3, wherein the C1D1 of ifosfamide is about 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/ ^m2 , ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), and the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg or ± 80 mg);

(iv) A single dose of carboplatin (C1D1) was administered on day 3, wherein the C1D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C1D1) on day 3, the second dose of etoposide (C1D2) on day 4, and the third dose of etoposide (C1D3) on day 5, wherein the C1D1, C1D2, and C1D3 of etoposide are each approximately 100 mg/ ^m2 (e.g., 100 mg/ ^m2 ± 1 mg/ ^m2 , ± 2.5 mg/ ^m2 , ± 5 mg/ ^m2 , or ± 10 mg/ ^m2 );

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab is administered on day 1, wherein the C2D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg);

(ii) Administer the first dose (C2D1) of rituximab on day 5, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 );

(iii) A single dose (C2D1) of ifosfamide is administered on day 6, wherein the C2D1 of ifosfamide is about 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/ ^m2 , ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), and the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg or ± 80 mg);

(iv) A single dose (C2D1) of carboplatin was administered on day 6, wherein the C2D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C2D1) on day 6, the second dose of etoposide (C2D2) on day 7, and the third dose of etoposide (C2D3) on day 8, wherein the C2D1, C2D2, and C2D3 of etoposide are each approximately 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/ ^m² ); and

(c) The third dosing cycle includes:

(i) A single dose (C3D1) of glimetuzumab is administered on day 1, wherein the C3D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg);

(ii) Administer the first dose of rituximab (C3D1) on day 5, wherein the C3D1 of rituximab is approximately 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 );

(iii) A single dose (C3D1) of ifosfamide is administered on day 6, wherein the C3D1 of ifosfamide is about 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/ ^m2 , ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), and the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg or ± 80 mg);

(iv) A single dose of carboplatin (C3D1) was administered on day 6, wherein the C3D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C3D1) on day 6, the second dose of etoposide (C3D2) on day 7, and the third dose of etoposide (C3D3) on day 8, wherein the C3D1, C3D2, and C3D3 of etoposide are each approximately 100 mg/ ^m2 (e.g., 100 mg/ ^m2 ± 1 mg/ ^m2 , ± 2.5 mg/ ^m2 , ± 5 mg/ ^m2 , or ± 10 mg/ ^m2 ).

In one embodiment, mesna is administered concurrently with any dose of ifosfamide. In one embodiment, mesna is administered intravenously at a dose of about 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ). In one embodiment, mesna is administered via continuous infusion over about 24 hours on day 3 of the first dosing cycle, day 6 of the second dosing cycle, and/or day 6 of each additional dosing cycle. In one embodiment, the CD20-positive proliferative disorder is relapsed and/or refractory DLBCL. In one embodiment, the CD20-positive proliferative disorder is relapsed and/or refractory mature B-cell NHL.

In one embodiment, the bispecific antibody binding to CD20 and CD3 comprises at least one Fab molecule that specifically binds to CD20, the Fab molecule containing the following six hypervariable regions (HVRs):

(i)HVR-H1, which contains the amino acid sequence of YSWIN (SEQ ID NO:1);

(ii) HVR-H2, which contains the amino acid sequence RIFPGDGDTDYNGKFKG (SEQ ID NO:2);

(iii) HVR-H3, which contains the amino acid sequence NVFDGYWLVY (SEQ ID NO:3);

(iv) HVR-L1, which contains the amino acid sequence RSSKSLLHSNGITYLY (SEQ ID NO:4);

(v)HVR-L2, which contains the amino acid sequence of QMSNLVS (SEQ ID NO:5); and

(vi)HVR-L3, which contains the amino acid sequence of AQNLELPYT (SEQ ID NO:6).

In one embodiment, the bispecific antibody binding to CD20 and CD3 comprises at least one Fab molecule that specifically binds to CD20, the Fab molecule comprising: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:7; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:8; or (c) the VH domain as in (a) and the VL domain as in (b). In one embodiment, the Fab molecule that specifically binds to CD20 comprises: (a) a VH domain comprising the amino acid sequence of SEQ ID NO:7; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:8.

In one embodiment, the bispecific antibody binding to CD20 and CD3 comprises at least one Fab molecule that specifically binds to CD3, the Fab molecule containing the following six HVRs:

(i)HVR-H1, which contains the amino acid sequence of TYAMN (SEQ ID NO:9);

(ii) HVR-H2, which contains the amino acid sequence RIRSKYNNYATYYADSVKG (SEQ ID NO:10);

(iii) HVR-H3, which contains the amino acid sequence HGNFGNSYVSWFAY (SEQ ID NO:11);

(iv) HVR-L1, which contains the amino acid sequence GSSTGAVTTSNYAN (SEQ ID NO:12);

(v)HVR-L2, which contains the amino acid sequence of GTNKRAP (SEQ ID NO: 13); and

(vi)HVR-L3, which contains the amino acid sequence of ALWYSNLWV (SEQ ID NO:14).

In one embodiment, the bispecific antibody binding to CD20 and CD3 comprises at least one Fab molecule that specifically binds to CD3, the Fab molecule comprising: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:15; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:16; or (c) the VH domain as in (a) and the VL domain as in (b).

In one embodiment, the Fab molecule that specifically binds to CD3 comprises: (a) a VH domain containing the amino acid sequence of SEQ ID NO:15; and (b) a VL domain containing the amino acid sequence of SEQ ID NO:16.

In one embodiment, the bispecific antibody binding to CD20 and CD3 is bivalent to CD20 and monovalent to CD3. In another embodiment, the bispecific antibody binding to CD20 and CD3 comprises two Fab molecules that specifically bind to CD20 and one Fab molecule that specifically binds to CD3.

In one embodiment, the bispecific antibody binding to CD20 and CD3 is a humanized antibody. In another embodiment, the bispecific antibody binding to CD20 and CD3 is glimetuzumab.

In one embodiment, a bispecific antibody that binds to CD20 and CD3 is administered intravenously.

In one embodiment, anti-CD20 antibody is administered intravenously.

In one embodiment, the CD20-positive proliferative disorder is a B-cell proliferative disorder. In one embodiment, the B-cell proliferative disorder is non-Hodgkin's lymphoma (NHL) or central nervous system lymphoma (CNSL). In one embodiment, NHL is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), high-grade B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma (PMLBCL), diffuse B-cell lymphoma, or small lymphocytic lymphoma. In one embodiment, NHL is Burkitt lymphoma (BL) or Burkitt leukemia (BAL). In one embodiment, NHL is aggressive and/or mature. In one embodiment, NHL is relapsed and/or refractory. In one embodiment, the B-cell proliferative disorder is relapsed and/or refractory mature B-cell NHL. In one embodiment, the subject has received no more than one prior systemic therapy.

In one embodiment, the prior systemic therapy includes an anti-CD20 antibody and anthracycline. In one embodiment, the subject is human. In one embodiment, the subject is eligible for transplantation or CAR-T cell therapy. In one embodiment, the subject receives an autologous stem cell transplantation (ASCT) after completing the dosing regimen described above. In one embodiment, the ASCT is an autologous hematopoietic stem cell transplantation. In one embodiment, the subject receives an allogeneic hematopoietic stem cell transplantation after completing the dosing regimen described above. In one embodiment, the subject receives CAR-T cell therapy after completing the dosing regimen described above.

Another aspect of the present invention relates to the invention as described herein.

Unless the context clearly indicates otherwise, each embodiment may be incorporated. Unless the context clearly indicates otherwise, each embodiment may be applied to various aspects of the invention.

Certain embodiments of the invention will become apparent from the following more detailed description of some preferred embodiments and claims.

Attached Figure Description

Figures 1A to 1N are schematic diagrams illustrating the configuration of an exemplary anti-CD20/anti-CD3 bispecific antibody.

Figure 2 is a schematic diagram showing the structure of gifertuzumab.

Figure 3 is a schematic diagram illustrating an overview of the study design as described in Example 1. ASCT = Autologous stem cell transplantation; CAR-T = Chimeric antigen receptor T cells; CR = Complete remission; DLBCL = Diffuse large B-cell lymphoma; EOT = End of treatment; Glofit-R-ICE = Glitzalofop-p-ethyl combined with rituximab plus ifosfamide, carboplatin, and etoposide; Gpt = Olinutuzumab pretreatment; PD = Disease progression; PR = Partial remission; R/R = Relapsed or refractory; SD = Stable disease. ^a : 2 to 3 cycles, depending on institutional standards. ^b : ASCT conditioning regimen and supportive care conforming to institutional standards.

Figure 4 is a schematic diagram illustrating the dosing regimen of the study as described in Example 1. D = days. ^a : Carboplatin dose in mg for a target AUC of 5 mg/mL/min.

Figure 5 is a schematic diagram illustrating the study protocols for Parts 1 and 2 of Example 2. B-NHL = B-cell non-Hodgkin lymphoma; Glofit = glimetuzumab; Ped = pediatric; PK = pharmacokinetics; R-ICE = rituximab, ifosfamide, carboplatin, and etoposide; Rec = recommended; R/R = relapsed/refractory; RR = response rate. In Part 1 of the study, the safety induction of the starting dose was based on population PK modeling and matched adult exposure with escalating dosing. Safety and pharmacokinetic assessments were performed on at least 3 participants before the recommended pediatric Part 2 dose was announced. At least 10 pediatric participants underwent early efficacy assessments of the recommended pediatric dose before Part 2 could begin. During Part 2 of the study, open enrollment included young adult participants under 30 years of age (inclusive), but they were not included in the 45-sample size.

Figure 6 is a schematic diagram illustrating the dosing regimen of rituximab combined with R-ICE as described in Example 2. C = cycle; CR = complete remission; D = day; G = rituximab; CR = complete remission; FD = full dose; G-CSF = granulocyte colony-stimulating factor; Glofit = rituximab; GpT = rituximab pretreatment; HSCT = hematopoietic stem cell transplantation; ICE = ifosfamide, carboplatin, and etoposide; PD = disease progression; R-ICE = rituximab plus ifosfamide, carboplatin, and etoposide; SUD = escalation dose. ^a. Rituximab pretreatment will be divided into one-tenth of the full dose on day 1 of the first dosing cycle (cycle 1) and nine-tenths of the full dose on day 2 of cycle 1.

Figure 7 is a schematic diagram illustrating the treatment administration schedule for pediatric patients (aged 6 months to 17 years) in Example 2. *: Arrows indicate forced initiation of granulocyte colony-stimulating factor (G-CSF) therapy. **: Participants with CNS disease and any histological features received intrathecal (IT) therapy on days 3, 10, and 17 of cycle 1, and on days 5, 12, and 19 of cycles 2 and 3. Participants with large B-cell lymphoma and CNS-negative received IT therapy only on day 3 of cycle 1. The single dose of olibutuzumab pretreatment was divided into one-tenth of the full dose on day 1 of cycle 1 and nine-tenths of the full dose on day 2 of cycle 1. Participants with Burkitt lymphoma (BL) and CNS-negative received IT therapy on day 3 of cycle 1 and on day 5 of cycles 2 and 3. Glucophage was administered in two escalation doses on days 8 and 15 of cycle 1, and in full dose on day 1 of cycles 2 and 3.

Figure 8 is a schematic diagram illustrating the treatment administration schedule for young adult patients (aged 18 to 30 years) in Example 2. *: Arrows indicate mandatory initiation of G-CSF therapy. **: Participants with CNS disease and any histological features received IT therapy on days 3, 10, and 17 of cycle 1, and on days 5, 12, and 19 of cycles 2 and 3. Participants with large B-cell lymphoma and CNS-negative received IT therapy only on day 3 of cycle 1. The single dose of olibutuzumab pretreatment was divided into one-tenth of the full dose on day 1 of cycle 1 and nine-tenths of the full dose on day 2 of cycle 1. Participants with BL and CNS-negative received IT therapy on day 3 of cycle 1 and on day 5 of cycles 2 and 3. G-CSF = Granulocyte Colony-Stimulating Factor. Glucophage was administered in two escalation doses on days 8 and 15 of cycle 1, and in full dose on day 1 of cycles 2 and 3.

Detailed Implementation

This invention provides a method for treating a subject with a CD20-positive proliferative disorder (e.g., B-cell proliferative disorder (e.g., non-Hodgkin's lymphoma (NHL) (e.g., relapsed and/or refractory NHL, diffuse large B-cell lymphoma (DLBCL) (e.g., relapsed and/or refractory DLBCL), follicular lymphoma (FL) (e.g., relapsed and/or refractory FL or transformed FL) or mantle cell lymphoma (MCL) (e.g., relapsed or refractory MCL)) or central nervous system lymphoma (CNSL))), the method comprising: administering to the subject a combination of an anti-CD20/anti-CD3 bispecific antibody with an anti-CD20 antibody and one or more chemotherapeutic agents selected from ifosfamide, carboplatin and/or etoposide).

(i) General Technology

Unless otherwise indicated, the present invention will be carried out using conventional techniques of molecular biology (including recombinant technology), microbiology, cell biology, biochemistry and immunology, which are within the scope of the art. The following references provide a comprehensive explanation of such techniques: “Molecular Cloning: A Laboratory Manual,” 2nd edition (Sambrook et al., 1989); “Oligonucleotide Synthesis” (edited by M.J. Gait, 1984); “Animal Cell Culture” (edited by R.I. Freshney, 1987); “Methods in Enzymology” (Academic Press, Inc.); “Current Protocols in Molecular Biology” (edited by F.M. Ausubel et al., 1987, and regularly updated); “PCR: The Polymerase Chain Reaction” (edited by Mullis et al., 1994); “A Practical Guide to Molecular Cloning” (Perbal Bernard V., 1988); and “Phage Display: A Laboratory Manual” (Barbas et al., 2001).

(ii) Definition

Unless otherwise defined below, the terminology used herein is as it is used in the art.

Unless otherwise specified, the terms “differentiation cluster 20” or “CD20” as used herein refer to any naturally occurring CD20 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). CD20 (also known as B-lymphocyte antigen CD20, B-lymphocyte surface antigen B1, Leu-16, Bp35, BM5, and LF5; human protein described in UniProt database registry number P11836) is a hydrophobic transmembrane protein with a molecular weight of approximately 35 kDa and expressed on pre-B and mature B lymphocytes (Valentine, M.A. et al., J. Biol. Chem. 264 (1989) 11282-11287; Tedder, T. F. et al., Proc. Natl. Acad. Sci. U.S.A. 85 (1988) 208-212; Stamenkovic, I. et al., J. Exp. Med. 167 (1988) 1975-1980; Einfeld, D.A. et al., EMBO J. 7 (1988) 711-717; Tedder, T.F. et al., J. Immunol. 142 (1989) 2560-2568). The corresponding human gene is a transmembrane 4 domain, subfamily A member 1, also known as MS4A1. This gene encodes a member of the transmembrane 4A gene family. Members of this neonatal protein family are characterized by common structural features and similar intron/exon splicing boundaries, and exhibit unique expression patterns in hematopoietic cells and non-lymphoid tissues. This gene encodes a B lymphocyte surface molecule that plays a role in B cell development and differentiation into plasma cells. This family member is located at 11q12 within the family member cluster. The term encompasses the “full-length” unprocessed CD20, as well as any form of CD20 produced through cellular processing. The term also covers naturally occurring variants of CD20, such as splice variants or allelic variants. Alternative splicing of this gene produces two transcript variants encoding the same protein. In one embodiment, CD20 is human CD20.

The terms "anti-CD20 antibody" and "CD20-binding antibody" refer to antibodies that bind to CD20 with sufficient affinity, making them usable as diagnostic and/or therapeutic agents targeting CD20. In one embodiment, the binding degree of an anti-CD20 antibody to unrelated non-CD20 proteins is less than about 10% of the binding degree of the antibody to CD20, as measured, for example by radioimmunoassay (RIA). In some embodiments, the CD20-binding antibody has a dissociation constant (K_D) of ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM, or ≤0.001 _nM (e.g., 10^{^-8 M or less, e.g., 10^-8 M to 10^-13 M} , e.g., 10 ^{^-9} M to 10^{^-13} M). In some embodiments, the anti-CD20 antibody binds to an epitope of CD20 that is conserved in CD20 from different species.

"Type II anti-CD20 antibody" refers to anti-CD20 antibodies that possess the binding properties and biological activity of type II anti-CD20 antibodies, as described in Cragg et al., Blood 103 (2004) 2738-2743; Cragg et al., Blood 101 (2003) 1045-1052; Klein et al., mAbs 5 (2013), 22-33, and are summarized in Table 1 below.

Table 1. Type I and Type II anti-CD20 antibodies

Type I anti-CD20 antibody Type II anti-CD20 antibody Binding to class I CD20 antigen epitopes Binding to class II CD20 antigen epitopes CD20 was positioned on the lipid raft. CD20 is not positioned on the lipid raft. High CDC* Low CDC* ADCC activity* ADCC activity* It can fully bind to B cells Its binding ability to B cells is reduced by about half. Weak homogeneous aggregation Homopolymer Low cell death induction Strong cell death induction

*If it is IgG ₁ isotype

Examples of type II anti-CD20 antibodies include, for example, olibutuzumab (GA101), tositumumab (B1), humanized B-Ly1 antibody IgG1 (such as the chimeric humanized IgG1 antibody disclosed in WO 2005/044859), 11B8 IgG1 (such as disclosed in WO 2004/035607), and AT80 IgG1.

Examples of type I anti-CD20 antibodies include, for example, rituximab, ofamumab, vetozumab, oxcartuzumab, orejuzumab, PRO131921, urorituximab, HI47IgG3 (ECACC, hybrid tumor), 2C6 IgG1 (as disclosed in WO2005/103081), 2F2 IgG1 (as disclosed in WO 2004/035607 and WO 2005/103081), and 2H7 IgG1 (as disclosed in WO 2004/056312).

Unless otherwise specified, “CD3” means any naturally occurring CD3 from any vertebrate source, including mammals such as primates (e.g., humans), non-human primates (e.g., cynomolgus monkeys), and rodents (e.g., mice and rats). The term covers “full-length” unprocessed CD3, as well as any form of CD3 produced through cellular processing. The term also covers naturally occurring variants of CD3, such as splice variants or allelic variants. In one embodiment, CD3 is human CD3, specifically the ε subunit of human CD3 (CD3ε). The amino acid sequence of human CD3ε is shown in UniProt (www.uniprot.org) accession number P07766 (version 144) or NCBI (www.ncbi.nlm.nih.gov/) RefSeq NP_000724.1. The amino acid sequence of cynomolgus monkey [Macaca fascicularis] CD3ε is shown in NCBI GenBank number BAB71849.1.

The terms "anti-CD20/anti-CD3 bispecific antibody" and "bispecific antibody binding to CD20 and CD3" refer to bispecific antibodies capable of binding to both CD20 and CD3 with sufficient affinity, thereby enabling the antibody to be used as a diagnostic and/or therapeutic agent targeting CD20 and/or CD3. In one embodiment, the bispecific antibody binding to CD20 and CD3 binds to unrelated, non-CD3 proteins and/or non-CD20 proteins to a degree less than about 10% of the antibody's binding to CD3 and/or CD20, as measured, for example, by radioimmunoassay (RIA). In some embodiments, the dissociation constant (K_{_D} ) of the bispecific antibody binding to CD20 and CD3 is ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM, or ≤0.001 nM (e.g., 10 ^{^-8} M or lower, e.g., 10 ^{^-8} M to 10^{^-13} M, e.g., 10 ^{^-9} to 10 ^{^-13} M). In some embodiments, the bispecific antibody binding to CD20 and CD3 binds to conserved CD3 antigenic epitopes between CD3 from different species and/or conserved CD20 antigenic epitopes between CD20 from different species. An example of an anti-CD20/anti-CD3 bispecific antibody is glimetuzumab (WHO Drug Information (International Nonproprietary Name of the Drug), Recommended INN: List 83, 2020, Vol. 34, No. 1, p. 39; Proposed INN: List 121 WHO Drug Information, Vol. 33, No. 2, 2019, p. 276, also known as CD20-TCB, RO7082859 or RG6026; CAS#: 2229047-91-8).

As used herein, the term “cytokine release” or “cytokine release” is synonymous with “cytokine storm” or “cytokine release syndrome” (abbreviated as “CRS”) and refers to an increase in the levels of cytokines, particularly tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin-2 (IL-2), and/or interleukin-8 (IL-8), in the blood of a subject during or shortly thereafter (e.g., within 1 day) of treatment administration, leading to adverse symptoms. Cytokine release is defined as a supraphysiological response resulting in or involving the activation of endogenous or infused T cells and/or other immune effector cells following administration of any immunotherapy. Symptoms may be progressive, always include fever at the onset, and may include hypotension, capillary leakage (hypoxia), and peripheral organ dysfunction (Lee et al. 2019). In some cases, such as after CAR-T cell administration, CRS may also occur several days later during CAR-T cell expansion. The incidence and severity usually decrease with subsequent infusions. Symptoms can range from mild discomfort to fatal events and may include fever, chills, dizziness, high blood pressure, low blood pressure, dyspnea, restlessness, sweating, flushing, rash, tachycardia, tachypnea, headache, tumor pain, nausea, vomiting, and/or organ failure.

As used herein, the term "amino acid mutation" encompasses amino acid substitution, deletion, insertion, and modification. Any combination of substitution, deletion, insertion, and modification can be implemented to obtain the final construct, provided that the final construct possesses the desired properties, such as reduced binding to the Fc receptor. Amino acid sequence deletions and insertions include deletions and insertions of the amino-terminus and/or carboxyl-terminus of amino acids. A specific amino acid mutation is an amino acid substitution. Non-conservative amino acid substitution, i.e., replacing an amino acid with another amino acid having a different structure and/or chemical properties, is particularly preferred for the purpose of altering, for example, the binding characteristics of the Fc region. Amino acid substitution includes substitution with a non-naturally occurring amino acid or with amino acid derivatives of the twenty naturally occurring standard amino acids (e.g., 4-hydroxyproline, 3-methylhistidine, ornithine, homoserine, 5-hydroxylysine). Amino acid mutations can be generated using genetic or chemical methods well known in the art. Genetic methods may include site-directed mutagenesis, PCR, gene synthesis, etc. It is also useful to consider methods that alter amino acid side chain groups by means other than genetic engineering, such as chemical modification. Various names may be used herein to refer to the same amino acid mutation. For example, replacing proline at position 329 of the Fc domain with glycine can be represented as 329G, G329, G ₃₂₉ , P329G, or Pro329Gly.

“Affinity” refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., a receptor) and its binding partner (e.g., a ligand). Unless otherwise specified, as used herein, “binding affinity” refers to intrinsic binding affinity, which reflects a 1:1 interaction between members of a binding pair (e.g., receptor and ligand). The affinity of molecule X for its partner Y is typically expressed by a dissociation constant (K_{_D} ), which is the ratio of the dissociation rate constant to the association rate constants (k_{_off} and k _{_on}, respectively). Therefore, equivalent affinity can include different rate constants, as long as the ratio of the rate constants remains the same. Affinity can be measured by established methods known in the art. A specific method for measuring affinity is surface plasmon resonance (SPR).

"Affinity-mature" antibodies are those that have one or more alterations in one or more hypervariable regions (HVRs), which result in improved affinity of the antibody for the antigen compared to parental antibodies that do not have such alterations.

As used herein, the term "antigen-binding moiety" refers to a polypeptide molecule that specifically binds to an antigenic determinant. In one embodiment, the antigen-binding moiety is capable of directing its attached entity (e.g., a cytokine or a second antigen-binding moiety) to a target site, such as to a specific type of tumor cell or tumor stroma bearing an antigenic determinant. Antigen-binding moieties include antibodies and fragments thereof as further defined herein. Preferred antigen-binding moieties include an antigen-binding domain of an antibody comprising a variable region of the antibody heavy chain and a variable region of the antibody light chain. In some embodiments, the antigen-binding moiety may include an antibody constant region as further defined herein and known in the art. Available heavy chain constant regions include any one of five isoforms: α, δ, ε, γ, or μ. Available light chain constant regions include any one of two isoforms: κ and λ.

"Binding,""specificbinding," or "specific for" means that the binding is selective for the antigen and can distinguish between unintended or non-specific interactions. The ability of an antigen-binding moiety to bind to a specific antigenic determinant can be measured by enzyme-linked immunosorbent assay (ELISA) or other techniques familiar to those skilled in the art, such as surface plasmon resonance (SPR) (analyzed on a BIAcore instrument) (Liljeblad et al., Glyco J. 17, 323-329 (2000)) and conventional binding assays (Heeley, EEndocr Res. 28, 217-229 (2002)). In one embodiment, for example, as measured by SPR, the degree of binding of the antigen-binding moiety to unrelated proteins is less than about 10% of the degree of binding of the antigen-binding moiety to the antigen. In some embodiments, the antigen-binding portion that binds to the antigen, or the antigen-binding molecule containing the antigen-binding portion, has the following dissociation constant (K_{_D} ): ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM, or ≤0.001 nM (e.g., 10 ^{^-8} M or less, e.g., from 10 ^{^-8} M to 10^{^-13} M, e.g., from 10 ^{^-9} M to 10 ^{^-13} M).

"Reduced binding" (e.g., reduced binding to the Fc receptor) refers to a decrease in affinity for the corresponding interaction, as measured, for example, by SPR. For clarity, the term also includes reducing the affinity to zero (or below the detection limit of the analytical method), i.e., completely eliminating the interaction. Conversely, "increased binding" refers to an increase in binding affinity for the corresponding interaction.

As used herein, the term "antigen-binding molecule" in its broadest sense refers to a molecule that specifically binds to an antigenic determinant. Examples of antigen-binding molecules are immunoglobulins and their derivatives, such as fragments thereof.

As used herein, the term “antigenic determinant” is synonymous with “antigen” and “epitope”, and refers to a site on a polypeptide macromolecule (e.g., a continuous amino acid sequence or a conformational configuration consisting of different regions of non-continuous amino acids) to which the antigen-binding moiety binds, thereby forming an antigen-binding moiety-antigen complex. Useful antigenic determinants can be found, for example, on the surface of tumor cells, on the surface of virus-infected cells, on the surface of other diseased cells, in free form in serum, and/or in the extracellular matrix (ECM). Unless otherwise stated, a protein referred to herein as an antigen (e.g., CD3) can be any naturally occurring form of protein from any vertebrate source, including mammals, such as primates (e.g., humans), and rodents (e.g., mice and rats). In one particular embodiment, the antigen is a human protein. When referring to a specific protein herein, the term covers “full-length,” unprocessed protein, and any form of protein produced by intracellular processing. The term also covers naturally occurring protein variants, such as splice variants or allelic variants. Exemplary human proteins that can be used as antigens are CD3, particularly the ε subunit of CD3 (see UniProt No. P07766 (130th edition), NCBI RefSeq No. NP_000724.1, for human sequences; or UniProt No. Q95LI5 (49th edition), NCBI GenBank No. BAB71849.1, for macaque [Macaca fascicularis] sequences). In some embodiments, the T-cell activating bispecific antigen-binding molecules disclosed herein bind to antigenic epitopes of CD3 or target cell antigens that are conserved between CD3 or target cell antigens from different species.

As used herein, the term "peptide" refers to a molecule composed of monomers (amino acids) linearly linked by amide bonds (also known as peptide bonds). The term "peptide" refers to any chain having two or more amino acids, not a specific length of product. Therefore, peptide, dipeptide, tripeptide, oligopeptide, "protein," "amino acid chain," or any other term used to refer to a chain having two or more amino acids is included within the definition of "peptide," and the term "peptide" may be used in place of any of these terms, or interchangeably with any of these terms. The term "peptide" is also intended to refer to post-expression modified products of peptides, including but not limited to glycosylation, acetylation, phosphorylation, amidation, derivatization with known protecting/blocking groups, proteolytic cleavage, or modification with non-naturally occurring amino acids. Peptides may be derived from natural biological sources or produced through recombinant technologies, and are not necessarily translated from a specified nucleic acid sequence. They can be generated in any manner, including through chemical synthesis. The polypeptides of this invention can be of about 3 or more, 5 or more, 10 or more, 20 or more, 25 or more, 50 or more, 75 or more, 100 or more, 200 or more, 500 or more, 1,000 or more, or 2,000 or more amino acids. Polypeptides can have a defined three-dimensional structure, but they do not necessarily have such a structure. Polypeptides with a defined three-dimensional structure are called folded; and polypeptides that do not have a defined three-dimensional structure but can take on a large number of different conformations are called unfolded.

"Isolated" polypeptides or variants or derivatives thereof mean polypeptides that are not in their native environment. Specific levels of purification are not required. For example, isolated polypeptides can be removed from their native or natural environment. Recombinant polypeptides and proteins expressed in host cells are considered to have been isolated for the purposes of this invention, as are native or recombinant polypeptides that have been isolated, fractionated, or partially or substantially purified by any suitable technique.

The "percentage of amino acid sequence identity (%)" relative to a reference polypeptide sequence is defined as the percentage of amino acid residues in the candidate sequence that are identical to those in the reference polypeptide sequence after aligning the candidate sequence with the reference polypeptide sequence and introducing vacancies (if necessary) to achieve the maximum percentage of sequence identity, without considering any conserved substitutions as part of sequence identity. Alignment used to determine the percentage of amino acid sequence identity can be performed in various ways within the scope of the art, such as using publicly available computer software, such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithm required to achieve maximum alignment across the full length of the sequences being compared. However, for the purposes of this document, the sequence comparison computer program ALIGN-2 is used to generate the amino acid sequence identity percentage. The ALIGN-2 sequence comparison computer program was developed by Genentech, Inc., and the source code has been submitted with user documentation to the U.S. Copyright Office, Washington D.C., 20559, registered thereunder U.S. Copyright Registry No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc. (South San Francisco, California) or can be compiled from the source code. The ALIGN-2 program should be compiled for use on UNIX operating systems, including Digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and remain unchanged. When using ALIGN-2 for amino acid sequence comparison, the percentage of amino acid sequence identity between a given amino acid sequence A and a given amino acid sequence B (which can be alternatively expressed as a given amino acid sequence A having or containing a certain amino acid sequence identity percentage with a given amino acid sequence B) is calculated as follows:

100 multiplied by the fraction X/Y

Where X is the number of amino acid residues that are scored as identical matches by the sequence alignment program ALIGN-2 in the alignment of A and B, and Y is the total number of amino acid residues in B. It should be understood that if the length of amino acid sequence A is not equal to the length of amino acid sequence B, the amino acid sequence identity % between A and B will not be equal to the amino acid sequence identity % between B and A. Unless otherwise specifically stated, all amino acid sequence identity % values used herein were obtained using the ALIGN-2 computer program as described in the preceding paragraph.

The term “antibody” is used in the broadest sense and encompasses a wide range of antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, as long as they exhibit the desired antigen-binding activity.

The terms “full-length antibody,” “intact antibody,” and “all antibody” are used interchangeably herein to refer to antibodies having a structure substantially similar to that of natural antibodies or having a heavy chain containing an Fc region as defined herein.

"Antibody fragment" refers to a molecule other than a complete antibody that contains a portion of the complete antibody that binds to the antigen bound by the complete antibody. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab') ₂ ; dimers; linear antibodies; single-chain antibody molecules (e.g., scFv); and multispecific antibodies formed from antibody fragments. As used herein, the term "antibody fragment" also encompasses single-domain antibodies.

The term "immunoglobulin molecule" refers to a protein that has the structure of naturally occurring antibodies. For example, IgG immunoglobulins are heterotetrameric glycoproteins of approximately 150,000 Daltons, composed of two light chains and two heavy chains linked by disulfide bonds. Each heavy chain has a variable region (VH) (also called a variable heavy chain domain or heavy chain variable domain) from the N-terminus to the C-terminus, followed by three constant domains (CH1, CH2, and CH3) (also called heavy chain constant regions). Similarly, each light chain has a variable region (VL) (also called a variable light chain domain or light chain variable domain) from the N-terminus to the C-terminus, followed by a constant light chain (CL) domain (also called a light chain constant region). The heavy chains of immunoglobulins can be assigned to one of five categories: α (IgA), δ (IgD), ε (IgE), γ (IgG), or μ (IgM), some of which can be further subdivided into subclasses such as _γ1 ( _IgG1 ), _γ2 ( _IgG2 ), _γ3 ( _IgG3 ), _γ4 ( _IgG4 ), _α1 ( _IgA1 ), and _α2 ( _IgA2 ). The light chains of immunoglobulins can be assigned to one of two types based on the amino acid sequence of their constant domains: kappa (κ) and lambda (λ). Immunoglobulins are essentially composed of two Fab molecules linked by an immunoglobulin hinge region and an Fc domain.

The term "antigen-binding domain" refers to a portion of an antibody that contains a region that specifically binds to and complements an antigen, in part or all of it. The antigen-binding domain can be provided by, for example, one or more antibody variable domains (also called antibody variable regions). Preferably, the antigen-binding domain comprises an antibody light chain variable region (VL) and an antibody heavy chain variable region (VH).

The term "variable region" or "variable domain" refers to a domain of the antibody heavy or light chain involved in antibody-antigen binding. The variable domains (VH and VL, respectively) of the heavy and light chains of natural antibodies typically have similar structures, with each domain containing four conserved frame regions (FRs) and three hypervariable regions (HVRs). See, for example, Kindt et al., Kuby Immunology, 6th ed., W.H. Freeman and Co., p. 91 (2007). A single VH or VL domain may be sufficient to confer antigen-binding specificity.

A "human antibody" is an antibody whose amino acid sequence corresponds to that of an antibody produced by a human or human cell, or to a non-human antibody derived from a complete library of human antibodies or other antibody-encoding sequences. This definition of a human antibody specifically excludes humanized antibodies containing non-human antigen-binding residues.

A "humanized" antibody is a chimeric antibody that comprises amino acid residues from a non-human HVR and amino acid residues from a human FR. In some embodiments, the humanized antibody will substantially contain at least one of all, typically two, variable domains, wherein all or substantially all HVRs (e.g., CDRs) correspond to the HVRs of the non-human antibody, and all or substantially all FRs correspond to the FRs of the human antibody. Optionally, the humanized antibody may contain at least a portion of the antibody constant region derived from the human antibody. An antibody in a "humanized form," such as a non-human antibody, refers to an antibody that has undergone humanization.

As used herein, the term "hypervariant region" or "HVR" refers to each of the regions of an antibody variable domain that are hypervariable in the sequence ("complementarity-determining region" or "CDR") and/or form a structurally defined loop ("hypervariant loop") and/or contain antigen contact residues ("antigen contact sites"). Typically, an antibody contains six HVRs: three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3). Exemplary HVRs in this document include:

(a) Highly variable rings appearing at the following amino acid residues: 26-32 (L1), 50-52

(L2), 91-96(L3), 26-32(H1), 53-55(H2) and 96-101(H3) (Chothia and Lesk, J.Mol.Biol.196:901-917(1987));

(b) CDRs appearing at the following amino acid residues: 24 to 34 (L1), 50 to 56

(L2), 89 to 97 (L3), 31 to 35b (H1), 50 to 65 (H2), and 95 to 102 (H3)

(Kabat et al., Sequences of Proteins of Immunological Interest, 5th Edition Public Health Service, National Institutes of Health, Bethesda, MD (1991));

(c) Antigen contact sites appearing at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al.)

J. Mol. Biol. 262: 732-745 (1996)); and

(d) Combinations of (a), (b) and/or (c), including HVR amino acid residues 46-56(L2), 47-56(L2), 48-56(L2), 49-56(L2), 26-35(H1), 26-35b(H1), 49-65

(H2), 93-102(H3) and 94-102(H3).

Unless otherwise specified, HVR residues and other residues (e.g., FR residues) in the variable domain are referenced herein by Kabat et al., ibid.

"Frame" or "FR" refers to the variable domain residues other than the hypervariable region (HVR) residues. A variable domain FR typically consists of four FR domains: FR1, FR2, FR3, and FR4. Therefore, the HVR and FR sequences usually appear in the VH (or VL) as follows: FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

The “human common framework” is a framework that represents the most frequently present amino acid residues in the selection of the human immunoglobulin VL or VH framework sequence. Typically, the selection of the human immunoglobulin VL or VH sequence is derived from a subgroup of variable domain sequences. Typically, the subgroups are those described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Edition, NIH Publication 91-3242, Bethesda MD (1991), Volumes 1-3. In one embodiment, for VL, the subgroup is subgroup κI as in Kabat et al., supra. In one embodiment, for VH, the subgroup is subgroup III as in Kabat et al. (ibid.).

For the purposes of this document, a “recipient human frame” is a frame that comprises an amino acid sequence of a light chain variable domain (VL) frame or a heavy chain variable domain (VH) frame derived from the human immunoglobulin frame or the human common frame as defined below. A recipient human frame “derived from” the human immunoglobulin frame or the human common frame may contain the same amino acid sequence as said human immunoglobulin frame or human common frame, or it may contain amino acid sequence variations. In some embodiments, the number of amino acid variations is 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, or 2 or fewer. In some embodiments, the VL recipient human frame is sequence-identical to the VL human immunoglobulin frame sequence or the human common frame sequence.

An antibody's "class" refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM. Some of these antibodies can be further subdivided into subclasses (isotypes), such as _IgG1 , _IgG2 , _IgG3 , _IgG4 , _IgA1 , and _IgA2 . The constant domains of the heavy chain corresponding to different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

As used herein, the term IgG “isotype” or “subclass” refers to any subclass of immunoglobulins defined by the chemical and antigenic characteristics of the immunoglobulin constant region.

The term "Fc domain" or "Fc region" used herein is used to define the C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. This term includes both native sequence Fc regions and variant Fc regions. Although the boundaries of the IgG heavy chain Fc region may vary slightly, the human IgG heavy chain Fc region is generally defined as extending from Cys226 or Pro230 to the C-terminus of the heavy chain. However, antibodies produced by host cells can undergo post-translational cleavage of one or more (particularly one or two) amino acids from the C-terminus of the heavy chain. Therefore, antibodies produced by host cells by expressing a specific nucleic acid molecule encoding the full-length heavy chain can include the full-length heavy chain, or the antibody can include a cleaved variant of the full-length heavy chain (also referred to herein as a "cleaved variant heavy chain"). This could be the case where the last two C-terminal amino acids of the heavy chain are glycine (G446) and lysine (K447, EU number). Therefore, the C-terminal lysine (Lys447) or C-terminal glycine (Gly446) and lysine (K447) in the Fc region may or may not be present. Unless otherwise stated herein, the amino acid residues in the Fc region or constant region are numbered according to the EU numbering system, also known as the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th edition Public Health Service, National Institutes of Health, Bethesda, MD, 1991 (see above). As used herein, a “subunit” of the Fc domain refers to one of two polypeptides that form a dimer Fc domain, namely a polypeptide that includes the C-terminal constant region of the immunoglobulin heavy chain and is capable of stable self-association. For example, the subunit of the IgG Fc domain contains the IgG CH2 and IgG CH3 constant domains.

"Modification that promotes association between the first and second subunits of the Fc domain" refers to manipulation of the peptide backbone or post-translational modification of the Fc domain subunits that reduces or prevents the association of a polypeptide containing an Fc domain subunit with the same polypeptide to form a homodimer. As used herein, association-promoting modifications specifically include individual modifications to each of the two Fc domain subunits (i.e., the first and second subunits of the Fc domain) to which association is desired, wherein the modifications are complementary to each other to promote association between the two Fc domain subunits. For example, association-promoting modifications may alter the structure or charge of one or both of the Fc domain subunits to make their association sterically or electrostatically favorable, respectively. Thus, (hetero)dimerization occurs between a polypeptide containing the first Fc domain subunit and a polypeptide containing the second Fc domain subunit, which may differ in the sense of inconsistency in the additional components (e.g., antigen-binding moieties) fused to each subunit. In some embodiments, association-promoting modifications include amino acid mutations in the Fc domain, particularly amino acid substitutions. In one particular embodiment, the association-promoting modification includes individual amino acid mutations, particularly amino acid substitutions, in each of the two subunits of the Fc domain.

"Activated Fc receptors" are Fc receptors that, upon binding to the Fc region of an antibody, trigger signal transduction events that stimulate receptor-carrying cells to perform effector functions. Activated Fc receptors include FcγRIIIa (CD16a), FcγRI (CD64), FcγRIIa (CD32), and FcαRI (CD89).

When discussing antibody use, the term "effective function" refers to those biological activities attributable to the Fc region of the antibody, which vary across antibody isotypes. Examples of antibody effector functions include: C1q binding and complement-dependent cytotoxicity (CDC), Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent phagocytosis (ADCP), cytokine secretion, antigen uptake by immune complex-mediated antigen-presenting cells, downregulation of cell surface receptors (e.g., B cell receptors), and B cell activation.

As used herein, the term "effective cell" refers to a population of lymphocytes that display effector portion receptors (e.g., cytokine receptors) and/or Fc receptors on their surface. These receptors allow them to bind to the Fc region of effector portions (e.g., cytokines) and/or antibodies, contributing to the destruction of target cells, such as tumor cells. Effector cells can, for example, mediate cytotoxic or phagocytic responses. Effector cells include, but are not limited to, effector T cells, such as CD8 ⁺ cytotoxic T cells, CD4 ⁺ helper T cells, γδ T cells, NK cells, lymphokine-activated killer (LAK) cells, and macrophages/monocytes.

As used herein, the terms “engineering,” “engineered,” and “engineered modification” are considered to include any manipulation of the peptide backbone or post-translational modification of naturally occurring or recombinant polypeptides or fragments thereof. Engineering modification includes modifications to the amino acid sequence, glycosylation pattern, or side chain groups of individual amino acids, as well as combinations of these methods. “Engineering modification” (especially with the prefix “glycosylation”) and the term “glycosylation engineering” include metabolic engineering of cellular glycosylation mechanisms, including genetic manipulation of oligosaccharide synthesis pathways to achieve altered glycosylation of glycoproteins expressed intracellularly. Furthermore, glycosylation engineering includes the effects of mutations and the cellular environment on glycosylation. In one embodiment, glycosylation engineering results in altered glycosyltransferase activity. In a particular embodiment, engineering leads to altered glucosamine aminotransferase activity and/or fucosyltransferase activity. Glycosylation engineering can be used to obtain “host cells with increased GnTIII activity” (e.g., host cells that have been manipulated to express increased levels of one or more peptides with β(1,4)-N-acetylglucosamine aminotransferase III (GnTIII) activity), “host cells with increased ManII activity” (e.g., host cells that have been manipulated to express increased levels of one or more peptides with α-mannosidase II (ManII) activity), or “host cells with decreased α(1,6)-fucosyltransferase activity” (e.g., host cells that have been manipulated to express decreased levels of α(1,6)-fucosyltransferase).

The terms “host cell,” “host cell line,” and “host cell culture” are used interchangeably and refer to cells in which exogenous nucleic acids have been introduced, including progeny cells of such cells. Host cells include “transformations” and “transformed cells,” which include primary transformed cells and progeny derived from those primary transformed cells, regardless of passage number. Progeny cells may not be identical to the nucleic acid contents of the parent cells and may contain mutations. This includes mutant progeny with the same function or biological activity as screened or selected in the original transformed cells. Host cells are any type of cell system that can be used to generate proteins used in the present invention. In one embodiment, the host cell is modified to allow the production of antibodies with modified oligosaccharides. In some embodiments, the host cell has been manipulated to express increased levels of one or more polypeptides with β(1,4)-N-acetylglucosamine aminotransferase III (GnTIII) activity. In some embodiments, the host cell has been further manipulated to express increased levels of one or more polypeptides with α-mannosidase II (ManII) activity. Host cells include cultured cells, for example, cultured mammalian cells such as CHO cells, BHK cells, NSO cells, SP2/0 cells, YO myeloma cells, P3X63 mouse myeloma cells, PER cells, PER.C6 cells or hybridoma cells, yeast cells, insect cells and plant cells, as well as cells included in transgenic animals, transgenic plants or cultured plant or animal tissues.

As used herein, the term "peptide with GnTIII activity" refers to a β-linked mannoside capable of catalyzing the addition of N-acetylglucosamine (GlcNAc) residues in a β-1,4 bond to the trimannose core of an N-linked oligosaccharide. This term includes fusion peptides exhibiting enzymatic activity (as measured in a specific bioassay and with or without dose dependence) similar to, but not necessarily identical to, that of β(1,4)-N-acetylglucosamine aminotransferase III (also known as β-1,4-mannosyl-glycoprotein 4-β-N-acetylglucosamine aminotransferase (EC 2.4.1.144), according to the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (NC-IUBMB)). Where dose dependence is indeed present, it need not be identical to GnTIII, but rather substantially similar to GnTIII in terms of dose dependence for a given activity (i.e., the candidate peptide will exhibit greater activity or less than about 25-fold, preferably less than about 10-fold, and most preferably less than about 3-fold, activity relative to GnTIII). In some embodiments, the peptide having GnTIII activity is a fusion peptide comprising the catalytic domain of GnTIII and the Golgi localization domain of a heterologous Golgi-resident peptide. In particular, the Golgi localization domain is the localization domain of mannosidase II or GnTI, most particularly the localization domain of mannosidase II. Alternatively, the Golgi localization domain is selected from the group consisting of the localization domain of mannosidase I, the localization domain of GnTII, and the localization domain of α1,6-core fucosyltransferase. Methods for generating the fusion polypeptide and for using it to generate antibodies with enhanced effector functions are disclosed in WO2004/065540, U.S. Provisional Patent Application No. 60/495,142 and U.S. Patent Application Publication No. 2004/0241817, the entire contents of which are expressly incorporated herein by reference.

As used herein, the term "Golgi localization domain" refers to the amino acid sequence of a Golgi-resident polypeptide that is responsible for anchoring the polypeptide to a location within the Golgi complex. Typically, the localization domain includes the amino-terminal "tail" of an enzyme.

As used herein, the term "peptide with ManII activity" refers to a peptide capable of catalyzing the hydrolysis of terminal 1,3- and 1,6-linked α-D-mannose residues in the branched mannose intermediate of N-linked oligosaccharides GlcNAcMan5 _{GlcNAc2 .} This term includes peptides exhibiting enzymatic activity similar to, but not necessarily identical to, Golgi α-mannosidase II (also known as mannosyl oligosaccharide 1,3-1,6-α-mannosidase II (EC 3.2.1.114), according to the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (NC-IUBMB)).

Antibody-dependent cell-mediated cytotoxicity (ADCC) is an immune mechanism that causes immune effector cells to lyse antibody-coated target cells. Target cells are cells that specifically bind to an antibody or a derivative thereof, including an Fc region, typically via the protein portion of the N-terminus of the Fc region. As used herein, the term “increased/decreased ADCC” is defined as an increase/decrease in the number of target cells lysed at a given concentration of antibody in the culture medium surrounding the target cells within a given time period via the ADCC mechanism defined above, and/or a decrease/increase in the concentration of antibody in the culture medium surrounding the target cells required to achieve the lysis of a given number of target cells within a given time period via the ADCC mechanism. An increase/decrease in ADCC is relative to ADCC mediated by the same antibody (but not modified) produced from the same type of host cells using the same standard methods of production, purification, formulation, and storage (methods known to those skilled in the art). For example, antibody-mediated ADCC is increased when host cells engineered by the methods disclosed herein to have altered glycosylation patterns (e.g., to express glycosyltransferases, GnTIII, or other glycosyltransferases) are used to generate ADCC, relative to the same antibody-mediated ADCC generated from the same type of unengineered host cells.

"Antibody with increased antibody-dependent cell-mediated cytotoxicity (ADCC)" means an antibody as defined herein that has an increased/decreased ADCC that can be measured by any suitable method known to those skilled in the art. A recognized in vitro ADCC assay is as follows:

1) This assay uses target cells known to express target antigens recognized by the antigen-binding region of the antibody;

2) This assay uses human peripheral blood mononuclear cells (PBMCs) isolated from blood of randomly selected healthy donors as effector cells;

3) This measurement was conducted according to the following protocol:

i) PBMCs were separated using a standard density centrifugation program and suspended in RPMI cell culture medium at a density of 5 × ^10⁶ cells/mL;

ii) Target cells were grown using standard tissue culture methods, harvested from the exponential growth phase, with cell viability greater than 90%, washed in RPMI cell culture medium, labeled with ^51Cr at 100 μCurie, washed twice with cell culture medium, and resuspended in cell culture medium at a density of ^10⁵ cells/mL.

iii) Transfer 100 μL of the final target cell suspension to each well of a 96-well microtiter plate;

iv) Serially dilute the antibody from 4000 ng/mL to 0.04 ng/mL in cell culture medium, and add 50 μL of the resulting antibody solution to target cells in a 96-well microtiter plate. Test various antibody concentrations in triplicate to cover the entire concentration range mentioned above.

v) For the maximum release (MR) control, 50 μL of 2% (v/v) nonionic detergent aqueous solution (Nonidet, Sigma, St. Louis) was added to the other 3 wells in the plate containing labeled target cells to replace the antibody solution (point iv above);

vi) For the spontaneous release (SR) control, 50 μL of RPMI cell culture medium was administered in place of the antibody solution in three additional wells of the plate containing labeled target cells (point iv above);

vii) Then the 96-well microtiter plate was centrifuged at 50×g for 1 minute and incubated at 4°C for 1 hour;

viii) Add 50 μL of PBMC suspension (point i above) to each well to obtain an effector:target cell ratio of 25:1, and incubate the plate in a 5% _CO2 atmosphere at 37°C for 4 hours.

ix) Harvest cell-free supernatant from each well and measure the radioactivity (ER) released in the experiment using a gamma counter;

x) Calculate the percentage of specific cleavage at each antibody concentration using the formula (ER-MR)/(MR-SR)×100, where ER is the average radioactivity quantified for that antibody concentration (see point ix above), MR is the average radioactivity quantified for the MR control (see point v above) (see point ix above), and SR is the average radioactivity quantified for the SR control (see point vi above) (see point ix above).

4) "Increased/decreased ADCC" is defined as an increase/decrease in the maximum percentage of specific cleavage observed within the antibody concentration range tested above, and/or a decrease/increase in the antibody concentration required to achieve half of the observed maximum percentage of specific cleavage within the antibody concentration range tested above. The increase/decrease in ADCC is relative to ADCC mediated by the same antibody (but not modified) produced from the same type of host cells using the same standard methods of generation, purification, formulation, and storage (methods known to those skilled in the art) (measured using the analysis described above).

As used herein, the term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous group of antibodies, meaning that, apart from possible variant antibodies (e.g., those containing naturally occurring mutations or generated during the production of a monoclonal antibody formulation, such variants are typically presented in small quantities), the individual antibodies comprising this group are identical and/or bind to the same epitopes. In contrast to polyclonal antibody formulations, which typically comprise different antibodies targeting different determinants (epitaxes), each monoclonal antibody in a monoclonal antibody formulation targets a single determinant on the antigen. Therefore, the modifier "monoclonal" indicates that the antibody is characterized by being obtained from a substantially homogeneous group of antibodies and should not be construed as requiring the antibody to be produced by any particular method. For example, monoclonal antibodies intended for use according to the invention can be prepared by a variety of techniques, including but not limited to hybridoma methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci, such methods and other exemplary methods for preparing monoclonal antibodies are described herein.

"Naked antibody" refers to an antibody that does not conjugate to a heterologous portion (e.g., a cytotoxic portion) or a radiolabeled portion. Naked antibodies can be present in pharmaceutical formulations.

"Natural antibodies" are naturally occurring immunoglobulin molecules with different structures. For example, natural IgG antibodies are heterotetrameric glycoproteins of approximately 150,000 Daltons, composed of two identical light chains and two identical heavy chains bonded by disulfides. Each heavy chain has a variable region (VH), also called a variable heavy chain domain or heavy chain variable domain, from the N-terminus to the C-terminus, followed by three constant domains (CH1, CH2, and CH3). Similarly, each light chain has a variable region (VL), also called a variable light chain domain or light chain variable domain, from the N-terminus to the C-terminus, followed by a constant light chain (CL) domain. The light chains of antibodies can be classified into one of two types based on the amino acid sequence of their constant domains, called kappa (κ) and lamuda (λ).

As used herein, the terms “first,” “second,” or “third,” etc., relating to antigen-binding portions or domains, are used to facilitate the distinction of each type of portion or domain when more than one portion or domain exists. Unless explicitly stated otherwise, the use of these terms is not intended to assign a particular order or orientation.

The terms "multispecific" and "bispecific" refer to the ability of an antigen-binding molecule to specifically bind to at least two different antigenic determinants. Typically, a bispecific antigen-binding molecule contains two antigen-binding sites, each of which is specific to a different antigenic determinant. In some embodiments, a bispecific antigen-binding molecule can bind to two antigenic determinants simultaneously, particularly two antigenic determinants expressed on two distinct cell types.

As used herein, the term "valence" or "valence state" indicates the presence of a specified number of antigen-binding sites in an antigen-binding molecule. Therefore, the term "monovalently bound to antigen" indicates the presence of one (and no more than one) antigen-binding site in an antigen-binding molecule that is specific to the antigen.

An "antigen binding site" is a site on an antigen-binding molecule that provides an interaction with an antigen; it is typically one or more amino acid residues. For example, the antigen binding site of an antibody contains amino acid residues from the complementarity-determining region (CDR). Natural immunoglobulin molecules usually have two antigen binding sites, while Fab molecules usually have a single antigen binding site.

As used herein, “activated T-cell antigen” refers to an antigenic determinant expressed by T lymphocytes (particularly cytotoxic T lymphocytes) that can induce or enhance T-cell activation upon interaction with antigen-binding molecules. Specifically, the interaction between antigen-binding molecules and activated T-cell antigens can induce T-cell activation by triggering a signaling cascade of the T-cell receptor complex. An exemplary activated T-cell antigen is CD3. In a particular embodiment, the activated T-cell antigen is CD3, particularly the ε subunit of CD3 (see UniProt No. P07766 (130th edition), NCBI RefSeq No. NP_000724.1, for human sequences; or UniProt No. Q95LI5 (49th edition), NCBI GenBank No. BAB71849.1, for macaque [long-tailed macaque] sequences).

As used herein, "T cell activation" refers to one or more cellular responses of T lymphocytes (particularly cytotoxic T lymphocytes), selected from: proliferation, differentiation, cytokine secretion, release of cytotoxic effector molecules, cytotoxic activity, and expression of activation markers. The T cell activation therapeutic agents used in this invention can induce T cell activation. Suitable assays for measuring T cell activation are known in the art as described herein.

As used herein, “target cell antigen” refers to an antigenic determinant present on the surface of a target cell, such as a cell in a tumor (e.g., a cancer cell or a cell in the tumor stroma). In a particular embodiment, the target cell antigen is CD20, particularly human CD20 (see UniProt number P11836).

As used in this article, “B cell antigen” refers to the antigenic determinants presented on the surface of B lymphocytes, especially malignant B lymphocytes (in which case the antigen is also called “malignant B cell antigen”).

As used in this article, "T cell antigen" refers to antigenic determinants present on the surface of T lymphocytes, particularly cytotoxic T lymphocytes.

"Fab molecule" refers to a protein composed of the VH and CH1 domains of the heavy chain ("Fab heavy chain") of an immunoglobulin and the VL and CL domains of the light chain ("Fab light chain").

"Fusion" means that components (e.g., Fab molecules and Fc domain subunits) are linked by peptide bonds, either directly or via one or more peptide linkers.

The “effective amount” of a drug refers to the amount required to produce physiological changes in the cells or tissues to which it is applied.

A "therapeuticly effective amount" of a pharmaceutical agent (e.g., a pharmaceutical composition) refers to the amount that effectively achieves the desired therapeutic or preventative outcome at the necessary dosage and time period. A therapeutically effective amount of a pharmaceutical agent may eliminate, reduce, delay, minimize, or prevent adverse effects of disease, for example.

"Therapeutic agent" means, for example, the active ingredient of a pharmaceutical composition, administered to a subject in an attempt to alter the natural course of a disease in the treated subject, and may be used for prevention or performed during a clinicopathological process. "Immunotherapy agent" refers to a therapeutic agent administered to a subject in an attempt to restore or enhance the subject's immune response (e.g., an immune response against a tumor).

The term "pharmaceutical composition" refers to a preparation in a form that makes the bioactivity of the active ingredient contained therein effective, and that the preparation does not contain any additional components that would have unacceptable toxicity to a subject who would administer the composition.

"Pharmaceutical carrier" refers to a component in a pharmaceutical composition that is non-toxic to the subject, excluding the active ingredient. Pharmaceutical carriers include, but are not limited to, buffer solutions, excipients, stabilizers, or preservatives.

The terms “packaging insert” or “instructions for use” are used to refer to instructions that are typically included in the commercial packaging of a therapeutic product, which include information on the indications, usage, dosage, administration, combination therapy, contraindications and/or warnings for using the therapeutic product.

The term “combination therapy” as used herein encompasses combined administration (where two or more therapeutic agents are included in the same or separate formulations); and separate administration, in which case the administration of an antibody as reported herein may occur before, simultaneously with, and/or after the administration of one or more additional therapeutic agents (preferably one or more antibodies).

A “crossfab” molecule (also called a “Crossfab”) refers to a Fab molecule in which the variable or constant domains of the Fab heavy and light chains are exchanged (i.e., replaced). Specifically, a crossfab molecule comprises a peptide chain consisting of a light chain variable domain VL and a heavy chain constant domain 1CH1 (VL-CH1, N-terminal to C-terminal direction), and a peptide chain consisting of a heavy chain variable domain VH and a light chain constant domain CL (VH-CL, N-terminal to C-terminal direction). For clarity, in a crossfab molecule in which the variable domains of the Fab light chain and the Fab heavy chain are exchanged, the peptide chain containing the heavy chain constant domain 1CH1 is referred to herein as the “heavy chain” of the (cross)fab molecule. Conversely, in a crossfab molecule in which the constant domains of the Fab light chain and the Fab heavy chain are exchanged, the peptide chain containing the heavy chain variable domain VH is referred to herein as the “heavy chain” of the (cross)fab molecule.

In contrast, "conventional" Fab molecules refer to Fab molecules in their natural form, namely, heavy chains consisting of variable and constant domains in the heavy chain (VH-CH1, in the direction from the N-terminus to the C-terminus), and light chains consisting of variable and constant domains in the light chain (VL-CL, in the direction from the N-terminus to the C-terminus).

The term "polynucleotide" refers to an isolated nucleic acid molecule or construct, such as messenger RNA (mRNA), viral RNA, or plasmid DNA (pDNA). Polynucleotides may contain conventional phosphodiester bonds or unconventional bonds (such as amide bonds, as present in peptide nucleic acids (PNA)). The term "nucleic acid molecule" refers to any one or more nucleic acid segments, such as DNA or RNA fragments, present in a polynucleotide.

"Isolated" nucleic acid molecules or polynucleotides refer to nucleic acid molecules, DNA, or RNA that have been removed from their natural environment. For example, recombinant polynucleotides encoding polypeptides contained in a vector are considered isolated for the purposes of this invention. Further examples of isolated polynucleotides include recombinant polynucleotides maintained in heterologous host cells or purified (partially or substantially purified) polynucleotides in solution. Isolated polynucleotides include polynucleotide molecules contained in cells that normally contain polynucleotide molecules, but which are present outside the chromosome or at a chromosomal location different from their natural chromosomal location. Isolated RNA molecules include in vivo or in vitro RNA transcripts of this invention, as well as positive-strand and negative-strand forms and double-stranded forms. Isolated polynucleotides or nucleic acids according to this invention also include such molecules produced by synthesis. Furthermore, polynucleotides or nucleic acids may be or may include regulatory elements, such as promoters, ribosome binding sites, or transcription terminators.

A nucleic acid or polynucleotide having at least, for example, 95% “identical” nucleotide sequence to the reference nucleotide sequence of the present invention means that the nucleotide sequence of the polynucleotide is identical to the reference sequence except that the polynucleotide sequence may include at most five point mutations per 100 nucleotides of the reference nucleotide sequence. In other words, to obtain a polynucleotide having at least 95% identical nucleotide sequence to the reference nucleotide sequence, at most 5% of the nucleotides in the reference sequence may be deleted or substituted by other nucleotides, or at most 5% of the total nucleotides in the reference sequence may be inserted into the reference sequence. These changes to the reference sequence may occur at the 5’ or 3’ end positions of the reference nucleotide sequence or at any position between those end positions, either individually scattered among the residues of the reference sequence or in one or more consecutive groups within the reference sequence. As is customary, known computer programs, such as those discussed below for peptides (e.g., ALIGN-2), can be used to conventionally determine whether any particular polynucleotide sequence is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the nucleotide sequence of the present invention.

The term "expression cassette" refers to a polynucleotide produced through recombination or synthesis, which has a specific set of nucleic acid elements that allow a particular nucleic acid to be transcribed in a target cell. Recombinant expression cassettes can be incorporated into plasmids, chromosomes, mitochondrial DNA, plastid DNA, viruses, or nucleic acid fragments. Typically, the recombinant expression cassette portion of an expression vector includes, among other sequences, the nucleic acid sequence to be transcribed and a promoter. In some embodiments, the expression cassette of the present invention comprises a polynucleotide sequence encoding a bispecific antigen-binding molecule or a fragment thereof.

The term "vector" or "expression vector" is synonymous with "expression construct" and refers to a DNA molecule used to introduce a specific gene into a target cell with which it is operatively associated and to direct the expression of that gene. This term includes vectors as self-replicating nucleic acid structures, as well as vectors incorporated into the genome of a host cell into which they have been introduced. The expression vector of the present invention comprises an expression cassette. The expression vector allows for the transcription of a large amount of stable mRNA. Once the expression vector is inside the target cell, a ribonucleic acid molecule or protein encoded by the gene is produced through cellular transcription and/or translation mechanisms. In one embodiment, the expression vector of the present invention comprises an expression cassette containing a multinucleotide sequence encoding a bispecific antigen-binding molecule or a fragment thereof of the present invention.

As used herein, the term "about" refers to a common range of error for a corresponding value that is readily known to those skilled in the art. References to "about" values or parameters herein include (and describe) embodiments relating to that value or parameter itself.

"B-cell proliferative disorder" refers to a disease in which the number of B cells in a patient is greater than the number of B cells in a healthy subject, and particularly, the increase in the number of B cells is a cause or marker of the disease. "CD20-positive B-cell proliferative disorder" is a B-cell proliferative disorder in which B cells, particularly malignant B cells (other than normal B cells), express CD20.

Exemplary B-cell proliferative disorders include non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL; e.g., relapsed or refractory DLBCL (NOS) unless otherwise specified), high-grade B-cell lymphoma (HGBCL; e.g., HGBCL NOS, double-hit HGBCL, and triple-hit HGBCL), primary mediastinal large B-cell lymphoma (PMBCL), and DLBCL caused by FL (transformed FL; trFL)); follicular lymphoma (FL), including grades 1-3b FL; mantle cell lymphoma (MCL); and marginal zone lymphoma (MZL), including spleen, lymph node, or extranodal MZL. In one embodiment, a CD20-positive B-cell proliferative disorder is Burkitt lymphoma (BL); Burkitt leukemia (BAL; mature B-cell leukemia FAB L3); DLBCL, or PMBCL. In one embodiment, the CD20-positive B-cell proliferative disorder is relapsed or refractory NHL (e.g., relapsed or refractory DLBCL, relapsed or refractory FL, or relapsed or refractory MCL). In one embodiment, BL, BAL, DLBCL, or PMBCL is relapsed and/or refractory. In one embodiment, BL, BAL, DLBCL, or PMBCL has relapsed or is refractory after first-line standard-of-care chemoimmunotherapy.

"Treatment-resistant disease" is defined as the failure to achieve complete remission with first-line therapy, including:

• Disease progression (PD) as the best response to first-line therapy

• Stable disease (SD) is the best response following at least four cycles of first-line therapy (e.g., four cycles of R-CHOP).

Partial remission (PR) is the best response after at least 6 cycles with biopsy-proven residual disease or subsequent disease progression.

“Relapsed disease” is defined as complete remission with first-line therapy. In one embodiment, disease relapse is demonstrated by biopsy. In one embodiment, a patient relapses or fails to achieve remission after at least two prior systemic therapy regimens, including at least one prior regimen containing anthracyclines and at least one anti-CD20-targeted therapy.

"Individual" or "subject" is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., human and non-human primates, such as monkeys), rabbits, and rodents (e.g., mice and rats). Preferably, the individual or subject is a human. In one case, each subject in the subject population is a human. In another case, each subject in the subject reference population is a human. In one embodiment, a subject is considered a pediatric patient if the pediatric patient is less than 18 years of age (i.e., 17 years or younger). In one embodiment, the pediatric patient's age is between 6 months and 17 years. In one embodiment, a subject is considered a young adult patient if the young adult patient's age is between 18 and 30 years.

Subjects who are “eligible for transplantation” or “eligible for autologous stem cell transplantation (SCT)” are those who are eligible for, recommended for, or can undergo SCT. In one embodiment, “eligible for transplantation” is defined as being medically eligible for intensive platinum-based salvage therapy followed by autologous stem cell transplantation (ASCT). In one embodiment, eligible subjects achieve an objective response and mobilize a target dose of at least 2,000,000 CD34+ hematopoietic stem cells/kg. In one embodiment, “eligible for transplantation” is defined as being medically eligible for two to three cycles of salvage therapy using R-ICE and glimepiride to achieve CR, followed by allogeneic or autologous hematopoietic stem cell transplantation (HSCT).

Subjects who “meet the criteria for CAR-T cell therapy” or “meet the criteria for CAR-T cell therapy” are subjects who meet the criteria for chimeric antigen receptor (CAR) T-cell therapy, are recommended for or are eligible for CAR-T cell therapy.

As used herein, “treatment” (and its grammatical variations) refers to an attempt to alter the natural course of a disease in an individual being treated, and is a clinical intervention that can be performed for prevention or may be performed during a clinicopathological process. The desired effects of treatment include, but are not limited to, preventing the onset or recurrence of disease, alleviating symptoms, attenuating any direct or indirect pathological consequences of the disease, preventing metastasis, slowing the rate of disease progression, improving or mitigating the disease state, and alleviating or improving prognosis. In some embodiments, the methods of the present invention are used to delay the development of a disease or slow its progression. In one embodiment, the disease being treated is a CD20-positive B-cell proliferative disorder, such as Burkitt lymphoma (BL); Burkitt leukemia (BAL; mature B-cell leukemia FAB L3); DLBCL, or PMBCL.

As used herein, “delayed progression” of a disease or condition means the postponement, impediment, mitigation, delay, stabilization, and/or postponement of the development of a disease or condition (e.g., CD20-positive B-cell proliferative disorders, such as NHL, DLBCL, Burkitt lymphoma (BL); Burkitt leukemia (BAL; mature B-cell leukemia FAB L3), or PMBCL). Such delay can vary in length depending on the individual’s medical history and/or treatment. It will be apparent to those skilled in the art that a sufficient or significant delay can effectively encompass prevention, as the individual will not develop the disease. For example, in advanced cancer, the development of central nervous system (CNS) metastases may be delayed.

"Reduction" or "inhibition" means resulting in an overall reduction, for example, by 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or more. For clarity, the term also includes reduction to zero (or below the detection limit of the analytical method), i.e., complete elimination or eradication. In some embodiments, reduction or inhibition may refer to the reduction or inhibition of undesirable events, such as cytokine-driven toxicities (e.g., cytokine release syndrome (CRS)), infusion-related reactions (IRR), macrophage activation syndrome (MAS), neurotoxicity, severe tumor lysis syndrome (TLS), neutropenia, thrombocytopenia, elevated liver enzymes, and/or central nervous system (CNS) toxicity, relative to a predetermined dose of the target dose using the bispecific antibody, after treatment with the anti-CD20/anti-CD3 bispecific antibody using the incremental dosing regimen of the present invention. In other embodiments, reduction or inhibition may refer to the effector function of an antibody mediated by its Fc region, specifically including complement-dependent cytotoxicity (CDC), antibody-dependent cytotoxicity (ADCC), and antibody-dependent phagocytosis (ADCP). In other embodiments, reduction or inhibition may refer to the symptoms, presence or size of metastases, or size of the primary tumor in the CD20-positive B-cell proliferative disorder being treated (e.g., NHL (e.g., DLBCL), FL (e.g., relapsed and/or refractory FL or transformed FL), MCL, high-grade B-cell lymphoma, or PMLBCL). In one embodiment, the CD20-positive B-cell proliferative disorder being treated is Burkitt lymphoma (BL); Burkitt leukemia (BAL; mature B-cell leukemia FAB L3); DLBCL, or PMBCL.

As used herein, “administration” means the method of administering a dose of a compound (e.g., an anti-CD20/anti-CD3 bispecific antibody) or a composition (e.g., a pharmaceutical composition, such as a pharmaceutical composition comprising an anti-CD20/anti-CD3 bispecific antibody) to a subject. The compounds and/or compositions used in the methods described herein may be administered intravenously (e.g., by intravenous infusion).

The term "fixed" or "uniform" dose for therapeutic agents (e.g., bispecific antibodies) in this article refers to the dose administered to a patient regardless of the patient's weight or body surface area (BSA). Therefore, a fixed dose is not provided as a mg/kg or mg/ ^m² dose, but rather as an absolute dose of the therapeutic agent (e.g., mg).

In this article, "target dose" refers to the dose of the anti-CD20/anti-CD3 bispecific antibody required to achieve the therapeutic effect, i.e., the desired clinical efficacy. For glimepiride, a possible target dose of 16 mg or 30 mg was found. In one embodiment, the target dose for pediatric subjects (i.e., aged 6 months to 17 years) is 0.5 mg/kg or 0.4 mg/kg, depending on the subject's weight. In a specific embodiment, the target dose is 0.5 mg/kg for pediatric subjects weighing 7.5 kg to <13 kg, 0.4 mg/kg for pediatric subjects weighing ≥13 kg to <45 kg, and a uniform dose of 30 mg for pediatric subjects weighing ≥45 kg.

"Using the same or predetermined dose of the target dose" and "treatment regimens without using an escalation dosing regimen" refer to a dosing regimen that uses the same dose in the first and second cycles and optionally any subsequent treatment cycles. This is different from escalation dosing, which uses a lower dose in the first few treatment cycles and only reaches the target dose in the second or subsequent treatment cycles.

As used herein, the term "treatment cycle" or "cycle" (abbreviated as "C") refers to a process of repeating one or more doses of an anti-CD20/anti-CD3 bispecific antibody in a regular protocol, optionally with rest periods (no treatment). In one aspect of the invention, a first treatment cycle comprises a first dose and a second dose of the anti-CD20/anti-CD3 bispecific antibody, followed by a rest period. In one such embodiment, a first treatment cycle comprises a first dose of the anti-CD20/anti-CD3 bispecific antibody on day 8 of the first cycle and a second dose of the anti-CD20/anti-CD3 bispecific antibody on day 15 of the first cycle, followed by a 6-day rest. In one embodiment, a second cycle and any subsequent cycles comprise a dose of the anti-CD20/anti-CD3 bispecific antibody given on day 8 of that cycle, followed by a 13-day rest. In one embodiment, a treatment cycle comprises 21 days. In another embodiment, a treatment cycle comprises 14 days. Treatment regimens according to the invention may comprise two or more treatment cycles, particularly three treatment cycles. In some embodiments, a treatment cycle is referred to as a "dosing cycle".

“Individual response” or “response” may be assessed using any endpoint that indicates benefit to the subject, including but not limited to (1) suppression of disease progression (e.g., progression of CD20-positive B-cell proliferative disorders, such as non-Hodgkin’s lymphoma (NHL)) to some extent, including slowing and complete cessation; (2) reduction of tumor size; (3) suppression (i.e., reduction, slowing or complete cessation) of the invasion of cancer cells into adjacent organs and/or tissues; (4) suppression (i.e., reduction, slowing or complete cessation) of metastasis; (5) relief to some extent of one or more symptoms associated with CD20-positive B-cell proliferative disorders, such as B-cell proliferative disorders; (6) increase or prolong the duration of survival (including overall survival and progression-free survival); and/or (7) reduction of mortality at a given time point after treatment.

As used herein, “complete remission” or “CR” refers to the disappearance of all target lesions. In one embodiment, the criteria for assessing NHL remission are used to determine CR. (Lugano Classification, Cheson et al. J Clin Oncol. 2014 Sep 20; 32(27):3059–3067.). In one embodiment, the CR rate is defined as the proportion of participants who achieve CR within three cycles of glofit-R-ICE, as determined by the investigator according to the Lugano criteria. In one embodiment, CR is defined as complete metabolic remission, as determined by PET/CT of lymph nodes and extraly lymphatic sites, where a score of 1, 2, or 3 indicates the presence or absence of residual mass at 5PS, where PET 5PS: 1 = no uptake above background; 2 = uptake > mediastinum; 3 = uptake > mediastinum, but ≤ liver; 4 = adequate uptake > liver; 5 = significantly higher uptake than liver and/or new lesions; X = new uptake areas unlikely to be associated with lymphoma. In one embodiment, CR is defined as complete radiological remission as determined by CT scans of lymph nodes and extralymphatic sites, wherein the target nodule/nodular mass must shrink to ≤1.5 cm in LDi (longest transverse diameter of the lesion) and no extralymphatic disease sites remain. For pediatric subjects (age <18 years), CR is assessed using the International Pediatric Non-Hodgkin Lymphoma Remission Criteria (Sandlund JT, Guillerman RP, Perkins SL et al. International pediatric non-Hodgkin lymphoma response secriteria. J. Clin. Oncol. 33:2106-2111, 2015).

As used herein, “partial remission” or “PR” refers to partial metabolic remission as determined by PET/CT of lymph nodes and extranodal sites and/or partial remission as determined by CT of lymph nodes and extranodal sites. In one embodiment, partial metabolic remission is defined by a score of 4 or 5b, a reduction in uptake compared to baseline, and any size of residual mass as determined by PET/CT of lymph nodes and extranodal sites, where PET 5PS: 1 = no uptake above background; 2 = uptake > mediastinum; 3 = uptake > mediastinum, but ≤ liver; 4 = uptake adequate > liver; 5 = significantly higher uptake than liver and/or new lesions; X = new uptake area unlikely to be associated with lymphoma. In one embodiment, partial remission is defined as a reduction of at least 50% in the product of diameters (SPD) of up to 6 measurable nodules and extranodal sites, with reference to baseline SPD. For pediatric subjects (aged <18 years), PR was assessed using the International Pediatric NHL Remission Criteria (Sandlund JT, Guillerman RP, Perkins SL et al. International pediatric non-Hodgkin lymphoma response secriteria. J. Clin. Oncol. 33:2106-2111, 2015).

A subject’s “effective response” to a drug or treatment, or a subject’s “responsiveness” and similar terms, refers to a clinical or therapeutically beneficial effect conferred on a subject who is at risk of or has a disease or condition such as cancer. In one embodiment, such benefit includes one or more of the following: prolonged survival (including overall survival and progression-free survival); objective remission (including complete remission or partial remission); or improvement of signs or symptoms of cancer.

The “Duration of Complete Remission (DOCR)” is defined as the time from the first documented occurrence of complete remission to disease progression or death from any cause (whichever comes first), as determined by the investigator according to the Lugano criteria (Cheson et al. J Clin Oncol. 2014 Sep 20; 32(27):3059–3067.). CR is assessed by the investigator using the International Pediatric NHL Remission Criteria for pediatric subjects <18 years of age (Sandlund JT, Guillerman RP, Perkins SL et al. International pediatric non-Hodgkin lymphoma response secriteria. J. Clin. Oncol. 33:2106-2111, 2015).

“Duration of objective response (DOR)” is defined as the time from the first recorded objective response (CR or PR) to disease progression or death from any cause (whichever comes first), as determined by the investigator according to the Lugano criteria (Cheson et al. J Clin Oncol. 2014 Sep 20; 32(27):3059–3067.). CR and/or PR are assessed by the investigator using the International Pediatric Non-Hodgkin Lymphoma Response Criteria for pediatric subjects <18 years of age (Sandlund JT, Guillerman RP, Perkins SL et al. International pediatric non-Hodgkin lymphoma response secriteria. J. Clin. Oncol. 33:2106-2111, 2015).

“Progression-free survival” (PFS) is defined as the time from the first use of anti-CD20/anti-CD3 bispecific antibody therapy to the first occurrence of disease progression or death from any cause (whichever comes first). In one embodiment, PFS is assessed based on the Lugano classification (Cheson et al. J Clin Oncol. 2014 Sep 20; 32(27):3059–3067.). PFS is assessed by investigators using the International Pediatric Non-Hodgkin Lymphoma Response Criteria for pediatric subjects <18 years of age (Sandlund JT, Guillerman RP, Perkins SL et al. International pediatric non-Hodgkin lymphoma response criteria. J. Clin. Oncol. 33:2106-2111, 2015).

Overall survival (OS) is defined as the time from the first treatment with anti-CD20/anti-CD3 bispecific antibodies to death from any cause.

As used in this article, “event-free survival” (EFS) is defined as the time from the first treatment with an anti-CD20/anti-CD3 bispecific antibody to the first occurrence of disease progression as determined by the investigator according to the Lugano criteria, the initiation of a new anti-lymphoma therapy (excluding planned ASCT), or death from any cause (whichever occurs first). EFS is assessed by the investigator using the International Pediatric NHL Response Criteria for pediatric subjects <18 years of age (Sandlund JT, Guillerman RP, Perkins SL et al. International pediatric non-Hodgkin lymphoma response criteria. J. Clin. Oncol. 33:2106-2111, 2015).

As used herein, “objective response rate (ORR)” is defined as the sum of the partial response (PR) rate and the complete response (CR) rate. In one embodiment, ORR is assessed based on the Lugano classification (Cheson et al. J Clin Oncol. 2014 Sep 20; 32(27):3059-3067). In another embodiment, ORR is defined as the proportion of participants who achieve CR or PR within three cycles of the anti-CD20/anti-CD3 bispecific antibody (e.g., glibenclamide) + R-ICE treatment regimen described herein. CR and/or PR are assessed by the investigator using the International Pediatric Non-Hodgkin Lymphoma Response Criteria for pediatric subjects <18 years of age (Sandlund JT, Guillerman RP, Perkins SL et al. International pediatric non-Hodgkin lymphoma response criteria. J. Clin. Oncol. 33:2106-2111, 2015).

As used in this article, "stable disease" or "SD" refers to the minimum SLD since the start of treatment, where the target lesion has neither shrunk sufficiently to meet PR nor increased sufficiently to meet PD.

As used in this article, “disease progression” or “PD” means an increase of at least 20% in the target lesion’s SLD relative to the minimum SLD recorded since the start of treatment, or an increase of at least 50% in the target lesion’s SPD relative to the minimum SPD recorded since the start of treatment, or the appearance of one or more new lesions.

As used herein, “infusion-related reaction,” “IRR,” or infusion-related adverse event refers to an adverse event that occurs in a patient or subject during or within 24 hours after administration of a drug (e.g., an anti-CD20/anti-CD3 bispecific antibody, such as glibenclamide; or an anti-CD20 antibody, such as olibutuzumab or rituximab). IRR can be graded from 1 to 5 according to, for example, NCI CTCAE v.4.

"Mobilization-adjusted response rate (MARR)" is defined as the percentage of patients who achieve an objective response and are mobilized with a target dose of 2,000,000 CD34+ hematopoietic stem cells/kg (usually the minimum requirement for ASCT).

As used herein, the term "R-ICE" refers to rituximab plus ifosfamide, carboplatin, etoposide, or etoposide phosphate.

(iii) Combination therapy of anti-CD20/anti-CD3 bispecific antibodies with anti-CD20 antibodies and chemotherapy

This invention provides a method for treating a subject with a CD20-positive proliferative disorder (e.g., B-cell proliferative disorder (e.g., non-Hodgkin's lymphoma (NHL) (e.g., relapsed and/or refractory NHL, diffuse large B-cell lymphoma (DLBCL) (e.g., relapsed and/or refractory DLBCL), follicular lymphoma (FL) (e.g., relapsed and/or refractory FL or transformed FL) or mantle cell lymphoma (MCL) (e.g., relapsed or refractory MCL)) or central nervous system lymphoma (CNSL))), the method comprising: administering to the subject a combination of an anti-CD20/anti-CD3 bispecific antibody with an anti-CD20 antibody and one or more chemotherapeutic agents selected from ifosfamide, carboplatin and/or etoposide).

In some cases, this method is used to treat subjects with relapsed and/or refractory NHL (e.g., invasive NHL (e.g., relapsed and/or refractory DLBCL, relapsed and/or refractory FL, or relapsed and/or refractory MCL)). In some cases, the subject relapses after one or more (e.g., one, two, three, four, five or more) prior therapies (e.g., one or more prior systemic therapies, such as one or more prior systemic chemotherapy therapies (e.g., one or more prior systemic therapies including administration of anthracycline), one or more prior stem cell therapies, or one or more prior CAR-T cell therapies) following a documented history of remission lasting at least 6 months from the end of that therapy (e.g., complete or partial remission). In some cases, the subject is refractory to any prior therapy (e.g., no remission to prior therapy, or progression within 6 months of completing the last dose of therapy). Therefore, in some embodiments, this dosing regimen is a second-line therapy. In some embodiments, this dosing regimen is a third-line therapy. In some embodiments, the subject has transformed FL, which is refractory to standard therapy for transformed FL. In some embodiments, FL is a graded FL (e.g., grade 1, 2, 3a or 3b FL).

In one aspect, the invention is characterized by a method of treating a subject suffering from a CD20-positive proliferative disorder such as a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and/or refractory NHL, DLBCL (e.g., relapsed and/or refractory DLBCL), FL (e.g., relapsed and/or refractory FL or transformed FL) or MCL (e.g., relapsed or refractory MCL)) or CNSL), the method comprising administering an effective amount to the subject in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle:

(a) Bispecific antibodies that bind to CD20 and CD3;

(b) Anti-CD20 antibody; and

(c) One or more chemotherapeutic agents selected from ifosfamide, carboplatin and/or etoposide.

In one embodiment, the first dosing cycle comprises a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody, wherein the C1D1 of the bispecific antibody is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of the bispecific antibody is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); and the second dosing cycle comprises a single dose of the bispecific antibody. The amount (C2D1) of the bispecific antibody is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg or ± 1 mg), about 16 mg (e.g., 16 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg or ± 1.6 mg), or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg). In a specific embodiment, the C1D1 of the bispecific antibody is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) and the C1D2 of the bispecific antibody is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg). In a specific embodiment, the C2D1 is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg). In certain embodiments, the C2D1 of the bispecific antibody is about 16 mg (e.g., 16 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, or ± 1.6 mg). In certain embodiments, the C2D1 of the bispecific antibody is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

In one embodiment, the first dosing cycle includes a first dose (C1D1) of the bispecific antibody and a second dose (C1D2) of the bispecific antibody, wherein the C1D1 of the bispecific antibody is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of the bispecific antibody is about 10 mg (e.g., 10 mg). ±0.05 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.5 mg, ±0.75 mg, or ±1 mg); and the second dosing cycle includes a single dose (C2D1) of the bispecific antibody, wherein the C2D1 of the bispecific antibody is about 30 mg (e.g., 30 mg ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg).

In one embodiment, the subject is given a first dose (C1D1) of the bispecific antibody and a second dose (C1D2) of the bispecific antibody on day 8 or before (±1 day) and day 15 or before (±1 day) of the first dosing cycle, respectively.

In one embodiment, a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody are administered to the subject on days 8 and 15 of the first dosing cycle, respectively. In another embodiment, C2D1 of the bispecific antibody is administered to the subject on or before day 8 of the second dosing cycle (±1 day).

In one embodiment, the anti-CD20 antibody is olibutuzumab and/or rituximab. In one embodiment, the first dosing cycle comprises a single dose of olibutuzumab (C1D1); and the second dosing cycle comprises a single dose of rituximab (C2D1).

In one embodiment, a single dose of olibutuzumab C1D1 is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg or ± 100 mg), and a single dose of rituximab is about 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 ).

In one embodiment, the anti-CD20 antibody is administered with a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein the first dosing cycle comprises a single dose of olibutuzumab on day 1 (C1D1); and the second dosing cycle comprises a single dose of rituximab on day 1 (C2D1).

In one aspect, the invention is characterized by a method of treating a subject suffering from a CD20-positive cell proliferative disorder, such as a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and/or refractory NHL, DLBCL (e.g., relapsed and/or refractory DLBCL), FL (e.g., relapsed and/or refractory FL or transformed FL) or MCL (e.g., relapsed or refractory MCL)) or CNSL), the method comprising: administering to the subject, in a first dosing cycle:

(a) Approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) as the first dose (C1D1) of the bispecific antibody binding to CD20 and CD3 and approximately 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg) as the second dose (C1D2) of the bispecific antibody binding to CD20 and CD3;

(b) A single dose of olibutuzumab (C1D1); and

(c) One or more chemotherapeutic agents selected from ifosfamide, carboplatin and/or etoposide;

Administered to subjects during the second dosing cycle:

(a) A single dose (C2D1) of approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg) of a bispecific antibody that binds to CD20 and CD3.

(b) A single dose of rituximab (C2D1); and

(c) One or more chemotherapeutic agents selected from ifosfamide, carboplatin and/or etoposide.

In one embodiment, a single dose of olibutuzumab C1D1 is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg or ± 100 mg), and a single dose of rituximab is about 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 ).

In one embodiment, the anti-CD20 antibody is administered with a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein the first dosing cycle comprises a single dose of olibutuzumab on day 1 (C1D1); and the second dosing cycle comprises a single dose of rituximab on day 1 (C2D1).

In one embodiment, the subject is given a first dose (C1D1) of the bispecific antibody and a second dose (C1D2) of the bispecific antibody on day 8 or before (±1 day) and day 15 or before (±1 day) of the first dosing cycle, respectively.

In one embodiment, a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody are administered to the subject on days 8 and 15 of the first dosing cycle, respectively. In another embodiment, C2D1 of the bispecific antibody is administered to the subject on or before day 8 of the second dosing cycle (±1 day).

In one embodiment of the method provided above, step c) includes all three chemotherapeutic agents.

In one embodiment, the first dosing cycle includes a single dose of ifosfamide (C1D1), a single dose of carboplatin (C1D1), and a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of etoposide; and the second cycle each includes a single dose of ifosfamide (C2D1), a single dose of carboplatin (C2D1), and a first dose (C2D1), a second dose (C2D2), and a third dose (C2D3) of etoposide.

In one aspect, the invention is characterized by a method of treating a subject suffering from a CD20-positive cell proliferative disorder, such as a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and/or refractory NHL, DLBCL (e.g., relapsed and/or refractory DLBCL), FL (e.g., relapsed and/or refractory FL or transformed FL) or MCL (e.g., relapsed or refractory MCL)) or CNSL), the method comprising: administering to the subject, in a first dosing cycle:

(a) Approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) as the first dose (C1D1) of the bispecific antibody binding to CD20 and CD3 and approximately 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg) as the second dose (C1D2) of the bispecific antibody binding to CD20 and CD3;

(b) A single dose of olibutuzumab (C1D1); and

(c) Single doses of ifosfamide (C1D1), single doses of carboplatin (C1D1), and first, second (C1D2), and third doses of etoposide (C1D3);

Administered to subjects during the second dosing cycle:

(a) A single dose (C2D1) of approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg) of a bispecific antibody that binds to CD20 and CD3.

(b) A single dose of rituximab (C2D1); and

(c) Single doses of ifosfamide (C2D1), single doses of carboplatin (C2D1), and first, second (C2D2), and third doses of etoposide (C2D3).

In one embodiment, a single dose of olibutuzumab C1D1 is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg or ± 100 mg), and a single dose of rituximab is about 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 ).

In one embodiment, the anti-CD20 antibody is administered with a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein the first dosing cycle comprises a single dose of olibutuzumab on day 1 (C1D1); and the second dosing cycle comprises a single dose of rituximab on day 1 (C2D1).

In one embodiment, the subject is given a first dose (C1D1) of the bispecific antibody and a second dose (C1D2) of the bispecific antibody on day 8 or before (±1 day) and day 15 or before (±1 day) of the first dosing cycle, respectively.

In one embodiment, a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody are administered to the subject on days 8 and 15 of the first dosing cycle, respectively. In another embodiment, C2D1 of the bispecific antibody is administered to the subject on or before day 8 of the second dosing cycle (±1 day).

In one embodiment of the method provided above, ifosfamide is administered at a dose of 5000 mg/ ^m² , 4000 mg/ ^m² , or 1666 mg/ ^m² . In one embodiment of the method provided above, ifosfamide is administered at a dose of 5000 mg/ ^m² . In one embodiment of the method provided above, carboplatin is administered at a dose of 750 mg, calculated in mg up to a target area under the curve (AUC) of 5 mg/mL/min. In one embodiment of the method provided above, etoposide is administered at a dose of 100 mg/ ^m² or 75 mg/ ^m² . In one embodiment of the method provided above, etoposide is administered at a dose of 100 mg/ ^m² .

In one embodiment of the method provided above, ifosfamide is administered at a dose of 5000 mg/ ^m² , 4000 mg/ ^m² , or 1666 mg/ ^m² , carboplatin is administered at a dose of 750 mg, up to a target area under the curve (AUC) of 5 mg/mL/min, and etoposide is administered at a dose of 100 mg/ ^m² or 75 mg/ ^m² .

In one embodiment of the method provided above, ifosfamide is administered at a dose of 5000 mg/ ^m² , carboplatin is administered at a dose of 750 mg, up to a target area under the curve (AUC) of 5 mg/mL/min, and etoposide is administered at a dose of 100 mg/ ^m² .

In one embodiment, the concentration is approximately 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ), approximately 4000 mg/ ^m² (e.g., 4000 mg/ ^m² ± 40 mg/ ^m² , ± 50 mg/ ^m² , ± 100 mg/m², ± 200 mg/ ^m² , ± 300 mg/ ^m² , or ± 400 mg/ ^{m² )} , or approximately 1666 mg/ ^m² (e.g., 1666 mg/ ^m² ± 25 mg/ ^m² , ± 50 mg/ ^m² , ± 100 mg/ ^m² , or ± 166.6 mg/m² ^). Ifosfamide is administered at a dose of approximately 5 × (25 + creatinine clearance (CrCl)) mg, with the largest dose being approximately 750 mg (e.g., 750 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 75 mg), and etoposide is administered at a dose of approximately 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/ ^m² ) or 75 mg/ ^m² (e.g., 0.5 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 7.5 mg/ ^m² ). In one embodiment, (a) the subject is male, and CrCl is calculated using the formula CrCl = ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]); or (b) the subject is female, and CrCl is calculated using the formula CrCl = 0.85 × ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]). In one embodiment, (a) the subject has a CrCl of < about 60 mL/min, and each single dose of ifosfamide is reduced to 4000 mg/ ^m² ; and/or (b) the subject has a CrCl of < about 50 mL/min, and each dose of etoposide is reduced to 75 mg/ ^m² . In one embodiment, the subject is given or will be given ifosfamide in an outpatient setting and is given ifosfamide at a dose of about 1666 mg/ ^m2 (e.g., 1666 mg/ ^m2 ± 25 mg/ ^m2 , ± 50 mg/ ^m2 , ± 100 mg/ ^m2 or ± 166.6 mg/ ^m2 ).

In one embodiment, ifosfamide and carboplatin are administered on day 2 of the first and second dosing cycles, and etoposide is administered on day 1, day 2, and day 3 of the first and second dosing cycles.

In one aspect, the invention is characterized by a method of treating a subject suffering from a CD20-positive cell proliferative disorder, such as a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and/or refractory NHL, DLBCL (e.g., relapsed and/or refractory DLBCL), FL (e.g., relapsed and/or refractory FL or transformed FL) or MCL (e.g., relapsed or refractory MCL)) or CNSL), the method comprising: administering to the subject, in a first dosing cycle:

(a) Approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) as the first dose (C1D1) of the bispecific antibody binding to CD20 and CD3 and approximately 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg) as the second dose (C1D2) of the bispecific antibody binding to CD20 and CD3;

(b) A single dose (C1D1) of approximately 1000 mg of olibutuzumab (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg); and

(c) A single dose (C1D1 ⁾ of ifosfamide at approximately 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/m2, ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), a single dose (C1D1) of carboplatin at a maximum of 750 mg of the target area under the curve (AUC) up to 5 mg/mL/min, and a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of etoposide at approximately 100 mg/ ^m2 ;

Administered to subjects during the second dosing cycle:

(a) A single dose (C2D1) of approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg) of a bispecific antibody that binds to CD20 and CD3.

(b) A single dose (C2D1) of rituximab at approximately 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ); and

(c) A single dose (C1D1 ⁾ of ifosfamide at approximately 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/m², ± 400 mg/ ^m² , or ± 500 mg/ ^m² ), a single dose (C1D1) of carboplatin at a maximum of 750 mg of the target area under the curve (AUC) up to 5 mg/mL/min, and a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of etoposide at approximately 100 mg/ ^m² .

In one aspect, the invention is characterized by a method of treating a subject suffering from a CD20-positive proliferative disorder such as a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and/or refractory NHL, DLBCL (e.g., relapsed and/or refractory DLBCL), FL (e.g., relapsed and/or refractory FL or transformed FL) or MCL (e.g., relapsed or refractory MCL)) or CNSL), the method comprising administering to the subject:

(a) Approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) as the first dose (C1D1) of the bispecific antibody binding to CD20 and CD3 on day 8 of the first dosing cycle; approximately 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg) as the second dose (C1D2) of the bispecific antibody binding to CD20 and CD3 on day 15; and approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg) as the first dose (C2D1) on day 8 of the second dosing cycle;

(b) A single dose (C1D1) of approximately 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg) of rituximab on day 1 of the first dosing cycle, and a single dose (C2D1) of approximately 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ) of rituximab on day 1 of the second dosing cycle; and

(c) A single dose (C1D1) of ifosfamide at approximately 5000 mg/ ^m² on day 2 of the first and second dosing cycles (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ), a single dose (C1D1) of carboplatin at a maximum of 750 mg of the target area under the curve (AUC) up to 5 mg/mL/min on day 2 of the first and second dosing cycles, and a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of approximately 100 mg/ ^m² on days 1, 2, and 3 of the first and second dosing cycles.

In some embodiments, the first and second dosing cycles are 14-day (e.g., 14 ± 3 days) dosing cycles. In some embodiments, the first and second dosing cycles are 21-day (e.g., 21 ± 3 days) dosing cycles. In a particular embodiment, the first and second dosing cycles are 21-day dosing cycles.

In some embodiments, the dosing regimen includes one or more additional dosing cycles. In some embodiments, the dosing regimen includes a total of three dosing cycles. In some embodiments, the additional dosing cycle is a 14-day (e.g., 14 ± 3 days) dosing cycle. In some embodiments, the additional dosing cycle is a 21-day (e.g., 21 ± 3 days) dosing cycle. In one embodiment, the method provided herein includes three 21-day dosing cycles.

In one embodiment, one or more additional dosing cycles include:

(a) An additional single dose of a bispecific antibody that binds to both CD20 and CD3.

(b) An additional single dose of anti-CD20 antibody, and

(c) Additional single doses of ifosfamide, additional single doses of carboplatin, and additional first, second, and third doses of etoposide.

In one embodiment, an additional single dose of the bispecific antibody is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

In one embodiment, the anti-CD20 antibody is rituximab. In one embodiment, the additional single dose of rituximab is about 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ). In one embodiment, this additional single dose of rituximab is administered on day 1 of the additional dosing cycle.

In one embodiment, the additional single dose of ifosfamide is about 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ), about 4000 mg/ ^m² (e.g., 4000 mg/ ^m² ± 40 mg/ ^m² , ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , or ± 400 mg/ ^m² ), or about 1666 mg/ ^m² (e.g., 1666 mg/ ^m² ± 25 mg/ ^m² , ± 50 mg/ ^m² , ± 100 mg/ ^m² , or ± 166.6 mg/m² ^). The additional single dose of carboplatin is approximately 5 mg/mL/min (e.g., 5 mg/mL/min ± 0.05 mg/mL/min, ± 0.1 mg/mL/min, ± 0.25 mg/mL/min, or ± 0.5 mg/mL/min), with the maximum dose being approximately 750 mg (e.g., 750 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 75 mg), and the additional first, second, and third doses of etoposide are 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/ ^m² ) or 75 mg/ ^m² (e.g., 0.5 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 7.5 mg/ ^m² ). In one embodiment, the additional single dose of ifosfamide is 5000 mg/ ^m² , 4000 mg/ ^m² , or 1666 mg/ ^m² , the additional single dose of carboplatin is 750 mg, up to a target area under the curve (AUC) of 5 mg/mL/min, and the additional first, second, and third doses of etoposide are 100 mg/ ^m² or 75 mg/ ^m² . In one embodiment, ifosfamide is administered at a dose of 5000 mg/ ^m² , carboplatin is administered at a dose of 750 mg, up to a target area under the curve (AUC) of 5 mg/mL/min, and etoposide is administered at a dose of 100 mg/ ^m² .

In one embodiment, the additional single dose of ifosfamide is about 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ), about 4000 mg/ ^m² (e.g., 4000 mg/ ^m² ± 40 mg/ ^m² , ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , or ± 400 mg/ ^m² ), or about 1666 mg/ ^m² (e.g., 1666 mg/ ^m² ± 25 mg/ ^m² , ± 50 mg/ ^m² , ± 100 mg/ ^m² , or ± 166.6 mg/m² ^). The additional single dose of carboplatin is approximately 5 × (25 + creatinine clearance (CrCl)) mg, with a maximum dose of approximately 750 mg (e.g., 750 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 75 mg), and the additional single dose of etoposide is approximately 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/ ^m² ) or 75 mg/ ^m² (e.g., 0.5 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 7.5 mg/ ^m² ). In one embodiment, (a) the subject is male, and CrCl is calculated using the formula CrCl = ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]); or (b) the subject is female, and CrCl is calculated using the formula CrCl = 0.85 × ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]). In one embodiment, (a) the subject has a CrCl of < about 60 mL/min, and the additional single dose of ifosfamide is reduced to 4000 mg/ ^m² ; and/or (b) the subject has a CrCl of < about 50 mL/min, and the additional single dose of etoposide is reduced to 75 mg/ ^m² . In one embodiment, the subject is given or will be given an additional single dose of ifosfamide in an outpatient setting, and the additional single dose of ifosfamide is about 1666 mg/ ^m2 (e.g., 1666 mg/ ^m2 ± 25 mg/ ^m2 , ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , or ± 166.6 mg/ ^m2 ).

In one embodiment, ifosfamide and carboplatin are administered on day 2 of the additional dosing cycle, and etoposide is administered on each of days 1, 2, and 3 of the additional dosing cycle.

In one aspect, the invention is characterized by a method of treating a subject suffering from a CD20-positive cell proliferative disorder, such as a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and/or refractory NHL, DLBCL (e.g., relapsed and/or refractory DLBCL), FL (e.g., relapsed and/or refractory FL or transformed FL) or MCL (e.g., relapsed or refractory MCL)) or CNSL), the method comprising: administering to the subject, in a first dosing cycle:

(a) Approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) as the first dose (C1D1) of the bispecific antibody binding to CD20 and CD3 and approximately 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg) as the second dose (C1D2) of the bispecific antibody binding to CD20 and CD3;

(b) A single dose of olibutuzumab (C1D1); and

(c) Single doses of ifosfamide (C1D1), single doses of carboplatin (C1D1), and first, second (C1D2), and third doses of etoposide (C1D3);

Administered to subjects during the second and third dosing cycles:

(a) A single dose of approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg) of a bispecific antibody that binds to CD20 and CD3 (C2D1 in cycle 2 and C3D1 in cycle 3);

(b) A single dose of rituximab (C2D1 in cycle 2 and C3D1 in cycle 3); and

(c) Single doses of ifosfamide (C2D1), single doses of carboplatin (C2D1 in cycle 2 and C3D1 in cycle 3), and first doses of etoposide (C2D1 in cycle 2 and C3D1 in cycle 3), second doses (C2D2 in cycle 2 and C3D2 in cycle 3) and third doses (C2D3 in cycle 2 and C3D3 in cycle 3).

In one aspect, the invention is characterized by a method of treating a subject suffering from a CD20-positive cell proliferative disorder, such as a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and/or refractory NHL, DLBCL (e.g., relapsed and/or refractory DLBCL), FL (e.g., relapsed and/or refractory FL or transformed FL) or MCL (e.g., relapsed or refractory MCL)) or CNSL), the method comprising: administering to the subject, in a first dosing cycle:

(a) Approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) as the first dose (C1D1) of the bispecific antibody binding to CD20 and CD3 and approximately 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg) as the second dose (C1D2) of the bispecific antibody binding to CD20 and CD3;

(b) A single dose (C1D1) of approximately 1000 mg of olibutuzumab (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg); and

(c) A single dose (C1D1 ⁾ of ifosfamide at approximately 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/m2, ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), a single dose (C1D1) of carboplatin at a maximum of 750 mg of the target area under the curve (AUC) up to 5 mg/mL/min, and a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of etoposide at approximately 100 mg/ ^m2 ;

Administered to subjects during the second and third dosing cycles:

(a) A single dose of approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg) of a bispecific antibody that binds to CD20 and CD3 (C2D1 in cycle 2 and C3D1 in cycle 3);

(b) A single dose of rituximab at approximately 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ) (C2D1 in cycle 2 and C3D1 in cycle 3); and

(c) A single dose of ifosfamide at approximately 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ) (C2D1 in cycle 2 and C3D1 in cycle 3), a single dose of carboplatin at a maximum of 750 mg (C2D1 in cycle 2 and C3D1 in cycle 3) of the target area under the curve (AUC) up to 5 mg/mL/min, and approximately 100 mg/m² of etoposide. The first dose of ² (C2D1 in cycle 2 and C3D1 in cycle 3), the second dose (C2D2 in cycle 2 and C3D2 in cycle 3), and the third dose (C2D3 in cycle 2 and C3D3 in cycle 3).

In one aspect, the invention is characterized by a method of treating a subject suffering from a CD20-positive proliferative disorder such as a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and/or refractory NHL, DLBCL (e.g., relapsed and/or refractory DLBCL), FL (e.g., relapsed and/or refractory FL or transformed FL) or MCL (e.g., relapsed or refractory MCL)) or CNSL), the method comprising administering to the subject:

(a) Approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) as the first dose (C1D1) of the bispecific antibody binding to CD20 and CD3 on day 8 of the first dosing cycle, and approximately 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.05 mg, ± 0.05 mg, ± 0.05 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 ... 0.5 mg, ±0.75 mg, or ±1 mg) as the second dose (C1D2) of the bispecific antibody binding to CD20 and CD3 on day 15, and about 30 mg (e.g., 30 mg ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg) as the first dose (C2D1) on day 8 of the second and third dosing cycles;

(b) A single dose (C1D1) of approximately 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg) of rituximab on day 1 of the first dosing cycle, and a single dose (C2D1) of approximately 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ) of rituximab on day 1 of the second and third dosing cycles; and

(c) A single dose (C1D1) of ifosfamide at approximately 5000 mg/ ^m² on day 2 of the first and second dosing cycles (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ), a single dose (C1D1) of carboplatin at the maximum of the target area under the curve (AUC) of 750 mg up to 5 mg/mL/min on day 2 of all three dosing cycles, and a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of approximately 100 mg/ ^m² on days 1, 2, and 3 of all three dosing cycles.

In some embodiments, the dosing cycle is a 14-day (e.g., 14 ± 3 days) dosing cycle. In some embodiments, the dosing cycle is a 21-day (e.g., 21 ± 3 days) dosing cycle. In a particular embodiment, the dosing cycle is a 21-day dosing cycle.

In some embodiments, the method characterized by the present invention further includes administering one or more additional therapeutic agents to a subject. In some embodiments, the one or more additional therapeutic agents are tocilizumab. In one embodiment, the subject weighs more than or equal to about 30 kg and tocilizumab is administered at a dose of about 8 mg/kg (e.g., 8 mg/kg ± 0.05 mg/kg, ± 0.1 mg/kg, ± 0.25 mg/kg, ± 0.5 mg/kg, or ± 0.8 mg/kg). In one embodiment, the subject weighs less than 30 kg and tocilizumab is administered at a dose of about 12 mg/kg (e.g., 12 mg/kg ± 0.05 mg/kg, ± 0.1 mg/kg, ± 0.25 mg/kg, ± 0.5 mg/kg, ± 0.75 mg/kg, ± 1 mg/kg, or ± 1.2 mg/kg). In some embodiments, the maximum dose of tocilizumab is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg).

In some embodiments, one or more additional therapeutic agents are corticosteroids. In some embodiments, corticosteroids include prednisone, prednisolone, methylprednisolone, or dexamethasone. In one embodiment, dexamethasone is administered intravenously at a dose of about 20 mg (e.g., 20 mg ± 0.1 mg, ± 0.25 mg, ± 0.5 mg, ± 1 mg, ± 1.5 mg, or ± 2 mg) at least one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before the administration of any dose of the bispecific antibody. In one embodiment, dexamethasone is administered intravenously at a dose of about 20 mg (e.g., 20 mg ± 0.1 mg, ± 0.25 mg, ± 0.5 mg, ± 1 mg, ± 1 mg, ± 1.5 mg, or ± 2 mg) at least about one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before any dose of olibutuzumab is administered. In one embodiment, methylprednisolone is administered intravenously at a dose of about 80 mg (e.g., 80 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, or ± 8 mg) at least about one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before any dose of the bispecific antibody is administered. In one embodiment, methylprednisolone is administered intravenously at a dose of about 80 mg (e.g., 80 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, or ± 8 mg) at least one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before any dose of olibutuzumab is administered. In one embodiment, prednisone is administered orally at a dose of about 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 8 mg, or ± 10 mg) at least about one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before any dose of the bispecific antibody is administered. In one embodiment, prednisolone is administered intravenously at a dose of about 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 8 mg, or ± 10 mg) at least one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before any dose of the bispecific antibody is administered.

In some embodiments, one or more additional therapeutic agents are antihistamines. In some embodiments, the antihistamine is diphenhydramine. In one embodiment, diphenhydramine is administered orally or intravenously at a dose of about 50 mg (e.g., 50 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, or ± 5 mg) at least 30 minutes (i.e., at least 30 minutes ± 3 minutes; for example, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before the administration of any dose of the bispecific antibody.

In some embodiments, one or more additional therapeutic agents include allopurinol and raburicase.

In some embodiments, one or more additional therapeutic agents are antipyretics. In one embodiment, the antipyretic is acetaminophen or paracetamol. In one embodiment, acetaminophen or paracetamol is administered orally at a dose between about 500 mg and about 1000 mg (e.g., at least 30 minutes ± 3 minutes; for example, at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before administration of any dose of the bispecific antibody. In one embodiment, acetaminophen or paracetamol is administered orally at a dose between about 500 mg and about 1000 mg (e.g., at least 30 minutes ± 3 minutes; for example, at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before administration of any dose of olibutuzumab.

In some embodiments, one or more additional therapeutic agents include granulocyte colony-stimulating factor (G-CSF). In one embodiment, G-CSF is administered approximately one to approximately two days (e.g., 24, 26, 28, 30, 32, 36, 38, 40, 42, 44, 46, or 48 hours) after administration of any dose of rituximab, ifosfamide, carboplatin, and/or etoposide.

In some embodiments, one or more additional therapeutic agents are mesna. In one embodiment, the concentration is approximately 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ), approximately 4000 mg/ ^m² (e.g., 4000 mg/ ^m² ± 40 mg/ ^m² , ± 50 mg/ ^m² , ± 100 mg/m², ± 200 mg/ ^m² , ± 300 mg/ ^m² , or ± 400 mg/ ^{m² )} , or approximately 1666 mg/ ^m² (e.g., 1666 mg/ ^m² ± 25 mg/ ^m² , ± 50 mg/ ^m² , ± 100 mg/ ^m² , or ± 166.6 mg/m² ^). Mesna was administered intravenously at a dose of 100 mg/dL.

In one embodiment, the bispecific antibody comprises at least one Fab molecule that specifically binds to CD20, the Fab molecule containing the following six hypervariable regions (HVRs):

(i)HVR-H1, which contains the amino acid sequence of YSWIN (SEQ ID NO:1);

(ii) HVR-H2, which contains the amino acid sequence RIFPGDGDTDYNGKFKG (SEQ ID NO:2);

(iii) HVR-H3, which contains the amino acid sequence NVFDGYWLVY (SEQ ID NO:3);

(iv) HVR-L1, which contains the amino acid sequence RSSKSLLHSNGITYLY (SEQ ID NO:4);

(v)HVR-L2, which contains the amino acid sequence of QMSNLVS (SEQ ID NO:5); and

(vi)HVR-L3, which contains the amino acid sequence of AQNLELPYT (SEQ ID NO:6).

In one embodiment, the bispecific antibody comprises at least one Fab molecule that specifically binds to CD20, the Fab molecule comprising (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:7; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:8; or (c) the VH domain as in (a) and the VL domain as in (b).

In one embodiment, the Fab molecule that specifically binds to CD20 comprises: (a) a VH domain containing the amino acid sequence of SEQ ID NO:7; and (b) a VL domain containing the amino acid sequence of SEQ ID NO:8.

In one embodiment, the bispecific antibody comprises at least one Fab molecule that specifically binds to CD3, the Fab molecule containing the following six HVRs:

(i)HVR-H1, which contains the amino acid sequence of TYAMN (SEQ ID NO:9);

(ii) HVR-H2, which contains the amino acid sequence RIRSKYNNYATYYADSVKG (SEQ ID NO:10);

(iii) HVR-H3, which contains the amino acid sequence HGNFGNSYVSWFAY (SEQ ID NO:11);

(iv) HVR-L1, which contains the amino acid sequence GSSTGAVTTSNYAN (SEQ ID NO:12);

(v)HVR-L2, which contains the amino acid sequence of GTNKRAP (SEQ ID NO: 13); and

(vi)HVR-L3, which contains the amino acid sequence of ALWYSNLWV (SEQ ID NO:14).

In one embodiment, the bispecific antibody comprises at least one Fab molecule that specifically binds to CD3, the Fab molecule comprising (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:15; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:16; or (c) the VH domain as in (a) and the VL domain as in (b).

In one embodiment, the Fab molecule that specifically binds to CD3 comprises: (a) a VH domain containing the amino acid sequence of SEQ ID NO:15; and (b) a VL domain containing the amino acid sequence of SEQ ID NO:16.

In one embodiment, the bispecific antibody is bivalent to CD20 and monovalent to CD3. In one embodiment, the bispecific antibody comprises two Fab molecules that specifically bind to CD20 and one Fab molecule that specifically binds to CD3. In one embodiment, the bispecific antibody is a humanized antibody.

In one aspect, the invention is characterized by a method of treating a subject suffering from a CD20-positive proliferative disorder such as a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and/or refractory NHL, DLBCL (e.g., relapsed and/or refractory DLBCL), FL (e.g., relapsed and/or refractory FL or transformed FL) or MCL (e.g., relapsed or refractory MCL)) or CNSL), the method comprising administering an effective amount to the subject in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle:

(a) A bispecific antibody that binds to CD20 and CD3, comprising at least one Fab molecule that specifically binds to CD20, the Fab molecule containing the following six hypervariable regions (HVRs):

(i)HVR-H1, which contains the amino acid sequence of YSWIN (SEQ ID NO:1);

(ii) HVR-H2, which contains the amino acid sequence RIFPGDGDTDYNGKFKG (SEQ ID NO:2);

(iii) HVR-H3, which contains the amino acid sequence NVFDGYWLVY (SEQ ID NO:3);

(iv) HVR-L1, which contains the amino acid sequence RSSKSLLHSNGITYLY (SEQ ID NO:4);

(v)HVR-L2, which contains the amino acid sequence of QMSNLVS (SEQ ID NO:5); and

(vi)HVR-L3, which contains the amino acid sequence of AQNLELPYT (SEQ ID NO: 6); and

And at least one Fab molecule that specifically binds to CD3, the Fab molecule comprising the following six HVRs:

(i)HVR-H1, which contains the amino acid sequence of TYAMN (SEQ ID NO:9);

(ii) HVR-H2, which contains the amino acid sequence RIRSKYNNYATYYADSVKG (SEQ ID NO:10);

(iii) HVR-H3, which contains the amino acid sequence HGNFGNSYVSWFAY (SEQ ID NO:11);

(iv) HVR-L1, which contains the amino acid sequence GSSTGAVTTSNYAN (SEQ ID NO:12);

(v)HVR-L2, which contains the amino acid sequence of GTNKRAP (SEQ ID NO: 13); and

(vi)HVR-L3, which contains the amino acid sequence of ALWYSNLWV (SEQ ID NO:14);

(b) Anti-CD20 antibody; and

(c) One or more chemotherapeutic agents selected from ifosfamide, carboplatin and/or etoposide.

In one embodiment, the first dosing cycle comprises a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody, wherein the C1D1 of the bispecific antibody is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of the bispecific antibody is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); and the second dosing cycle comprises a single dose of the bispecific antibody. The amount (C2D1) of the bispecific antibody is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg or ± 1 mg), about 16 mg (e.g., 16 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg or ± 1.6 mg), or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg). In a specific embodiment, the C1D1 of the bispecific antibody is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) and the C1D2 of the bispecific antibody is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg). In a specific embodiment, the C2D1 is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg). In certain embodiments, the C2D1 of the bispecific antibody is about 16 mg (e.g., 16 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, or ± 1.6 mg). In certain embodiments, the C2D1 of the bispecific antibody is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

In one embodiment, the first dosing cycle includes a first dose (C1D1) of the bispecific antibody and a second dose (C1D2) of the bispecific antibody, wherein the C1D1 of the bispecific antibody is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of the bispecific antibody is about 10 mg (e.g., 10 mg). ±0.05 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.5 mg, ±0.75 mg, or ±1 mg); and the second dosing cycle includes a single dose (C2D1) of the bispecific antibody, wherein the C2D1 of the bispecific antibody is about 30 mg (e.g., 30 mg ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg).

In one embodiment, the subject is given a first dose (C1D1) of the bispecific antibody and a second dose (C1D2) of the bispecific antibody on day 8 or before (±1 day) and day 15 or before (±1 day) of the first dosing cycle, respectively.

In one embodiment, a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody are administered to the subject on days 8 and 15 of the first dosing cycle, respectively. In another embodiment, C2D1 of the bispecific antibody is administered to the subject on or before day 8 of the second dosing cycle (±1 day).

In one embodiment, the anti-CD20 antibody is olibutuzumab and/or rituximab. In one embodiment, the first dosing cycle comprises a single dose of olibutuzumab (C1D1); and the second dosing cycle comprises a single dose of rituximab (C2D1).

In one embodiment, a single dose of olibutuzumab C1D1 is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg or ± 100 mg), and a single dose of rituximab is about 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 ).

In one embodiment, the anti-CD20 antibody is administered with a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein the first dosing cycle comprises a single dose of olibutuzumab on day 1 (C1D1); and the second dosing cycle comprises a single dose of rituximab on day 1 (C2D1).

In one aspect, the invention is characterized by a method of treating a subject suffering from a CD20-positive cell proliferative disorder, such as a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and/or refractory NHL, DLBCL (e.g., relapsed and/or refractory DLBCL), FL (e.g., relapsed and/or refractory FL or transformed FL) or MCL (e.g., relapsed or refractory MCL)) or CNSL), the method comprising: administering to the subject, in a first dosing cycle:

(a) Approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) as the first dose (C1D1) of the bispecific antibody binding to CD20 and CD3 and approximately 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg) as the second dose (C1D2) of the bispecific antibody binding to CD20 and CD3;

(b) A single dose of olibutuzumab (C1D1); and

(c) One or more chemotherapeutic agents selected from ifosfamide, carboplatin and/or etoposide;

Administered to subjects during the second dosing cycle:

(a) A single dose (C2D1) of approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg) of a bispecific antibody that binds to CD20 and CD3.

(b) A single dose of rituximab (C2D1); and

(c) One or more chemotherapeutic agents selected from ifosfamide, carboplatin, and/or etoposide, wherein the bispecific antibody binding to CD20 and CD3 comprises at least one Fab molecule that specifically binds to CD20, the Fab molecule containing the following six hypervariable regions (HVR):

(i)HVR-H1, which contains the amino acid sequence of YSWIN (SEQ ID NO:1);

(ii) HVR-H2, which contains the amino acid sequence RIFPGDGDTDYNGKFKG (SEQ ID NO:2);

(iii) HVR-H3, which contains the amino acid sequence NVFDGYWLVY (SEQ ID NO:3);

(iv) HVR-L1, which contains the amino acid sequence RSSKSLLHSNGITYLY (SEQ ID NO:4);

(v)HVR-L2, which contains the amino acid sequence of QMSNLVS (SEQ ID NO:5); and

(vi)HVR-L3, which contains the amino acid sequence of AQNLELPYT (SEQ ID NO:6);

And at least one Fab molecule that specifically binds to CD3, the Fab molecule comprising the following six HVRs:

(i)HVR-H1, which contains the amino acid sequence of TYAMN (SEQ ID NO:9);

(ii) HVR-H2, which contains the amino acid sequence RIRSKYNNYATYYADSVKG (SEQ ID NO:10);

(iii) HVR-H3, which contains the amino acid sequence HGNFGNSYVSWFAY (SEQ ID NO:11);

(iv) HVR-L1, which contains the amino acid sequence GSSTGAVTTSNYAN (SEQ ID NO:12);

(v)HVR-L2, which contains the amino acid sequence of GTNKRAP (SEQ ID NO: 13); and

(vi)HVR-L3, which contains the amino acid sequence of ALWYSNLWV (SEQ ID NO:14).

In one embodiment, a single dose of olibutuzumab C1D1 is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg or ± 100 mg), and a single dose of rituximab is about 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 ).

In one embodiment, the anti-CD20 antibody is administered with a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein the first dosing cycle comprises a single dose of olibutuzumab on day 1 (C1D1); and the second dosing cycle comprises a single dose of rituximab on day 1 (C2D1).

In one embodiment, the subject is given a first dose (C1D1) of the bispecific antibody and a second dose (C1D2) of the bispecific antibody on day 8 or before (±1 day) and day 15 or before (±1 day) of the first dosing cycle, respectively.

In one embodiment, a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody are administered to the subject on days 8 and 15 of the first dosing cycle, respectively. In another embodiment, C2D1 of the bispecific antibody is administered to the subject on or before day 8 of the second dosing cycle (±1 day).

In one embodiment of the method provided above, step c) includes all three chemotherapeutic agents.

In one embodiment, the first dosing cycle includes a single dose of ifosfamide (C1D1), a single dose of carboplatin (C1D1), and a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of etoposide; and the second cycle each includes a single dose of ifosfamide (C2D1), a single dose of carboplatin (C2D1), and a first dose (C2D1), a second dose (C2D2), and a third dose (C2D3) of etoposide.

In one aspect, the invention is characterized by a method of treating a subject suffering from a CD20-positive cell proliferative disorder, such as a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and/or refractory NHL, DLBCL (e.g., relapsed and/or refractory DLBCL), FL (e.g., relapsed and/or refractory FL or transformed FL) or MCL (e.g., relapsed or refractory MCL)) or CNSL), the method comprising: administering to the subject, in a first dosing cycle:

(a) Approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) as the first dose (C1D1) of the bispecific antibody binding to CD20 and CD3 and approximately 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg) as the second dose (C1D2) of the bispecific antibody binding to CD20 and CD3;

(b) A single dose of olibutuzumab (C1D1); and

(c) Single doses of ifosfamide (C1D1), single doses of carboplatin (C1D1), and first, second (C1D2), and third doses of etoposide (C1D3);

Administered to subjects during the second dosing cycle:

(a) A single dose (C2D1) of approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg) of a bispecific antibody that binds to CD20 and CD3.

(b) A single dose of rituximab (C2D1); and

(c) Single doses of ifosfamide (C2D1), single doses of carboplatin (C2D1), and first, second (C2D2), and third doses of etoposide (C2D3),

The bispecific antibodies that bind to CD20 and CD3 include at least one Fab molecule that specifically binds to CD20, and this Fab molecule contains the following six hypervariable regions (HVRs):

(i)HVR-H1, which contains the amino acid sequence of YSWIN (SEQ ID NO:1);

(ii) HVR-H2, which contains the amino acid sequence RIFPGDGDTDYNGKFKG (SEQ ID NO:2);

(iii) HVR-H3, which contains the amino acid sequence NVFDGYWLVY (SEQ ID NO:3);

(iv) HVR-L1, which contains the amino acid sequence RSSKSLLHSNGITYLY (SEQ ID NO:4);

(v)HVR-L2, which contains the amino acid sequence of QMSNLVS (SEQ ID NO:5); and

(vi)HVR-L3, which contains the amino acid sequence AQNLELPYT (SEQ ID NO:6),

And at least one Fab molecule that specifically binds to CD3, the Fab molecule comprising the following six HVRs:

(i)HVR-H1, which contains the amino acid sequence of TYAMN (SEQ ID NO:9);

(ii) HVR-H2, which contains the amino acid sequence RIRSKYNNYATYYADSVKG (SEQ ID NO:10);

(iii) HVR-H3, which contains the amino acid sequence HGNFGNSYVSWFAY (SEQ ID NO:11);

(iv) HVR-L1, which contains the amino acid sequence GSSTGAVTTSNYAN (SEQ ID NO:12);

(v)HVR-L2, which contains the amino acid sequence of GTNKRAP (SEQ ID NO: 13); and

(vi)HVR-L3, which contains the amino acid sequence of ALWYSNLWV (SEQ ID NO:14).

In one embodiment, a single dose of olibutuzumab C1D1 is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg or ± 100 mg), and a single dose of rituximab is about 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 ).

In one embodiment, the anti-CD20 antibody is administered with a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein the first dosing cycle comprises a single dose of olibutuzumab on day 1 (C1D1); and the second dosing cycle comprises a single dose of rituximab on day 1 (C2D1).

In one embodiment, the subject is given a first dose (C1D1) of the bispecific antibody and a second dose (C1D2) of the bispecific antibody on day 8 or before (±1 day) and day 15 or before (±1 day) of the first dosing cycle, respectively.

In one embodiment, a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody are administered to the subject on days 8 and 15 of the first dosing cycle, respectively. In another embodiment, C2D1 of the bispecific antibody is administered to the subject on or before day 8 of the second dosing cycle (±1 day).

In one embodiment of the method provided above, ifosfamide is administered at a dose of 5000 mg/ ^m² , 4000 mg/ ^m² , or 1666 mg/ ^m² . In one embodiment of the method provided above, ifosfamide is administered at a dose of 5000 mg/ ^m² . In one embodiment of the method provided above, carboplatin is administered at a dose of 750 mg, calculated in mg up to a target area under the curve (AUC) of 5 mg/mL/min. In one embodiment of the method provided above, etoposide is administered at a dose of 100 mg/ ^m² or 75 mg/ ^m² . In one embodiment of the method provided above, etoposide is administered at a dose of 100 mg/ ^m² .

In one embodiment of the method provided above, ifosfamide is administered at a dose of 5000 mg/ ^m² , 4000 mg/ ^m² , or 1666 mg/ ^m² , carboplatin is administered at a dose of 750 mg, up to a target area under the curve (AUC) of 5 mg/mL/min, and etoposide is administered at a dose of 100 mg/ ^m² or 75 mg/ ^m² .

In one embodiment of the method provided above, ifosfamide is administered at a dose of 5000 mg/ ^m² , carboplatin is administered at a dose of 750 mg, up to a target area under the curve (AUC) of 5 mg/mL/min, and etoposide is administered at a dose of 100 mg/ ^m² .

In one embodiment, ifosfamide and carboplatin are administered on day 2 of the first and second dosing cycles, and etoposide is administered on day 1, day 2, and day 3 of the first and second dosing cycles.

In one aspect, the invention is characterized by a method of treating a subject suffering from a CD20-positive cell proliferative disorder, such as a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and/or refractory NHL, DLBCL (e.g., relapsed and/or refractory DLBCL), FL (e.g., relapsed and/or refractory FL or transformed FL) or MCL (e.g., relapsed or refractory MCL)) or CNSL), the method comprising: administering to the subject, in a first dosing cycle:

(a) Approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) as the first dose (C1D1) of the bispecific antibody binding to CD20 and CD3 and approximately 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg) as the second dose (C1D2) of the bispecific antibody binding to CD20 and CD3;

(b) A single dose (C1D1) of approximately 1000 mg of olibutuzumab (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg); and

(c) A single dose (C1D1 ⁾ of ifosfamide at approximately 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/m2, ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), a single dose (C1D1) of carboplatin at a maximum of 750 mg of the target area under the curve (AUC) up to 5 mg/mL/min, and a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of etoposide at approximately 100 mg/ ^m2 ;

Administered to subjects during the second dosing cycle:

(a) A single dose (C2D1) of approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg) of a bispecific antibody that binds to CD20 and CD3.

(b) A single dose (C2D1) of rituximab at approximately 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ); and

(c) A single dose (C1D1 ⁾ of ifosfamide at approximately 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/m², ± 400 mg/ ^m² , or ± 500 mg/ ^m² ), a single dose (C1D1) of carboplatin at a maximum of 750 mg of the target area under the curve (AUC) up to 5 mg/mL/min, and a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of etoposide at approximately 100 mg/ ^m² .

The bispecific antibodies that bind to CD20 and CD3 include at least one Fab molecule that specifically binds to CD20, and this Fab molecule contains the following six hypervariable regions (HVRs):

(i)HVR-H1, which contains the amino acid sequence of YSWIN (SEQ ID NO:1);

(ii) HVR-H2, which contains the amino acid sequence RIFPGDGDTDYNGKFKG (SEQ ID NO:2);

(iii) HVR-H3, which contains the amino acid sequence NVFDGYWLVY (SEQ ID NO:3);

(iv) HVR-L1, which contains the amino acid sequence RSSKSLLHSNGITYLY (SEQ ID NO:4);

(v)HVR-L2, which contains the amino acid sequence of QMSNLVS (SEQ ID NO:5); and

(vi)HVR-L3, which contains the amino acid sequence AQNLELPYT (SEQ ID NO:6),

And at least one Fab molecule that specifically binds to CD3, the Fab molecule comprising the following six HVRs:

(i)HVR-H1, which contains the amino acid sequence of TYAMN (SEQ ID NO:9);

(ii) HVR-H2, which contains the amino acid sequence RIRSKYNNYATYYADSVKG (SEQ ID NO:10);

(iii) HVR-H3, which contains the amino acid sequence HGNFGNSYVSWFAY (SEQ ID NO:11);

(iv) HVR-L1, which contains the amino acid sequence GSSTGAVTTSNYAN (SEQ ID NO:12);

(v)HVR-L2, which contains the amino acid sequence of GTNKRAP (SEQ ID NO: 13); and

(vi)HVR-L3, which contains the amino acid sequence of ALWYSNLWV (SEQ ID NO:14).

In one aspect, the invention is characterized by a method of treating a subject suffering from a CD20-positive proliferative disorder such as a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and/or refractory NHL, DLBCL (e.g., relapsed and/or refractory DLBCL), FL (e.g., relapsed and/or refractory FL or transformed FL) or MCL (e.g., relapsed or refractory MCL)) or CNSL), the method comprising administering to the subject:

(a) Approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) as the first dose (C1D1) of the bispecific antibody binding to CD20 and CD3 on day 8 of the first dosing cycle; approximately 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg) as the second dose (C1D2) of the bispecific antibody binding to CD20 and CD3 on day 15; and approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg) as the first dose (C2D1) on day 8 of the second dosing cycle;

(b) A single dose (C1D1) of approximately 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg) of rituximab on day 1 of the first dosing cycle, and a single dose (C2D1) of approximately 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ) of rituximab on day 1 of the second dosing cycle; and

(c) A single dose (C1D1) of ifosfamide at approximately 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/m², ± 300 mg/ ^m² , ± 400 mg/ ^{m² ,} or ± 500 mg/ ^m² ) on day 2 of the first and second dosing cycles; a single dose (C1D1) of carboplatin at a maximum of 750 mg of the target area under the curve (AUC) up to 5 mg/mL/min on day 2 of the first and second dosing cycles; and a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of etoposide at approximately 100 mg/ ^m² on days 1, 2, and 3 of the first and second dosing cycles.

The bispecific antibodies that bind to CD20 and CD3 include at least one Fab molecule that specifically binds to CD20, and this Fab molecule contains the following six hypervariable regions (HVRs):

(i)HVR-H1, which contains the amino acid sequence of YSWIN (SEQ ID NO:1);

(ii) HVR-H2, which contains the amino acid sequence RIFPGDGDTDYNGKFKG (SEQ ID NO:2);

(iii) HVR-H3, which contains the amino acid sequence NVFDGYWLVY (SEQ ID NO:3);

(iv) HVR-L1, which contains the amino acid sequence RSSKSLLHSNGITYLY (SEQ ID NO:4);

(v)HVR-L2, which contains the amino acid sequence of QMSNLVS (SEQ ID NO:5); and

(vi)HVR-L3, which contains the amino acid sequence of AQNLELPYT (SEQ ID NO:6);

And at least one Fab molecule that specifically binds to CD3, the Fab molecule comprising the following six HVRs:

(i)HVR-H1, which contains the amino acid sequence of TYAMN (SEQ ID NO:9);

(ii) HVR-H2, which contains the amino acid sequence RIRSKYNNYATYYADSVKG (SEQ ID NO:10);

(iii) HVR-H3, which contains the amino acid sequence HGNFGNSYVSWFAY (SEQ ID NO:11);

(iv) HVR-L1, which contains the amino acid sequence GSSTGAVTTSNYAN (SEQ ID NO:12);

(v)HVR-L2, which contains the amino acid sequence of GTNKRAP (SEQ ID NO: 13); and

(vi)HVR-L3, which contains the amino acid sequence of ALWYSNLWV (SEQ ID NO:14).

In some embodiments, the first and second dosing cycles are 14-day (e.g., 14 ± 3 days) dosing cycles. In some embodiments, the first and second dosing cycles are 21-day (e.g., 21 ± 3 days) dosing cycles. In a particular embodiment, the first and second dosing cycles are 21-day dosing cycles.

In some embodiments, the dosing regimen includes one or more additional dosing cycles. In some embodiments, the dosing regimen includes a total of three dosing cycles. In some embodiments, the additional dosing cycle is a 14-day (e.g., 14 ± 3 days) dosing cycle. In some embodiments, the additional dosing cycle is a 21-day (e.g., 21 ± 3 days) dosing cycle. In one embodiment, the method provided herein includes three 21-day dosing cycles.

In one embodiment, one or more additional dosing cycles include:

(a) An additional single dose of a bispecific antibody that binds to both CD20 and CD3.

(b) An additional single dose of anti-CD20 antibody, and

(c) Additional single doses of ifosfamide, additional single doses of carboplatin, and additional first, second, and third doses of etoposide.

The bispecific antibodies that bind to CD20 and CD3 include at least one Fab molecule that specifically binds to CD20, and this Fab molecule contains the following six hypervariable regions (HVRs):

(i)HVR-H1, which contains the amino acid sequence of YSWIN (SEQ ID NO:1);

(ii) HVR-H2, which contains the amino acid sequence RIFPGDGDTDYNGKFKG (SEQ ID NO:2);

(iii) HVR-H3, which contains the amino acid sequence NVFDGYWLVY (SEQ ID NO:3);

(iv) HVR-L1, which contains the amino acid sequence RSSKSLLHSNGITYLY (SEQ ID NO:4);

(v)HVR-L2, which contains the amino acid sequence of QMSNLVS (SEQ ID NO:5); and

(vi)HVR-L3, which contains the amino acid sequence of AQNLELPYT (SEQ ID NO:6),

And at least one Fab molecule that specifically binds to CD3, the Fab molecule comprising the following six HVRs:

(i)HVR-H1, which contains the amino acid sequence of TYAMN (SEQ ID NO:9);

(ii) HVR-H2, which contains the amino acid sequence RIRSKYNNYATYYADSVKG (SEQ ID NO:10);

(iii) HVR-H3, which contains the amino acid sequence HGNFGNSYVSWFAY (SEQ ID NO:11);

(iv) HVR-L1, which contains the amino acid sequence GSSTGAVTTSNYAN (SEQ ID NO:12);

(v)HVR-L2, which contains the amino acid sequence of GTNKRAP (SEQ ID NO: 13); and

(vi)HVR-L3, which contains the amino acid sequence of ALWYSNLWV (SEQ ID NO:14).

In one embodiment, an additional single dose of the bispecific antibody is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

In one embodiment, the anti-CD20 antibody is rituximab. In one embodiment, the additional single dose of rituximab is about 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ). In one embodiment, this additional single dose of rituximab is administered on day 1 of the additional dosing cycle.

In one embodiment, the additional single dose of ifosfamide is about 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ), about 4000 mg/ ^m² (e.g., 4000 mg/ ^m² ± 40 mg/ ^m² , ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , or ± 400 mg/ ^m² ), or about 1666 mg/ ^m² (e.g., 1666 mg/ ^m² ± 25 mg/ ^m² , ± 50 mg/ ^m² , ± 100 mg/ ^m² , or ± 166.6 mg/m² ^). The additional single dose of carboplatin is approximately 5 mg/mL/min (e.g., 5 mg/mL/min ± 0.05 mg/mL/min, ± 0.1 mg/mL/min, ± 0.25 mg/mL/min, or ± 0.5 mg/mL/min), with the maximum dose being approximately 750 mg (e.g., 750 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 75 mg), and the additional first, second, and third doses of etoposide are 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/ ^m² ) or 75 mg/ ^m² (e.g., 0.5 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 7.5 mg/ ^m² ). In one embodiment, the additional single dose of ifosfamide is 5000 mg/ ^m² , 4000 mg/ ^m² , or 1666 mg/ ^m² , the additional single dose of carboplatin is 750 mg, up to a target area under the curve (AUC) of 5 mg/mL/min, and the additional first, second, and third doses of etoposide are 100 mg/ ^m² or 75 mg/ ^m² . In one embodiment, ifosfamide is administered at a dose of 5000 mg/ ^m² , carboplatin is administered at a dose of 750 mg, up to a target area under the curve (AUC) of 5 mg/mL/min, and etoposide is administered at a dose of 100 mg/ ^m² .

In one embodiment, ifosfamide and carboplatin are administered on day 2 of the additional dosing cycle, and etoposide is administered on each of days 1, 2, and 3 of the additional dosing cycle.

In one aspect, the invention is characterized by a method of treating a subject suffering from a CD20-positive cell proliferative disorder, such as a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and/or refractory NHL, DLBCL (e.g., relapsed and/or refractory DLBCL), FL (e.g., relapsed and/or refractory FL or transformed FL) or MCL (e.g., relapsed or refractory MCL)) or CNSL), the method comprising: administering to the subject, in a first dosing cycle:

(a) Approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) as the first dose (C1D1) of the bispecific antibody binding to CD20 and CD3 and approximately 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg) as the second dose (C1D2) of the bispecific antibody binding to CD20 and CD3;

(b) A single dose of olibutuzumab (C1D1); and

(c) Single doses of ifosfamide (C1D1), single doses of carboplatin (C1D1), and first, second (C1D2), and third doses of etoposide (C1D3);

Administered to subjects during the second and third dosing cycles:

(a) A single dose of approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg) of a bispecific antibody that binds to CD20 and CD3 (C2D1 in cycle 2 and C3D1 in cycle 3);

(b) A single dose of rituximab (C2D1 in cycle 2 and C3D1 in cycle 3); and

(c) Single doses of ifosfamide (C2D1 in cycle 2 and C3D1 in cycle 3), single doses of carboplatin (C2D1 in cycle 2 and C3D1 in cycle 3), and first, second, third (C2D2 in cycle 2 and C3D2 in cycle 3) doses of etoposide (C2D1 in cycle 2 and C3D1 in cycle 3), wherein the bispecific antibody binding to CD20 and CD3 comprises at least one Fab molecule that specifically binds to CD20, the Fab molecule containing the following six hypervariable regions (HVR):

(i)HVR-H1, which contains the amino acid sequence of YSWIN (SEQ ID NO:1);

(ii) HVR-H2, which contains the amino acid sequence RIFPGDGDTDYNGKFKG (SEQ ID NO:2);

(iii) HVR-H3, which contains the amino acid sequence NVFDGYWLVY (SEQ ID NO:3);

(iv) HVR-L1, which contains the amino acid sequence RSSKSLLHSNGITYLY (SEQ ID NO:4);

(v)HVR-L2, which contains the amino acid sequence of QMSNLVS (SEQ ID NO:5); and

(vi)HVR-L3, which contains the amino acid sequence AQNLELPYT (SEQ ID NO:6),

And at least one Fab molecule that specifically binds to CD3, the Fab molecule comprising the following six HVRs:

(i)HVR-H1, which contains the amino acid sequence of TYAMN (SEQ ID NO:9);

(ii) HVR-H2, which contains the amino acid sequence RIRSKYNNYATYYADSVKG (SEQ ID NO:10);

(iii) HVR-H3, which contains the amino acid sequence HGNFGNSYVSWFAY (SEQ ID NO:11);

(iv) HVR-L1, which contains the amino acid sequence GSSTGAVTTSNYAN (SEQ ID NO:12);

(v)HVR-L2, which contains the amino acid sequence of GTNKRAP (SEQ ID NO: 13); and

(vi)HVR-L3, which contains the amino acid sequence of ALWYSNLWV (SEQ ID NO:14).

In one aspect, the invention is characterized by a method of treating a subject suffering from a CD20-positive cell proliferative disorder, such as a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and/or refractory NHL, DLBCL (e.g., relapsed and/or refractory DLBCL), FL (e.g., relapsed and/or refractory FL or transformed FL) or MCL (e.g., relapsed or refractory MCL)) or CNSL), the method comprising: administering to the subject, in a first dosing cycle:

(a) Approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) as the first dose (C1D1) of the bispecific antibody binding to CD20 and CD3 and approximately 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg) as the second dose (C1D2) of the bispecific antibody binding to CD20 and CD3;

(b) A single dose (C1D1) of approximately 1000 mg of olibutuzumab (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg); and

(c) A single dose (C1D1 ⁾ of ifosfamide at approximately 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/m2, ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), a single dose (C1D1) of carboplatin at a maximum of 750 mg of the target area under the curve (AUC) up to 5 mg/mL/min, and a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of etoposide at approximately 100 mg/ ^m2 ;

Administered to subjects during the second and third dosing cycles:

(a) A single dose of approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg) of a bispecific antibody that binds to CD20 and CD3 (C2D1 in cycle 2 and C3D1 in cycle 3);

(b) A single dose of rituximab at approximately 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ) (C2D1 in cycle 2 and C3D1 in cycle 3); and

(c) A single dose of ifosfamide at approximately 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ) (C2D1 in cycle 2 and C3D1 in cycle 3), a single dose of carboplatin at a maximum of 750 mg (C2D1 in cycle 2 and C3D1 in cycle 3) of the target area under the curve (AUC) up to 5 mg/mL/min, and approximately 100 mg/m² of etoposide. The dosages of ^the first dose (C2D1 in cycle 2 and C3D1 in cycle 3), the second dose (C2D2 in cycle 2 and C3D2 in cycle 3), and the third dose (C2D3 in cycle 2 and C3D3 in cycle 3) are as follows.

The bispecific antibodies that bind to CD20 and CD3 include at least one Fab molecule that specifically binds to CD20, and this Fab molecule contains the following six hypervariable regions (HVRs):

(i)HVR-H1, which contains the amino acid sequence of YSWIN (SEQ ID NO:1);

(ii) HVR-H2, which contains the amino acid sequence RIFPGDGDTDYNGKFKG (SEQ ID NO:2);

(iii) HVR-H3, which contains the amino acid sequence NVFDGYWLVY (SEQ ID NO:3);

(iv) HVR-L1, which contains the amino acid sequence RSSKSLLHSNGITYLY (SEQ ID NO:4);

(v)HVR-L2, which contains the amino acid sequence of QMSNLVS (SEQ ID NO:5); and

(vi)HVR-L3, which contains the amino acid sequence of AQNLELPYT (SEQ ID NO:6);

And at least one Fab molecule that specifically binds to CD3, the Fab molecule comprising the following six HVRs:

(i)HVR-H1, which contains the amino acid sequence of TYAMN (SEQ ID NO:9);

(ii) HVR-H2, which contains the amino acid sequence RIRSKYNNYATYYADSVKG (SEQ ID NO:10);

(iii) HVR-H3, which contains the amino acid sequence HGNFGNSYVSWFAY (SEQ ID NO:11);

(iv) HVR-L1, which contains the amino acid sequence GSSTGAVTTSNYAN (SEQ ID NO:12);

(v)HVR-L2, which contains the amino acid sequence of GTNKRAP (SEQ ID NO: 13); and

(vi)HVR-L3, which contains the amino acid sequence of ALWYSNLWV (SEQ ID NO:14).

In one aspect, the invention is characterized by a method of treating a subject suffering from a CD20-positive proliferative disorder such as a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and/or refractory NHL, DLBCL (e.g., relapsed and/or refractory DLBCL), FL (e.g., relapsed and/or refractory FL or transformed FL) or MCL (e.g., relapsed or refractory MCL)) or CNSL), the method comprising administering to the subject:

(a) Approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) as the first dose (C1D1) of the bispecific antibody binding to CD20 and CD3 on day 8 of the first dosing cycle, and approximately 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg) as the bispecific antibody binding to CD20 and CD3. The bispecific antibody is administered as a second dose on day 15 (C1D2), and approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg) as a first dose on day 8 of the second and third dosing cycles (C2D1), wherein the bispecific antibody binding to CD20 and CD3 comprises at least one Fab molecule that specifically binds to CD20, the Fab molecule containing the following six hypervariable regions (HVR):

(i)HVR-H1, which contains the amino acid sequence of YSWIN (SEQ ID NO:1);

(ii) HVR-H2, which contains the amino acid sequence RIFPGDGDTDYNGKFKG (SEQ ID NO:2);

(iii) HVR-H3, which contains the amino acid sequence NVFDGYWLVY (SEQ ID NO:3);

(iv) HVR-L1, which contains the amino acid sequence RSSKSLLHSNGITYLY (SEQ ID NO:4);

(v)HVR-L2, which contains the amino acid sequence of QMSNLVS (SEQ ID NO:5); and

(vi)HVR-L3, which contains the amino acid sequence of AQNLELPYT (SEQ ID NO:6),

And at least one Fab molecule that specifically binds to CD3, the Fab molecule comprising the following six HVRs:

(i)HVR-H1, which contains the amino acid sequence of TYAMN (SEQ ID NO:9);

(ii) HVR-H2, which contains the amino acid sequence RIRSKYNNYATYYADSVKG (SEQ ID NO:10);

(iii) HVR-H3, which contains the amino acid sequence HGNFGNSYVSWFAY (SEQ ID NO:11);

(iv) HVR-L1, which contains the amino acid sequence GSSTGAVTTSNYAN (SEQ ID NO:12);

(v)HVR-L2, which contains the amino acid sequence of GTNKRAP (SEQ ID NO: 13); and

(vi)HVR-L3, which contains the amino acid sequence of ALWYSNLWV (SEQ ID NO:14);

(b) A single dose (C1D1) of approximately 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg) of rituximab on day 1 of the first dosing cycle, and a single dose (C2D1) of approximately 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ) of rituximab on day 1 of the second and third dosing cycles; and

(c) A single dose (C1D1) of ifosfamide at approximately 5000 mg/ ^m² on day 2 of the first and second dosing cycles (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ), a single dose (C1D1) of carboplatin at the maximum of the target area under the curve (AUC) of 750 mg up to 5 mg/mL/min on day 2 of all three dosing cycles, and a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of approximately 100 mg/m² on days 1, 2, and 3 of all three dosing cycles.

In some embodiments, the dosing cycle is a 14-day (e.g., 14 ± 3 days) dosing cycle. In some embodiments, the dosing cycle is a 21-day (e.g., 21 ± 3 days) dosing cycle. In a particular embodiment, the dosing cycle is a 21-day dosing cycle.

In some embodiments, the method characterized by the present invention further includes administering one or more additional therapeutic agents to a subject. In some embodiments, the one or more additional therapeutic agents are tocilizumab. In some embodiments, the one or more additional therapeutic agents are corticosteroids. In some embodiments, corticosteroids include prednisone, prednisolone, methylprednisolone, or dexamethasone. In some embodiments, the one or more additional therapeutic agents are antihistamines. In some embodiments, the antihistamine is diphenhydramine. In some embodiments, the one or more additional therapeutic agents include allopurinol and raburicase. In some embodiments, the one or more additional therapeutic agents are antipyretics. In some embodiments, the one or more additional therapeutic agents include granulocyte colony-stimulating factor (G-CSF). In some embodiments, the one or more additional therapeutic agents are mesna.

In one embodiment, the bispecific antibody is bivalent to CD20 and monovalent to CD3. In one embodiment, the bispecific antibody comprises two Fab molecules that specifically bind to CD20 and one Fab molecule that specifically binds to CD3. In one embodiment, the bispecific antibody is a humanized antibody.

In one aspect, the invention is characterized by a method of treating a subject suffering from a CD20-positive proliferative disorder such as a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and/or refractory NHL, DLBCL (e.g., relapsed and/or refractory DLBCL), FL (e.g., relapsed and/or refractory FL or transformed FL) or MCL (e.g., relapsed or refractory MCL)) or CNSL), the method comprising administering an effective amount to the subject in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle:

(a) A bispecific antibody that binds to CD20 and CD3, wherein the bispecific antibody comprises:

At least one Fab molecule that specifically binds to CD20, the at least one Fab molecule comprising: (a) a VH domain containing the amino acid sequence of SEQ ID NO:7; and (b) a VL domain containing the amino acid sequence of SEQ ID NO:8; and

At least one Fab molecule that specifically binds to CD3, the at least one Fab molecule comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO:15; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:16;

(b) Anti-CD20 antibody; and

(c) One or more chemotherapeutic agents selected from ifosfamide, carboplatin and/or etoposide.

In one embodiment, the first dosing cycle comprises a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody, wherein the C1D1 of the bispecific antibody is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of the bispecific antibody is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); and the second dosing cycle comprises a single dose of the bispecific antibody. The amount (C2D1) of the bispecific antibody is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg or ± 1 mg), about 16 mg (e.g., 16 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg or ± 1.6 mg), or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg). In a specific embodiment, the C1D1 of the bispecific antibody is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) and the C1D2 of the bispecific antibody is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg). In a specific embodiment, the C2D1 is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg). In certain embodiments, the C2D1 of the bispecific antibody is about 16 mg (e.g., 16 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, or ± 1.6 mg). In certain embodiments, the C2D1 of the bispecific antibody is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

In one embodiment, the first dosing cycle includes a first dose (C1D1) of the bispecific antibody and a second dose (C1D2) of the bispecific antibody, wherein the C1D1 of the bispecific antibody is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of the bispecific antibody is about 10 mg (e.g., 10 mg). ±0.05 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.5 mg, ±0.75 mg, or ±1 mg); and the second dosing cycle includes a single dose (C2D1) of the bispecific antibody, wherein the C2D1 of the bispecific antibody is about 30 mg (e.g., 30 mg ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg).

In one embodiment, the subject is given a first dose (C1D1) of the bispecific antibody and a second dose (C1D2) of the bispecific antibody on day 8 or before (±1 day) and day 15 or before (±1 day) of the first dosing cycle, respectively.

In one embodiment, a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody are administered to the subject on days 8 and 15 of the first dosing cycle, respectively. In another embodiment, C2D1 of the bispecific antibody is administered to the subject on or before day 8 of the second dosing cycle (±1 day).

In one embodiment, the anti-CD20 antibody is olibutuzumab and/or rituximab. In one embodiment, the first dosing cycle comprises a single dose of olibutuzumab (C1D1); and the second dosing cycle comprises a single dose of rituximab (C2D1).

In one embodiment, a single dose of olibutuzumab C1D1 is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg or ± 100 mg), and a single dose of rituximab is about 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 ).

In one embodiment, the anti-CD20 antibody is administered with a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein the first dosing cycle comprises a single dose of olibutuzumab on day 1 (C1D1); and the second dosing cycle comprises a single dose of rituximab on day 1 (C2D1).

In one aspect, the invention is characterized by a method of treating a subject suffering from a CD20-positive cell proliferative disorder, such as a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and/or refractory NHL, DLBCL (e.g., relapsed and/or refractory DLBCL), FL (e.g., relapsed and/or refractory FL or transformed FL) or MCL (e.g., relapsed or refractory MCL)) or CNSL), the method comprising: administering to the subject, in a first dosing cycle:

(a) Approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) as the first dose (C1D1) of the bispecific antibody binding to CD20 and CD3 and approximately 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg) as the second dose (C1D2) of the bispecific antibody binding to CD20 and CD3;

(b) A single dose of olibutuzumab (C1D1); and

(c) One or more chemotherapeutic agents selected from ifosfamide, carboplatin and/or etoposide;

Administered to subjects during the second dosing cycle:

(a) A single dose (C2D1) of approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg) of a bispecific antibody that binds to CD20 and CD3.

(b) A single dose of rituximab (C2D1); and

(c) One or more chemotherapeutic agents selected from ifosfamide, carboplatin and/or etoposide,

The bispecific antibody includes:

At least one Fab molecule that specifically binds to CD20, the at least one Fab molecule comprising: (a) a VH domain containing the amino acid sequence of SEQ ID NO:7; and (b) a VL domain containing the amino acid sequence of SEQ ID NO:8; and

At least one Fab molecule that specifically binds to CD3, the at least one Fab molecule comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO:15; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:16.

In one embodiment, a single dose of olibutuzumab C1D1 is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg or ± 100 mg), and a single dose of rituximab is about 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 ).

In one embodiment, the anti-CD20 antibody is administered with a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein the first dosing cycle comprises a single dose of olibutuzumab on day 1 (C1D1); and the second dosing cycle comprises a single dose of rituximab on day 1 (C2D1).

In one embodiment, the subject is given a first dose (C1D1) of the bispecific antibody and a second dose (C1D2) of the bispecific antibody on day 8 or before (±1 day) and day 15 or before (±1 day) of the first dosing cycle, respectively.

In one embodiment, a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody are administered to the subject on days 8 and 15 of the first dosing cycle, respectively. In another embodiment, C2D1 of the bispecific antibody is administered to the subject on or before day 8 of the second dosing cycle (±1 day).

In one embodiment of the method provided above, step c) includes all three chemotherapeutic agents.

In one embodiment, the first dosing cycle includes a single dose of ifosfamide (C1D1), a single dose of carboplatin (C1D1), and a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of etoposide; and the second cycle each includes a single dose of ifosfamide (C2D1), a single dose of carboplatin (C2D1), and a first dose (C2D1), a second dose (C2D2), and a third dose (C2D3) of etoposide.

In one aspect, the invention is characterized by a method of treating a subject suffering from a CD20-positive cell proliferative disorder, such as a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and/or refractory NHL, DLBCL (e.g., relapsed and/or refractory DLBCL), FL (e.g., relapsed and/or refractory FL or transformed FL) or MCL (e.g., relapsed or refractory MCL)) or CNSL), the method comprising: administering to the subject, in a first dosing cycle:

(a) Approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) as the first dose (C1D1) of the bispecific antibody binding to CD20 and CD3 and approximately 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg) as the second dose (C1D2) of the bispecific antibody binding to CD20 and CD3;

(b) A single dose of olibutuzumab (C1D1); and

(c) Single doses of ifosfamide (C1D1), single doses of carboplatin (C1D1), and first, second (C1D2), and third doses of etoposide (C1D3);

Administered to subjects during the second dosing cycle:

(a) A single dose (C2D1) of approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg) of a bispecific antibody that binds to CD20 and CD3.

(b) A single dose of rituximab (C2D1); and

(c) Single doses of ifosfamide (C2D1), single doses of carboplatin (C2D1), and first, second (C2D2), and third doses of etoposide (C2D3),

The bispecific antibody includes:

At least one Fab molecule that specifically binds to CD20, the at least one Fab molecule comprising: (a) a VH domain containing the amino acid sequence of SEQ ID NO:7; and (b) a VL domain containing the amino acid sequence of SEQ ID NO:8; and

At least one Fab molecule that specifically binds to CD3, the at least one Fab molecule comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO:15; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:16.

In one embodiment, a single dose of olibutuzumab C1D1 is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg or ± 100 mg), and a single dose of rituximab is about 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 ).

In one embodiment, the anti-CD20 antibody is administered with a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein the first dosing cycle comprises a single dose of olibutuzumab on day 1 (C1D1); and the second dosing cycle comprises a single dose of rituximab on day 1 (C2D1).

In one embodiment, the subject is given a first dose (C1D1) of the bispecific antibody and a second dose (C1D2) of the bispecific antibody on day 8 or before (±1 day) and day 15 or before (±1 day) of the first dosing cycle, respectively.

In one embodiment, a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody are administered to the subject on days 8 and 15 of the first dosing cycle, respectively. In another embodiment, C2D1 of the bispecific antibody is administered to the subject on or before day 8 of the second dosing cycle (±1 day).

In one embodiment of the method provided above, ifosfamide is administered at a dose of 5000 mg/ ^m² , 4000 mg/ ^m² , or 1666 mg/ ^m² . In one embodiment of the method provided above, ifosfamide is administered at a dose of 5000 mg/ ^m² . In one embodiment of the method provided above, carboplatin is administered at a dose of 750 mg, calculated in mg up to a target area under the curve (AUC) of 5 mg/mL/min. In one embodiment of the method provided above, etoposide is administered at a dose of 100 mg/ ^m² or 75 mg/ ^m² . In one embodiment of the method provided above, etoposide is administered at a dose of 100 mg/ ^m² .

In one embodiment of the method provided above, ifosfamide is administered at a dose of 5000 mg/ ^m² , 4000 mg/ ^m² , or 1666 mg/ ^m² , carboplatin is administered at a dose of 750 mg, up to a target area under the curve (AUC) of 5 mg/mL/min, and etoposide is administered at a dose of 100 mg/ ^m² or 75 mg/ ^m² .

In one embodiment of the method provided above, ifosfamide is administered at a dose of 5000 mg/ ^m² , carboplatin is administered at a dose of 750 mg, up to a target area under the curve (AUC) of 5 mg/mL/min, and etoposide is administered at a dose of 100 mg/ ^m² .

In one embodiment, ifosfamide and carboplatin are administered on day 2 of the first and second dosing cycles, and etoposide is administered on day 1, day 2, and day 3 of the first and second dosing cycles.

In one aspect, the invention is characterized by a method of treating a subject suffering from a CD20-positive cell proliferative disorder, such as a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and/or refractory NHL, DLBCL (e.g., relapsed and/or refractory DLBCL), FL (e.g., relapsed and/or refractory FL or transformed FL) or MCL (e.g., relapsed or refractory MCL)) or CNSL), the method comprising: administering to the subject, in a first dosing cycle:

(a) Approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) as the first dose (C1D1) of the bispecific antibody binding to CD20 and CD3 and approximately 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg) as the second dose (C1D2) of the bispecific antibody binding to CD20 and CD3; and

(b) A single dose (C1D1) of approximately 1000 mg of olibutuzumab (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg); and

(c) A single dose (C1D1 ⁾ of ifosfamide at approximately 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/m2, ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), a single dose (C1D1) of carboplatin at a maximum of 750 mg of the target area under the curve (AUC) up to 5 mg/mL/min, and a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of etoposide at approximately 100 mg/ ^m2 ;

Administered to subjects during the second dosing cycle:

(a) A single dose (C2D1) of approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg) of a bispecific antibody that binds to CD20 and CD3.

(b) A single dose (C2D1) of rituximab at approximately 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ); and

(c) A single dose (C1D1 ⁾ of ifosfamide at approximately 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/m2, ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), a single dose (C1D1) of carboplatin at a maximum of 750 mg of the target area under the curve (AUC) up to 5 mg/mL/min, and a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of etoposide at approximately 100 mg/ ^m2 ;

The bispecific antibody includes:

At least one Fab molecule that specifically binds to CD20, the at least one Fab molecule comprising: (a) a VH domain containing the amino acid sequence of SEQ ID NO:7; and (b) a VL domain containing the amino acid sequence of SEQ ID NO:8; and

At least one Fab molecule that specifically binds to CD3, the at least one Fab molecule comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO:15; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:16.

In one aspect, the invention is characterized by a method of treating a subject suffering from a CD20-positive proliferative disorder such as a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and/or refractory NHL, DLBCL (e.g., relapsed and/or refractory DLBCL), FL (e.g., relapsed and/or refractory FL or transformed FL) or MCL (e.g., relapsed or refractory MCL)) or CNSL), the method comprising administering to the subject:

(a) Approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) as the first dose (C1D1) of the bispecific antibody binding to CD20 and CD3 on day 8 of the first dosing cycle; approximately 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg) as the second dose (C1D2) of the bispecific antibody binding to CD20 and CD3 on day 15; and approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg) as the first dose (C2D1) on day 8 of the second dosing cycle;

(b) A single dose (C1D1) of approximately 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg) of rituximab on day 1 of the first dosing cycle, and a single dose (C2D1) of approximately 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ) of rituximab on day 1 of the second dosing cycle; and

(c) A single dose (C1D1) of ifosfamide at approximately 5000 mg/ ^m² on day 2 of the first and second dosing cycles (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ), a single dose (C1D1) of carboplatin at a maximum of 750 mg of the target area under the curve (AUC) up to 5 mg/mL/min on day 2 of the first and second dosing cycles, and a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of approximately 100 mg/ ^m² on days 1, 2, and 3 of the first and second dosing cycles.

The bispecific antibody includes:

At least one Fab molecule that specifically binds to CD20, the at least one Fab molecule comprising: (a) a VH domain containing the amino acid sequence of SEQ ID NO:7; and (b) a VL domain containing the amino acid sequence of SEQ ID NO:8; and

At least one Fab molecule that specifically binds to CD3, the at least one Fab molecule comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO:15; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:16.

In some embodiments, the first and second dosing cycles are 14-day (e.g., 14 ± 3 days) dosing cycles. In some embodiments, the first and second dosing cycles are 21-day (e.g., 21 ± 3 days) dosing cycles. In a particular embodiment, the first and second dosing cycles are 21-day dosing cycles.

In some embodiments, the dosing regimen includes one or more additional dosing cycles. In some embodiments, the dosing regimen includes a total of three dosing cycles. In some embodiments, the additional dosing cycle is a 14-day (e.g., 14 ± 3 days) dosing cycle. In some embodiments, the additional dosing cycle is a 21-day (e.g., 21 ± 3 days) dosing cycle. In one embodiment, the method provided herein includes three 21-day dosing cycles.

In one embodiment, one or more additional dosing cycles include:

(a) An additional single dose of a bispecific antibody that binds to CD20 and CD3, wherein the bispecific antibody comprises:

At least one Fab molecule that specifically binds to CD20, the at least one Fab molecule comprising: (a) a VH domain containing the amino acid sequence of SEQ ID NO:7; and (b) a VL domain containing the amino acid sequence of SEQ ID NO:8; and

At least one Fab molecule that specifically binds to CD3, the at least one Fab molecule comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO:15; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:16;

(b) An additional single dose of anti-CD20 antibody; and

(c) Additional single doses of ifosfamide, additional single doses of carboplatin, and additional first, second, and third doses of etoposide.

In one embodiment, an additional single dose of the bispecific antibody is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

In one embodiment, the anti-CD20 antibody is rituximab. In one embodiment, the additional single dose of rituximab is about 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ). In one embodiment, this additional single dose of rituximab is administered on day 1 of the additional dosing cycle.

In one embodiment, the additional dose of ifosfamide is about 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ), about 4000 mg/ ^m² (e.g., 4000 mg/ ^m² ± 40 mg/ ^m² , ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , or ± 400 mg/ ^m² ), or about 1666 mg/ ^m² (e.g., 1666 mg/ ^m² ± 25 mg/ ^m² , ± 50 mg/ ^m² , ± 100 mg/ ^m² , or ± 166.6 mg/m² ^). The additional single dose of carboplatin is approximately 5 mg/mL/min (e.g., 5 mg/mL/min ± 0.05 mg/mL/min, ± 0.1 mg/mL/min, ± 0.25 mg/mL/min, or ± 0.5 mg/mL/min), with the largest dose being approximately 750 mg (e.g., 750 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 75 mg), and the additional first, second, and third doses of etoposide are 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/ ^m² ) or 75 mg/ ^m² (e.g., 0.5 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 7.5 mg/m² ^). In one embodiment, an additional single dose of ifosfamide is 5000 mg/ ^m² , 4000 mg/ ^m² , or 1666 mg/ ^m² , an additional single dose of carboplatin is 750 mg (up to a target area under the curve (AUC) of 5 mg/mL/min), and additional first, second, and third doses of etoposide are 100 mg/ ^m² or 75 mg/ ^m² . In one embodiment, ifosfamide is administered at a dose of 5000 mg/ ^m² , carboplatin is administered at a dose of 750 mg (up to a target area under the curve (AUC) of 5 mg/mL/min), and etoposide is administered at a dose of 100 mg/ ^m² .

In one embodiment, ifosfamide and carboplatin are administered on day 2 of the additional dosing cycle, and etoposide is administered on each of days 1, 2, and 3 of the additional dosing cycle.

In one aspect, the invention is characterized by a method of treating a subject suffering from a CD20-positive cell proliferative disorder, such as a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and/or refractory NHL, DLBCL (e.g., relapsed and/or refractory DLBCL), FL (e.g., relapsed and/or refractory FL or transformed FL) or MCL (e.g., relapsed or refractory MCL)) or CNSL), the method comprising: administering to the subject, in a first dosing cycle:

(a) Approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) as the first dose (C1D1) of the bispecific antibody binding to CD20 and CD3 and approximately 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg) as the second dose (C1D2) of the bispecific antibody binding to CD20 and CD3;

(b) A single dose of olibutuzumab (C1D1); and

(c) Single doses of ifosfamide (C1D1), single doses of carboplatin (C1D1), and first, second (C1D2), and third doses of etoposide (C1D3);

Administered to subjects during the second and third dosing cycles:

(a) A single dose of approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg) of a bispecific antibody that binds to CD20 and CD3 (C2D1 in cycle 2 and C3D1 in cycle 3);

(b) A single dose of rituximab (C2D1 in cycle 2 and C3D1 in cycle 3); and

(c) Single doses of ifosfamide (C2D1 in cycle 2 and C3D1 in cycle 3), single doses of carboplatin (C2D1 in cycle 2 and C3D1 in cycle 3), and first doses (C2D1 in cycle 2 and C3D2 in cycle 3), second doses (C2D2 in cycle 2 and C3D2 in cycle 3), and third doses (C2D3 in cycle 2 and C3D3 in cycle 3) of etoposide;

The bispecific antibody includes:

At least one Fab molecule that specifically binds to CD20, the at least one Fab molecule comprising: (a) a VH domain containing the amino acid sequence of SEQ ID NO:7; and (b) a VL domain containing the amino acid sequence of SEQ ID NO:8; and

At least one Fab molecule that specifically binds to CD3, the at least one Fab molecule comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO:15; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:16.

In one aspect, the invention is characterized by a method of treating a subject suffering from a CD20-positive cell proliferative disorder, such as a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and/or refractory NHL, DLBCL (e.g., relapsed and/or refractory DLBCL), FL (e.g., relapsed and/or refractory FL or transformed FL) or MCL (e.g., relapsed or refractory MCL)) or CNSL), the method comprising: administering to the subject, in a first dosing cycle:

(a) Approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) as the first dose (C1D1) of the bispecific antibody binding to CD20 and CD3 and approximately 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg) as the second dose (C1D2) of the bispecific antibody binding to CD20 and CD3;

(b) A single dose (C1D1) of approximately 1000 mg of olibutuzumab (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg); and

(c) A single dose (C1D1 ⁾ of ifosfamide at approximately 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/m2, ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), a single dose (C1D1) of carboplatin at a maximum of 750 mg of the target area under the curve (AUC) up to 5 mg/mL/min, and a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of etoposide at approximately 100 mg/ ^m2 ;

Administered to subjects during the second and third dosing cycles:

(a) A single dose of approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg) of a bispecific antibody that binds to CD20 and CD3 (C2D1 in cycle 2 and C3D1 in cycle 3);

(b) A single dose of rituximab at approximately 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ) (C2D1 in cycle 2 and C3D1 in cycle 3); and

(c) A single dose of ifosfamide at approximately 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ) (C2D1 in cycle 2 and C3D1 in cycle 3), a single dose of carboplatin at a maximum of 750 mg (C2D1 in cycle 2 and C3D1 in cycle 3) of the target area under the curve (AUC) up to 5 mg/mL/min, and approximately 100 mg/m² of etoposide. The dosages of ^the first dose (C2D1 in cycle 2 and C3D1 in cycle 3), the second dose (C2D2 in cycle 2 and C3D2 in cycle 3), and the third dose (C2D3 in cycle 2 and C3D3 in cycle 3) are as follows.

The bispecific antibody includes:

At least one Fab molecule that specifically binds to CD20, the at least one Fab molecule comprising: (a) a VH domain containing the amino acid sequence of SEQ ID NO:7; and (b) a VL domain containing the amino acid sequence of SEQ ID NO:8; and

At least one Fab molecule that specifically binds to CD3, the at least one Fab molecule comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO:15; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:16.

In one aspect, the invention is characterized by a method of treating a subject suffering from a CD20-positive proliferative disorder such as a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and/or refractory NHL, DLBCL (e.g., relapsed and/or refractory DLBCL), FL (e.g., relapsed and/or refractory FL or transformed FL) or MCL (e.g., relapsed or refractory MCL)) or CNSL), the method comprising administering to the subject:

(a) Approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) as the first dose (C1D1) of the bispecific antibody binding to CD20 and CD3 on day 8 of the first dosing cycle, and approximately 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.25 mg) as the first dose of the bispecific antibody binding to CD20 and CD3 on day 8 of the first dosing cycle. 0.75 mg or ±1 mg) as the second dose (C1D2) of the bispecific antibody binding to CD20 and CD3 on day 15, and about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg) as the first dose (C2D1) on day 8 of the second and third dosing cycles, wherein the bispecific antibody comprises:

At least one Fab molecule that specifically binds to CD20, the at least one Fab molecule comprising: (a) a VH domain containing the amino acid sequence of SEQ ID NO:7; and (b) a VL domain containing the amino acid sequence of SEQ ID NO:8; and

At least one Fab molecule that specifically binds to CD3, the at least one Fab molecule comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO:15; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:16;

(b) A single dose (C1D1) of approximately 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg) of rituximab on day 1 of the first dosing cycle, and a single dose (C2D1) of approximately 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ) of rituximab on day 1 of the second and third dosing cycles; and

(c) A single dose (C1D1) of ifosfamide at approximately 5000 mg/ ^m² on day 2 of the first and second dosing cycles (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ), a single dose (C1D1) of carboplatin at the maximum of the target area under the curve (AUC) of 750 mg up to 5 mg/mL/min on day 2 of all three dosing cycles, and a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of approximately 100 mg/ ^m² on days 1, 2, and 3 of all three dosing cycles.

In some embodiments, the dosing cycle is a 14-day (e.g., 14 ± 3 days) dosing cycle. In some embodiments, the dosing cycle is a 21-day (e.g., 21 ± 3 days) dosing cycle. In a particular embodiment, the dosing cycle is a 21-day dosing cycle.

In some embodiments, the method characterized by the present invention further includes administering one or more additional therapeutic agents to a subject. In some embodiments, the one or more additional therapeutic agents are tocilizumab. In some embodiments, the one or more additional therapeutic agents are corticosteroids. In some embodiments, corticosteroids include prednisone, prednisolone, methylprednisolone, or dexamethasone. In some embodiments, the one or more additional therapeutic agents are antihistamines. In some embodiments, the antihistamine is diphenhydramine. In some embodiments, the one or more additional therapeutic agents include allopurinol and raburicase. In some embodiments, the one or more additional therapeutic agents are antipyretics. In some embodiments, the one or more additional therapeutic agents include granulocyte colony-stimulating factor (G-CSF). In some embodiments, the one or more additional therapeutic agents are mesna.

In one embodiment, the bispecific antibody is bivalent to CD20 and monovalent to CD3. In one embodiment, the bispecific antibody comprises two Fab molecules that specifically bind to CD20 and one Fab molecule that specifically binds to CD3. In one embodiment, the bispecific antibody is a humanized antibody. In one embodiment, the bispecific antibody is glimepiride.

In one aspect, the invention is characterized by a method of treating a subject suffering from a CD20-positive proliferative disorder such as a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and/or refractory NHL, DLBCL (e.g., relapsed and/or refractory DLBCL), FL (e.g., relapsed and/or refractory FL or transformed FL) or MCL (e.g., relapsed or refractory MCL)) or CNSL), the method comprising administering an effective amount to the subject in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle:

(a) Gluciferumab;

(b) Anti-CD20 antibody; and

(c) One or more chemotherapeutic agents selected from ifosfamide, carboplatin and/or etoposide.

In one embodiment, the first dosing cycle comprises a first dose (C1D1) and a second dose (C1D2) of glimetuzumab, wherein the C1D1 of glimetuzumab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of glimetuzumab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); and the second dosing cycle comprises a single dose of glimetuzumab (C1D1). C2D1), wherein the C2D1 of glimetuzumab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg or ± 1 mg), about 16 mg (e.g., 16 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg or ± 1.6 mg), or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg). In certain embodiments, the C1D1 of glimetuzumab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) and the C1D2 of glimetuzumab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg). In certain embodiments, the C2D1 is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg). In certain embodiments, the C2D1 of glimetuzumab is about 16 mg (e.g., 16 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, or ± 1.6 mg). In certain embodiments, the C2D1 of glimetuzumab is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

In one embodiment, the first dosing cycle comprises a first dose (C1D1) of glimetuzumab and a second dose (C1D2) of glimetuzumab, wherein the C1D1 of glimetuzumab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of glimetuzumab is about 10 mg (e.g., 10 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg). 0.05 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.5 mg, ±0.75 mg, or ±1 mg); and the second dosing cycle includes a single dose (C2D1) of glimetuzumab, wherein the C2D1 of the bispecific antibody is approximately 30 mg (e.g., 30 mg ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg).

In one embodiment, the subject was given a first dose (C1D1) of glimetuzumab and a second dose (C1D2) of glimetuzumab on or before day 8 of the first dosing cycle and on or before day 15 of the first dosing cycle (±1 day).

In one embodiment, a first dose (C1D1) of glimetuzumab and a second dose (C1D2) of glimetuzumab are administered to the subject on days 8 and 15 of the first dosing cycle, respectively. In some embodiments, C2D1 of glimetuzumab is administered to the subject on or before day 8 of the second dosing cycle (±1 day). In some embodiments, C2D1 of glimetuzumab is administered to the subject on or before day 8 of the second dosing cycle.

In one embodiment, the anti-CD20 antibody is olibutuzumab and/or rituximab. In one embodiment, the first dosing cycle comprises a single dose of olibutuzumab (C1D1); and the second dosing cycle comprises a single dose of rituximab (C2D1).

In one embodiment, a single dose of olibutuzumab C1D1 is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg or ± 100 mg), and a single dose of rituximab is about 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 ).

In one embodiment, the anti-CD20 antibody is administered with a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein the first dosing cycle comprises a single dose of olibutuzumab on day 1 (C1D1); and the second dosing cycle comprises a single dose of rituximab on day 1 (C2D1).

In one aspect, the invention is characterized by a method of treating a subject suffering from a CD20-positive cell proliferative disorder, such as a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and/or refractory NHL, DLBCL (e.g., relapsed and/or refractory DLBCL), FL (e.g., relapsed and/or refractory FL or transformed FL) or MCL (e.g., relapsed or refractory MCL)) or CNSL), the method comprising: administering to the subject, in a first dosing cycle:

(a) Approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) as the first dose (C1D1) of glimetuzumab and approximately 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg) as the second dose (C1D2) of glimetuzumab;

(b) A single dose of olibutuzumab (C1D1); and

(c) One or more chemotherapeutic agents selected from ifosfamide, carboplatin and/or etoposide;

Administered to subjects during the second dosing cycle:

(a) A single dose (C2D1) of approximately 30 mg of glimepiride (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

(b) A single dose of rituximab (C2D1); and

(c) One or more chemotherapeutic agents selected from ifosfamide, carboplatin and/or etoposide.

In one embodiment, a single dose of olibutuzumab C1D1 is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg or ± 100 mg), and a single dose of rituximab is about 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 ).

In one embodiment, the anti-CD20 antibody is administered with a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein the first dosing cycle comprises a single dose of olibutuzumab on day 1 (C1D1); and the second dosing cycle comprises a single dose of rituximab on day 1 (C2D1).

In one embodiment, the subject was given a first dose (C1D1) of glimetuzumab and a second dose (C1D2) of glimetuzumab on or before day 8 of the first dosing cycle and on or before day 15 of the first dosing cycle (±1 day).

In one embodiment, a first dose (C1D1) of glimetuzumab and a second dose (C1D2) of glimetuzumab are administered to the subject on days 8 and 15 of the first dosing cycle, respectively. In some embodiments, C2D1 of glimetuzumab is administered to the subject on or before day 8 of the second dosing cycle (±1 day). In some embodiments, C2D1 of glimetuzumab is administered to the subject on or before day 8 of the second dosing cycle.

In one embodiment of the method provided above, step c) includes all three chemotherapeutic agents.

In one embodiment, the first dosing cycle includes a single dose of ifosfamide (C1D1), a single dose of carboplatin (C1D1), and a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of etoposide; and the second cycle each includes a single dose of ifosfamide (C2D1), a single dose of carboplatin (C2D1), and a first dose (C2D1), a second dose (C2D2), and a third dose (C2D3) of etoposide.

In one aspect, the invention is characterized by a method of treating a subject suffering from a CD20-positive cell proliferative disorder, such as a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and/or refractory NHL, DLBCL (e.g., relapsed and/or refractory DLBCL), FL (e.g., relapsed and/or refractory FL or transformed FL) or MCL (e.g., relapsed or refractory MCL)) or CNSL), the method comprising: administering to the subject, in a first dosing cycle:

(a) Approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) as the first dose (C1D1) of glimetuzumab and approximately 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg) as the second dose (C1D2) of glimetuzumab;

(b) A single dose of olibutuzumab (C1D1); and

(c) Single doses of ifosfamide (C1D1), single doses of carboplatin (C1D1), and first, second (C1D2), and third doses of etoposide (C1D3);

Administered to subjects during the second dosing cycle:

(a) A single dose (C2D1) of approximately 30 mg of glimetuzumab (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg);

(b) A single dose of rituximab (C2D1); and

(c) Single doses of ifosfamide (C2D1), single doses of carboplatin (C2D1), and first, second (C2D2), and third doses of etoposide (C2D3).

In one embodiment, a single dose of olibutuzumab C1D1 is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg or ± 100 mg), and a single dose of rituximab is about 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 ).

In one embodiment, the anti-CD20 antibody is administered with a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein the first dosing cycle comprises a single dose of olibutuzumab on day 1 (C1D1); and the second dosing cycle comprises a single dose of rituximab on day 1 (C2D1).

In one embodiment, the subject was given a first dose (C1D1) of glimetuzumab and a second dose (C1D2) of glimetuzumab on or before day 8 of the first dosing cycle and on or before day 15 of the first dosing cycle (±1 day).

In one embodiment, a first dose (C1D1) of glimetuzumab and a second dose (C1D2) of glimetuzumab are administered to the subject on days 8 and 15 of the first dosing cycle, respectively. In some embodiments, C2D1 of glimetuzumab is administered to the subject on or before day 8 of the second dosing cycle (±1 day). In some embodiments, C2D1 of glimetuzumab is administered to the subject on or before day 8 of the second dosing cycle.

In one embodiment of the method provided above, ifosfamide is administered at a dose of 5000 mg/ ^m² , 4000 mg/ ^m² , or 1666 mg/ ^m² . In one embodiment of the method provided above, ifosfamide is administered at a dose of 5000 mg/ ^m² . In one embodiment of the method provided above, carboplatin is administered at a dose of 750 mg, calculated in mg up to a target area under the curve (AUC) of 5 mg/mL/min. In one embodiment of the method provided above, etoposide is administered at a dose of 100 mg/ ^m² or 75 mg/ ^m² . In one embodiment of the method provided above, etoposide is administered at a dose of 100 mg/ ^m² .

In one embodiment of the method provided above, ifosfamide is administered at a dose of 5000 mg/ ^m² , 4000 mg/ ^m² , or 1666 mg/ ^m² , carboplatin is administered at a dose of 750 mg, up to a target area under the curve (AUC) of 5 mg/mL/min, and etoposide is administered at a dose of 100 mg/ ^m² or 75 mg/ ^m² .

In one embodiment of the method provided above, ifosfamide is administered at a dose of 5000 mg/ ^m² , carboplatin is administered at a dose of 750 mg, up to a target area under the curve (AUC) of 5 mg/mL/min, and etoposide is administered at a dose of 100 mg/ ^m² .

In one embodiment, ifosfamide and carboplatin are administered on day 2 of the first and second dosing cycles, and etoposide is administered on day 1, day 2, and day 3 of the first and second dosing cycles.

In one aspect, the invention is characterized by a method of treating a subject suffering from a CD20-positive cell proliferative disorder, such as a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and/or refractory NHL, DLBCL (e.g., relapsed and/or refractory DLBCL), FL (e.g., relapsed and/or refractory FL or transformed FL) or MCL (e.g., relapsed or refractory MCL)) or CNSL), the method comprising: administering to the subject, in a first dosing cycle:

(a) Approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) as the first dose (C1D1) of glimetuzumab and approximately 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg) as the second dose (C1D2) of glimetuzumab;

(b) A single dose (C1D1) of approximately 1000 mg of olibutuzumab (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg); and

(c) A single dose (C1D1 ⁾ of ifosfamide at approximately 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/m2, ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), a single dose (C1D1) of carboplatin at a maximum of 750 mg of the target area under the curve (AUC) up to 5 mg/mL/min, and a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of etoposide at approximately 100 mg/ ^m2 ;

Administered to subjects during the second dosing cycle:

(a) A single dose (C2D1) of approximately 30 mg of glimetuzumab (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg);

(b) A single dose (C2D1) of rituximab at approximately 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ); and

(c) A single dose (C1D1 ⁾ of ifosfamide at approximately 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/m², ± 400 mg/ ^m² , or ± 500 mg/ ^m² ), a single dose (C1D1) of carboplatin at a maximum of 750 mg of the target area under the curve (AUC) up to 5 mg/mL/min, and a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of etoposide at approximately 100 mg/ ^m² .

In one aspect, the invention is characterized by a method of treating a subject suffering from a CD20-positive proliferative disorder such as a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and/or refractory NHL, DLBCL (e.g., relapsed and/or refractory DLBCL), FL (e.g., relapsed and/or refractory FL or transformed FL) or MCL (e.g., relapsed or refractory MCL)) or CNSL), the method comprising administering to the subject:

(a) Approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) as the first dose of glimetuzumab on day 8 of the first dosing cycle (C1D1), approximately 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg) as the second dose of glimetuzumab on day 15 (C1D2), and approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg) as the first dose on day 8 of the second dosing cycle (C2D1);

(b) A single dose (C1D1) of approximately 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg) of rituximab on day 1 of the first dosing cycle, and a single dose (C2D1) of approximately 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ) of rituximab on day 1 of the second dosing cycle; and

(c) A single dose (C1D1) of ifosfamide at approximately 5000 mg/ ^m² on day 2 of the first and second dosing cycles (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ), a single dose (C1D1) of carboplatin at a maximum of 750 mg of the target area under the curve (AUC) up to 5 mg/mL/min on day 2 of the first and second dosing cycles, and a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of approximately 100 mg/ ^m² on days 1, 2, and 3 of the first and second dosing cycles.

In some embodiments, the first and second dosing cycles are 14-day (e.g., 14 ± 3 days) dosing cycles. In some embodiments, the first and second dosing cycles are 21-day (e.g., 21 ± 3 days) dosing cycles. In a particular embodiment, the first and second dosing cycles are 21-day dosing cycles.

In some embodiments, the dosing regimen includes one or more additional dosing cycles. In some embodiments, the dosing regimen includes a total of three dosing cycles. In some embodiments, the additional dosing cycle is a 14-day (e.g., 14 ± 3 days) dosing cycle. In some embodiments, the additional dosing cycle is a 21-day (e.g., 21 ± 3 days) dosing cycle. In one embodiment, the method provided herein includes three 21-day dosing cycles.

In one embodiment, one or more additional dosing cycles include:

(a) An additional single dose of glimepiride,

(b) An additional single dose of anti-CD20 antibody, and

(c) Additional single doses of ifosfamide, additional single doses of carboplatin, and additional first, second, and third doses of etoposide.

In one embodiment, an additional single dose of glimetuzumab is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

In one embodiment, the anti-CD20 antibody is rituximab. In one embodiment, the additional single dose of rituximab is about 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ). In one embodiment, this additional single dose of rituximab is administered on day 1 of the additional dosing cycle.

In one embodiment, the additional single dose of ifosfamide is about 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ), about 4000 mg/ ^m² (e.g., 4000 mg/ ^m² ± 40 mg/ ^m² , ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , or ± 400 mg/ ^m² ), or about 1666 mg/ ^m² (e.g., 1666 mg/ ^m² ± 25 mg/ ^m² , ± 50 mg/ ^m² , ± 100 mg/ ^m² , or ± 166.6 mg/m² ^). The additional single dose of carboplatin is approximately 5 mg/mL/min (e.g., 5 mg/mL/min ± 0.05 mg/mL/min, ± 0.1 mg/mL/min, ± 0.25 mg/mL/min, or ± 0.5 mg/mL/min), with the maximum dose being approximately 750 mg (e.g., 750 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 75 mg), and the additional first, second, and third doses of etoposide are 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/ ^m² ) or 75 mg/ ^m² (e.g., 0.5 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 7.5 mg/ ^m² ). In one embodiment, the additional single dose of ifosfamide is 5000 mg/ ^m² , 4000 mg/ ^m² , or 1666 mg/ ^m² , the additional single dose of carboplatin is 750 mg, up to a target area under the curve (AUC) of 5 mg/mL/min, and the additional first, second, and third doses of etoposide are 100 mg/ ^m² or 75 mg/ ^m² . In one embodiment, ifosfamide is administered at a dose of 5000 mg/ ^m² , carboplatin is administered at a dose of 750 mg, up to a target area under the curve (AUC) of 5 mg/mL/min, and etoposide is administered at a dose of 100 mg/ ^m² .

In one embodiment, the additional single dose of ifosfamide is about 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ), about 4000 mg/ ^m² (e.g., 4000 mg/ ^m² ± 40 mg/ ^m² , ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , or ± 400 mg/ ^m² ), or about 1666 mg/ ^m² (e.g., 1666 mg/ ^m² ± 25 mg/ ^m² , ± 50 mg/ ^m² , ± 100 mg/ ^m² , or ± 166.6 mg/m² ^). The additional single dose of carboplatin is approximately 5 × (25 + creatinine clearance (CrCl)) mg, with a maximum dose of approximately 750 mg (e.g., 750 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 75 mg), and the additional single dose of etoposide is approximately 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/ ^m² ) or 75 mg/ ^m² (e.g., 0.5 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 7.5 mg/ ^m² ). In one embodiment, (a) the subject is male, and CrCl is calculated using the formula CrCl = ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]); or (b) the subject is female, and CrCl is calculated using the formula CrCl = 0.85 × ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]). In one embodiment, (a) the subject has a CrCl of < about 60 mL/min, and the additional single dose of ifosfamide is reduced to 4000 mg/ ^m² ; and/or (b) the subject has a CrCl of < about 50 mL/min, and the additional single dose of etoposide is reduced to 75 mg/ ^m² . In one embodiment, the subject is given or will be given an additional single dose of ifosfamide in an outpatient setting, and the additional single dose of ifosfamide is about 1666 mg/ ^m2 (e.g., 1666 mg/ ^m2 ± 25 mg/ ^m2 , ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , or ± 166.6 mg/ ^m2 ).

In one embodiment, ifosfamide and carboplatin are administered on day 2 of the additional dosing cycle, and etoposide is administered on each of days 1, 2, and 3 of the additional dosing cycle.

In one aspect, the invention is characterized by a method of treating a subject suffering from a CD20-positive cell proliferative disorder, such as a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and/or refractory NHL, DLBCL (e.g., relapsed and/or refractory DLBCL), FL (e.g., relapsed and/or refractory FL or transformed FL) or MCL (e.g., relapsed or refractory MCL)) or CNSL), the method comprising: administering to the subject, in a first dosing cycle:

(a) Approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) as the first dose (C1D1) of glimetuzumab and approximately 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg) as the second dose (C1D2) of glimetuzumab;

(b) A single dose of olibutuzumab (C1D1); and

(c) Single doses of ifosfamide (C1D1), single doses of carboplatin (C1D1), and first, second (C1D2), and third doses of etoposide (C1D3);

Administered to subjects during the second and third dosing cycles:

(a) A single dose of approximately 30 mg of glimepiride (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg) (C2D1 in cycle 2 and C3D1 in cycle 3);

(b) A single dose of rituximab (C2D1 in cycle 2 and C3D1 in cycle 3); and

(c) Single doses of ifosfamide (C2D1 in cycle 2 and C3D1 in cycle 3), single doses of carboplatin (C2D1 in cycle 2 and C3D1 in cycle 3), and first, second, third (C2D2 in cycle 2 and C3D2 in cycle 3) doses of etoposide (C2D3 in cycle 2 and C3D1 in cycle 3), and third doses (C2D3 in cycle 2 and C3D3 in cycle 3).

In one aspect, the invention is characterized by a method of treating a subject suffering from a CD20-positive cell proliferative disorder, such as a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and/or refractory NHL, DLBCL (e.g., relapsed and/or refractory DLBCL), FL (e.g., relapsed and/or refractory FL or transformed FL) or MCL (e.g., relapsed or refractory MCL)) or CNSL), the method comprising: administering to the subject, in a first dosing cycle:

(a) Approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) as the first dose of glimetuzumab (C1D1) and approximately 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg) as the second dose of glimetuzumab that binds to CD20 and CD3 (C1D2);

(b) A single dose (C1D1) of approximately 1000 mg of olibutuzumab (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg); and

(c) A single dose (C1D1 ⁾ of ifosfamide at approximately 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/m2, ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), a single dose (C1D1) of carboplatin at a maximum of 750 mg of the target area under the curve (AUC) up to 5 mg/mL/min, and a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of etoposide at approximately 100 mg/ ^m2 ;

Administered to subjects during the second and third dosing cycles:

(a) A single dose of approximately 30 mg of glimepiride (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg) (C2D1 in cycle 2 and C3D1 in cycle 3);

(b) A single dose of rituximab at approximately 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ) (C2D1 in cycle 2 and C3D1 in cycle 3); and

(c) A single dose of ifosfamide at approximately 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ) (C2D1 in cycle 2 and C3D1 in cycle 3), a single dose of carboplatin at a maximum of 750 mg (C2D1 in cycle 2 and C3D1 in cycle 3) of the target area under the curve (AUC) up to 5 mg/mL/min, and approximately 100 mg/m² of etoposide. The first dose of ² (C2D1 in cycle 2 and C3D1 in cycle 3), the second dose (C2D2 in cycle 2 and C3D2 in cycle 3), and the third dose (C2D3 in cycle 2 and C3D3 in cycle 3).

In one embodiment, carboplatin is administered at a dose of about 5 × (25 + creatinine clearance (CrCl)) mg, with the largest dose being about 750 mg (e.g., 750 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 75 mg). In one embodiment, (a) the subject is male, and CrCl is calculated using the formula CrCl = ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]); or (b) the subject is female, and CrCl is calculated using the formula CrCl = 0.85 × ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]).

In one aspect, the invention is characterized by a method of treating a subject suffering from a CD20-positive proliferative disorder such as a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and/or refractory NHL, DLBCL (e.g., relapsed and/or refractory DLBCL), FL (e.g., relapsed and/or refractory FL or transformed FL) or MCL (e.g., relapsed or refractory MCL)) or CNSL), the method comprising administering to the subject:

(a) Approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg) as the first dose of glimetuzumab on day 8 of the first dosing cycle (C1D1), approximately 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg) as the second dose of glimetuzumab on day 15 (C1D2), and approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg) as the first dose on day 8 of the second and third dosing cycles (C2D1);

(b) A single dose (C1D1) of approximately 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg) of rituximab on day 1 of the first dosing cycle, and a single dose (C2D1) of approximately 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ) of rituximab on day 1 of the second and third dosing cycles; and

(c) A single dose (C1D1) of ifosfamide at approximately 5000 mg/ ^m² on day 2 of the first and second dosing cycles (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ), a single dose (C1D1) of carboplatin at the maximum of the target area under the curve (AUC) of 750 mg up to 5 mg/mL/min on day 2 of all three dosing cycles, and a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of approximately 100 mg/ ^m² on days 1, 2, and 3 of all three dosing cycles.

In one aspect, the invention is characterized by a method for treating a subject aged between 6 months and 17 years with CD20-positive proliferative disorders, the method comprising administering an effective amount to the subject in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle:

(a) Bispecific antibodies that bind to CD20 and CD3;

(b) Anti-CD20 antibody; and

(c) One or more chemotherapeutic agents selected from ifosfamide, carboplatin and/or etoposide.

In one embodiment, the first dosing cycle includes a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody, wherein the C1D1 of the bispecific antibody is about 0.03 mg/kg (e.g., 0.03 mg/kg ± 0.0005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg, or ± 0.003 mg/kg), about 0.04 mg/kg (e.g., 0.04 mg/kg ± 0.0005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg, ± 0.003 mg/kg, or ± 0.004 mg/kg), or about 2.5 mg/kg. mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of the bispecific antibody is about 0.15 mg/kg (e.g., 0.15 mg/kg ± 0.001 mg/kg, ± 0.0025 mg/kg, ± 0.005 mg/kg, ± 0.01 mg/kg, or ± 0.015 mg/kg) or about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); and

The second dosing cycle includes a single dose (C2D1) of the bispecific antibody, wherein the C2D1 of the bispecific antibody is about 0.4 mg/kg (e.g., 0.4 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg or ± 0.04 mg/kg), about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, ± 0.04 mg/kg or ± 0.05 mg/kg), or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg).

In one embodiment, (a) the subject's weight is greater than or equal to about 7.5 kg and less than about 13 kg, and the C1D1 of the bispecific antibody is about 0.04 mg/kg (e.g., 0.04 mg/kg ± 0.0005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg, ± 0.003 mg/kg, or ± 0.004 mg/kg), and the C1D2 of the bispecific antibody is about 0.15 mg/kg (e.g., 0.15 mg/kg). The C2D1 of the bispecific antibody is approximately 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.001 mg/kg, ± 0.0025 mg/kg, ± 0.005 mg/kg, ± 0.01 mg/kg, or ± 0.015 mg/kg), and the C2D1 of the bispecific antibody is approximately 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, ± 0.04 mg/kg, or ± 0.05 mg/kg).

(b) The subject's weight is greater than or equal to about 13 kg and less than about 45 kg, and the C1D1 of the bispecific antibody is about 0.03 mg/kg (e.g., 0.03 mg/kg ± 0.0005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg, or ± 0.003 mg/kg), the C1D2 of the bispecific antibody is about 0.15 mg/kg (e.g., 0.15 mg/kg ± 0.001 mg/kg, ± 0.0025 mg/kg, ± 0.005 mg/kg, ± 0.01 mg/kg, or ± 0.015 mg/kg), and the C2D1 of the bispecific antibody is about 0.4 mg/kg (e.g., 0.4 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, or ± 0.04 mg/kg); or

(c) The subject weighs 45 kg or more and has a C1D1 dose of about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg or ± 0.25 mg), a C1D2 dose of about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg or ± 1 mg), and a C2D1 dose of about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg).

In one embodiment, the bispecific antibody C1D1 and bispecific antibody C1D2 are administered to the subject on days 8 and 15 of the first dosing cycle, respectively. In another embodiment, the bispecific antibody C2D1 is administered to the subject on day 1 of the second dosing cycle.

In one embodiment, the anti-CD20 antibody is olibutuzumab and/or rituximab.

In one embodiment, the first dosing cycle includes a first dose (C1D1) of olibutuzumab and a second dose (C1D2) of olibutuzumab. In one embodiment, (a) the subject's weight is greater than or equal to about 7.5 kg and less than about 13 kg, and the sum of C1D1 and C1D2 of olibutuzumab is about 38 mg/kg (e.g., 38 mg/kg ± 0.25 mg/kg, ± 0.5 mg/kg, ± 1 mg/kg, ± 2 mg/kg, ± 3 mg/kg, or ± 3.8 mg/kg); (b) the subject's weight is greater than or equal to about 13 kg and less than about 20 kg, and the sum of the C1D1 and C1D2 of olibutuzumab is about 28 mg/kg (e.g., 28 mg/kg ± 0.25 mg/kg, ± 0.5 mg/kg, ± 1 mg/kg, ± 2 mg/kg, or ± 2.8 mg/kg); (c) the subject's weight is greater than or equal to about 20 kg and less than about 32 kg, and the sum of the C1D1 and C1D2 of olibutuzumab is about 38 mg/kg (e.g., 28 mg/kg ± 0.25 mg/kg, ± 0.5 mg/kg, ± 1 mg/kg, ± 2 mg/kg, or ± 2.8 mg/kg); The sum of C1D1 and C1D2 is about 23 mg/kg (e.g., 23 mg/kg ± 0.25 mg/kg, ± 0.5 mg/kg, ± 1 mg/kg, ± 2 mg/kg, or ± 2.3 mg/kg); (d) the subject weighs more than or equal to about 32 kg and less than about 45 kg, and the sum of C1D1 and C1D2 of olibutuzumab is about 20 mg/kg (e.g., 23 mg/kg ± 0.25 mg/kg, ± 0.5 mg/kg, ± 1 mg/kg, or ± 2 mg/kg); or (e) the subject weighs more than or equal to about 45 kg, and the sum of C1D1 and C1D2 of olibutuzumab is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg).

In one embodiment, the C1D1 of oxytocinumab is about one-tenth the sum of the C1D1 and C1D2 of oxytocinumab, and the C1D2 of oxytocinumab is about nine-tenths the sum of the C1D1 and C1D2 of oxytocinumab. In one embodiment, (a) the subject's weight is greater than or equal to about 7.5 kg and less than about 13 kg, and the C1D1 of olibutuzumab is about 3.8 mg/kg (e.g., 3.8 mg/kg ± 0.05 mg/kg, 0.1 mg/kg, ± 0.2 mg/kg, ± 0.3 mg/kg, or ± 0.38 mg/kg) and the C1D2 of olibutuzumab is about 34.2 mg/kg (e.g., 34.2 mg/kg ± 0.5 mg/kg, 1 mg/kg, ± 2 mg/kg, ± 3 mg/kg, or ± 3.42 mg/kg); (b) the subject's weight is greater than or equal to about 13 kg and less than about 20 kg, and the C1D2 of olibutuzumab is about 3.8 mg/kg (e.g., 3.8 mg/kg ± 0.05 mg/kg, 0.1 mg/kg, ± 0.2 mg/kg, ± 0.3 mg/kg, or ± 0.38 mg/kg) and the C1D2 of olibutuzumab is about 34.2 mg/kg (e.g., 34.2 mg/kg ± 0.5 mg/kg, 1 mg/kg, ± 2 mg/kg, ± 3 mg/kg, or ± 3.42 mg/kg); The C1D1 of olibutuzumab is about 2.8 mg/kg (e.g., 2.8 mg/kg ± 0.05 mg/kg, 0.1 mg/kg, ± 0.2 mg/kg, or ± 0.28 mg/kg), and the C1D2 of olibutuzumab is about 35.2 mg/kg (e.g., 35.2 mg/kg ± 0.5 mg/kg, 1 mg/kg, ± 2 mg/kg, ± 3 mg/kg, or ± 3.52 mg/kg); (c) the subject's weight is greater than or equal to about 20 kg and less than about 32 kg, and the C1D1 of olibutuzumab is about 2.3 mg/kg (e.g., 2.3 mg/kg ± 0.05 mg/kg, 0.1 mg/kg, ± 0.2 mg/kg, or ± 0.28 mg/kg). (d) The subject's weight is greater than or equal to about 32 kg and less than about 45 kg, and the C1D1 of olibutuzumab is about 2.0 mg/kg (e.g., 2.0 mg/kg ± 0.05 mg/kg, 0.1 mg/kg or ± 0.2 mg/kg), and the C1D2 of olibutuzumab is about 36.0 mg/kg (e.g., 36 mg/kg ± 0.2 mg/kg, ± 0.23 ... (e) The subject's weight is greater than or equal to about 45 kg, and the C1D1 of olibutuzumab is about 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 8 mg or ± 10 mg) and the C1D2 of olibutuzumab is about 900 mg (e.g., 900 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 40 mg, ± 50 mg, ± 60 mg, ± 70 mg, ± 80 mg or ± 90 mg).

In one embodiment, the subject is given C1D1 of bisacodyltocilizumab on day 1 of the first dosing cycle and C1D2 of bisacodyltocilizumab on day 2 of the first dosing cycle.

In one embodiment, the second dosing cycle comprises a single dose (C2D1) of rituximab. In one embodiment, the C2D1 of rituximab is approximately 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ). In one embodiment, rituximab is administered to the subject on day 5 of the second dosing cycle.

In one embodiment, the method includes administering ifosfamide, carboplatin, and etoposide to a subject.

In one embodiment, the first dosing cycle includes:

(a) The first dose of ifosfamide (C1D1), the second dose of ifosfamide (C1D2), and the third dose of ifosfamide (C1D3);

(b) A single dose of carboplatin (C1D1); and

(c) The first dose of etoposide (C1D1), the second dose of etoposide (C1D2), and the third dose of etoposide (C1D3);

And the second cycle includes:

(a) The first dose of ifosfamide (C2D1), the second dose of ifosfamide (C2D2), and the third dose of ifosfamide (C2D3);

(b) A single dose of carboplatin (C2D1); and

(c) The first dose of etoposide (C2D1), the second dose of etoposide (C2D2), and the third dose of etoposide (C2D3).

In one embodiment, ifosfamide is administered at a dose of approximately 3000 mg/ ^m² (e.g., 3000 mg/ ^m² ± 40 mg/ ^m² , ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , or ± 300 mg/ ^m² ). For each dose of ifosfamide, carboplatin is administered at a dose of approximately 635 mg/ ^m² (e.g., 635 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , ± 50 mg/ ^m² , ± 60 mg/ ^m² , or ± 63.5 mg/ ^m² ), and carboplatin is administered at a dose of approximately 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/m² ^). Etoposide is administered at each dose of etoposide. In one embodiment, (a) ifosfamide C1D1, C1D2, and C1D3 are administered on days 3, 4, and 5 of the first dosing cycle, respectively; (b) carboplatin C1D1 is administered on day 3 of the first dosing cycle; (c) etoposide C1D1, C1D2, and C1D3 are administered on days 3, 4, and 5 of the first dosing cycle, respectively; (d) ifosfamide C2D1, C2D2, and C2D3 are administered on days 6, 7, and 8 of the second dosing cycle, respectively; (e) carboplatin C2D1 is administered on day 6 of the second dosing cycle; and (f) etoposide C2D1, C2D2, and C2D3 are administered on days 6, 7, and 8 of the second dosing cycle, respectively.

In one embodiment, the first and second dosing cycles are each 21-day dosing cycles. In one embodiment, the dosing regimen includes one or more additional dosing cycles. In one embodiment, the one or more additional dosing cycles are each 21-day dosing cycles. In one embodiment, the dosing regimen includes a total of three dosing cycles.

In one embodiment, one or more additional dosing cycles each include:

(a) An additional single dose of a bispecific antibody that binds to both CD20 and CD3.

(b) An additional single dose of anti-CD20 antibody, and

(c) Additional first, second, and third doses of ifosfamide; an additional single dose of carboplatin; and additional first, second, and third doses of etoposide. In one embodiment, (a) the subject weighs more than or equal to about 7.5 kg and less than about 13 kg, and the additional single dose of the bispecific antibody is about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, ± 0.04 mg/kg, or ± 0.05 mg/kg); (b) the subject weighs more than or equal to about 13 kg and less than about 45 kg, and the additional single dose of the bispecific antibody is... (c) The subject weighs more than or equal to about 45 kg, and the additional single dose of the bispecific antibody is about 30 mg (e.g., 0.4 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg or ± 0.04 mg/kg); or (d) the subject weighs more than or equal to about 45 kg, and the additional single dose of the bispecific antibody is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg).

In one embodiment, an additional single dose of the bispecific antibody is administered to the subject on day 1 of each of one or more additional dosing cycles.

In one embodiment, the anti-CD20 antibody is rituximab. In one embodiment, the additional single dose of rituximab is about 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ). In one embodiment, the additional single dose of rituximab is administered on day 5 of each of one or more additional dosing cycles.

In one embodiment, the additional first, second, and third doses of ifosfamide are each about 3000 mg/ ^m² (e.g., 3000 mg/ ^m² ± 40 mg/ ^m² , ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , or ± 300 mg/ ^m² ), the additional single dose of carboplatin is about 635 mg/ ^m² (e.g., 635 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , ± 50 mg/ ^m² , ± 60 mg/ ^m² , or ± 63.5 mg/ ^m² ), and the additional first, second, and third doses of etoposide are each about 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/m²). ² or ±10 mg/ ^m² ). In one embodiment, (a) the subject is given an additional first dose, an additional second dose, and an additional third dose of ifosfamide on days 6, 7, and 8 of each of the one or more additional dosing cycles; (b) an additional single dose of carboplatin is given on day 6 of each of the one or more additional dosing cycles; and (c) an additional first dose, an additional second dose, and an additional third dose of etoposide are given to the subject on days 6, 7, and 8 of each of the one or more additional dosing cycles.

In one embodiment, the method further includes administering one or more additional therapeutic agents to the subject.

In one embodiment, one or more additional therapeutic agents are tocilizumab. In one embodiment, the subject weighs more than or equal to about 30 kg and is administered tocilizumab at a dose of about 8 mg/kg (e.g., 8 mg/kg ± 0.05 mg/kg, ± 0.1 mg/kg, ± 0.25 mg/kg, ± 0.5 mg/kg, or ± 0.8 mg/kg), or the subject weighs less than 30 kg and is administered tocilizumab at a dose of about 12 mg/kg (e.g., 12 mg/kg ± 0.05 mg/kg, ± 0.1 mg/kg, ± 0.25 mg/kg, ± 0.5 mg/kg, ± 0.75 mg/kg, ± 1 mg/kg, or ± 1.2 mg/kg), wherein the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg).

In one embodiment, one or more additional therapeutic agents are corticosteroids. In one embodiment, corticosteroids include prednisone, prednisolone, methylprednisolone, or dexamethasone.

In one embodiment, the corticosteroid is dexamethasone. In one embodiment, dexamethasone is administered intravenously at a dose between about 0.15 mg/kg (e.g., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) and about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.001 mg/kg, ± 0.0025 mg/kg, ± 0.005 mg/kg, ± 0.01 mg/kg, or ± 0.015 mg/kg) before any dose of the bispecific antibody, and wherein the maximum daily dose is 10 mg. In one embodiment, dexamethasone is administered intravenously at a dose between about 0.15 mg/kg (e.g., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) and about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.001 mg/kg, ± 0.0025 mg/kg, ± 0.005 mg/kg, ± 0.01 mg/kg or ± 0.015 mg/kg) and about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, ± 0.04 mg/kg or ± 0.05 mg/kg) before administration of any dose of olibutuzumab, and wherein the maximum daily dose is 10 mg.

In one embodiment, the corticosteroid is methylprednisolone. In one embodiment, methylprednisolone is administered intravenously at a dose between about 1 mg/kg and about 2 mg/kg (e.g., 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.9 or 2.0 mg/kg) at least one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) prior to the administration of any dose of the bispecific antibody. In one embodiment, methylprednisolone is administered intravenously at a dose between about 1 mg/kg and about 2 mg/kg (e.g., 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.9 or 2.0 mg/kg) for at least about one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) prior to the administration of any dose of olibutuzumab.

In one embodiment, the corticosteroid is prednisone or prednisolone. In one embodiment, prednisone or prednisolone is administered intravenously at a dose of about 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 8 mg, or ± 10 mg) or about 2 mg/kg at least one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) or about 2 mg/kg before administration of any dose of the bispecific antibody. In one embodiment, prednisone or prednisolone is administered intravenously at a dose of about 100 mg (e.g., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) or at least about 2 mg/kg, at least one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before any dose of olibutuzumab is administered.

In one embodiment, one or more additional therapeutic agents are antihistamines. In one embodiment, the antihistamine is diphenhydramine. In one embodiment, the subject is between 2 and 17 years of age, and diphenhydramine is administered intravenously at a dose of about 10 mg to 20 mg (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg), wherein the maximum single dose is about 1.25 mg/kg. In one embodiment, the subject is less than two years of age, and diphenhydramine is administered rectally at a dose of about 20 mg (e.g., 20 mg ± 0.1 mg, ± 0.25 mg, ± 0.5 mg, ± 1 mg, ± 1.5 mg, or ± 2 mg). In one embodiment, diphenhydramine is administered at least about 30 minutes (i.e., at least 30 minutes ± 3 minutes; for example, at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) prior to the administration of any dose of the bispecific antibody and/or anti-CD20 antibody.

In one embodiment, one or more additional therapeutic agents include granulocyte colony-stimulating factor (G-CSF). In one embodiment, G-CSF is administered approximately one to approximately two days (e.g., 24, 26, 28, 30, 32, 36, 38, 40, 42, 44, 46, or 48 hours) following administration of any dose of rituximab, ifosfamide, carboplatin, and/or etoposide. In one embodiment, G-CSF is administered intravenously or subcutaneously at a dose of about 5 μg/kg/day (e.g., 5 μg/kg/day ± 0.05 μg/kg/day, ± 0.1 μg/kg/day, ± 0.2 μg/kg/day, ± 0.3 μg/kg/day, ± 0.4 μg/kg/day, ± 0.5 μg/kg/day) or about 10 μg/kg/day (e.g., 10 μg/kg/day ± 0.1 μg/kg/day, ± 0.2 μg/kg/day, ± 0.4 μg/kg/day, ± 0.6 μg/kg/day, ± 0.8 μg/kg/day, ± 1 μg/kg/day). In one embodiment, G-CSF is administered at a dose of about 5 μg/kg/day in the first dosing cycle (e.g., 5 μg/kg/day ± 0.05 μg/kg/day, ± 0.1 μg/kg/day, ± 0.2 μg/kg/day, ± 0.3 μg/kg/day, ± 0.4 μg/kg/day, ± 0.5 μg/kg/day) in the second dosing cycle and/or each additional dosing cycle at a dose of about 10 μg/kg/day (e.g., 10 μg/kg/day ± 0.1 μg/kg/day, ± 0.2 μg/kg/day, ± 0.4 μg/kg/day, ± 0.6 μg/kg/day, ± 0.8 μg/kg/day, ± 1 μg/kg/day).

In one embodiment, one or more additional therapeutic agents are antipyretics. In one embodiment, the antipyretic is acetaminophen or paracetamol. In one embodiment, acetaminophen or paracetamol is administered orally or intravenously at a dose between about 500 and about 1000 mg (e.g., 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg). In one embodiment, acetaminophen or paracetamol is administered at least about 30 minutes (i.e., at least 30 minutes ± 3 minutes; e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before the administration of any dose of the bispecific antibody and/or anti-CD20 antibody.

In one embodiment, one or more additional therapeutic agents are mesna. In one embodiment, mesna is administered intravenously daily in five doses totaling 3000 mg/ ^m² . In one embodiment, mesna is administered intravenously at a first dose of about 600 mg/ ^m² and four repeated doses of about 600 mg/ ^m² prior to any dose of ifosfamide, each repeated dose approximately three hours, six hours, and 12 hours after the first dose of ifosfamide, respectively. In one embodiment, mesna is administered to the subject daily on days 3, 4, and 5 of the first dosing cycle, days 6, 7, and 8 of the second dosing cycle, and/or on days 6, 7, and 8 of each additional dosing cycle.

In one aspect, the invention is characterized by a method for treating a subject aged 18 to 30 years with a CD20-positive proliferative disorder, the method comprising administering an effective amount to the subject in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle:

(a) Bispecific antibodies that bind to CD20 and CD3;

(b) Anti-CD20 antibody; and

(c) One or more chemotherapeutic agents selected from ifosfamide, carboplatin and/or etoposide.

In one embodiment, the first dosing cycle includes a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody, wherein the C1D1 of the bispecific antibody is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of the bispecific antibody is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); and

The second dosing cycle includes a single dose (C2D1) of the bispecific antibody, wherein the C2D1 of the bispecific antibody is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

In one embodiment, the bispecific antibody C1D1 and bispecific antibody C1D2 were administered to the subject on day 8 and day 15 of the first dosing cycle, respectively.

In one embodiment, the subject is given the bispecific antibody C2D1 on day 1 of the second dosing cycle.

In one embodiment, the anti-CD20 antibody is olibutuzumab and/or rituximab.

In one embodiment, the first dosing cycle comprises a first dose (C1D1) of olibutuzumab and a second dose (C1D2) of olibutuzumab. In one embodiment, the sum of olibutuzumab C1D1 and C1D2 is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg). In one embodiment, the olibutuzumab C1D1 is about one-tenth the amount of the sum of olibutuzumab C1D1 and C1D2, and the olibutuzumab C1D2 is about nine-tenths the amount of the sum of olibutuzumab C1D1 and C1D2. In one embodiment, the C1D1 of olibutuzumab is about 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 8 mg, or ± 10 mg) and the C1D2 of olibutuzumab is about 900 mg (e.g., 900 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 40 mg, ± 50 mg, ± 60 mg, ± 70 mg, ± 80 mg, or ± 90 mg). In one embodiment, the C1D1 of olibutuzumab is administered to the subject on day 1 of the first dosing cycle, and the C1D2 of olibutuzumab is administered to the subject on day 2 of the first dosing cycle.

In one embodiment, the second dosing cycle comprises a single dose (C2D1) of rituximab. In one embodiment, the C2D1 of rituximab is approximately 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ). In one embodiment, the C2D1 of rituximab is administered to the subject on day 5 of the second dosing cycle.

In one embodiment, the method includes administering ifosfamide, carboplatin, and etoposide to a subject. In one embodiment, the first dosing cycle includes:

(a) A single dose of ifosfamide (C1D1);

(b) A single dose of carboplatin (C1D1); and

(c) The first dose of etoposide (C1D1), the second dose of etoposide (C1D2), and the third dose of etoposide (C1D3);

And the second cycle includes:

(a) A single dose of ifosfamide (C2D1);

(b) A single dose of carboplatin (C2D1); and

(c) The first dose of etoposide (C2D1), the second dose of etoposide (C2D2), and the third dose of etoposide (C2D3).

In one embodiment, ifosfamide is administered at a dose of about 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 ^mg / ^m² , ± 100 mg/m², ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ), carboplatin is administered at a dose of about 5 × (25 + creatinine clearance (CrCl)) mg, with the largest dose being about 750 mg (e.g., 750 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 75 mg), and etoposide is administered at a dose of about 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/ ^m² ) for each dose of etoposide.

In one embodiment, (a) the subject is male, and CrCl is calculated using the formula CrCl = ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]); or (b) the subject is female, and CrCl is calculated using the formula CrCl = 0.85 × ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]).

In one embodiment, (a) the subject has < about 60 mL/min of CrCl, and each single dose of ifosfamide is reduced to 4000 mg/ ^m² ; and/or (b) the subject has < about 50 mL/min of CrCl, and each dose of etoposide is reduced to 75 mg/ ^m² .

In one embodiment, (a) C1D1 ifosfamide is administered on day 3 of the first dosing cycle;

(b) Administer carboplatin C1D1 on day 3 of the first dosing cycle;

(c) Etoposide C1D1, C1D2 and C1D3 were administered on days 3, 4 and 5 of the first dosing cycle, respectively;

(d) Administer C2D1 of ifosfamide on day 6 of the second dosing cycle;

(e) Administer carboplatin C2D1 on day 6 of the second dosing cycle; and

(f) Etoposide C2D1, C2D2 and C2D3 were administered on days 6, 7 and 8 of the second dosing cycle, respectively.

In one embodiment, the first and second dosing cycles are each 21-day dosing cycles. In one embodiment, the dosing regimen includes one or more additional dosing cycles. In one embodiment, the one or more additional dosing cycles are each 21-day dosing cycles. In one embodiment, the dosing regimen includes a total of three dosing cycles.

In one embodiment, one or more additional dosing cycles each include:

(a) An additional single dose of a bispecific antibody that binds to both CD20 and CD3.

(b) An additional single dose of anti-CD20 antibody, and

(c) Additional single doses of ifosfamide; additional single doses of carboplatin; and additional first, second and third doses of etoposide.

In one embodiment, an additional single dose of the bispecific antibody is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg). In one embodiment, an additional single dose of the bispecific antibody is administered to the subject on day 1 of each of one or more additional dosing cycles.

In one embodiment, the anti-CD20 antibody is rituximab. In one embodiment, the additional single dose of rituximab is about 375 mg/ ^m² (e.g., 375 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , or ± 37.5 mg/ ^m² ). In one embodiment, the additional single dose of rituximab is administered on day 5 of each of one or more additional dosing cycles.

In one embodiment, the additional single dose of ifosfamide is about 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ), the additional single dose of carboplatin is about 5 × (25 + creatinine clearance (CrCl)) mg, with the maximum dose being about 750 mg (e.g., 750 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 75 mg), and the additional first, second, and third doses of etoposide are each about 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/ ^m² ).

In one embodiment, (a) the subject is male, and CrCl is calculated using the formula CrCl = ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]); or (b) the subject is female, and CrCl is calculated using the formula CrCl = 0.85 × ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]).

In one embodiment, (a) the subject has < about 60 mL/min of CrCl, and the additional single dose of ifosfamide is reduced to 4000 mg/ ^m² ; and/or (b) the subject has < about 50 mL/min of CrCl, and each additional dose of etoposide is reduced to 75 mg/ ^m² .

In one embodiment, (a) an additional single dose of ifosfamide is administered on day 6 of each of one or more additional dosing cycles;

(b) Administer an additional single dose of carboplatin on day 6 of each of these one or more additional dosing cycles; and

(c) The subject is given an additional first dose, an additional second dose, and an additional third dose of etoposide on days 6, 7, and 8 of each of the one or more additional dosing cycles.

In one embodiment, the method further includes administering one or more additional therapeutic agents to the subject.

In one embodiment, one or more additional therapeutic agents are tocilizumab. In one embodiment, the subject weighs more than or equal to about 30 kg and is administered tocilizumab at a dose of about 8 mg/kg (e.g., 8 mg/kg ± 0.05 mg/kg, ± 0.1 mg/kg, ± 0.25 mg/kg, ± 0.5 mg/kg, or ± 0.8 mg/kg), or the subject weighs less than 30 kg and is administered tocilizumab at a dose of about 12 mg/kg (e.g., 12 mg/kg ± 0.05 mg/kg, ± 0.1 mg/kg, ± 0.25 mg/kg, ± 0.5 mg/kg, ± 0.75 mg/kg, ± 1 mg/kg, or ± 1.2 mg/kg), wherein the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg, or ± 80 mg).

In one embodiment, one or more additional therapeutic agents are corticosteroids.

In one embodiment, the corticosteroid includes prednisone, prednisolone, methylprednisolone, or dexamethasone.

In one embodiment, the corticosteroid is dexamethasone. In one embodiment, dexamethasone is administered intravenously at a dose between about 0.15 mg/kg (e.g., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) and about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.001 mg/kg, ± 0.0025 mg/kg, ± 0.005 mg/kg, ± 0.01 mg/kg, or ± 0.015 mg/kg) before any dose of the bispecific antibody, and wherein the maximum daily dose is 10 mg. In one embodiment, dexamethasone is administered intravenously at a dose between about 0.15 mg/kg (e.g., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) and about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.001 mg/kg, ± 0.0025 mg/kg, ± 0.005 mg/kg, ± 0.01 mg/kg or ± 0.015 mg/kg) and about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, ± 0.04 mg/kg or ± 0.05 mg/kg) before administration of any dose of olibutuzumab, and wherein the maximum daily dose is 10 mg.

In one embodiment, the corticosteroid is methylprednisolone. In one embodiment, methylprednisolone is administered intravenously at a dose between about 1 mg/kg and about 2 mg/kg (e.g., 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.9 or 2.0 mg/kg) at least one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) prior to the administration of any dose of the bispecific antibody. In one embodiment, methylprednisolone is administered intravenously at a dose between about 1 mg/kg and about 2 mg/kg (e.g., 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.9 or 2.0 mg/kg) for at least about one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) prior to the administration of any dose of olibutuzumab.

In one embodiment, the corticosteroid is prednisone or prednisolone. In one embodiment, prednisone or prednisolone is administered intravenously at a dose of about 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 8 mg, or ± 10 mg) or about 2 mg/kg at least one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) or about 2 mg/kg before any dose of the bispecific antibody is administered. In one embodiment, prednisone or prednisolone is administered intravenously at a dose of about 100 mg (e.g., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) or about 2 mg/kg, at least one hour (i.e., at least one hour ± 6 minutes; for example, at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before any dose of olibutuzumab.

In one embodiment, one or more additional therapeutic agents are antihistamines. In one embodiment, the antihistamine is diphenhydramine. In one embodiment, diphenhydramine is administered orally or intravenously at a dose of about 50 mg (e.g., 50 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 3 mg, ± 4 mg, or ± 5 mg). In one embodiment, diphenhydramine is administered at least about 30 minutes (i.e., at least 30 minutes ± 3 minutes; e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before the administration of any dose of the bispecific antibody and/or anti-CD20 antibody.

In one embodiment, one or more additional therapeutic agents include granulocyte colony-stimulating factor (G-CSF). In one embodiment, G-CSF is administered approximately one to approximately two days (e.g., 24, 26, 28, 30, 32, 36, 38, 40, 42, 44, 46, or 48 hours) following administration of any dose of rituximab, ifosfamide, carboplatin, and/or etoposide. In one embodiment, G-CSF is administered intravenously or subcutaneously at a dose of about 5 μg/kg/day (e.g., 5 μg/kg/day ± 0.05 μg/kg/day, ± 0.1 μg/kg/day, ± 0.2 μg/kg/day, ± 0.3 μg/kg/day, ± 0.4 μg/kg/day, ± 0.5 μg/kg/day) or about 10 μg/kg/day (e.g., 10 μg/kg/day ± 0.1 μg/kg/day, ± 0.2 μg/kg/day, ± 0.4 μg/kg/day, ± 0.6 μg/kg/day, ± 0.8 μg/kg/day, ± 1 μg/kg/day). In one embodiment, G-CSF is administered at a dose of about 5 μg/kg/day in the first dosing cycle (e.g., 5 μg/kg/day ± 0.05 μg/kg/day, ± 0.1 μg/kg/day, ± 0.2 μg/kg/day, ± 0.3 μg/kg/day, ± 0.4 μg/kg/day, ± 0.5 μg/kg/day) in the second dosing cycle and/or each additional dosing cycle at a dose of about 10 μg/kg/day (e.g., 10 μg/kg/day ± 0.1 μg/kg/day, ± 0.2 μg/kg/day, ± 0.4 μg/kg/day, ± 0.6 μg/kg/day, ± 0.8 μg/kg/day, ± 1 μg/kg/day).

In one embodiment, one or more additional therapeutic agents are antipyretics. In one embodiment, the antipyretic is acetaminophen or paracetamol. In one embodiment, acetaminophen or paracetamol is administered orally or intravenously at a dose between about 500 and about 1000 mg (e.g., 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg). In one embodiment, acetaminophen or paracetamol is administered at least about 30 minutes (i.e., at least 30 minutes ± 3 minutes; e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or more) before the administration of any dose of the bispecific antibody and/or anti-CD20 antibody.

In one embodiment, one or more additional therapeutic agents are mesna. In one embodiment, mesna is administered intravenously at a dose of about 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± ¹⁰⁰ mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/m², ± 400 mg/ ^m² , or ± 500 mg/ ^m² ). In one embodiment, mesna is administered via continuous infusion over about 24 hours on day 3 of the first dosing cycle, day 6 of the second dosing cycle, and/or day 6 of each additional dosing cycle. In one embodiment, mesna is administered concurrently with any dose of ifosfamide.

In one aspect, the invention is characterized by a method of treating a subject with a CD20-positive proliferative disorder, the method comprising administering to the subject effective amounts of glimepiride, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein:

(a) The first dosing cycle comprises administering a first dose (C1D1) of glimetuzumab on day 8 and a second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of glimetuzumab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); and

(b) The second dosing cycle consists of a single dose (C2D1) of glimetuzumab administered on day 8, wherein the C2D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

In one aspect, the invention is characterized by a method of treating a subject with CD20-positive proliferative disorder, the method comprising administering to the subject effective amounts of glimepiride, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle, wherein:

(a) The first dosing cycle consists of administering the first dose (C1D1) of glimetuzumab on day 8 and the second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg or ± 0.25 mg), and the C1D2 of glimetuzumab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg or ± 1 mg);

(b) The second dosing cycle comprises a single dose (C2D1) of glimetuzumab administered on day 8, wherein the C2D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg); and

(c) The third dosing cycle includes a single dose (C3D1) of glimetuzumab administered on day 8, wherein the C3D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

In one aspect, the invention is characterized by a method of treating a subject with a CD20-positive proliferative disorder, the method comprising administering to the subject effective amounts of glimepiride, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein:

(a) The first dosing cycle includes:

(i) Administer the first dose (C1D1) of glimetuzumab on day 8 and the second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg or ± 0.25 mg), and the C1D2 of glimetuzumab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg or ± 1 mg);

(ii) Administer the first dose (C1D1) of olibutuzumab on day 1, wherein the C1D1 of olibutuzumab is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg or ± 100 mg);

(iii) A single dose (C1D1) of ifosfamide is administered on day 2, wherein the C1D1 of ifosfamide is about 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/ ^m2 , ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), and the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg or ± 80 mg);

(iv) A single dose (C1D1) of carboplatin was administered on day 2, wherein the C1D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C1D1) on day 1, the second dose of etoposide (C1D2) on day 2, and the third dose of etoposide (C1D3) on day 3, wherein the C1D1, C1D2, and C1D3 of etoposide are each approximately 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/ ^m² ); and

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab is administered on day 8, wherein the C2D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg);

(ii) Administer the first dose of rituximab (C2D1) on day 1, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 );

(iii) A single dose (C2D1) of ifosfamide is administered on day 2, wherein the C2D1 of ifosfamide is about 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/ ^m2 , ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), and the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg or ± 80 mg);

(iv) A single dose (C2D1) of carboplatin was administered on day 2, wherein the C2D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C2D1) on day 1, the second dose of etoposide (C2D2) on day 2, and the third dose of etoposide (C2D3) on day 3, wherein the C2D1, C2D2, and C2D3 of etoposide are each approximately 100 mg/ ^m2 (e.g., 100 mg/ ^m2 ± 1 mg/ ^m2 , ± 2.5 mg/ ^m2 , ± 5 mg/ ^m2 , or ± 10 mg/ ^m2 ).

In one aspect, the invention is characterized by a method of treating a subject with CD20-positive proliferative disorder, the method comprising administering to the subject effective amounts of glimepiride, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle, wherein:

(a) The first dosing cycle includes:

(i) Administer the first dose (C1D1) of glimetuzumab on day 8 and the second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg or ± 0.25 mg), and the C1D2 of glimetuzumab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg or ± 1 mg);

(ii) Administer the first dose (C1D1) of olibutuzumab on day 1, wherein the C1D1 of olibutuzumab is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg or ± 100 mg);

(iii) A single dose (C1D1) of ifosfamide is administered on day 2, wherein the C1D1 of ifosfamide is about 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/ ^m2 , ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), and the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg or ± 80 mg);

(iv) A single dose (C1D1) of carboplatin was administered on day 2, wherein the C1D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C1D1) on day 1, the second dose of etoposide (C1D2) on day 2, and the third dose of etoposide (C1D3) on day 3, wherein the C1D1, C1D2, and C1D3 of etoposide are each approximately 100 mg/ ^m2 (e.g., 100 mg/ ^m2 ± 1 mg/ ^m2 , ± 2.5 mg/ ^m2 , ± 5 mg/ ^m2 , or ± 10 mg/ ^m2 );

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab is administered on day 8, wherein the C2D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg);

(ii) Administer the first dose of rituximab (C2D1) on day 1, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 );

(iii) A single dose (C2D1) of ifosfamide is administered on day 2, wherein the C2D1 of ifosfamide is about 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/ ^m2 , ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), and the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg or ± 80 mg);

(iv) A single dose (C2D1) of carboplatin was administered on day 2, wherein the C2D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C2D1) on day 1, the second dose of etoposide (C2D2) on day 2, and the third dose of etoposide (C2D3) on day 3, wherein the C2D1, C2D2, and C2D3 of etoposide are each approximately 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/ ^m² ); and

(c) The third dosing cycle includes:

(i) A single dose (C3D1) of glimetuzumab is administered on day 8, wherein the C3D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg);

(ii) Administer the first dose of rituximab (C3D1) on day 1, wherein the C3D1 of rituximab is approximately 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 );

(iii) A single dose (C3D1) of ifosfamide is administered on day 2, wherein the C3D1 of ifosfamide is about 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/ ^m2 , ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), and the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg or ± 80 mg);

(iv) A single dose of carboplatin (C3D1) was administered on day 2, wherein the C3D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C3D1) on day 1, the second dose of etoposide (C3D2) on day 2, and the third dose of etoposide (C3D3) on day 3, wherein the C3D1, C3D2, and C3D3 of etoposide are each approximately 100 mg/ ^m2 (e.g., 100 mg/ ^m2 ± 1 mg/ ^m2 , ± 2.5 mg/ ^m2 , ± 5 mg/ ^m2 , or ± 10 mg/ ^m2 ).

In one embodiment, mesna is administered concurrently with any dose of ifosfamide. In one embodiment, mesna is administered intravenously at a dose of about 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ). In one embodiment, mesna is administered via continuous infusion over about 24 hours on day 2 of each dosing cycle.

In one aspect, the invention is characterized by a method of treating a subject aged between 6 months and 17 years with CD20-positive proliferative disorders, the method comprising administering to the subject effective amounts of glimepiride, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein:

(a) The first dosing cycle comprises administering the first dose (C1D1) of glimetuzumab on day 8 and the second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is approximately 0.03 mg/kg (e.g., 0.03 mg/kg ± 0.0005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg, or ± 0.003 mg/kg), approximately 0.04 mg/kg (e.g., 0.04 mg/kg ± 0.0005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg, ± 0.003 mg/kg, or ± 0.004 mg/kg), or approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of glimepiride is about 0.15 mg/kg (e.g., 0.15 mg/kg ± 0.001 mg/kg, ± 0.0025 mg/kg, ± 0.005 mg/kg, ± 0.01 mg/kg, or ± 0.015 mg/kg) or about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); and

(b) The second dosing cycle consists of a single dose (C2D1) of glimetuzumab administered on day 8, wherein the C2D1 of glimetuzumab is about 0.4 mg/kg (e.g., 0.4 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg or ± 0.04 mg/kg), about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, ± 0.04 mg/kg or ± 0.05 mg/kg), or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg).

In one aspect, the invention is characterized by a method of treating a subject aged 6 months to 17 years with CD20-positive proliferative disorder, the method comprising administering to the subject effective amounts of glimepiride, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle, wherein:

(a) The first dosing cycle comprises administering a first dose (C1D1) of glimetuzumab on day 8 and a second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is approximately 0.03 mg/kg (e.g., 0.03 mg/kg ± 0.0005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg, or ± 0.003 mg/kg), approximately 0.04 mg/kg (e.g., 0.04 mg/kg ± 0.0005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg, ± 0.003 mg/kg, or ± 0.004 mg/kg), or Approximately 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of glimepiride is approximately 0.15 mg/kg (e.g., 0.15 mg/kg ± 0.001 mg/kg, ± 0.0025 mg/kg, ± 0.005 mg/kg, ± 0.01 mg/kg, or ± 0.015 mg/kg) or approximately 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg);

(b) The second dosing cycle comprises a single dose (C2D1) of glimetuzumab administered on day 8, wherein the C2D1 of glimetuzumab is approximately 0.4 mg/kg (e.g., 0.4 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, or ± 0.04 mg/kg), approximately 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, ± 0.04 mg/kg, or ± 0.05 mg/kg), or approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg); and

(c) The third dosing cycle consists of a single dose (C3D1) of glimetuzumab administered on day 8, wherein the C3D1 of glimetuzumab is about 0.4 mg/kg (e.g., 0.4 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg or ± 0.04 mg/kg), about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, ± 0.04 mg/kg or ± 0.05 mg/kg), or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg).

In one aspect, the invention is characterized by a method of treating a subject aged between 6 months and 17 years with CD20-positive proliferative disorders, the method comprising administering to the subject effective amounts of glimepiride, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein:

(a) The first dosing cycle includes:

(i) Administer the first dose (C1D1) of glimetuzumab on day 8 and the second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 dose of glimetuzumab is approximately 0.03 mg/kg (e.g., 0.03 mg/kg ± 0.0005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg, or ± 0.003 mg/kg), approximately 0.04 mg/kg (e.g., 0.04 mg/kg ± 0.0005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg, ± 0.003 mg/kg, or ± 0.004 mg/kg), or approximately 2.5 mg/kg. mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of glimepiride is about 0.15 mg/kg (e.g., 0.15 mg/kg ± 0.001 mg/kg, ± 0.0025 mg/kg, ± 0.005 mg/kg, ± 0.01 mg/kg, or ± 0.015 mg/kg) or about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg);

(ii) Administer the first dose (C1D1) of olibutuzumab on day 1 and the second dose (C1D2) of olibutuzumab on day 2, wherein the C1D1 of olibutuzumab is approximately one-tenth the sum of the C1D1 and C1D2 of olibutuzumab, and the C1D2 of olibutuzumab is approximately nine-tenths the sum of the C1D1 and C1D2 of olibutuzumab, and wherein the sum of the C1D1 and C1D2 of olibutuzumab is approximately 38 mg/kg (e.g., 38 mg/kg ± 0.25 mg/kg, ± 0.5 mg/kg, ± 1 mg/kg, ± 2 mg/kg). ±3 mg/kg or ±3.8 mg/kg), approximately 28 mg/kg (e.g., 28 mg/kg ±0.25 mg/kg, ±0.5 mg/kg, ±1 mg/kg, ±2 mg/kg or ±2.8 mg/kg), approximately 23 mg/kg (e.g., 23 mg/kg ±0.25 mg/kg, ±0.5 mg/kg, ±1 mg/kg, ±2 mg/kg or ±2.3 mg/kg), approximately 20 mg/kg or approximately 1000 mg (e.g., 1000 mg ±5 mg, ±10 mg, ±20 mg, ±30 mg, ±50 mg, ±75 mg or ±100 mg);

(iii) Administer the first dose of ifosfamide (C1D1) on day 3, the second dose of ifosfamide (C1D2) on day 4, and the third dose of ifosfamide (C1D3) on day 5, wherein the C1D1, C1D2 and C1D3 of ifosfamide are each about 3000 mg/ ^m2 (e.g., 3000 mg/ ^m2 ± 40 mg/ ^m2 , ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 or ± 300 mg/ ^m2 );

(iv) A single dose (C1D1) of carboplatin is administered on day 3, wherein the C1D1 of carboplatin is approximately 635 mg/ ^m² (e.g., 635 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , ± 50 mg/ ^m² , ± 60 mg/ ^m² , or ± 63.5 mg/ ^m² ); and

(v) Administer the first dose of etoposide (C1D1) on day 3, the second dose of etoposide (C1D2) on day 4, and the third dose of etoposide (C1D3) on day 5, wherein the C1D1, C1D2, and C1D3 of etoposide are each approximately 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/ ^m² ); and

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab is administered on day 1, wherein the C2D1 of glimetuzumab is about 0.4 mg/kg (e.g., 0.4 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg or ± 0.04 mg/kg), about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, ± 0.04 mg/kg or ± 0.05 mg/kg) or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg);

(ii) Administer the first dose (C2D1) of rituximab on day 5, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 );

(iii) Administer the first dose of ifosfamide (C2D1) on day 6, the second dose of ifosfamide (C2D2) on day 7, and the third dose of ifosfamide (C2D3) on day 8, wherein the C2D1, C2D2 and C2D3 of ifosfamide are each about 3000 mg/ ^m2 (e.g., 3000 mg/ ^m2 ± 40 mg/ ^m2 , ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 or ± 300 mg/ ^m2 );

(iv) A single dose (C2D1) of carboplatin was administered on day 6, wherein the C2D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C2D1) on day 6, the second dose of etoposide (C2D2) on day 7, and the third dose of etoposide (C2D3) on day 8, wherein the C2D1, C2D2 and C2D3 of etoposide are each about 100 mg/ ^m2 (e.g., 100 mg/ ^m2 ± 1 mg/ ^m2 , ± 2.5 mg/ ^m2 , ± 5 mg/ ^m2 or ± 10 mg/ ^m2 ).

In one aspect, the invention is characterized by a method of treating a subject aged 6 months to 17 years with CD20-positive proliferative disorder, the method comprising administering to the subject effective amounts of glimepiride, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle, wherein:

(a) The first dosing cycle includes:

(i) Administer the first dose (C1D1) of glimetuzumab on day 8 and the second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is about 0.03 mg/kg, about 0.04 mg/kg (e.g., 0.04 mg/kg ± 0.0005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg, ± 0.003 mg/kg, or ± 0.004 mg/kg) or about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.004 mg/kg). 3 mg, ±0.05 mg, ±0.1 mg, ±0.2 mg or ±0.25 mg), and the C1D2 of glimepiride is about 0.15 mg/kg (e.g., 0.15 mg/kg ±0.001 mg/kg, ±0.0025 mg/kg, ±0.005 mg/kg, ±0.01 mg/kg or ±0.015 mg/kg) or about 10 mg (e.g., 10 mg ±0.05 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.5 mg, ±0.75 mg or ±1 mg);

(ii) Administer the first dose (C1D1) of olibutuzumab on day 1 and the second dose (C1D2) of olibutuzumab on day 2, wherein the C1D1 of olibutuzumab is approximately one-tenth the sum of the C1D1 and C1D2 of olibutuzumab, and the C1D2 of olibutuzumab is approximately nine-tenths the sum of the C1D1 and C1D2 of olibutuzumab, wherein the sum of the C1D1 and C1D2 of olibutuzumab is approximately 38 mg/kg (e.g., 38 mg/kg ± 0.25 mg/kg, ± 0.5 mg/kg, ± 1 mg/kg, ± 2 mg/kg, ± 3 mg/kg, or ± 3.8 mg/kg), approximately 28 mg/kg. g/kg (e.g., 28 mg/kg ± 0.25 mg/kg, ± 0.5 mg/kg, ± 1 mg/kg, ± 2 mg/kg or ± 2.8 mg/kg), about 23 mg/kg (e.g., 23 mg/kg ± 0.25 mg/kg, ± 0.5 mg/kg, ± 1 mg/kg, ± 2 mg/kg or ± 2.3 mg/kg), about 20 mg/kg (e.g., 23 mg/kg ± 0.25 mg/kg, ± 0.5 mg/kg, ± 1 mg/kg or ± 2 mg/kg) or about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg or ± 100 mg);

(iii) Administer the first dose of ifosfamide (C1D1) on day 3, the second dose of ifosfamide (C1D2) on day 4, and the third dose of ifosfamide (C1D3) on day 5, wherein the C1D1, C1D2 and C1D3 of ifosfamide are each about 3000 mg/ ^m2 (e.g., 3000 mg/ ^m2 ± 40 mg/ ^m2 , ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 or ± 300 mg/ ^m2 );

(iv) A single dose (C1D1) of carboplatin is administered on day 3, wherein the C1D1 of carboplatin is approximately 635 mg/ ^m² (e.g., 635 mg/ ^m² ± 5 mg/ ^m² , ± 10 mg/ ^m² , ± 25 mg/ ^m² , ± 50 mg/ ^m² , ± 60 mg/ ^m² , or ± 63.5 mg/ ^m² ); and

(v) Administer the first dose of etoposide (C1D1) on day 3, the second dose of etoposide (C1D2) on day 4, and the third dose of etoposide (C1D3) on day 5, wherein the C1D1, C1D2, and C1D3 of etoposide are each approximately 100 mg/ ^m2 (e.g., 100 mg/ ^m2 ± 1 mg/ ^m2 , ± 2.5 mg/ ^m2 , ± 5 mg/ ^m2 , or ± 10 mg/ ^m2 );

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab is administered on day 1, wherein the C2D1 of glimetuzumab is about 0.4 mg/kg (e.g., 0.4 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg or ± 0.04 mg/kg), about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, ± 0.04 mg/kg or ± 0.05 mg/kg) or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg);

(ii) Administer the first dose (C2D1) of rituximab on day 5, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 );

(iii) Administer the first dose of ifosfamide (C2D1) on day 6, the second dose of ifosfamide (C2D2) on day 7, and the third dose of ifosfamide (C2D3) on day 8, wherein the C2D1, C2D2 and C2D3 of ifosfamide are each about 3000 mg/ ^m2 (e.g., 3000 mg/ ^m2 ± 40 mg/ ^m2 , ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 or ± 300 mg/ ^m2 );

(iv) A single dose (C2D1) of carboplatin was administered on day 6, wherein the C2D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C2D1) on day 6, the second dose of etoposide (C2D2) on day 7, and the third dose of etoposide (C2D3) on day 8, wherein the C2D1, C2D2, and C2D3 of etoposide are each approximately 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/ ^m² ); and

(c) The third dosing cycle includes:

(i) A single dose (C3D1) of glimetuzumab is administered on day 1, wherein the C3D1 of glimetuzumab is about 0.4 mg/kg (e.g., 0.4 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg or ± 0.04 mg/kg), about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, ± 0.04 mg/kg or ± 0.05 mg/kg) or about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg);

(ii) Administer the first dose of rituximab (C3D1) on day 5, wherein the C3D1 of rituximab is approximately 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 );

(iii) Administer the first dose of ifosfamide (C3D1) on day 6, the second dose of ifosfamide (C3D2) on day 7, and the third dose of ifosfamide (C3D3) on day 8, wherein the C3D1, C3D2 and C3D3 of ifosfamide are each about 3000 mg/ ^m2 (e.g., 3000 mg/ ^m2 ± 40 mg/ ^m2 , ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 or ± 300 mg/ ^m2 );

(iv) A single dose of carboplatin (C3D1) was administered on day 6, wherein the C3D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C3D1) on day 6, the second dose of etoposide (C3D2) on day 7, and the third dose of etoposide (C3D3) on day 8, wherein the C3D1, C3D2, and C3D3 of etoposide are each approximately 100 mg/ ^m2 (e.g., 100 mg/ ^m2 ± 1 mg/ ^m2 , ± 2.5 mg/ ^m2 , ± 5 mg/ ^m2 , or ± 10 mg/ ^m2 ).

In one embodiment, (a) the subject's weight is greater than or equal to about 7.5 kg and less than about 13 kg, and the C1D1 of glimetuzumab is about 0.04 mg/kg (e.g., 0.04 mg/kg ± 0.0005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg, ± 0.003 mg/kg, or ± 0.004 mg/kg), and the C1D2 of glimetuzumab is about 0.15 mg/kg (e.g., 0.15 mg/kg ± 0.001 mg/kg, ± 0.0025 mg/kg, ± 0.005 mg/kg, ± 0.01 mg/kg, or ± 0.015 mg/kg), and And the C2D1 and/or C3D1 of glimetuzumab is about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, ± 0.04 mg/kg or ± 0.05 mg/kg); (b) the subject's weight is greater than or equal to about 13 kg and less than about 45 kg, and the C1D1 of glimetuzumab is about 0.03 mg/kg (e.g., 0.03 mg/kg ± 0.0005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg or ± 0.003 mg/kg), and the C2D1 and/or C3D1 of glimetuzumab is about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg or ± 0.003 mg/kg), and the C3D1 of glimetuzumab is about 0.5 mg/kg (e.g., 0.5 mg/kg ± 0.005 mg/kg, ± 0.001 mg/kg, ± 0.002 mg/kg or ± 0.003 mg/kg). The C2D1 and/or C3D1 of glimetuzumab is approximately 0.15 mg/kg (e.g., 0.15 mg/kg ± 0.001 mg/kg, ± 0.0025 mg/kg, ± 0.005 mg/kg, ± 0.01 mg/kg, or ± 0.015 mg/kg), and the C2D1 and/or C3D1 of glimetuzumab is approximately 0.4 mg/kg (e.g., 0.4 mg/kg ± 0.005 mg/kg, ± 0.01 mg/kg, ± 0.02 mg/kg, ± 0.03 mg/kg, or ± 0.04 mg/kg); or (c) the subject's weight is greater than or equal to approximately 45 kg, and the C1D1 of glimetuzumab is approximately 2.5 mg/kg. (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), the C1D2 of glimetuzumab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg), and the C2D1 and/or C3D1 of glimetuzumab is about 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

In one embodiment, (a) the subject's weight is greater than or equal to about 7.5 kg and less than about 13 kg, and the sum of C1D1 and C1D2 of olibutuzumab is about 38 mg/kg (e.g., 38 mg/kg ± 0.25 mg/kg, ± 0.5 mg/kg, ± 1 mg/kg, ± 2 mg/kg, ± 3 mg/kg, or ± 3.8 mg/kg); (b) the subject's weight is greater than or equal to about 13 kg and less than about 20 kg, and the sum of the C1D1 and C1D2 of olibutuzumab is about 28 mg/kg (e.g., 28 mg/kg ± 0.25 mg/kg, ± 0.5 mg/kg, ± 1 mg/kg, ± 2 mg/kg, or ± 2.8 mg/kg); (c) the subject's weight is greater than or equal to about 20 kg and less than about 32 kg, and the sum of the C1D1 and C1D2 of olibutuzumab is about 38 mg/kg (e.g., 28 mg/kg ± 0.25 mg/kg, ± 0.5 mg/kg, ± 1 mg/kg, ± 2 mg/kg, or ± 2.8 mg/kg); The sum of C1D1 and C1D2 is about 23 mg/kg (e.g., 23 mg/kg ± 0.25 mg/kg, ± 0.5 mg/kg, ± 1 mg/kg, ± 2 mg/kg, or ± 2.3 mg/kg); (d) the subject weighs more than or equal to about 32 kg and less than about 45 kg, and the sum of C1D1 and C1D2 of olibutuzumab is about 20 mg/kg (e.g., 23 mg/kg ± 0.25 mg/kg, ± 0.5 mg/kg, ± 1 mg/kg, or ± 2 mg/kg); or (e) the subject weighs more than or equal to about 45 kg, and the sum of C1D1 and C1D2 of olibutuzumab is about 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg, or ± 100 mg).

In one embodiment, the C1D1 of oxytocinumab is about one-tenth the sum of the C1D1 and C1D2 of oxytocinumab, and the C1D2 of oxytocinumab is about nine-tenths the sum of the C1D1 and C1D2 of oxytocinumab. In one embodiment, (a) the subject's weight is greater than or equal to about 7.5 kg and less than about 13 kg, and the C1D1 of olibutuzumab is about 3.8 mg/kg (e.g., 3.8 mg/kg ± 0.05 mg/kg, 0.1 mg/kg, ± 0.2 mg/kg, ± 0.3 mg/kg, or ± 0.38 mg/kg) and the C1D2 of olibutuzumab is about 34.2 mg/kg (e.g., 34.2 mg/kg ± 0.5 mg/kg, 1 mg/kg, ± 2 mg/kg, ± 3 mg/kg, or ± 3.42 mg/kg); (b) the subject's weight is greater than or equal to about 13 kg and less than about 20 kg, and the C1D2 of olibutuzumab is about 3.8 mg/kg (e.g., 3.8 mg/kg ± 0.05 mg/kg, 0.1 mg/kg, ± 0.2 mg/kg, ± 0.3 mg/kg, or ± 0.38 mg/kg) and the C1D2 of olibutuzumab is about 34.2 mg/kg (e.g., 34.2 mg/kg ± 0.5 mg/kg, 1 mg/kg, ± 2 mg/kg, ± 3 mg/kg, or ± 3.42 mg/kg); The C1D1 of olibutuzumab is about 2.8 mg/kg (e.g., 2.8 mg/kg ± 0.05 mg/kg, 0.1 mg/kg, ± 0.2 mg/kg, or ± 0.28 mg/kg), and the C1D2 of olibutuzumab is about 35.2 mg/kg (e.g., 35.2 mg/kg ± 0.5 mg/kg, 1 mg/kg, ± 2 mg/kg, ± 3 mg/kg, or ± 3.52 mg/kg); (c) the subject's weight is greater than or equal to about 20 kg and less than about 32 kg, and the C1D1 of olibutuzumab is about 2.3 mg/kg (e.g., 2.3 mg/kg ± 0.05 mg/kg, 0.1 mg/kg, ± 0.2 mg/kg, or ± 0.28 mg/kg). (d) The subject's weight is greater than or equal to about 32 kg and less than about 45 kg, and the C1D1 of olibutuzumab is about 2.0 mg/kg (e.g., 2.0 mg/kg ± 0.05 mg/kg, 0.1 mg/kg or ± 0.2 mg/kg), and the C1D2 of olibutuzumab is about 36.0 mg/kg (e.g., 36 mg/kg ± 0.2 mg/kg, ± 0.23 ... (e) The subject's weight is greater than or equal to about 45 kg, and the C1D1 of olibutuzumab is about 100 mg (e.g., 100 mg ± 0.5 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, ± 4 mg, ± 6 mg, ± 8 mg or ± 10 mg) and the C1D2 of olibutuzumab is about 900 mg (e.g., 900 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 40 mg, ± 50 mg, ± 60 mg, ± 70 mg, ± 80 mg or ± 90 mg).

In one embodiment, mesna is administered to the subject on days 3, 4, and 5 of the first dosing cycle, days 6, 7, and 8 of the second dosing cycle, and/or days 6, 7, and 8 of each additional dosing cycle. In one embodiment, mesna is administered intravenously daily at five doses totaling 3000 mg/ ^m² . In one embodiment, mesna is administered intravenously at a first dose of approximately 600 mg/ ^m² and four repeated doses of approximately 600 mg/ ^m² prior to any dose of ifosfamide, each repeated dose approximately three hours, approximately six hours, and approximately 12 hours after the first dose of ifosfamide.

In one aspect, the invention is characterized by a method of treating a subject aged 18 to 30 years with CD20-positive proliferative disorders, the method comprising administering to the subject effective amounts of glimepiride, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein:

(a) The first dosing cycle comprises administering a first dose (C1D1) of glimetuzumab on day 8 and a second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, or ± 0.25 mg), and the C1D2 of glimetuzumab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, or ± 1 mg); and

(b) The second dosing cycle consists of a single dose (C2D1) of glimetuzumab administered on day 1, wherein the C2D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

In one aspect, the invention is characterized by a method of treating a subject aged 18 to 30 years with CD20-positive proliferative disorders, the method comprising administering to the subject effective amounts of glimepiride, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle, wherein:

(a) The first dosing cycle consists of administering the first dose (C1D1) of glimetuzumab on day 8 and the second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg or ± 0.25 mg), and the C1D2 of glimetuzumab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg or ± 1 mg);

(b) The second dosing cycle comprises a single dose (C2D1) of glimetuzumab administered on day 1, wherein the C2D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg); and

(c) The third dosing cycle consists of a single dose (C3D1) of glimetuzumab administered on day 1, wherein the C3D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg).

In one aspect, the invention is characterized by a method of treating a subject aged 18 to 30 years with CD20-positive proliferative disorders, the method comprising administering to the subject effective amounts of glimepiride, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein:

(a) The first dosing cycle includes:

(i) Administer the first dose (C1D1) of glimetuzumab on day 8 and the second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg or ± 0.25 mg), and the C1D2 of glimetuzumab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg or ± 1 mg);

(ii) Administer a first dose (C1D1) of olibutuzumab on day 1 and a second dose (C1D2) of olibutuzumab on day 2, wherein the C1D1 of olibutuzumab is approximately one-tenth of the sum of the C1D1 and C1D2 of olibutuzumab, and the C1D2 of olibutuzumab is approximately nine-tenths of the sum of the C1D1 and C1D2 of olibutuzumab, and wherein the sum of the C1D1 and C1D2 of olibutuzumab is approximately 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg or ± 100 mg);

(iii) A single dose (C1D1) of ifosfamide is administered on day 3, wherein the C1D1 of ifosfamide is about 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/ ^m2 , ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), and the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg or ± 80 mg);

(iv) A single dose of carboplatin (C1D1) was administered on day 3, wherein the C1D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C1D1) on day 3, the second dose of etoposide (C1D2) on day 4, and the third dose of etoposide (C1D3) on day 5, wherein the C1D1, C1D2, and C1D3 of etoposide are each approximately 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/ ^m² ); and

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab is administered on day 1, wherein the C2D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg);

(ii) Administer the first dose (C2D1) of rituximab on day 5, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 );

(iii) A single dose (C2D1) of ifosfamide is administered on day 6, wherein the C2D1 of ifosfamide is about 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/ ^m2 , ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), and the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg or ± 80 mg);

(iv) A single dose (C2D1) of carboplatin was administered on day 6, wherein the C2D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C2D1) on day 6, the second dose of etoposide (C2D2) on day 7, and the third dose of etoposide (C2D3) on day 8, wherein the C2D1, C2D2 and C2D3 of etoposide are each about 100 mg/ ^m2 (e.g., 100 mg/ ^m2 ± 1 mg/ ^m2 , ± 2.5 mg/ ^m2 , ± 5 mg/ ^m2 or ± 10 mg/ ^m2 ).

In one aspect, the invention is characterized by a method of treating a subject aged 18 to 30 years with CD20-positive proliferative disorders, the method comprising administering to the subject effective amounts of glimepiride, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle, wherein:

(a) The first dosing cycle includes:

(i) Administer the first dose (C1D1) of glimetuzumab on day 8 and the second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg (e.g., 2.5 mg ± 0.01 mg, ± 0.02 mg, ± 0.03 mg, ± 0.05 mg, ± 0.1 mg, ± 0.2 mg or ± 0.25 mg), and the C1D2 of glimetuzumab is about 10 mg (e.g., 10 mg ± 0.05 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg or ± 1 mg);

(ii) Administer a first dose (C1D1) of olibutuzumab on day 1 and a second dose (C1D2) of olibutuzumab on day 2, wherein the C1D1 of olibutuzumab is approximately one-tenth of the sum of the C1D1 and C1D2 of olibutuzumab, and the C1D2 of olibutuzumab is approximately nine-tenths of the sum of the C1D1 and C1D2 of olibutuzumab, and wherein the sum of the C1D1 and C1D2 of olibutuzumab is approximately 1000 mg (e.g., 1000 mg ± 5 mg, ± 10 mg, ± 20 mg, ± 30 mg, ± 50 mg, ± 75 mg or ± 100 mg);

(iii) A single dose (C1D1) of ifosfamide is administered on day 3, wherein the C1D1 of ifosfamide is about 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/ ^m2 , ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), and the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg or ± 80 mg);

(iv) A single dose of carboplatin (C1D1) was administered on day 3, wherein the C1D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C1D1) on day 3, the second dose of etoposide (C1D2) on day 4, and the third dose of etoposide (C1D3) on day 5, wherein the C1D1, C1D2, and C1D3 of etoposide are each approximately 100 mg/ ^m2 (e.g., 100 mg/ ^m2 ± 1 mg/ ^m2 , ± 2.5 mg/ ^m2 , ± 5 mg/ ^m2 , or ± 10 mg/ ^m2 );

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab is administered on day 1, wherein the C2D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg);

(ii) Administer the first dose (C2D1) of rituximab on day 5, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 );

(iii) A single dose (C2D1) of ifosfamide is administered on day 6, wherein the C2D1 of ifosfamide is about 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/ ^m2 , ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), and the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg or ± 80 mg);

(iv) A single dose (C2D1) of carboplatin was administered on day 6, wherein the C2D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C2D1) on day 6, the second dose of etoposide (C2D2) on day 7, and the third dose of etoposide (C2D3) on day 8, wherein the C2D1, C2D2, and C2D3 of etoposide are each approximately 100 mg/ ^m² (e.g., 100 mg/ ^m² ± 1 mg/ ^m² , ± 2.5 mg/ ^m² , ± 5 mg/ ^m² , or ± 10 mg/ ^m² ); and

(c) The third dosing cycle includes:

(i) A single dose (C3D1) of glimetuzumab is administered on day 1, wherein the C3D1 of glimetuzumab is approximately 30 mg (e.g., 30 mg ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg or ± 3 mg);

(ii) Administer the first dose of rituximab (C3D1) on day 5, wherein the C3D1 of rituximab is approximately 375 mg/ ^m2 (e.g., 375 mg/ ^m2 ± 5 mg/ ^m2 , ± 10 mg/ ^m2 , ± 25 mg/ ^m2 or ± 37.5 mg/ ^m2 );

(iii) A single dose (C3D1) of ifosfamide is administered on day 6, wherein the C3D1 of ifosfamide is about 5000 mg/ ^m2 (e.g., 5000 mg/ ^m2 ± 50 mg/ ^m2 , ± 100 mg/ ^m2 , ± 200 mg/ ^m2 , ± 300 mg/ ^m2 , ± 400 mg/ ^m2 or ± 500 mg/ ^m2 ), and the maximum dose is about 800 mg (e.g., 800 mg ± 10 mg, ± 25 mg, ± 50 mg or ± 80 mg);

(iv) A single dose of carboplatin (C3D1) was administered on day 6, wherein the C3D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C3D1) on day 6, the second dose of etoposide (C3D2) on day 7, and the third dose of etoposide (C3D3) on day 8, wherein the C3D1, C3D2, and C3D3 of etoposide are each approximately 100 mg/ ^m2 (e.g., 100 mg/ ^m2 ± 1 mg/ ^m2 , ± 2.5 mg/ ^m2 , ± 5 mg/ ^m2 , or ± 10 mg/ ^m2 ).

In one embodiment, mesna is administered concurrently with any dose of ifosfamide. In one embodiment, mesna is administered intravenously at a dose of about 5000 mg/ ^m² (e.g., 5000 mg/ ^m² ± 50 mg/ ^m² , ± 100 mg/ ^m² , ± 200 mg/ ^m² , ± 300 mg/ ^m² , ± 400 mg/ ^m² , or ± 500 mg/ ^m² ). In one embodiment, mesna is administered via continuous infusion over about 24 hours on day 3 of the first dosing cycle, day 6 of the second dosing cycle, and/or day 6 of each additional dosing cycle. In one embodiment, the CD20-positive proliferative disorder is relapsed and/or refractory DLBCL. In one embodiment, the CD20-positive proliferative disorder is relapsed and/or refractory mature B-cell NHL.

In some embodiments, the dosing cycle is a 14-day (e.g., 14 ± 3 days) dosing cycle. In some embodiments, the dosing cycle is a 21-day (e.g., 21 ± 3 days) dosing cycle. In a particular embodiment, the dosing cycle is a 21-day dosing cycle.

In some embodiments, the method characterized by the present invention further includes administering one or more additional therapeutic agents to a subject. In some embodiments, the one or more additional therapeutic agents are tocilizumab. In some embodiments, the one or more additional therapeutic agents are corticosteroids. In some embodiments, corticosteroids include prednisone, prednisolone, methylprednisolone, or dexamethasone. In some embodiments, the one or more additional therapeutic agents are antihistamines. In some embodiments, the antihistamine is diphenhydramine. In some embodiments, the one or more additional therapeutic agents include allopurinol and raburicase. In some embodiments, the one or more additional therapeutic agents are antipyretics. In some embodiments, the one or more additional therapeutic agents include granulocyte colony-stimulating factor (G-CSF). In some embodiments, the one or more additional therapeutic agents are mesna.

In one embodiment, an anti-CD20 antibody (e.g., glimetuzumab) is administered intravenously.

In one embodiment, the CD20-positive cell proliferative disorder is a B-cell proliferative disorder. In another embodiment, the B-cell proliferative disorder is non-Hodgkin's lymphoma (NHL) or central nervous system lymphoma (CNSL).

In one embodiment, NHL is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), high-grade B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma (PMLBCL), diffuse B-cell lymphoma, or small lymphocytic lymphoma. In one embodiment, NHL is Burkitt lymphoma (BL) or Burkitt leukemia (BAL). In one embodiment, NHL is aggressive and/or mature. In one embodiment, NHL is relapsed and/or refractory. In one embodiment, B-cell proliferative disorder is relapsed and/or refractory mature B-cell NHL.

In one embodiment, the subject has received one prior systemic therapy. In one embodiment, the subject has received no more than one prior systemic therapy. In one embodiment, the prior systemic therapy includes an anti-CD20 antibody and anthracycline. In one embodiment, the subject is human. In one embodiment, the subject is eligible for transplantation or CAR-T cell therapy. In one embodiment, the subject receives an autologous stem cell transplantation (ASCT) after completing the dosing regimen described above. In one embodiment, the ASCT is an autologous hematopoietic stem cell transplantation. In one embodiment, the subject receives an allogeneic hematopoietic stem cell transplantation after completing the dosing regimen described above. In one embodiment, the subject receives CAR-T cell therapy after completing the dosing regimen described above.

In one embodiment, rituximab may be administered on the same day as glucentumab. In one embodiment, the subject has not previously received an IRR with rituximab or a CRS with glucentumab.

In one embodiment, etoposide phosphate can be replaced by the same dose of etoposide.

In one embodiment, oxetuzumab is administered before ICE in the first cycle. In another embodiment, the start of ICE (cycle 1) is delayed by one day to facilitate the completion of oxetuzumab administration.

In one embodiment, the subject achieves objective remission and mobilization of a target dose of 2,000,000 CD34+ hematopoietic stem cells/kg (typically the minimum requirement for ASCT).

(iv) Therapeutic agents used in the methods of the present invention

A. Anti-CD20/anti-CD3 bispecific antibody

This invention provides novel combination therapies using anti-CD20/anti-CD3 bispecific antibodies and anti-CD20 antibodies, along with one or more chemotherapeutic agents selected from ifosfamide, carboplatin, and/or etoposide. In one embodiment, the antibody is a monoclonal antibody. In one embodiment, the anti-CD20/anti-CD3 bispecific antibody is a polyclonal antibody. In one embodiment, the anti-CD20/anti-CD3 bispecific antibody is a human antibody. In one embodiment, the anti-CD20/anti-CD3 bispecific antibody is a humanized antibody. In one embodiment, the anti-CD20/anti-CD3 bispecific antibody is a chimeric antibody. In one embodiment, the anti-CD20/anti-CD3 bispecific antibody is a full-length antibody. In one embodiment, the anti-CD20/anti-CD3 bispecific antibody is an IgG antibody, particularly an IgG1 subclass antibody. In one embodiment, the anti-CD20/anti-CD3 bispecific antibody is a recombinant antibody.

In some embodiments, the anti-CD20/anti-CD3 bispecific antibody comprises an antibody fragment. Antibody fragments include, but are not limited to, Fab, Fab', Fab'-SH, F(ab') ₂ , Fv, and scFv fragments, as well as other fragments described below. For a review of certain antibody fragments, see Hudson et al., Nat. Med. 9:129-134 (2003). For a review of scFv fragments, see, for example, Pluckthün, The harmacology of Monoclonal Antibodies, Vol. 113, Rosenburg and Moore eds., (Springer-Verlag, New York), pp. 269-315 (1994); also see WO 93/16185; and U.S. Patent Nos. 5,571,894 and 5,587,458. For a discussion of Fab and F(ab') ₂ fragments containing rescue receptor-binding epitope residues and having an extended in vivo half-life, see U.S. Patent No. 5,869,046. In one embodiment, the antibody fragment is a Fab fragment or an scFv fragment.

Biantibodies are antibody fragments with two antigen-binding sites, and can be bivalent or bispecific. See, for example, EP 404,097; WO 1993/01161; Hudson et al., Nat. Med. 9:129-134 (2003); and Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993). Descriptions of trisomic and tetrasomic antibodies can also be found in Hudson et al., Nat. Med. 9:129-134 (2003).

A single-domain antibody is an antibody fragment containing all or part of the heavy chain variable domain or all or part of the light chain variable domain. In some embodiments, the single-domain antibody is a human single-domain antibody (Domantis, Inc., Waltham, MA; see, for example, U.S. Patent No. 6,248,516B1).

Antibody fragments can be prepared using a variety of techniques, including but not limited to the proteolytic digestion of intact antibodies and the production of recombinant host cells (e.g., Escherichia coli or bacteriophages), as described herein.

In some embodiments, the anti-CD20/anti-CD3 bispecific antibody is a chimeric antibody. Certain chimeric antibodies are described, for example, in U.S. Patent No. 4,816,567 and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984). In one instance, the chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate such as a monkey) and a human constant region. In another instance, the chimeric antibody is a “class-switching” antibody in which the class or subclass has been changed from that of the parent antibody. Chimeric antibodies include their antigen-binding fragment.

In some embodiments, the anti-CD20/anti-CD3 bispecific antibody is a humanized antibody. Typically, non-human antibodies are humanized to reduce immunogenicity in humans while retaining the specificity and affinity of the parental non-human antibody. Typically, humanized antibodies comprise one or more variable domains, wherein the HVR, such as the CDR (or a portion thereof), is derived from the non-human antibody, and the FR (or a portion thereof) is derived from the human antibody sequence. The humanized antibody may optionally also comprise at least a portion of the human constant region. In some embodiments, some FR residues in the humanized antibody are substituted with corresponding residues from the non-human antibody (e.g., the antibody from which the HVR residues are derived), for example, to restore or improve antibody specificity or affinity.

Humanized antibodies and their preparation methods are reviewed in, for example, Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008), and further described in, for example, Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat'l Acad. Sci. USA 86:10029-10033 (1989); US Patent Nos. 5,821,337, 7,527,791, 6,982,321 and 7,087,409; Kashmi Ri et al., Methods 36:25-34 (2005) (describes specific determination region (SDR) transplantation); Padlan, Mol. Immunol. 28:489-498 (1991) (describes “surface reshaping”); Dall’Acqua et al., Methods 36:43-60 (2005) (describes “FR reshaping”); and Osbourn et al., Methods 36:61-68 (2005) and Klimka et al., Br. J. Cancer, 83:252-260 (2000) (describes the “guided selection” approach to FR reshaping).

Human frame regions that can be used for humanization include, but are not limited to: frame regions selected using a “best fit” method (see, for example, Sims et al. J. Immunol. 151:2296 (1993)); frame regions derived from the common sequence of human antibodies derived from specific subgroups of the light chain or heavy chain variable region (see, for example, Carter et al. Proc. Natl. Acad. Sci. USA, 89:4285 (1992); and Presta et al. J. Immunol., 151:2623 (1993)). 3)); human maturation (somatic mutation) framework region or human germline framework region (see, e.g., Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008)); and framework regions derived from screening FR libraries (see, e.g., Baca et al., J. Biol. Chem. 272:10678-10684 (1997) and Rosok et al., J. Biol. Chem. 271:22611-22618 (1996)).

In some embodiments, the anti-CD20/anti-CD3 bispecific antibody is a human antibody. Human antibodies can be generated using various techniques known in the art. A general description of human antibodies can be found in: van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5: 368-74 (2001) and Lonberg, Curr. Opin. Immunol. 20: 450-459 (2008).

Human antibodies can be prepared by administering an immunogen to a transgenic animal that has been modified to produce a complete human antibody or a complete antibody with a human variable region in response to antigen stimulation. Such animals typically contain all or part of a human immunoglobulin locus, which replaces an endogenous immunoglobulin locus, or is present outside the animal's chromosome or randomly integrated into the animal's chromosome. In such transgenic mice, the endogenous immunoglobulin locus is typically inactivated. For a review of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23:1117-1125 (2005). See also, for example, U.S. Patent Nos. 6,075,181 and 6,150,584 describing the XENOMOUSE ^™ technology; U.S. Patent No. 5,770,429 describing the technology; U.S. Patent No. 7,041,870 describing the KM technology; and U.S. Patent Application Publication No. US 2007/0061900 describing the technology. The human variable region derived from the complete antibody produced by such animals can be further modified, for example, by combining it with different human constant regions.

Human antibodies can also be prepared using hybridoma-based methods. Human myeloma and mouse-human hybrid myeloma cell lines used to produce human monoclonal antibodies have been described. (See, for example, Kozbor J. Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987); and Boerner et al., J. Immunol., 147:86 (1991)). Human antibodies produced by human B-cell hybridoma technology can also be described in Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006). Other methods include, for example, those described in U.S. Patent No. 7,189,826 (which describes the production of monoclonal human IgM antibodies from hybridoma cell lines) and Ni, Xiandai Mianyixue, 26(4):265-268 (2006) (which describes human-human hybridoma). Human hybridoma technology (Trioma technology) is also described in Vollmers and Brandlein, Histology and Histopathology, 20(3):927-937 (2005) and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology, 27(3):185-91 (2005).

Human antibodies can also be generated by isolating variable domain sequences of Fv clones selected from human phage display libraries. These variable domain sequences can then be bound to the desired human constant domain. The technique for selecting human antibodies from antibody libraries is described below.

Binding domains, including those in anti-CD20/anti-CD3 bispecific antibodies, can be isolated by screening combinatorial libraries containing binding moieties with the desired activity or activity. For example, various methods are known in the art for generating phage display libraries and screening such libraries to obtain antibodies with the desired binding characteristics. Such methods are reviewed, for example, by Hoogenboom et al., in Methods in Molecular Biology 178:1-37 (edited by O’Brien et al., Human Press, Totowa, NJ, 2001), and further described, for example, by McCafferty et al., Nature 348:552-554; Clackson et al., Nature 352:624-628 (1991); Marks et al., J. Mol. Biol. 222:581-597 (1992); Marks and Bradbury, in Methods In Molecular Biology 248:161-175 (Lo, ed., Human Press, Totowa, NJ, 2003); Sidhu et al., J.Mol.Biol.338(2):299-310 (2004); Lee et al., J.Mol.Biol.340(5):1073-1093 (2004); Fellouse, Proc.Natl.Acad.Sci.USA 101(34):12467-12472 (2004); and Lee et al., J.Immunol.Methods284(1-2):119-132 (2004).

In some phage display methods, all components of the VH and VL genes are cloned individually by polymerase chain reaction (PCR) and randomly recombined in a phage library. Antigen-binding phages can then be screened from this phage library, as described in Winter et al., Ann. Rev. Immunol., 12:433-455 (1994). Phages typically display antibody fragments as single-chain Fv (scFv) fragments or Fab fragments. Libraries from immunized sources provide high-affinity antibodies against immunogens without the need for hybridoma construction. Alternatively, an initial library (e.g., from humans) can be cloned to provide a single source of antibodies against a wide range of non-self and self antigens without any immunization, as described in Griffiths et al., EMBO J, 12:725-734 (1993). Finally, the initial library can also be synthesized by cloning the unrearranged V gene segment from stem cells; and by using PCR primers containing random sequences to encode the highly variable CDR3 region and perform in vitro rearrangement, as described in Hoogenboom and Winter, J. Mol. Biol., 227:381-388 (1992). Patent publications describing human antibody phage libraries include, for example, U.S. Patent No. 5,750,373, and U.S. Publications Nos. 2005/0079574, 2005/0119455, 2005/0266000, 2007/0117126, 2007/0160598, 2007/0237764, 2007/0292936, and 2009/0002360.

In this paper, antibodies or antibody fragments isolated from human antibody libraries are considered to be human antibodies or human antibody fragments.

Techniques for preparing bispecific antibodies include, but are not limited to, recombinant co-expression of heavy-light chain pairs of two immunoglobulins with different specificities (see Milstein and Cuello, Nature 305:537 (1983), WO 93/08829, and Traunecker et al., EMBO J.10:3655 (1991)) and mortar engineering (see, for example, U.S. Patent No. 5,731,168). Multispecific antibodies can also be prepared by: engineering electrostatic redirection effects for the preparation of antibody Fc-heterodimer molecules (WO 2009/089004A1); crosslinking two or more antibodies or fragments (see, for example, U.S. Patent No. 4,676,980, and Brennan et al., Science, 229:81(1985)); or using leucine zippers to generate bispecific antibodies (see, for example, Kostelny et al., J. Immunol., 148(5):1547-1553(1)). 992); preparation of bispecific antibody fragments using the “dual antibody” technique (see, for example, Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993)); and preparation of trispecific antibodies using single-chain Fv (scFv) dimers (see, for example, Gruber et al., J. Immunol., 152:5368 (1994)); and preparation of trispecific antibodies as described below: for example, Tutt et al., J. Immunol. 147:60 (1991).

Engineered antibodies having three or more functional antigen-binding sites, including “octopus antibodies,” are also included in this document (see, for example, US2006/0025576A1).

The anti-CD20/anti-CD3 bispecific antibodies mentioned in this article also include “dual-acting FAbs” or “DAFs”, which include antigen-binding sites that bind to two different antigens (see, for example, US 2008/0069820).

The “Crossmab” antibody is also included in this article (see, for example, WO2009080251, WO2009080252, WO2009080253, WO2009080254).

Another technique for preparing bispecific antibody fragments is the “bispecific T-cell adaptor” or method (see, for example, WO2004/106381, WO2005/061547, WO2007/042261, and WO2008/119567). This method utilizes two variable antibody domains arranged on a single polypeptide. For example, the single polypeptide chain comprises two single-chain Fv (scFv) fragments, each having a variable heavy chain (VH) and a variable light chain (VL) domain separated by a polypeptide linker of sufficient length to allow intramolecular association between the two domains. The single polypeptide further includes a polypeptide spacer sequence between the two scFv fragments. Each scFv recognizes a different epitope, and these epitopes can be specific to different cell types, so that when each scFv binds to its homologous epitope, cells of two different cell types will approach or bind together closely. One specific embodiment of the method includes an scFv that recognizes a cell surface antigen expressed by immune cells (e.g., a CD3 peptide on T cells), which is linked to another scFv that recognizes a cell surface antigen expressed by target cells (such as malignant or tumor cells).

Because it is a single polypeptide, the bispecific T-cell adaptor can be expressed using any prokaryotic or eukaryotic cell expression system known in the art (e.g., CHO cell lines). However, specific purification techniques (see, for example, EP1691833) may be required to separate the monomeric bispecific T-cell adaptor from other multimeric species that may have biological activities different from the intended activity of the monomer. In one exemplary purification protocol, a solution containing the secreted polypeptide is first subjected to metal affinity chromatography, and the polypeptide is eluted with an imidazole concentration gradient. The eluent is further purified using anion exchange chromatography, and the polypeptide is eluted with a sodium chloride concentration gradient. Finally, the eluent is subjected to size exclusion chromatography to separate the monomer from the multimer.

In some embodiments, the anti-CD20/anti-CD3 bispecific antibody may be further modified to include additional non-protein portions known in the art and readily available. Suitable derivatization portions for anti-CD20/anti-CD3 bispecific antibodies include, but are not limited to, water-soluble polymers. Non-limiting examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), copolymers of ethylene glycol/propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene/maleic anhydride copolymers, polyamino acids (homogeneous or random copolymers) and dextran or poly(n-vinylpyrrolidone) polyethylene glycol, propylene glycol homopolymers, polypropylene oxide/ethylene oxide copolymers, polyoxyethyleneized polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. PEG-propionaldehyde may be advantageous in manufacturing due to its stability in water. The polymer can have any molecular weight and can be branched or unbranched. The number of polymers linked to an antibody can vary, and if more than one polymer is linked, they can be the same or different molecules. Typically, the number and/or type of polymers used for derivatization can be determined based on considerations including, but not limited to, the specific property or function of the antibody to be improved, and whether the antibody derivative will be used for a specific therapeutic purpose.

Anti-CD20/anti-CD3 bispecific antibodies can also be conjugated to one or more cytotoxic agents, such as chemotherapeutic agents or drugs, growth inhibitors, toxins (e.g., protein toxins, enzymatically active toxins or fragments thereof derived from bacteria, fungi, plants or animals), or radioactive isotopes.

In one embodiment, the anti-CD20/anti-CD3 bispecific antibody comprises an antibody-drug conjugate (ADC) wherein the antibody is conjugated to one or more drugs, including but not limited to mastamycin compounds (see U.S. Patent Nos. 5,208,020, 5,416,064 and European Patent EP 0 425235B1); aurestatin, such as monomethylaurestatin drug portions DE and DF (MMAE and MMAF) (see U.S. Patent Nos. 5,635,483 and 5,780,588 and 7,4...). 98,298); scalyxin; calichimycin or derivatives thereof (see U.S. Patent Nos. 5,712,374, 5,714,586, 5,739,116, 5,767,285, 5,770,701, 5,770,710, 5,773,001 and 5,877,296; Hinman et al., Cancer Res. 53:3336-3342 (1993); and Lode et al., Cancer Res. 58:2925-2928 (1993). 98); Anthracyclines, such as doxorubicin or doxycycline (see Kratz et al., Current Med. Chem. 13:477-523 (2006); Jeffrey et al., Bioorganic & Med. Chem. Letters 16:358-362 (2006); Torgov et al., Bioconj. Chem. 16:717-721 (2005); Nagy et al., Proc. Natl. Acad. Sci. U SA 97:829-834 (2000); Dubowchik et al., Bioorg. & Med. Chem. Letters 12:1529-1532 (2002); King et al., J. Med. Chem. 45:4336-4343 (2002); and U.S. Patent No. 6,630,579); methotrexate; vinorelbine; taxanes, such as docetaxel, paclitaxel, larokolpaclitaxel, tercetaxel, and ozaprol; trichothecene; and CC1065.

In another embodiment, an anti-CD20/anti-CD3 bispecific antibody is conjugated to an enzymatically active toxin or a fragment thereof, including but not limited to diphtheria A chain, a non-conjugated active fragment of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modisocyanate A chain, α-Dacococcus, tung oil protein, carnation toxin, pokeweed protein (PAPI, PAPII, and PAP-S), bitter melon inhibitor, curcumin, croton toxin, soapwort inhibitor, white tree toxin, mitochondriin, localized aspergillin, phenolmycin, enoxamin, and trichothecene toxins.

In another embodiment, an anti-CD20/anti-CD3 bispecific antibody is conjugated to a radioactive atom to form a radioactive conjugate. A variety of radioactive isotopes can be used to prepare the radioactive conjugate. Examples include radioactive isotopes of At ²¹¹ , I ¹³¹ , I ¹²⁵ , Y ⁹⁰ , Re ¹⁸⁶ , Re ¹⁸⁸ , Sm ¹⁵³ , Bi ²¹² , P ³² , Pb ²¹² , and Lu. When the radioactive conjugate is used for detection, it may contain radioactive atoms for scintillation studies, such as Tc ^99m or I ¹²³ , or spin labels for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, MRI), such as iodine-123 (again), iodine-131, indium-111, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese, or iron.

Conjugates of anti-CD20/anti-CD3 bispecific antibodies with cytotoxic agents can be prepared using a variety of bifunctional protein conjugates, such as N-succinimide-3-(2-pyridyldithio)propionate (SPDP), succinimide-4-(N-maleimidemethyl)cyclohexane-1-carboxylate (SMCC), iminothiones (IT), bifunctional derivatives of imino esters (such as dimethyl adipate HCl), active esters (such as bissuccinimide octanoic acid), aldehydes (such as glutaraldehyde), diazid compounds (such as bis(p-azidobenzoyl)hexamethylenediamine), diazide derivatives (such as bis-(p-diazobenzoyl)-ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and biactive fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). For example, ricin immunotoxin can be prepared as described in Vitetta et al., Science 238:1098 (1987). Carbon-14 labeled 1-isothiocyanobenzyl-3-methyldiethylenetriaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent used to conjugate radioactive nucleotides to antibodies. See WO94/11026. The linker can be a “cleavable linker” that promotes the release of cytotoxic drugs from cells. For example, acid-labile linkers, peptidase-sensitive linkers, light-labile linkers, dimethyl linkers, or disulfide-containing linkers can be used (Chari et al., Cancer Res. 52:127-131 (1992); US Patent No. 5,208,020).

In one embodiment, an anti-CD20/anti-CD3 bispecific antibody is indicated for the treatment of cancer. In one embodiment, the cancer is a B-cell proliferative disorder. In one embodiment, the cancer is a CD20-positive B-cell proliferative disorder. In one embodiment, the cancer is non-Hodgkin's lymphoma (NHL). In one embodiment, NHL is diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma (HGBCL), FL-derived DLBCL [transformed FL; trFL], primary mediastinal large B-cell lymphoma (PMBCL), or marginal zone lymphoma (MZL). MZL can be classified as splenic MZL, nodular MZL, and extranodal MZL. In one embodiment, NHL is mantle cell lymphoma (MCL). In one embodiment, NHL is grade 1-3a follicular lymphoma (FL). In one embodiment, the CD20-positive B-cell proliferative disorder is a relapsed or refractory B-cell proliferative disorder. In one embodiment, relapsed or refractory B-cell proliferative disorders are relapsed or refractory NHL (e.g., relapsed or refractory DLBCL, relapsed or refractory FL, or relapsed or refractory MCL).

In one embodiment, the anti-CD20/anti-CD3 bispecific antibody binds specifically to CD3ε.

In one embodiment, the anti-CD20/anti-CD3 bispecific antibody can be combined with antibody H2C (PCT Publication No. WO2008/119567), antibody V9 (Rodrigues et al., Int J Cancer Suppl. 7, 45-50 (1992) and US Patent No. 6,054,297), antibody FN18 (Nooij et al., Eur J Immunol. 19, 981-984 (1986)), antibody SP34 (Pessano et al., EMBO J. 4, 337-3). Antibody 40 (1985)), antibody OKT3 (Kung et al., Science 206, 347-349 (1979)), antibody WT31 (Spits et al., J Immunol. 135, 1922 (1985)), antibody UCHT1 (Burns et al., J Immunol. 129, 1451-1457 (1982)), antibody 7D6 (Coulie et al., Eur J Immunol. 21, 1703-1709 (1991)) or antibody Leu-4 competitively bind. In some embodiments, the anti-CD20/anti-CD3 bispecific antibody may also include an antigen-binding portion that specifically binds to CD3, as described in the following: WO 2005/040220, WO 2005/118635, WO 2007/042261, WO 2008/119567, WO 2008/119565, WO 2012/162067, WO 2013/158856, WO 2013/188693, W O2013/186613、WO 2014/110601、WO 2014/145806、WO 2014/191113、WO 2014/047231、WO2015/095392、W O 2015/181098, WO 2015/001085, WO 2015/104346, WO 2015/172800, WO2016/020444 or WO 2016/014974.

In some embodiments, the anti-CD20/anti-CD3 bispecific antibody may include an antibody or antigen-binding portion of rituximab, olibutuzumab, olibutuzumab, olibutuzumab, oxcartuzumab, vetuzumab, and ulrituximab.

In one embodiment, the anti-CD20/anti-CD3 bispecific antibody is REGN1979. In another embodiment, the anti-CD20/anti-CD3 bispecific antibody is FBTA05 (Lymphomun). In yet another embodiment, the anti-CD20/anti-CD3 bispecific antibody is glimetuzumab.

In some embodiments, anti-CD20/anti-CD3 bispecific antibodies may include general, biosimilar or incomparable biological antibody forms as named herein.

In one embodiment, the anti-CD20/anti-CD3 bispecific antibody includes at least one antigen-binding domain that specifically binds to CD20, the antigen-binding domain including a heavy chain variable region, the heavy chain variable region comprising:

(i) HVR-H1, which contains the amino acid sequence of SEQ ID NO:1;

(ii) HVR-H2, which contains the amino acid sequence of SEQ ID NO:2; and

(iii) HVR-H3, which contains the amino acid sequence of SEQ ID NO:3;

And the light chain variable region, which includes:

(i) HVR-L1, which contains the amino acid sequence of SEQ ID NO:4;

(ii) HVR-L2, which contains the amino acid sequence of SEQ ID NO:5; and

(iii) HVR-L3, which contains the amino acid sequence of SEQ ID NO:6.

In one embodiment, the anti-CD20/anti-CD3 bispecific antibody includes at least one antigen-binding domain that specifically binds to CD20. This antigen-binding domain includes a heavy chain variable region sequence and a light chain variable region sequence. The heavy chain variable region sequence is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the sequence in SEQ ID NO:7, and the light chain variable region sequence is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the sequence in SEQ ID NO:8. In another embodiment, the anti-CD20/anti-CD3 bispecific antibody includes at least one antigen-binding domain that specifically binds to CD20. This antigen-binding domain includes the heavy chain variable region sequence of SEQ ID NO:7 and the light chain variable region sequence of SEQ ID NO:8.

In one embodiment, the anti-CD20/anti-CD3 bispecific antibody includes at least one antigen-binding domain that specifically binds to CD3, the antigen-binding domain including a heavy chain variable region, the heavy chain variable region comprising:

(i) HVR-H1, which contains the amino acid sequence of SEQ ID NO:9;

(ii) HVR-H2, which contains the amino acid sequence of SEQ ID NO:10; and

(iii) HVR-H3, which contains the amino acid sequence of SEQ ID NO:11;

And the light chain variable region, which includes:

(i) HVR-L1, which contains the amino acid sequence of SEQ ID NO:12;

(ii) HVR-L2, which contains the amino acid sequence of SEQ ID NO:13; and

(iii) HVR-L3, which contains the amino acid sequence of SEQ ID NO:14.

In one embodiment, the anti-CD20/anti-CD3 bispecific antibody includes at least one antigen-binding domain that specifically binds to CD3. This antigen-binding domain includes a heavy chain variable region sequence and a light chain variable region sequence. The heavy chain variable region sequence is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the sequence in SEQ ID NO:15, and the light chain variable region sequence is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the sequence in SEQ ID NO:16. In another embodiment, the anti-CD20/anti-CD3 bispecific antibody includes at least one antigen-binding domain that specifically binds to CD3. This antigen-binding domain includes the heavy chain variable region sequence of SEQ ID NO:15 and the light chain variable region sequence of SEQ ID NO:16.

In one embodiment, the anti-CD20/anti-CD3 bispecific antibody includes

(i) at least one antigen-binding domain that specifically binds to CD20, the antigen-binding domain comprising a heavy chain variable region, the heavy chain variable region comprising:

a) HVR-H1, which contains the amino acid sequence of SEQ ID NO:1;

b) HVR-H2, which contains the amino acid sequence of SEQ ID NO:2; and

c) HVR-H3, which contains the amino acid sequence of SEQ ID NO:3;

and light chain variable regions, which include:

a) HVR-L1, which contains the amino acid sequence of SEQ ID NO:4;

b) HVR-L2, which contains the amino acid sequence of SEQ ID NO:5; and

c) HVR-L3, which contains the amino acid sequence of SEQ ID NO:6; and

(ii) at least one antigen-binding domain that specifically binds to CD3, the antigen-binding domain comprising a heavy chain variable region, the heavy chain variable region comprising:

a) HVR-H1, which contains the amino acid sequence of SEQ ID NO:9;

b) HVR-H2, which contains the amino acid sequence of SEQ ID NO:10; and

c) HVR-H3, which contains the amino acid sequence of SEQ ID NO:11; and

The variable region of the light chain includes:

a) HVR-L1, which contains the amino acid sequence of SEQ ID NO:12;

b) HVR-L2, which contains the amino acid sequence of SEQ ID NO:13; and

c) HVR-L3, which contains the amino acid sequence of SEQ ID NO:14.

In one embodiment, the anti-CD20/anti-CD3 bispecific antibody includes

(i) at least one antigen-binding domain that specifically binds to CD20, the antigen-binding domain comprising the heavy chain variable region sequence of SEQ ID NO:7 and the light chain variable region sequence of SEQ ID NO:8, and

(ii) At least one antigen-binding domain that specifically binds to CD3, the antigen-binding domain comprising the heavy chain variable region sequence of SEQ ID NO:15 and the light chain variable region sequence of SEQ ID NO:16.

In one embodiment, the antigen-binding domain that specifically binds to the anti-CD20/anti-CD3 bispecific antibody is an antibody fragment, particularly a Fab molecule or an scFv molecule, more particularly a Fab molecule. In a specific embodiment, the antigen-binding domain that specifically binds to the anti-CD20/anti-CD3 bispecific antibody is a cross-linked Fab molecule, wherein the variable or constant domains of the Fab heavy chain and the Fab light chain are exchanged (i.e., substituted for each other).

In one embodiment, the anti-CD20/anti-CD3 bispecific antibody includes at least one antigen-binding domain that specifically binds to CD20 and one antigen-binding domain that specifically binds to CD3. In one embodiment, the anti-CD20/anti-CD3 bispecific antibody includes a first antigen-binding domain that specifically binds to CD3 and a second and a third antigen-binding domain that specifically bind to CD20. In one embodiment, the first antigen-binding domain is a cross-linked Fab molecule, while the second and third antigen-binding domains are each conventional Fab molecules. In one embodiment, the anti-CD20/anti-CD3 bispecific antibody further includes an Fc domain. The anti-CD20/anti-CD3 bispecific antibody may include modifications in the Fc region and/or the antigen-binding domain as described herein. In one embodiment, the anti-CD20/anti-CD3 bispecific antibody includes an IgG1 Fc domain containing one or more amino acid substitutions that reduce binding to the Fc receptor and/or effector function. In one embodiment, the anti-CD20/anti-CD3 bispecific antibody includes an IgG1 Fc domain comprising amino acid substitutions for L234A, L235A, and P329G (EU number).

In one embodiment, the anti-CD20/anti-CD3 bispecific antibody includes

(i) An antigen-binding domain that specifically binds to CD3, which is fused at the C-terminus of the first subunit of the Fc domain to the N-terminus of the Fab heavy chain.

(ii) a first antigen-binding domain that specifically binds to CD20, fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fc heavy chain containing an antigen-binding domain that specifically binds to CD3; and

(iii) A second antigen-binding domain that specifically binds to CD20, which is fused at the C-terminus of the second subunit of the Fc domain to the N-terminus of the Fab heavy chain.

In a specific embodiment, the anti-CD20/anti-CD3 bispecific antibody includes

a) The first Fab molecule, which specifically binds to CD3, particularly CD3ε; and in which the variable domains VL and VH of the Fab light chain and Fab heavy chain are interchanged.

b) Second and third Fab molecules that specifically bind to CD20, wherein in the constant domain CL of the second and third Fab molecules, the amino acid at position 124 is replaced by lysine (K) (according to Kabat numbering), and the amino acid at position 123 is replaced by either lysine (K) or arginine (R) (especially arginine (R)) (according to Kabat numbering), and wherein in the constant domain CH1 of the second and third Fab molecules, the amino acid at position 147 is replaced by glutamic acid (E) (EU numbering), and the amino acid at position 213 is replaced by glutamic acid (E) (EU numbering); and

c) The Fc domain is composed of a first subunit and a second subunit that can stably associate.

In one embodiment, the anti-CD20/anti-CD3 bispecific antibody includes two antigen-binding domains that specifically bind to CD20 and one antigen-binding domain that specifically binds to CD3.

In one embodiment, the anti-CD20/anti-CD3 bispecific antibody is bivalent to CD20 and monovalent to CD3.

In one embodiment, the first Fab molecule under a) is fused at the C-terminus of the Fab heavy chain to the N-terminus of a subunit of the Fc domain under c), the second Fab molecule under b) is fused at the C-terminus of the Fab heavy chain to the N-terminus of the heavy chain of the first Fab molecule under a), and the third Fab molecule under b) is fused at the C-terminus of the Fab heavy chain to the N-terminus of another subunit of the Fc domain under c). In one embodiment, the first Fab molecule under a) comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region being at least 95%, 96%, 97%, 98%, or 99% identical to the sequence SEQ ID NO:15, and the light chain variable region being at least 95%, 96%, 97%, 98%, or 99% identical to the sequence SEQ ID NO:16.

In another embodiment, the first Fab molecule under a) comprises the heavy chain variable region sequence of SEQ ID NO:15 and the light chain variable region sequence of SEQ ID NO:16.

In one embodiment, the second Fab molecule and the third Fab molecule under b) each include a heavy chain variable region sequence and a light chain variable region sequence, wherein the heavy chain variable region is at least 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO:7, and the light chain variable region is at least 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO:8.

In one embodiment, the second Fab molecule and the third Fab molecule under b) each include the heavy chain variable region sequence of SEQ ID NO:7 and the light chain variable region sequence of SEQ ID NO:8.

In a specific embodiment, the anti-CD20/anti-CD3 bispecific antibody comprises: a polypeptide that is at least 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO:17; a polypeptide that is at least 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO:18; a polypeptide that is at least 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO:19; and a polypeptide that is at least 95%, 96%, 97%, 98%, or 99% identical to the sequence of SEQ ID NO:20. In another specific embodiment, the bispecific antibody comprises: the polypeptide sequence of SEQ ID NO:17; the polypeptide sequence of SEQ ID NO:18; the polypeptide sequence of SEQ ID NO:19; and the polypeptide sequence of SEQ ID NO:20. In another specific embodiment, the bispecific antibody comprises: a polypeptide chain comprising SEQ ID NO:17; a polypeptide chain comprising SEQ ID NO:18; a polypeptide chain comprising SEQ ID NO:19; and two polypeptide chains comprising SEQ ID NO:20.

Specific anti-CD20/anti-CD3 bispecific antibodies are described in PCT Publication No. WO 2016/020309 and European Patent Application Nos. EP15188093 and EP16169160 (each incorporated herein by reference in its entirety).

Glucetuzumab

In one embodiment, the anti-CD20/anti-CD3 bispecific antibody that can be used in the methods provided herein is glimetuzumab. Gglimetuzumab (WHO Drug Information (International Nonproprietary Name of the Drug), Recommended INN: List 83, 2020, Vol. 34, No. 1, p. 39; Proposed INN: List 121 WHO Drug Information, Vol. 33, No. 2, 2019, p. 276, also known as CD20-TCB, RO7082859 or RG6026; CAS#: 2229047-91-8) is a novel T-cell binding bispecific (TCB) full-length antibody with a 2:1 molecular configuration for bivalent binding to CD20 on B cells and monovalent binding to CD3 (particularly the CD3ε chain (CD3e)) on T cells. Its CD3 binding region is fused to one of the CD20 binding regions in a head-to-tail manner via a flexible linker. This structure endows glimetuzumab with superior in vitro potency compared to other CD20-CD3 bispecific antibodies with a 1:1 configuration, and it exhibits significant antitumor efficacy in preclinical DLBCL models. The CD20 bivalent retains this potency in the presence of competitive anti-CD20 antibodies, thus providing opportunities for pre-treatment or co-treatment with these drugs. Gglimetuzumab includes an engineered heterodimeric Fc region in which binding to FcgR and C1q is completely absent. By simultaneously binding to CD3e of the T cell receptor (TCR) complex on tumor cells expressing human CD20, it also induces tumor cell lysis in addition to T cell activation, proliferation, and cytokine release. Gglimetuzumab-mediated B cell lysis is CD20-specific and does not occur in the absence of CD20 expression or in the absence of simultaneous binding (crosslinking) between CD20-expressing cells and T cells. In addition to killing, T cells are also activated by CD3 cross-linking, as detected by increased T cell activation markers (CD25 and CD69), cytokine release (IFNγ, TNFα, IL-2, IL-6, IL-10), cytotoxic granule release (granzyme B), and T cell proliferation. A schematic diagram of the molecular structure of glimetuzumab is shown in Figure 2. The sequence of glimetuzumab is summarized in Table 2.

Table 2. Sequence IDs of Gfinolumab

B. Antibody form

1. Anti-CD20/anti-CD3 bispecific antibody

The components of the anti-CD20/anti-CD3 bispecific antibody that can be used in the methods provided herein can be fused together in various configurations. Exemplary configurations are depicted in Figure 1.

In a specific embodiment, the antigen-binding portion included in the anti-CD20/anti-CD3 bispecific antibody is a Fab molecule. In such embodiments, the first antigen-binding portion, the second antigen-binding portion, the third antigen-binding portion, etc., may be referred to herein as a first Fab molecule, a second Fab molecule, a third Fab molecule, etc. Additionally, in a specific embodiment, the anti-CD20/anti-CD3 bispecific antibody includes an Fc domain composed of a first subunit and a second subunit capable of stable association.

In some embodiments, the first Fab molecule is fused at the C-terminus of the first or second subunit of the Fc domain to the N-terminus of the Fab heavy chain.

In one such embodiment, the second Fab molecule is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the first Fab molecule. In a specific embodiment of this type, the anti-CD20/anti-CD3 bispecific antibody essentially consists of a first Fab molecule and a second Fab molecule, an Fc domain composed of a first subunit and a second subunit, and optionally one or more peptide linkers, wherein the first Fab molecule is fused at the C-terminus of the Fab heavy chain to the N-terminus of a first or second subunit of the Fc domain, and the second Fab molecule is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the first Fab molecule. This configuration is schematically depicted in Figures 1G and 1K. Optionally, the Fab light chains of the first Fab molecule and the Fab light chains of the second Fab molecule may additionally fuse to each other.

In another embodiment, the second Fab molecule is fused at the C-terminus of the Fab heavy chain to the N-terminus of either the first or second subunit of the Fc domain. In a specific embodiment of this type, the antibody essentially consists of a first Fab molecule and a second Fab molecule, an Fc domain formed by the first and second subunits, and optionally one or more peptide linkers, wherein each of the first and second Fab molecules is fused at the C-terminus of the Fab heavy chain to the N-terminus of one of the subunits of the Fc domain. This configuration is schematically depicted in Figures 1A and 1D. The first and second Fab molecules can be fused to the Fc domain directly or via peptide linkers. In a particular embodiment, the first and second Fab molecules are each fused to the Fc domain via an immunoglobulin hinge region. In a particular embodiment, the immunoglobulin hinge region is the human IgG ₁ hinge region, particularly when the Fc domain is the IgG ₁ Fc domain.

In other embodiments, the second Fab molecule is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first or second subunit of the Fc domain. In one such embodiment, the first Fab molecule is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the second Fab molecule. In a particularly such embodiment, the antibody essentially consists of a first Fab molecule and a second Fab molecule, an Fc domain formed by the first and second subunits, and optionally one or more peptide linkers, wherein the first Fab molecule is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the second Fab molecule, and the second Fab molecule is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first or second subunit of the Fc domain. Such configurations are schematically illustrated in Figures 1H and 1L. Optionally, the Fab light chains of the first Fab molecule and the Fab light chains of the second Fab molecule may additionally fuse to each other.

Fab molecules can be fused directly to each other with Fc domains or fused to Fc domains via a peptide linker comprising one or more amino acids, typically about 2-20 amino acids. Peptide linkers are known in the art and described herein. Suitable non-immunogenic peptide linkers include, for example, ( _G4S ) _n (SEQ ID NO:21) peptide linkers, ( _SG4 ) _n (SEQ ID NO:22) peptide linkers, or _G4 ( _SG4 ) _n (SEQ ID NO:23) peptide linkers. “n” is typically an integer from 1 to 10, typically from 2 to 4. In one embodiment, the peptide linker is at least 5 amino acids long, in another embodiment it is 5 to 100 amino acids long, and in yet another embodiment it is 10 to 50 amino acids long. In one embodiment, the peptide linker is (GxS) _n or (GxS) _{nGm ,} where G = glycine, S = serine, and (x = 3, n = 3, 4, 5, or 6, and m = 0, 1, 2, or 3) or (x = 4, n = 2, 3, 4, or 5, and m = 0, 1, 2, or 3). In one embodiment, x = 4 and n = 2 or 3, and in another embodiment, x = 4 and n = 2 (SEQ ID NO: 25-56). In one embodiment, the peptide linker is (G ₄ S) ₂ (SEQ ID NO 29). A particularly suitable peptide linker for fusing the Fab light chains of a first Fab molecule and a second Fab molecule to each other is (G ₄ S) ₂ (SEQ ID NO: 29). An exemplary peptide linker suitable for linking the Fab heavy chains of a first Fab fragment and a second Fab fragment includes the sequence (D)-(G ₄ S) ₂ (SEQ ID NO: 29 and 57). Another suitable such linker includes the sequence (G ₄ S) ₄ (SEQ ID NO: 24). Additionally, the linker may include a portion of an immunoglobulin hinge region. In particular, in the case of fusion of the Fab molecule with the N-terminus of an Fc domain subunit, fusion may occur via the immunoglobulin hinge region or a portion thereof, with or without an additional peptide linker.

Antibodies with a single antigen-binding moiety (such as a Fab molecule) capable of specifically binding to target cell antigens can be used (e.g., as shown in Figures 1A, 1D, 1G, 1H, 1K, and 1L), particularly where the target cell antigen is expected to be internalized after binding to a high-affinity antigen-binding moiety. In this case, the presence of more than one antigen-binding moiety specific to the target cell antigen may enhance the internalization of the target cell antigen, thereby reducing its usability.

However, in many other cases, antibodies that include two or more antigen-binding moieties (such as Fab molecules) that are specific to the target cell antigens (see examples shown in Figures 1B, 1C, 1E, 1F, 1I, 1J, 1M, or 1N) would be advantageous, for example, to optimize targeting of the target site or to allow cross-linking of the target cell antigens.

Accordingly, in a specific embodiment, the anti-CD20/anti-CD3 bispecific antibody comprises two anti-CD20 binding moieties, for example, two CD20-targeting Fab molecules. In one embodiment, the two CD20-targeting Fab molecules are conventional Fab molecules. In another embodiment, the two CD20-targeting Fab molecules contain the same heavy and light chain amino acid sequences and have the same domain arrangement (i.e., conventional or cross-linked).

In alternative embodiments, the anti-CD20/anti-CD3 bispecific antibody comprises two anti-CD3 binding moieties, for example, two CD3-targeting Fab molecules. In one such embodiment, both CD3-targeting Fab molecules are cross-linked Fab molecules (a Fab molecule in which the variable domains VH and VL or constant domains CL and CH1 of the Fab heavy and light chains are exchanged/substituted for each other). In another such embodiment, the two CD3-targeting Fab molecules contain the same heavy and light chain amino acid sequences and have the same domain arrangement (i.e., conventional or cross-linked).

In one embodiment, the third Fab molecule is fused at the C-terminus of the first or second subunit of the Fc domain to the N-terminus of the Fab heavy chain.

In a particular embodiment, the second and third Fab molecules are each fused at the C-terminus of the Fab heavy chain to the N-terminus of one of the subunits of the Fc domain, and the first Fab molecule is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the second Fab molecule. In a specific embodiment of this kind, the antibody is substantially composed of a first Fab molecule, a second Fab molecule, and a third Fab molecule, an Fc domain formed by the first and second subunits, and optionally one or more peptide linkers, wherein the first Fab molecule is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the second Fab molecule, and the second Fab molecule is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first subunit of the Fc domain, and the third Fab molecule is fused at the C-terminus of the Fab heavy chain to the N-terminus of the second subunit of the Fc domain. Such configurations are schematically depicted in Figures 1B and 1E (examples, where the third Fab molecule is a conventional Fab molecule and is the same as the second Fab molecule) and Figures 1I and 1M (examples, where the third Fab molecule is a cross-linked Fab molecule and preferably the same as the first Fab molecule). The second and third Fab molecules can be fused to the Fc domain directly or via peptide linkers. In one specific embodiment, the second and third Fab molecules are each fused to the Fc domain via an immunoglobulin hinge region. In one specific embodiment, the immunoglobulin hinge region is the human _IgG1 hinge region, particularly when the Fc domain is the _IgG1 Fc domain. Optionally, the Fab light chains of the first Fab molecule and the second Fab molecule can be further fused to each other.

In another embodiment, the second and third Fab molecules are each fused at the C-terminus of the Fab heavy chain to the N-terminus of one of the subunits of the Fc domain, and the first Fab molecule is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the second Fab molecule. In a particularly such embodiment, the antibody essentially comprises a first Fab molecule, a second Fab molecule, and a third Fab molecule, an Fc domain formed by the first and second subunits, and optionally one or more peptide linkers, wherein the first Fab molecule is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the second Fab molecule, and the second Fab molecule is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first subunit of the Fc domain, and the third Fab molecule is fused at the C-terminus of the Fab heavy chain to the N-terminus of the second subunit of the Fc domain. Such configurations are schematically depicted in Figures 1C and 1F (examples, where the third Fab molecule is a conventional Fab molecule and is identical to the second Fab molecule), and Figures 1J and 1N (examples, where the third Fab molecule is a cross-linked Fab molecule and is identical to the first Fab molecule). The first and third Fab molecules can be fused to the Fc domain directly or via peptide linkers. In one specific embodiment, the second and third Fab molecules are each fused to the Fc domain via an immunoglobulin hinge region. In one specific embodiment, the immunoglobulin hinge region is the human IgG ₁ hinge region, particularly when the Fc domain is the IgG ₁ Fc domain. Optionally, the Fab light chains of the first Fab molecule and the second Fab molecule can be additionally fused to each other.

In this embodiment, the Fab molecule is fused at the C-terminus of the Fab heavy chain via an immunoglobulin hinge region to the N-terminus of each subunit of the Fc domain in an antibody conformation. The two Fab molecules, the hinge region, and the Fc domain essentially form an immunoglobulin molecule. In a particular embodiment, the immunoglobulin molecule is an IgG class immunoglobulin. In an even more specific embodiment, the immunoglobulin is an IgG ₁ subclass immunoglobulin. In another embodiment, the immunoglobulin is an IgG ₄ subclass immunoglobulin. In yet another specific embodiment, the immunoglobulin is a human immunoglobulin. In other embodiments, the immunoglobulin is a chimeric immunoglobulin or a humanized immunoglobulin.

In some antibodies, the Fab light chain of a first Fab molecule is fused to the Fab light chain of a second Fab molecule, optionally via a peptide linker. Depending on the configuration of the first and second Fab molecules, the Fab light chain of the first Fab molecule may be fused at its C-terminus to the N-terminus of the Fab light chain of the second Fab molecule, or vice versa. The fusion of the Fab light chains of the first and second Fab molecules further reduces mismatches between the Fab heavy and light chains and also reduces the number of plasmids required to express some antibodies.

In some embodiments, the antibody comprises: a polypeptide wherein a variable region of the Fab light chain of a first Fab molecule shares a carboxyl-terminal peptide bond with a constant region of the Fab heavy chain of the first Fab molecule (i.e., the first Fab molecule comprises a cross-linked Fab heavy chain in which the variable region of the heavy chain is replaced by a variable region of the light chain), which in turn shares a carboxyl-terminal peptide bond with an Fc domain subunit (VL ₍₁₎ -CH1 ₍₁₎ -CH2-CH3(-CH4)); and a polypeptide wherein the Fab heavy chain of a second Fab molecule shares a carboxyl-terminal peptide bond with an Fc domain subunit (VH ₍₂₎ -CH1 ₍₂₎ -CH2-CH3(-CH4)). In some embodiments, the antibody further comprises: a polypeptide wherein a variable region of the Fab heavy chain of the first Fab molecule shares a carboxyl-terminal peptide bond with a constant region of the Fab light chain of the first Fab molecule (VH ₍₁₎ -CL ₍₁₎ ) and shares a carboxyl-terminal peptide bond with a polypeptide of the Fab light chain of the second Fab molecule (VL ₍₂₎ -CL ₍₂₎ ). In some embodiments, the polypeptides are covalently linked, for example, by disulfide bonds.

In some embodiments, the antibody comprises: a polypeptide wherein a variable region of the Fab heavy chain of a first Fab molecule shares a carboxyl-terminal peptide bond with a constant region of the Fab light chain of the first Fab molecule (i.e., the first Fab molecule comprises a cross-linked Fab heavy chain in which the heavy chain constant region is replaced by a light chain constant region), which in turn shares a carboxyl-terminal peptide bond with an Fc domain subunit (VH ₍₁₎ -CL ₍₁₎ -CH2-CH3(-CH4)); and a polypeptide wherein the Fab heavy chain of a second Fab molecule shares a carboxyl-terminal peptide bond with an Fc domain subunit (VH ₍₂₎ -CH1 ₍₂₎ -CH2-CH3(-CH4)). In some embodiments, the antibody further comprises: a polypeptide wherein a variable region of the Fab light chain of the first Fab molecule shares a carboxyl-terminal peptide bond with a constant region of the Fab heavy chain of the first Fab molecule (VL ₍₁₎ -CH1 ₍₁₎ ) and shares a carboxyl-terminal peptide bond with a polypeptide of the Fab light chain of the second Fab molecule (VL ₍₂₎ -CL ₍₂₎ ). In some embodiments, the polypeptides are covalently linked, for example, by disulfide bonds.

In some embodiments, the antibody comprises a polypeptide wherein the Fab light chain variable region of a first Fab molecule shares a carboxyl-terminal peptide bond with the Fab heavy chain constant region of the first Fab molecule (i.e., the first Fab molecule contains a cross-linked Fab heavy chain, wherein the heavy chain variable region is replaced by the light chain variable region), which in turn shares a carboxyl-terminal peptide bond with the Fab heavy chain of a second Fab molecule, which in turn shares a carboxyl-terminal peptide bond with an Fc domain subunit (VL ₍₁₎ -CH1 ₍₁₎ -VH ₍₂₎ -CH1 ₍₂₎ -CH2-CH3(-CH4)). In other embodiments, the antibody comprises a polypeptide wherein the Fab heavy chain of the second Fab molecule shares a C-terminal peptide bond with the variable region of the Fab light chain of the first Fab molecule, and subsequently shares a C-terminal peptide bond with the constant region of the Fab heavy chain of the first Fab molecule (i.e., the first Fab molecule comprises a cross-linked Fab heavy chain, wherein the variable region of the heavy chain is replaced by the variable region of the light chain), and subsequently shares a C-terminal peptide bond (VH ₍₂₎ -CH1 ₍₂₎ -VL ₍₁₎ -CH1 ₍₁₎ -CH2-CH3(-CH4)) with the Fc domain subunit.

In some of these embodiments, the antibody further comprises: a cross-linked Fab light chain polypeptide of a first Fab molecule, wherein the variable region of the Fab heavy chain of the first Fab molecule shares a carboxyl-terminal peptide bond (VH ₍₁₎ - CL ₍₁₎ ) with the constant region of the Fab light chain of the first Fab molecule, and shares a carboxyl-terminal peptide bond (VL ₍₂₎ - CL ₍₂₎ ) with the Fab light chain polypeptide of a second Fab molecule. In other embodiments of these examples, the antibody further comprises: a polypeptide wherein the variable region of the Fab heavy chain of the first Fab molecule shares a C-terminal peptide bond with the constant region of the Fab light chain of the first Fab molecule, and subsequently shares a C-terminal peptide bond with the Fab light chain polypeptide of the second Fab molecule (VH ₍₁₎ -CL ₍₁₎ -VL ₍₂₎ -CL ₍₂₎ ); or a polypeptide wherein the Fab light chain polypeptide of the second Fab molecule shares a C-terminal peptide bond with the variable region of the Fab heavy chain of the first Fab molecule, and subsequently shares a C-terminal peptide bond with the constant region of the Fab light chain of the first Fab molecule (VL ₍₂₎ -CL ₍₂₎ -VH ₍₁₎ -CL ₍₁₎ ) (where appropriate).

The antibodies according to these embodiments may further comprise: (i) an Fc domain subunit polypeptide (CH2-CH3(-CH4)), or (ii) a polypeptide wherein the Fab heavy chain of the third Fab molecule shares a carboxyl-terminal peptide bond (VH ₍₃₎ -CH1 ₍₃₎ -CH2-CH3(-CH4)) with the Fc domain subunit and shares a carboxyl-terminal peptide bond (VL ₍₃₎ -CL ₍₃₎ ) with the Fab light chain polypeptide of the third Fab molecule. In some embodiments, the polypeptides are covalently linked, for example, by disulfide bonds.

In some embodiments, the antibody comprises a polypeptide wherein the variable region of the Fab heavy chain of the second Fab molecule shares a carboxyl-terminal peptide bond with the constant region of the Fab light chain of the first Fab molecule (i.e., the first Fab molecule contains a cross-linked Fab heavy chain in which the heavy chain constant region is replaced by the light chain constant region), which in turn shares a carboxyl-terminal peptide bond with the Fab heavy chain of the second Fab molecule, and which in turn shares a carboxyl-terminal peptide bond with the Fc domain subunit (VH ₍₁₎ -CL ₍₁₎ -VH ₍₂₎ -CH1 ₍₂₎ -CH2-CH3(-CH4)). In other embodiments, the antibody comprises a polypeptide wherein the Fab heavy chain of the second Fab molecule shares a C-terminal peptide bond with the variable region of the Fab heavy chain of the first Fab molecule, and subsequently shares a C-terminal peptide bond with the constant region of the Fab light chain of the first Fab molecule (i.e., the first Fab molecule comprises a cross-linked Fab heavy chain, wherein the heavy chain constant region is replaced by the light chain constant region), and subsequently shares a C-terminal peptide bond with an Fc domain subunit (VH ₍₂₎ -CH1 ₍₂₎ -VH ₍₁₎ -CL ₍₁₎ -CH2-CH3(-CH4)).

In some of these embodiments, the antibody further comprises: a cross-linked Fab light chain polypeptide of a first Fab molecule, wherein the variable region of the Fab light chain of the first Fab molecule shares a carboxyl-terminal peptide bond (VL ₍₁₎ - CH1 ₍₁₎ ) with the constant region of the Fab heavy chain of the first Fab molecule, and shares a carboxyl-terminal peptide bond (VL ₍₂₎ - CL ₍₂₎ ) with the Fab light chain polypeptide of a second Fab molecule. In other embodiments of these embodiments, the antibody further comprises: a polypeptide wherein the variable region of the Fab light chain of the first Fab molecule shares a C-terminal peptide bond with the constant region of the Fab heavy chain of the first Fab molecule, and subsequently shares a C-terminal peptide bond with the Fab light chain polypeptide of the second Fab molecule (VL ₍₁₎ -CH1 ₍₁₎ -VL ₍₂₎ -CL ₍₂₎ ); or a polypeptide wherein the Fab light chain polypeptide of the second Fab molecule shares a C-terminal peptide bond with the variable region of the Fab heavy chain of the first Fab molecule, and subsequently shares a C-terminal peptide bond with the constant region of the Fab light chain of the first Fab molecule (VL ₍₂₎ -CL ₍₂₎ -VH ₍₁₎ -CL ₍₁₎ ) (as applicable).

The antibodies according to these embodiments may further comprise: (i) an Fc domain subunit polypeptide (CH2-CH3(-CH4)), or (ii) a polypeptide wherein the Fab heavy chain of the third Fab molecule shares a carboxyl-terminal peptide bond (VH ₍₃₎ -CH1 ₍₃₎ -CH2-CH3(-CH4)) with the Fc domain subunit and shares a carboxyl-terminal peptide bond (VL ₍₃₎ -CL ₍₃₎ ) with the Fab light chain polypeptide of the third Fab molecule. In some embodiments, the polypeptides are covalently linked, for example, by disulfide bonds.

In some embodiments, the antibody comprises a polypeptide wherein the Fab heavy chain of a first Fab molecule shares a C-terminal peptide bond with the variable region of the Fab light chain of a second Fab molecule, and subsequently shares a C-terminal peptide bond with the constant region of the Fab heavy chain of the second Fab molecule (i.e., the second Fab molecule comprises a cross-linked Fab heavy chain, wherein the heavy chain variable region is replaced by the light chain variable region) (VH ₍₁₎ -CH1 ₍₁₎ -VL ₍₂₎ -CH1 ₍₂₎ ). In some embodiments, the antibody further comprises a polypeptide wherein the variable region of the Fab heavy chain of the second Fab molecule shares a C-terminal peptide bond with the constant region of the Fab light chain of the second Fab molecule (VH ₍₂₎ -CL ₍₂₎ ) and shares a C-terminal peptide bond with the Fab light chain polypeptide of the first Fab molecule (VL ₍₁₎ -CL ₍₁₎ ).

In some embodiments, the antibody comprises a polypeptide wherein the variable region of the Fab light chain of the second Fab molecule shares a C-terminal peptide bond with the constant region of the Fab heavy chain of the second Fab molecule (i.e., the second Fab molecule comprises a cross-linked Fab heavy chain, wherein the heavy chain variable region is replaced by the light chain variable region), which in turn shares a C-terminal peptide bond with the Fab heavy chain of the first Fab molecule (VL ₍₂₎ -CH1 ₍₂₎ -VH ₍₁₎ -CH1 ₍₁₎ ). In some embodiments, the antibody further comprises a polypeptide wherein the variable region of the Fab heavy chain of the second Fab molecule shares a C-terminal peptide bond with the constant region of the Fab light chain of the second Fab molecule (VH ₍₂₎ -CL ₍₂₎ ) and shares a C-terminal peptide bond with the Fab light chain polypeptide of the first Fab molecule (VL ₍₁₎ -CL ₍₁₎ ).

In some embodiments, the antibody comprises a polypeptide wherein the variable region of the Fab heavy chain of the second Fab molecule shares a C-terminal peptide bond with the constant region of the Fab light chain of the second Fab molecule (i.e., the second Fab molecule comprises a cross-linked Fab heavy chain, wherein the heavy chain variable region is replaced by a light chain variable region), which in turn shares a C-terminal peptide bond (VH ₍₂₎ -CL ₍₂₎ -VH ₍₁₎ -CH1 ₍₁₎ ) with the Fab heavy chain of the first Fab molecule. In some embodiments, the antibody further comprises a polypeptide wherein the variable region of the Fab light chain of the second Fab molecule shares a C-terminal peptide bond (VL ₍₂₎ -CH1 ₍₂₎ ) with the constant region of the Fab heavy chain of the second Fab molecule, and shares a C-terminal peptide bond (VL ₍₁₎ -CL ₍₁₎ ) with the Fab light chain polypeptide of the first Fab molecule.

In some embodiments, the antibody comprises a polypeptide wherein the Fab heavy chain of a third Fab molecule shares a C-terminal peptide bond with the Fab heavy chain of a first Fab molecule, and subsequently shares a C-terminal peptide bond with the variable region of the Fab light chain of a second Fab molecule, and subsequently shares a C-terminal peptide bond with the constant region of the Fab heavy chain of a second Fab molecule (i.e., the second Fab molecule comprises a cross-linked Fab heavy chain wherein the variable region of the heavy chain is replaced by a variable region of the light chain) (VH ₍₃₎ -CH1 ₍₃₎ -VH ₍₁₎ -CH1 ₍₁₎ -VL ₍₂₎ -CH1 ₍₂₎ ). In some embodiments, the antibody further comprises a polypeptide wherein the variable region of the Fab heavy chain of a second Fab molecule shares a C-terminal peptide bond with the constant region of the Fab light chain of a second Fab molecule (VH ₍₂₎ -CL ₍₂₎ ) and shares a C-terminal peptide bond with the Fab light chain polypeptide of the first Fab molecule (VL ₍₁₎ -CL ₍₁₎ ). In some embodiments, the antibody further comprises a Fab light chain polypeptide of a third Fab molecule (VL ₍₃₎ -CL ₍₃₎ ).

In some embodiments, the antibody comprises a polypeptide wherein the Fab heavy chain of a third Fab molecule shares a C-terminal peptide bond with the Fab heavy chain of a first Fab molecule, and subsequently shares a C-terminal peptide bond with the variable region of the Fab heavy chain of a second Fab molecule, and subsequently shares a C-terminal peptide bond with the constant region of the Fab light chain of the second Fab molecule (i.e., the second Fab molecule comprises a cross-linked Fab heavy chain wherein the heavy chain constant region is replaced by the light chain constant region) (VH ₍₃₎ -CH1 ₍₃₎ -VH ₍₁₎ -CH1 ₍₁₎ -VH ₍₂₎ -CL ₍₂₎ ). In some embodiments, the antibody further comprises a polypeptide wherein the variable region of the Fab light chain of a second Fab molecule shares a C-terminal peptide bond with the constant region of the Fab heavy chain of the second Fab molecule (VL ₍₂₎ -CH1 ₍₂₎ ) and shares a C-terminal peptide bond with the Fab light chain polypeptide of the first Fab molecule (VL ₍₁₎ -CL ₍₁₎ ). In some embodiments, the antibody further comprises a Fab light chain polypeptide of a third Fab molecule (VL ₍₃₎ -CL ₍₃₎ ).

In some embodiments, the antibody comprises a polypeptide wherein the variable region of the Fab light chain of a second Fab molecule shares a C-terminal peptide bond with the constant region of the Fab heavy chain of the second Fab molecule (i.e., the second Fab molecule comprises a cross-linked Fab heavy chain, wherein the heavy chain variable region is replaced by the light chain variable region), which in turn shares a C-terminal peptide bond with the Fab heavy chain of a first Fab molecule, which in turn shares a C-terminal peptide bond with the Fab heavy chain of a third Fab molecule (VL ₍₂₎ -CH1 ₍₂₎ -VH ₍₁₎ -CH1 ₍₁₎ -VH ₍₃₎ -CH1 ₍₃₎ ). In some embodiments, the antibody further comprises a polypeptide wherein the variable region of the Fab heavy chain of the second Fab molecule shares a C-terminal peptide bond with the constant region of the Fab light chain of the second Fab molecule (VH ₍₂₎ -CL ₍₂₎ ) and shares a C-terminal peptide bond with the Fab light chain polypeptide of the first Fab molecule (VL ₍₁₎ -CL ₍₁₎ ). In some embodiments, the antibody further comprises a Fab light chain polypeptide of a third Fab molecule (VL ₍₃₎ -CL ₍₃₎ ).

In some embodiments, the antibody comprises a polypeptide wherein the variable region of the Fab heavy chain of a second Fab molecule shares a C-terminal peptide bond with the constant region of the Fab light chain of the second Fab molecule (i.e., the second Fab molecule comprises a cross-linked Fab heavy chain, wherein the heavy chain constant region is replaced by the light chain constant region), which in turn shares a C-terminal peptide bond with the Fab heavy chain of a first Fab molecule, which in turn shares a C-terminal peptide bond with the Fab heavy chain of a third Fab molecule (VH ₍₂₎ -CL ₍₂₎ -VH ₍₁₎ -CH1 ₍₁₎ -VH ₍₃₎ -CH1 ₍₃₎ ). In some embodiments, the antibody further comprises a polypeptide wherein the variable region of the Fab light chain of the second Fab molecule shares a C-terminal peptide bond with the constant region of the Fab heavy chain of the second Fab molecule (VL ₍₂₎ -CH1 ₍₂₎ ) and shares a C-terminal peptide bond with the Fab light chain polypeptide of the first Fab molecule (VL ₍₁₎ -CL ₍₁₎ ). In some embodiments, the antibody further comprises a Fab light chain polypeptide of a third Fab molecule (VL ₍₃₎ -CL ₍₃₎ ).

In some embodiments, the antibody comprises a polypeptide wherein the Fab heavy chain of a first Fab molecule shares a C-terminal peptide bond with the variable region of the Fab light chain of a second Fab molecule, and subsequently shares a C-terminal peptide bond with the constant region of the Fab heavy chain of the second Fab molecule (i.e., the second Fab molecule comprises a cross-linked Fab heavy chain, wherein the variable region of the heavy chain is replaced by the variable region of the light chain), and subsequently shares a C-terminal peptide bond with the variable region of the Fab light chain of a third Fab molecule, and subsequently shares a C-terminal peptide bond with the constant region of the Fab heavy chain of the third Fab molecule (i.e., the third Fab molecule comprises a cross-linked Fab heavy chain, wherein the variable region of the heavy chain is replaced by the variable region of the light chain) (VH ₍₁₎ -CH1 ₍₁₎ -VL _{(2) -CH1 (2)} -VL ₍₃₎ -CH1 ₍₃₎ ). In some embodiments, the antibody further comprises a polypeptide, wherein the variable region of the Fab heavy chain of the second Fab molecule shares a carboxyl-terminal peptide bond (VH ₍₂₎ -CL ₍₂₎ ) with the constant region of the Fab light chain of the second Fab molecule, and shares a carboxyl-terminal peptide bond (VL ₍₁₎ -CL ₍₁₎ ) with the polypeptide of the Fab light chain of the first Fab molecule. In some embodiments, the antibody further comprises a polypeptide, wherein the variable region of the Fab heavy chain of the third Fab molecule shares a carboxyl-terminal peptide bond (VH ₍₃₎ -CL ₍₃₎ ) with the constant region of the Fab light chain of the third Fab molecule.

In some embodiments, the antibody comprises a polypeptide wherein the Fab heavy chain of a first Fab molecule shares a C-terminal peptide bond with the variable region of the Fab heavy chain of a second Fab molecule, and subsequently shares a C-terminal peptide bond with the constant region of the Fab light chain of the second Fab molecule (i.e., the second Fab molecule comprises a cross-linked Fab heavy chain, wherein the heavy chain constant region is replaced by the light chain constant region), and subsequently shares a C-terminal peptide bond with the variable region of the Fab heavy chain of a third Fab molecule, and subsequently shares a C-terminal peptide bond with the constant region of the Fab light chain of the third Fab molecule (i.e., the third Fab molecule comprises a cross-linked Fab heavy chain, wherein the heavy chain constant region is replaced by the light chain constant region) (VH ₍₁₎ -CH1 ₍ 1) -VH ( ₂₎ -CL ₍₂₎ -VH ₍₃₎ -CL ₍₃₎ ). In some embodiments, the antibody further comprises a polypeptide, wherein the variable region of the Fab light chain of the second Fab molecule shares a carboxyl-terminal peptide bond (VL ₍₂₎ -CH1 ₍₂₎ ) with the constant region of the Fab heavy chain of the second Fab molecule, and shares a carboxyl-terminal peptide bond (VL ₍₁₎ -CL ₍₁₎ ) with the polypeptide of the Fab light chain of the first Fab molecule. In some embodiments, the antibody further comprises a polypeptide, wherein the variable region of the Fab light chain of the third Fab molecule shares a carboxyl-terminal peptide bond (VL ₍₃₎ -CH1 ₍₃₎ ) with the constant region of the Fab heavy chain of the third Fab molecule.

In some embodiments, the antibody comprises a polypeptide in which the Fab light chain variable region of a third Fab molecule shares a C-terminal peptide bond with the Fab heavy chain constant region of the third Fab molecule (i.e., the third Fab molecule contains a cross-linked Fab heavy chain in which the heavy chain variable region is replaced by the light chain variable region), which in turn shares a C-terminal peptide bond with the Fab light chain variable region of a second Fab molecule, which in turn shares a C-terminal peptide bond with the Fab heavy chain constant region of the second Fab molecule (i.e., the second Fab molecule contains a cross-linked Fab heavy chain in which the heavy chain variable region is replaced by the light chain variable region), which in turn shares a C-terminal peptide bond with the Fab heavy chain of a first Fab molecule (VL ₍₃₎ -CH1 ₍₃₎ -VL ₍₂₎ -CH1 ₍₂₎ -VH ₍₁₎ -CH1 ₍₁₎ ). In some embodiments, the antibody further comprises a polypeptide, wherein the variable region of the Fab heavy chain of the second Fab molecule shares a carboxyl-terminal peptide bond (VH ₍₂₎ -CL ₍₂₎ ) with the constant region of the Fab light chain of the second Fab molecule, and shares a carboxyl-terminal peptide bond (VL ₍₁₎ -CL ₍₁₎ ) with the polypeptide of the Fab light chain of the first Fab molecule. In some embodiments, the antibody further comprises a polypeptide, wherein the variable region of the Fab heavy chain of the third Fab molecule shares a carboxyl-terminal peptide bond (VH ₍₃₎ -CL ₍₃₎ ) with the constant region of the Fab light chain of the third Fab molecule.

In some embodiments, the antibody comprises a polypeptide in which the variable region of the Fab heavy chain of a third Fab molecule shares a C-terminal peptide bond with the constant region of the Fab light chain of the third Fab molecule (i.e., the third Fab molecule contains a cross-linked Fab heavy chain in which the heavy chain constant region is replaced by the light chain constant region), which in turn shares a C-terminal peptide bond with the variable region of the Fab heavy chain of a second Fab molecule, which in turn shares a C-terminal peptide bond with the constant region of the Fab light chain of the second Fab molecule (i.e., the second Fab molecule contains a cross-linked Fab heavy chain in which the heavy chain constant region is replaced by the light chain constant region), which in turn shares a C-terminal peptide bond with the Fab heavy chain of a first Fab molecule (VH ₍₃₎ -CL ₍₃₎ -VH ₍₂₎ -CL ₍₂₎ -VH ₍₁₎ -CH1 ₍₁₎ ). In some embodiments, the antibody further comprises a polypeptide, wherein the variable region of the Fab light chain of the second Fab molecule shares a carboxyl-terminal peptide bond (VL ₍₂₎ -CH1 ₍₂₎ ) with the constant region of the Fab heavy chain of the second Fab molecule, and shares a carboxyl-terminal peptide bond (VL ₍₁₎ -CL ₍₁₎ ) with the polypeptide of the Fab light chain of the first Fab molecule. In some embodiments, the antibody further comprises a polypeptide, wherein the variable region of the Fab light chain of the third Fab molecule shares a carboxyl-terminal peptide bond (VL ₍₃₎ -CH1 ₍₃₎ ) with the constant region of the Fab heavy chain of the third Fab molecule.

According to any of the embodiments described above, antibody components (e.g., Fab molecules, Fc domains) can be fused directly or via various linkers, particularly via peptide linkers comprising one or more amino acids (typically about 2 to 20 amino acids) as described herein or known in the art. Suitable non-immunogenic peptide linkers include, for example, ( _G4S ) _n (SEQ ID NO 21) peptide linkers, ( _SG4 ) _n (SEQ ID NO 22) peptide linkers, or _G4 ( _SG4 ) _n (SEQ ID NO 23) peptide linkers, where n is typically an integer from 1 to 10, typically from 2 to 4.

2. Fc structural domain

Anti-CD20/anti-CD3 bispecific antibodies that can be used in methods as described herein may comprise an Fc domain consisting of a pair of polypeptide chains, each including a heavy chain domain of the antibody molecule. For example, the Fc domain of an immunoglobulin G (IgG) molecule is a dimer, each subunit of which contains CH2 and CH3 IgG heavy chain constant domains. The two subunits of the Fc domain are capable of stably associating with each other.

In one embodiment, the Fc domain is an IgG Fc domain. In a particular embodiment, the Fc domain is an IgG ₁ Fc domain. In another embodiment, the Fc domain is an IgG ₄ Fc domain. In a more specific embodiment, the Fc domain is an IgG ₄ Fc domain comprising an amino acid substitution at position S228 (Kabat number), specifically amino acid substitution S228P. This amino acid substitution reduces Fab arm exchange of the IgG ₄ antibody in vivo (see, Stubenrauch et al., Drug Metabolism and Disposition 38, 84-91 (2010)). In yet another specific embodiment, the Fc domain is a human Fc domain.

(i) Modification of Fc domains to promote heterodimerization

Anti-CD20/anti-CD3 bispecific antibodies that can be used in methods such as those presented herein may comprise different components (e.g., antigen-binding domains) fused to one or the other of the two subunits of the Fc domain, thus the two subunits of the Fc domain are typically comprised in two different polypeptide chains. Recombinant co-expression and subsequent dimerization of these polypeptides result in several possible combinations of the two polypeptides. To improve the yield and purity of such antibodies in recombinant production, it would be advantageous to introduce modifications into the Fc domain of the antibody that promote the association of the desired polypeptide.

Accordingly, in a particular embodiment, the Fc domain includes modifications that promote association between the first and second subunits of the Fc domain. The most extensive protein-protein interaction site between the two subunits of the human IgG Fc domain is located in the CH3 domain of the Fc domain. Therefore, in one embodiment, the modification is located in the CH3 domain of the Fc domain.

Several methods for modifying the CH3 domain of the Fc domain to enhance heterodimerization are well described in, for example, WO96/27011, WO 98/050431, EP 1870459, WO 2007/110205, WO 2007/147901, WO 2009/089004, WO 2010/129304, WO 2011/90754, WO 2011/143545, WO 2012058768, WO2013157954, and WO 2013096291. Typically, in all such methods, the CH3 domains of the first subunit and the second subunit of the Fc domain are engineered in a complementary manner, such that each CH3 domain (or the heavy chain containing it) is no longer homodimerized with itself, but is instead forced to heterodimerize with the other complementaryly engineered CH3 domains (so that the first and second CH3 domains heterodimerize and no homodimers are formed between the two first or two second CH3 domains). These different methods for improving heavy chain heterodimerization are considered as different options in conjunction with heavy-light chain modifications (e.g., variable or constant region exchange/replacement in the Fab arm, or the introduction of substituents with charged amino acids of opposite charge in the CH1/CL interface), which reduce light chain mismatches and Bence Jones-type byproducts.

In one specific embodiment, the modification that promotes association between the first and second subunits of the Fc domain is a so-called "protrusion-to-pore" modification, which includes "protrusion" modification in one subunit of the two subunits of the Fc domain and "pore" modification in the other subunit of the two subunits of the Fc domain.

The "mortar and pestle" technique is described, for example, in: US 5,731,168; US 7,695,936; Ridgway et al., Prot Eng. 9,617-621 (1996) and Carter, J Immunol Meth. 248,7-15 (2001). Typically, this method involves introducing a protrusion ("mortar") at the interface of a first polypeptide and a corresponding cavity ("pot") at the interface of a second polypeptide, such that the protrusion can be positioned within the cavity to promote the formation of a heterodimer and inhibit the formation of a homodimer. The protrusion is constructed by replacing a small amino acid side chain from the interface of the first polypeptide with a larger side chain (e.g., tyrosine or tryptophan). A compensating cavity of the same or similar size as the protrusion is created at the interface of the second polypeptide by replacing the large amino acid side chain with a smaller amino acid side chain (e.g., alanine or threonine).

Accordingly, in a specific embodiment, in the CH3 domain of the first subunit of the Fc domain, an amino acid residue is replaced with an amino acid residue having a larger side chain volume, thereby creating a protrusion in the CH3 domain of the first subunit. This protrusion can be positioned in a cavity within the CH3 domain of the second subunit. Furthermore, in the CH3 domain of the second subunit of the Fc domain, an amino acid residue is replaced with an amino acid residue having a smaller side chain volume, thereby creating a cavity within the CH3 domain of the second subunit. The protrusion in the CH3 domain of the first subunit can be positioned within this cavity.

Preferably, the amino acid residues with a large side chain volume are selected from the group consisting of arginine (R), phenylalanine (F), tyrosine (Y), and tryptophan (W).

Preferably, the amino acid residues with smaller side chain volume are selected from the group consisting of alanine (A), serine (S), threonine (T) and valine (V).

Protrusions and cavities can be prepared by altering the nucleic acids encoding polypeptides (e.g., through site-specific mutagenesis or through peptide synthesis).

In a specific embodiment, in the CH3 domain (“mortar” subunit) of the first subunit of the Fc domain, the threonine residue at position 366 is replaced with a tryptophan residue (T366W), and in the CH3 domain (“mortar” subunit) of the second subunit of the Fc domain, the tyrosine residue at position 407 is replaced with a valine residue (Y407V) (EU number). In one embodiment, additionally in the second subunit of the Fc domain, the threonine residue at position 366 is replaced with a serine residue (T366S), and the leucine residue at position 368 is replaced with an alanine residue (L368A) (EU number).

In yet another embodiment, in the first subunit of the Fc domain, the serine residue at position 354 is replaced with a cysteine residue (S354C) or the glutamate residue at position 356 is replaced with a cysteine residue (E356C), and in the second subunit of the Fc domain, the tyrosine residue at position 349 is replaced with a cysteine residue (Y349C) (EU designation). The introduction of these two cysteine residues results in the formation of a disulfide bridge between the two subunits of the Fc domain, thereby further stabilizing the dimer (Carter, J Immunol Methods 248, 7-15 (2001)).

In a particular embodiment, the first subunit of the Fc domain includes amino acid substitutions S354C and T366W, and the second subunit of the Fc domain includes amino acid substitutions Y349C, T366S, L368A, and Y407V (EU designation).

In a particular embodiment, the CD3 antigen-binding moiety disclosed herein is fused to a first subunit of the Fc domain (including a "clump" modification). It is not expected, theoretically speaking, that the fusion of the CD3 antigen-binding moiety with a clump-containing subunit of the Fc domain will (further) minimize the generation of bispecific antibodies comprising two CD3 antigen-binding moieties (stereochemical conflict between two clump-containing peptides).

Other techniques for CH3 modification used in forced heterodimerization can be envisioned as alternatives to the present invention, and such techniques are disclosed, for example, in WO 96/27011, WO 98/050431, EP1870459, WO 2007/110205, WO 2007/147901, WO 2009/089004, WO 2010/129304, WO 2011/90754, WO 2011/143545, WO 2012/058768, WO 2013/157954, and WO 2013/096291.

In one embodiment, the heterodimerization method disclosed in EP 1870459 A1 is used alternatively. This method is based on introducing charged amino acids with opposite charges at specific amino acid positions in the CH3/CH3 domain interface between the two subunits of the Fc domain. A preferred embodiment is the amino acid mutations R409D and K370E in one of the two CH3 domains of the Fc domain; and the amino acid mutations D399K and E357K (EU number) in the other of the two CH3 domains of the Fc domain.

In another embodiment, the anti-CD20/anti-CD3 bispecific antibody may include amino acid mutations T366W in the CH3 domain of the first subunit of the Fc domain and amino acid mutations T366S, L368A, and Y407V in the CH3 domain of the second subunit of the Fc domain, and additionally, amino acid mutations R409D and K370E in the CH3 domain of the first subunit of the Fc domain and amino acid mutations D399K and E357K (EU numbers) in the CH3 domain of the second subunit of the Fc domain.

In another embodiment, the anti-CD20/anti-CD3 bispecific antibody comprises amino acid mutations S354C and T366W in the CH3 domain of the first subunit of the Fc domain and amino acid mutations Y349C, T366S, L368A, and Y407V in the CH3 domain of the second subunit of the Fc domain, or the antibody comprises amino acid mutations Y349C and T366W in the CH3 domain of the first subunit of the Fc domain and amino acid mutations S354C, T366S, L368A, and Y407V in the CH3 domain of the second subunit of the Fc domain, and additionally, amino acid mutations R409D and K370E in the CH3 domain of the first subunit of the Fc domain and amino acid mutations D399K and E357K in the CH3 domain of the second subunit of the Fc domain (all EU numbers).

In one embodiment, the heterodimerization method described in WO 2013/157953 is used alternatively. In one embodiment, the first CH3 domain includes the amino acid mutation T366K, and the second CH3 domain includes the amino acid mutation L351D (EU number). In another embodiment, the first CH3 domain includes the amino acid mutation L351K (EU number). In yet another embodiment, the second CH3 domain further includes an amino acid mutation selected from Y349E, Y349D, and L368E (preferably L368E) (EU number).

In one embodiment, the heterodimerization method described in WO 2012/058768 is used instead. In one embodiment, the first CH3 domain comprises amino acid mutations L351Y and Y407A, and the second CH3 domain comprises amino acid mutations T366A and K409F (EU number). In another embodiment, the second CH3 domain includes a further amino acid mutation at position T411, D399, S400, F405, N390, or K392, selected from, for example: a) T411N, T411R, T411Q, T411K, T411D, T411E, or T411W; b) D399R, D399W, D399Y, or D399K; c) S400E, S400D, S400R, or S400K; d) F405I, F405M, F405T, F405S, F405V, or F405W; e) N390R, N390K, or N390D; or f) K392V, K392M, K392R, K392L, K392F, or K392E (EU number). In another embodiment, the first CH3 domain includes amino acid mutations L351Y and Y407A, and the second CH3 domain includes amino acid mutations T366V and K409F (EU number). In another embodiment, the first CH3 domain includes amino acid mutation Y407A, and the second CH3 domain includes amino acid mutations T366A and K409F (EU number). In another embodiment, the second CH3 domain further includes amino acid mutations K392E, T411E, D399R, and S400R (EU number).

In one embodiment, the heterodimerization method disclosed in WO 2011/143545 may be used alternatively, for example, by modifying amino acids at positions selected from 368 and 409 (EU numbers).

In one embodiment, the heterodimerization method described in WO 2011/090762 is used alternatively, which also employs the aforementioned protrusion-in-pore technique. In one embodiment, the first CH3 domain comprises the amino acid mutation T366W, and the second CH3 domain comprises the amino acid mutation Y407A (EU number). In another embodiment, the first CH3 domain comprises the amino acid mutation T366Y, and the second CH3 domain comprises the amino acid mutation Y407T (EU number).

In one embodiment, the Fc domain of the anti-CD20/anti-CD3 bispecific antibody or the anti-CD20/anti-CD3 bispecific antibody belongs to the _IgG2 subclass and can be obtained using the heterodimerization method described in WO 2010/129304.

In alternative embodiments, modifications that promote association between the first and second subunits of the Fc domain include modifications that mediate electrostatic reorientation, such as those disclosed in PCT Publication WO 2009/089004. Typically, this method involves replacing one or more amino acid residues at the interface between the two Fc domain subunits with charged amino acid residues, making homodimer formation electrostatically unfavorable but heterodimerization electrostatically favorable. In one such embodiment, the first CH3 domain comprises a negatively charged amino acid substitution for K392 and N392 (e.g., glutamic acid (E) or aspartic acid (D), preferably K392D or N392D), and the second CH3 domain comprises a positively charged amino acid substitution for D399, E356, D356, or E357 (e.g., lysine (K) or arginine (R), preferably D399K, E356K, D356K, or E357K, and more preferably D399K and E356K). In another embodiment, the first CH3 domain further comprises a negatively charged amino acid substitution for K409 or R409 (e.g., glutamic acid (E) or aspartic acid (D), preferably K409D or R409D). In another embodiment, the first CH3 domain further or alternatively includes a substitution of K439 and/or K370 with a negatively charged amino acid (e.g., glutamic acid (E) or aspartic acid (D)) (EU number).

In yet another embodiment, the heterodimerization method described in WO 2007/147901 is used instead. In one embodiment, the first CH3 domain comprises amino acid mutations K253E, D282K, and K322D, and the second CH3 domain comprises amino acid mutations D239K, E240K, and K292D (EU number).

In yet another embodiment, the heterodimerization method disclosed in WO 2007/110205 may be used.

In one embodiment, the first subunit of the Fc domain comprises amino acid substitutions K392D and K409D, and the second subunit of the Fc domain comprises amino acid substitutions D356K and D399K (EU number).

(ii) Fc domain modifications that reduce Fc receptor binding and/or effector function

The Fc domain endows antibodies (such as anti-CD20/anti-CD3 bispecific antibodies) with favorable pharmacokinetic properties, including a long serum half-life, which facilitates good accumulation and a favorable tissue-blood partition ratio in target tissues. However, at the same time, it can lead to undesirable targeting of the antibody to cells expressing the Fc receptor, rather than to cells carrying the preferred antigen. Furthermore, co-activation of the Fc receptor signaling pathway can result in cytokine release, which, in combination with other immunostimulatory properties that the antibody may possess and the antibody's long half-life, can lead to overactivation of cytokine receptors and serious side effects after systemic administration.

Accordingly, in certain embodiments, the Fc domain of an anti-CD20/anti-CD3 bispecific antibody exhibits decreased binding affinity to the Fc receptor and/or reduced effector function compared to the native IgG1 _Fc domain. In one such embodiment, the Fc domain (or a molecule containing the native _{IgG1 Fc} domain, e.g., an antibody) exhibits less than 50%, preferably less than 20%, more preferably less than 10%, and most preferably less than 5% binding affinity to the Fc receptor compared to the native IgG1 _Fc domain (or a corresponding molecule containing the native _IgG1 Fc domain), and/or exhibits less than 50%, preferably less than 20%, more preferably less than 10%, and most preferably less than 5% effector function compared to the native IgG1 Fc domain (or a corresponding molecule containing the native IgG1 Fc domain). In one embodiment, the Fc domain (or a molecule containing the Fc domain, e.g., an antibody) substantially does not bind to the Fc receptor and/or induce effector function. In one particular embodiment, the Fc receptor is an Fcγ receptor. In one embodiment, the Fc receptor is a human Fc receptor. In one embodiment, the Fc receptor is an activated Fc receptor. In a specific embodiment, the Fc receptor is an activated human Fcγ receptor, more particularly human FcγRIIIa, FcγRI, or FcγRIIa, and most particularly human FcγRIIIa. In one embodiment, the effector function is one or more effector functions selected from the group consisting of CDC, ADCC, ADCP, and cytokine secretion. In a particular embodiment, the effector function is ADCC. In one embodiment, the Fc domain exhibits substantially similar binding affinity to the nascent Fc receptor (FcRn) compared to the native _IgG1 Fc domain. Substantially similar binding to FcRn is achieved when the Fc domain (or a molecule including the Fc domain, e.g., an antibody) exhibits a binding affinity greater than about 70%, particularly greater than about 80%, more particularly greater than about 90% of that of the native _IgG1 Fc domain (or a corresponding molecule including the _IgG1 Fc domain) for FcRn.

In some embodiments, the Fc domain is engineered to have reduced binding affinity to the Fc receptor and/or reduced effector function compared to an unengineered Fc domain. In specific embodiments, the Fc domain comprises one or more amino acid mutations that reduce the binding affinity of the Fc domain to the Fc receptor and/or effector function. Typically, the same one or more amino acid mutations are present in each of the two subunits of the Fc domain. In one embodiment, the amino acid mutation reduces the binding affinity of the Fc domain to the Fc receptor. In one embodiment, the amino acid mutation reduces the binding affinity of the Fc domain to the Fc receptor by at least 2-fold, at least 5-fold, or at least 10-fold. In embodiments where more than one amino acid mutation reducing the binding affinity of the Fc domain to the Fc receptor is present, the combination of these amino acid mutations can reduce the binding affinity of the Fc domain to the Fc receptor by at least 10-fold, at least 20-fold, or even at least 50-fold. In some embodiments, molecules including engineered Fc domains (e.g., antibodies) exhibit less than 20%, particularly less than 10%, and more particularly less than 5% binding affinity to the Fc receptor compared to corresponding molecules including non-engineered Fc domains. In one particular embodiment, the Fc receptor is an Fcγ receptor. In some embodiments, the Fc receptor is a human Fc receptor. In some embodiments, the Fc receptor is an activated Fc receptor. In one specific embodiment, the Fc receptor is an activated human Fcγ receptor, more particularly human FcγRIIIa, FcγRI, or FcγRIIa, and most particularly human FcγRIIIa. Preferably, binding affinity to each of these receptors is reduced. In some embodiments, binding affinity to complement components, particularly to C1q, is also reduced. In one embodiment, binding affinity to the nascent Fc receptor (FcRn) is not reduced. When an Fc domain (or a molecule including the Fc domain, such as an antibody) exhibits a binding affinity greater than about 70% for the unengineered form of the Fc domain (or a corresponding molecule including the unengineered form of the Fc domain) to FcRn, substantially similar binding to FcRn is achieved; that is, the binding affinity of the Fc domain to the receptor is maintained. An Fc domain or a molecule including the Fc domain (such as an antibody) can exhibit such affinity greater than about 80% and even greater than about 90%. In some embodiments, the Fc domain is engineered to have a mutation that results in reduced effector function compared to the unengineered Fc domain. The reduced effector function may include, but is not limited to, one or more of the following: reduced complement-dependent cytotoxicity (CDC), reduced antibody-dependent cell-mediated cytotoxicity (ADCC), reduced antibody-dependent phagocytosis (ADCP), reduced cytokine secretion, reduced immune complex-mediated antigen uptake by antigen-presenting cells, reduced binding to NK cells, reduced binding to macrophages, reduced binding to monocytes, reduced binding to polymorphonuclear cells, reduced direct signal transduction-induced apoptosis, reduced cross-linking of target-binding antibodies, reduced dendritic cell maturation, or reduced T cell sensitization. In one embodiment, the reduced effector function is one or more of the reduced effector functions selected from the group consisting of reduced CDC, reduced ADCC, reduced ADCP, and reduced cytokine secretion. In a particular embodiment, the reduced effector function is reduced ADCC. In one embodiment, the reduced ADCC is less than 20% of ADCC induced by an unmodified Fc domain (or a corresponding molecule including an unmodified Fc domain).

In one embodiment, the amino acid mutation that reduces the binding affinity of the Fc domain to the Fc receptor and/or the effector function is an amino acid substitution. In one embodiment, the Fc domain includes an amino acid substitution at a position selected from the group consisting of E233, L234, L235, N297, P331, and P329 (EU number). In a more specific embodiment, the Fc domain includes an amino acid substitution at a position selected from the group consisting of L234, L235, and P329 (EU number). In some embodiments, the Fc domain includes amino acid substitutions L234A and L235A (EU number). In one such embodiment, the Fc domain is an IgG ₁ Fc domain, particularly a human IgG ₁ Fc domain. In one embodiment, the Fc domain includes an amino acid substitution at position P329. In a more specific embodiment, the amino acid substitution is P329A or P329G, particularly P329G (EU number). In one embodiment, the Fc domain includes an amino acid substitution at position P329, and further amino acid substitutions at positions selected from E233, L234, L235, N297, and P331 (EU number). In a more specific embodiment, the further amino acid substitutions are E233P, L234A, L235A, L235E, N297A, N297D, or P331S. In a particular embodiment, the Fc domain includes amino acid substitutions at positions P329, L234, and L235 (EU number). In a more specific embodiment, the Fc domain includes amino acid mutations L234A, L235A, and P329G (“P329G LALA”). In one such embodiment, the Fc domain is an IgG ₁ Fc domain, particularly a human IgG ₁ Fc domain. The amino acid-substituted “P329G LALA” combination almost completely eliminates Fcγ receptor (and complement) binding to the human _IgG1 Fc domain, as described in PCT Publication WO2012/130831, which is incorporated herein by reference in its entirety. WO 2012/130831 also describes methods for preparing such mutant Fc domains and methods for determining their properties, such as Fc receptor binding or effector function.

Compared to _IgG1 antibodies, _IgG4 antibodies exhibit reduced binding affinity to the Fc receptor and reduced effector function. Therefore, in some embodiments, the Fc domain is the _IgG4 Fc domain, particularly the human _IgG4 Fc domain. In one embodiment, the _IgG4 Fc domain includes an amino acid substitution at position S228, specifically amino acid substitution S228P (EU number). To further reduce its binding affinity to the Fc receptor and/or its effector function, in one embodiment, the _IgG4 Fc domain includes an amino acid substitution at position L235, specifically amino acid substitution L235E (EU number). In another embodiment, the _IgG4 Fc domain includes an amino acid substitution at position P329, specifically amino acid substitution P329G (EU number). In specific embodiments, the _IgG4 Fc domain includes amino acid substitutions at positions S228, L235, and P329, specifically amino acid substitutions S228P, L235E, and P329G (EU numbers). These IgG ₄ Fc domain mutants and their Fcγ receptor binding properties are described in PCT Publication No. WO 2012/130831, the entire contents of which are incorporated herein by reference.

In certain embodiments, the Fc domain exhibiting reduced binding affinity to the Fc receptor and/or reduced effector function compared to the natural _IgG1 Fc domain is a human _IgG1 Fc domain comprising amino acid substitutions L234A, L235A and optionally P329G, or a human IgG4 _Fc domain comprising amino acid substitutions S228P, L235E and optionally P329G (EU number).

In some embodiments, N-glycosylation of the Fc domain has been eliminated. In one such embodiment, the Fc domain includes an amino acid mutation at position N297, specifically, asparagine is replaced by an amino acid substitution of alanine (N297A), aspartic acid (N297D), or glycine (N297G) (EU number).

In addition to the Fc domains disclosed above and in PCT Publication No. WO 2012/130831, Fc domains with reduced Fc receptor binding and/or effector function also include those with substitutions at one or more of Fc domain residues 238, 265, 269, 270, 297, 327, and 329 (US Patent No. 6,737,056) (EU No.). Such Fc mutants include Fc mutants with substitutions at two or more of amino acid positions 265, 269, 270, 297, and 327, including the so-called “DANA” Fc mutant, in which residues 265 and 297 are substituted with alanine (US Patent No. 7,332,581).

Mutant Fc domains can be prepared using genetic or chemical methods well-known in the art, through amino acid deletion, substitution, insertion, or modification. Genetic methods may include site-specific mutagenesis of coding DNA sequences, PCR, gene synthesis, etc. Correct nucleotide changes can be verified, for example, by sequencing.

Binding to the Fc receptor can be readily determined, for example, by ELISA or by surface plasmon resonance (SPR) using standard instruments such as BIAcore instruments (GE Healthcare) and the Fc receptor can be obtained, for example, through recombinant expression. Alternatively, the binding affinity of the Fc domain or molecules including the Fc domain to the Fc receptor can be assessed using cell lines known to express a specific Fc receptor, such as human NK cells expressing the FcγIIIa receptor.

The effector function of an Fc domain or a molecule including such an Fc domain (e.g., an antibody) can be measured by methods known in the art. Suitable assays for measuring ADCC are described herein. Other examples of in vitro assays for assessing the ADCC activity of a target molecule are described in U.S. Patent No. 5,500,362; Hellstrom et al., Proc Natl Acad Sci USA. 83,7059-7063 (1986) and Hellstrom et al., Proc Natl Acad Sci USA. 82,1499-1502 (1985); U.S. Patent No. 5,821,337; Bruggemann et al., J Exp Med 166,1351-1361 (1987). Alternatively, non-radioactive assays can be used (see, for example: ACTI ^™ non-radioactive cytotoxicity assay for flow cytometry (Cell Technology, Inc. Mountain View, CA); and CytoTox non-radioactive cytotoxicity assay (Promega, Madison, WI)). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cells. Alternatively or additionally, for example, the ADCC activity of the molecule of interest can be assessed in animal models (such as those disclosed in Clynes et al., Proc Natl Acad Sci USA 95, 652-656 (1998)).

In some embodiments, the binding of the Fc domain to complement components, particularly C1q, is reduced. Therefore, in some embodiments, the Fc domain is engineered to have reduced effector functions, including reduced CDC. A C1q binding assay can be performed to determine whether the Fc domain, or a molecule including the Fc domain (e.g., an antibody), can bind C1q and thus have CDC activity. See, for example, C1q and C3c binding ELISAs in WO 2006/029879 and WO 2005/100402. To assess complement activation, a CDC assay can be performed (see, for example: Gazzano-Santoro et al., JImmunol Methods 202, 163 (1996); Cragg et al., Blood 101, 1045-1052 (2003); and Cragg and Glennie, Blood 103, 2738-2743 (2004)).

3. Substitution, Insertion, and Deletion

In some cases, anti-CD20/anti-CD3 bispecific antibody variants with one or more amino acid substitutions are provided for use in the therapeutics presented herein. Target sites for substitution mutations include HVR and FR. Conservative substitutions are shown under the heading “Preferred Substitutions” in Table 3. Further substantial changes are provided under the heading “Exemplary Substitutions” in Table 3 and are further described below with reference to the amino acid side chain categories. Amino acid substitutions can be introduced into the target antibody, and the product can be screened for desired activities (e.g., preserved/improved antigen binding, reduced immunogenicity, or improved ADCC or CDC).

Table 3. Exemplary and preferred amino acid substitutions

Amino acids can be grouped based on their common side-chain characteristics:

(1) Hydrophobicity: Leucine, Met, Ala, Val, Leu, Ile;

(2) Neutral hydrophilicity: Cys, Ser, Thr, Asn, Gln;

(3) Acidity: Asp, Glu;

(4) Alkaline: His, Lys, Arg;

(5) Residues that affect chain orientation: Gly, Pro;

(6) Fang tribe: Trp, Tyr, Phe.

Non-conservative substitution would require swapping members of one of these categories for members of another category.

One type of substitution variant involves substituting one or more highly variable region residues of a parent antibody (e.g., a humanized or human antibody). Typically, one or more resulting variants selected for further research will alter (e.g., improve) certain biological properties (e.g., increased affinity, decreased immunogenicity) and/or will substantially retain certain biological properties of the parent antibody relative to the parent antibody. Exemplary substitution variants are affinity-matured antibodies, which can be conveniently generated, for example, using phage display-based affinity maturation techniques, such as those described herein. In short, one or more HVR residues are mutated and the variant antibody is displayed on a phage and screened for a specific biological activity (e.g., binding affinity).

For example, HVR can be altered (e.g., substituted) to improve antibody affinity. Such modifications can be made in HVR “hotspots,” where codon-encoded residues undergo high-frequency mutations during somatic maturation (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)) and/or in contact with the antigen, where the binding affinity of the resulting variant VH or VL is tested. Affinity maturation by constructing a secondary library and reselecting from it has been disclosed, for example, in Hoogenboom et al., Methods in Molecular Biology 178:1-37 (edited by O’Brien et al., Human Press, Totowa, NJ (2001)). In some instances of affinity maturation, diversity is introduced into a variable gene selected for maturation purposes using any of a variety of methods (e.g., error-prone PCR, strand truncation, or oligonucleotide directed mutagenesis). A secondary library is then created. The library is then screened to identify any antibody variants with the desired affinity. Another approach to introducing diversity involves HVR-directed methods, where several HVR residues (e.g., 4-6 residues at a time) are randomized. Alanine scan mutagenesis or modeling can be used, for example, to specifically identify HVR residues involved in antigen binding. Specifically, CDR-H3 and CDR-L3 are often targeted.

In some instances, substitutions, insertions, or deletions may occur within one or more HVRs, as long as such changes do not substantially reduce the antibody's ability to bind to the antigen. For example, conserved changes (e.g., conserved substitutions as described herein) that do not substantially reduce binding affinity may be made in the HVR. Such changes may occur outside the antigen-contact residues of the HVR. In some cases of the variant VH and VL sequences provided above, each HVR remains unchanged or contains no more than one, two, or three amino acid substitutions.

A method for identifying antibody residues or regions that can be targeted for mutagenesis is called "alanine scan mutagenesis," as described by Cunningham and Wells (1989) Science, 244:1081-1085. In this method, a residue or a group of target residues (e.g., charged residues such as Arg, Asp, His, Lys, and Glu) is identified and replaced with a neutral or negatively charged amino acid (e.g., alanine or polyalanine) to determine if the antibody-antigen interaction is affected. Other substitutions can be introduced at amino acid positions that exhibit functional sensitivity to the initial substitution. Alternatively or additionally, the contact points between the antibody and antigen can be identified using the crystal structure of the antigen-antibody complex. Such contact residues and adjacent residues can be targeted or eliminated as candidates for substitution. Variants can be screened to determine if they possess the desired properties.

Amino acid sequence insertions include the fusion of amino and/or carboxyl termini of polypeptides ranging in length from one residue to one hundred or more residues, as well as intra-sequence insertions of one or more amino acid residues. Examples of terminal insertions include antibodies having an N-terminal methionine residue. Other insertion variants of antibody molecules include enzymes fused to the N- or C-terminus of the antibody (e.g., for ADEPT) or polypeptides that increase the serum half-life of the antibody.

4. Glycosylation

In some instances, the anti-CD20/anti-CD3 bispecific antibody of the present invention can be modified to increase or decrease the degree of antibody glycosylation. The addition or deletion of glycosylation sites in the anti-CD20/anti-CD3 bispecific antibody of the present invention can be conveniently achieved by altering the amino acid sequence to generate or remove one or more glycosylation sites.

When an antibody contains an Fc region, the carbohydrates attached thereto can be modified. Natural antibodies produced by mammalian cells typically contain branched biantennary oligosaccharides, which are usually linked via N-bonds to Asn297 of the CH2 domain of the Fc region. See, for example, Wright et al., TIBTECH 15:26-32 (1997). Oligosaccharides can include various carbohydrates, such as mannose, N-acetylglucosamine (GlcNAc), galactose, and sialic acid, as well as fucose of GlcNAc attached to the “backbone” of the biantennary oligosaccharide structure. In some cases, the oligosaccharides in the antibodies of the present invention are modified to produce antibody variants with certain improved properties.

In one instance, an anti-CD20/anti-CD3 bispecific antibody variant is provided, having a carbohydrate structure lacking (directly or indirectly) fucose linked to the Fc region. For example, the fucose content in such antibodies can be 1% to 80%, 1% to 65%, 5% to 65%, or 20% to 40%. The fucose content is determined by calculating the average fucose content in the Asn297 glycan chain, relative to the sum of all sugar structures (e.g., complexes, mixtures, and high-mannose structures) linked to Asn297, as determined by MALDI-TOF mass spectrometry, for example, as described in WO 2008/077546. Asn297 refers to the asparagine residue (EU number of Fc region residues) located at approximately position 297 in the Fc region; however, due to minor sequence variations in the antibody, Asn297 can also be located approximately ±3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300. Such fucoidylated variants may possess improved ADCC function. See, for example, U.S. Patent Publication Nos. US 2003/0157108 (Presta, L.); US2004/0093621 (Kyowa Hakko Kogyo Co., Ltd.). Examples of publications related to “defucosylated” or “fucosylated” antibody variants include: US2003/0157108; WO 2000/61739; WO 2001/29246; US 2003/0115614; US2002/0164328; US2004/0093621; US2004/0132140; US2004/0110704; US2004/0110282; US2004/0109 865; WO 2003/085119; WO 2003/084570; WO 2005/035586; WO 2005/035778; WO 2005/053742; WO 2002/03 1140; Okazaki et al., J. Mol. Biol. 336:1239-1249 (2004); Yamane-Ohnuki et al., Biotech. Bioeng. 87:614 (2004). Examples of cell lines capable of producing defucosylated antibodies include Lec13 CHO cells lacking protein fucosylation (Ripka et al., Arch. Biochem. Biophys. 249:533-545 (1986); US Patent Application No. US2003/0157108 A1, Presta, L; and WO 2004/056312 A1, Adams et al., especially in Example 11); and knockout cell lines, such as CHO cells with the α-1,6-fucosylation gene FUT8 knocked out (see, for example, Yamane-Ohnuki et al., Biotech. Bioeng. 87:614 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94(4):680-688 (2006); and WO 2003/085107).

In view of the above, in some instances, the method of the present invention includes administering to a subject a bispecific anti-CD20/anti-CD3 antibody variant comprising a glycosylation-free site mutation in the context of a fractionated, dose-escalation dosing regimen. In some cases, the deglycosylation site mutation reduces the effector function of the antibody. In some cases, the deglycosylation mutation is a substitution mutation. In some cases, the antibody contains a substitution mutation in the Fc region that reduces effector function. In some cases, the substitution mutation is at amino acid residues N297, L234, L235, and/or D265 (EU number). In some cases, the substitution mutation is selected from the group consisting of: N297G, N297A, L234A, L235A, D265A, and P329G. In some cases, the substitution mutation is at amino acid residue N297. In a preferred embodiment, the substitution mutation is N297A.

Further provided are anti-CD20/anti-CD3 bispecific antibody variants having bipartite oligosaccharides, for example, wherein the bitendril oligosaccharide linked to the Fc region of the antibody is bipartite by GlcNAc. Such antibody variants may have reduced fucosylation and/or improved ADCC function. Examples of such antibody variants are disclosed, for example, in WO 2003/011878; U.S. Patent No. 6,602,684; and U.S. 2005/0123546. Antibody variants having at least one galactose residue in the oligosaccharide linked to the Fc region are also provided. Such antibody variants may have improved CDC function. Such antibody variants are disclosed, for example, in WO 1997/30087, WO 1998/58964, and WO 1999/22764.

5. Antibody derivatives

In some cases, anti-CD20/anti-CD3 bispecific antibodies for the treatments described herein are further modified to include additional non-protein moieties known in the art and readily available. Suitable moieties for antibody derivatization include, but are not limited to, water-soluble polymers. Non-limiting examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), ethylene glycol/propylene glycol copolymers, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1,3-dioxane, poly-1,3,6-trioxane, ethylene/maleic anhydride copolymers, polyamino acids (homogeneous or random copolymers), and dextran or poly(n-vinylpyrrolidone) polyethylene glycol, propylene glycol homopolymers, polypropylene oxide/ethylene oxide copolymers, polyoxyethyleneized polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. PEG-propionaldehyde may be advantageous in manufacturing due to its stability in water. The polymer can have any molecular weight and can be branched or unbranched. The number of polymers attached to an antibody can vary, and if more than one polymer is attached, they can be the same or different molecules. Typically, the number and/or type of polymers used for derivatization can be determined based on considerations including, but not limited to, the specific property or function of the antibody to be improved, and whether the antibody derivative will be used for a specific therapeutic purpose.

In another example, an antibody and a conjugate of a non-protein fraction that can be selectively heated by exposure to radiation are provided. In one example, the non-protein fraction is carbon nanotubes (Kam et al., Proc. Natl. Acad. Sci. USA 102:11600-11605 (2005)). The radiation can be of any wavelength and includes, but is not limited to, wavelengths that do not harm normal cells but heat the non-protein fraction to a temperature at which cells proximal to the antibody-non-protein fraction are killed.

6. Immunoconjugates

The present invention also provides immunoconjugates or antibody-drug conjugates comprising anti-CD20/anti-CD3 bispecific antibodies, which are conjugated to one or more cytotoxic agents, such as chemotherapeutic agents or drugs, growth inhibitors, toxins (e.g., protein toxins, enzymatically active toxins or fragments thereof derived from bacteria, fungi, plants or animals) or radioisotopes.

In some cases, the immune conjugate is an antibody-drug conjugate (ADC), wherein the antibody is conjugated to one or more drugs, including but not limited to aurestatins such as the monomethylaurestatin drug portions DE and DF (MMAE and MMAF) (see U.S. Patent Nos. 5,635,483, 5,780,588, 7,498,298 and 8,088,378); mastamycin compounds (see U.S. Patent Nos. 5,208,020 and 5,416,064 and European Patent EP 0 425 2). 35 B1); scalyxin; calichimycin or derivatives thereof (see U.S. Patent Nos. 5,712,374, 5,714,586, 5,739,116, 5,767,285, 5,770,701, 5,770,710, 5,773,001 and 5,877,296; Hinman et al., Cancer Res. 53:3336-3342 (1993); and Lode et al., Cancer Res. 58:2925-2928 (1998)). Anthracyclines, such as doxorubicin or doxycycline (see Kratz et al., Current Med. Chem. 13:477-523 (2006); Jeffrey et al., Bioorganic & Med. Chem. Letters 16:358-362 (2006); Torgov et al., Bioconj. Chem. 16:717-721 (2005); Nagy et al., Proc. Natl. Acad. Sci. USA 97:829-834 (2000); Dubowchik et al., Bioorg. & Med. Chem. Letters 12:1529-1532 (2002); King et al., J. Med. Chem. 45:4336-4343 (2002); and U.S. Patent No. 6,630,579); methotrexate; vinorelbine; taxanes, such as docetaxel, paclitaxel, larokolpaclitaxel, tercetaxel, and ozaprol; trichothecene; and CC1065.

In another instance, the immunoconjugate comprises an anti-CD20/anti-CD3 bispecific antibody bound to an enzymatically active toxin or a fragment thereof, including but not limited to diphtheria A chain, non-bound active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modisocyanate A chain, α-Dacococcus, tung oil protein, carnation toxin, pokeweed protein (PAPI, PAPII, and PAP-S), bitter melon inhibitor, lactudin, croton toxin, soapwort inhibitor, white tree toxin, mitochondriin, localized aspergillin, phenolmycin, enomycin, and crescent toxin.

In another example, the immunoconjugate comprises an anti-CD20/anti-CD3 bispecific antibody that binds to a radioactive atom to form a radioconjugate. A variety of radioisotopes can be used to prepare radioconjugates. Examples include radioisotopes of ^211At , ^131I , ^125I , ^90Y , ^186Re , ^188Re , ^153Re , ^212Bi , ^32P , ^212Pb , and Lu. When the radioconjugate is used for detection, it may contain radioactive atoms used for scintillation studies, such as tc99m or I123, or spin labels used for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, MRI), such as iodine-123 (again), iodine-131, indium-111, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese, or iron.

A variety of bifunctional protein conjugates, such as N-succinimino-3-(2-pyridyldithio)propionate (SPDP), 4-(N-maleiminomethyl)cyclohexane-1-carboxylic acid succinimide ester (SMCC), iminothiacyclopentane (IT), bifunctional derivatives of imino esters (such as dimethyl adipate hydrochloride), active esters (such as disuccinimino octanoate), aldehydes (such as glutaraldehyde), diazido compounds (such as bis(p-azidobenzoyl)hexamethylenediamine), diazido derivatives (such as bis-(p-diazobenzoyl)-ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and biactive fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene), can be used to prepare conjugates of antibodies and cytotoxic agents. For example, ricin immunotoxin can be prepared as described in Vitetta et al., Science 238:1098 (1987). Carbon-14 labeled 1-isothiocyanobenzyl-3-methyldiethylenetriaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugating radioactive nucleotides to antibodies. See WO94/11026. The linker can be a “cleavable linker” that promotes the release of cytotoxic drugs from cells. For example, acid-labile linkers, peptidase-sensitive linkers, light-labile linkers, dimethyl linkers, or disulfide-containing linkers can be used (Chari et al., Cancer Res. 52:127-131 (1992); US Patent No. 5,208,020).

The immunoconjugates or ADCs described herein are explicitly considered, but not limited to, such conjugates prepared using crosslinking agents, including but not limited to commercially available (e.g., purchased from Pierce Biotechnology, Inc. (Rockford, IL., U.S.A)) BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfon-EMCS, sulfon-GMBS, sulfon-KMUS, sulfon-MBS, sulfon-SIAB, sulfon-SMCC, and sulfon-SMPB, as well as SVSB (succinimino-(4-vinyl sulfone)benzoate).

Alternatively, any antibody described herein (e.g., anti-CD20/anti-CD3 bispecific antibody) may be a naked antibody.

C. Recombination generation methods

The anti-CD20/anti-CD3 bispecific antibodies that can be used for combination therapies of the present invention can be produced using recombinant methods and compositions, for example, as described in U.S. Patent No. 4,816,567, which is incorporated herein by reference in its entirety.

For the recombinant generation of anti-CD20/anti-CD3 bispecific antibodies, the nucleic acid encoding the antibody is isolated and inserted into one or more vectors for further cloning and/or expression in host cells. Such nucleic acids can be readily isolated and sequenced using routine procedures (e.g., by using oligonucleotide probes capable of specifically binding to genes encoding the heavy and light chains of the antibody).

Suitable host cells for cloning or expressing vectors encoding antibodies include prokaryotic or eukaryotic cells as described herein. Antibodies can be generated in bacteria, for example, particularly when glycosylation and Fc effector function are not required. For information on the expression of antibody fragments and peptides in bacteria, see, for example, U.S. Patent Nos. 5,648,237, 5,789,199, and 5,840,523. (See also Charlton, Methods in Molecular Biology, Vol. 248 (edited by B.K.C. Lo, Humana Press, Totowa, NJ, 2003), pp. 245-254, which describes the expression of antibody fragments in *E. coli*.) After expression, the antibody can be separated from the bacterial cell paste in a soluble fraction and can be further purified.

Besides prokaryotes, eukaryotic microorganisms such as filamentous fungi or yeasts are also suitable cloning or expression hosts for antibody-encoding vectors. These eukaryotic microorganisms include fungal and yeast strains whose glycosylation pathways have been "humanized," thereby enabling the production of antibodies with partial or complete human glycosylation patterns. See Gerngross, Nat. Biotech. 22:1409-1414 (2004); and Li et al., Nat. Biotech. 24:210-215 (2006).

Suitable host cells for expressing glycosylated antibodies also originate from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant cells and insect cells. Many baculovirus strains have been identified that can be used with insect cells, particularly for transfecting Spodoptera frugiperda cells.

Plant cell cultures can also be used as hosts. See, for example, U.S. Patent Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (described in PLATNIBODIES ^™ technology for generating antibodies in transgenic plants).

Vertebrate cells can also be used as hosts. For example, mammalian cell lines adapted for growth in suspension may be useful. Other examples of available mammalian host cell lines include: monkey kidney CV1 transformed from SV40 (COS-7); human embryonic kidney lines (such as 293 or 293 cells as described, for example, in Graham et al., J. Gen Virol. 36:59 (1977)); young hamster kidney cells (BHK); mouse testicular supporting cells (such as TM4 cells as described, for example, in Mather, Biol. Reprod. 23:243-251 (1980)); monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical cancer cells (HELA); canine kidney cells (MDCK); Buffalo rat hepatocytes (BRL 3A); human lung cells (W138); human hepatocytes (Hep G2); mouse mammary tumors (MMT 060562); TRI cells, such as those described, for example in Mather et al., Annals As described in NYAcad.Sci.383:44-68 (1982); MRC 5 cells; and FS4 cells. Other useful mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR ^- CHO cells (Urlaub et al., Proc.Natl.Acad.Sci.USA 77:4216 (1980)); and myeloma cell lines such as Y0, NSO, and Sp2/0. For reviews of certain mammalian host cell lines suitable for antibody production, see, for example: Yazaki and Wu, Methods in Molecular Biology, Vol. 248 (edited by BKCLo, HumanaPress, Totowa, NJ), pp. 255-268 (2003).

(v) CRS Risk Mitigation Strategies

This invention relates to novel combination therapies using anti-CD20/anti-CD3 bispecific antibodies and anti-CD20 antibodies, as well as one or more chemotherapeutic agents selected from ifosfamide, carboplatin, and/or etoposide.

Bispecific antibody therapies involving T-cell activation have been associated with cytokine release syndrome (CRS). CRS is a potentially life-threatening complex caused by the excessive release of cytokines by immune effectors or target cells during an excessive and sustained immune response. CRS can be triggered by a variety of factors, including infection with toxic pathogens, or by agents that activate or enhance the immune response to produce a pronounced and sustained immune response.

Regardless of the triggering factor, severe or life-threatening CRS constitutes a medical emergency. If not successfully managed, it can lead to significant disability or death. Current clinical management focuses on treating individual signs and symptoms, providing supportive care, and attempting to suppress the inflammatory response with high-dose corticosteroids. However, this approach is not always successful, especially in cases of late intervention. Furthermore, steroids can negatively affect T-cell function, potentially diminishing the clinical benefits of immunomodulatory therapies in cancer treatment.

A. CRS Symptoms and Classifications

CRS is graded according to the modified cytokine release syndrome grading system established by Lee et al., Blood, 124:188-195, 2014 or Lee et al., Biol Blood Marrow Transplant, 25(4):625-638, 2019, as described in Table 4. In addition to the diagnostic criteria, recommended CRS management based on severity (including early intervention with corticosteroids and/or anti-cytokine therapy) is also provided and mentioned in Tables 4 and 5.

Table 4. Grading System for Cytokine Release Syndromes

Lee 2014 criteria: Lee et al., Blood, 124:188-195, 2014.

ASTCT consensus classification: Lee et al., Biol Blood Marrow Transplant, 25(4):625-638, 2019.

^a. Low-dose vasopressors: Single vasopressors at doses lower than those shown in Table 4.

^b. High-dose vasopressors: as defined in Table 4.

*Fever is defined as a body temperature ≥38°C that is not attributable to any other cause. In CRS patients who subsequently receive antipyretics or anticytokine therapy (such as tocilizumab or steroids), fever is no longer required for grading the severity of subsequent CRS. In this case, CRS grading is driven by hypotension and/or hypoxia.

CRS grade is determined by more serious events: hypotension or hypoxia that cannot be attributed to any other cause. For example, a patient with a body temperature of 39.5°C, hypotension requiring one vasopressor, and hypoxia requiring a low-flow nasal cannula is classified as grade 3 CRS.

Low-flow nasal cannula is defined as delivering oxygen at a rate of ≤6 L/min. Low flow also includes blowing oxygen, sometimes used in pediatrics. High-flow nasal cannula is defined as delivering oxygen at a rate of >6 L/min.

Table 5. High-dose vasopressors

min = minutes; VASST = Vasopressin and Septic Shock Test.

^a VASST vasopressor equivalent equation: Norepinephrine equivalent dose = [Norepinephrine (μg/min)] + [Dopamine (μg/kg/min) ÷ 2] + [Epinephrine (μg/min)] + [Phenylephrine (μg/min) ÷ 10].

Mild to moderate CRS and/or infusion-related reactions (IRR) may include symptoms such as fever, headache, and myalgia, and can be treated symptomatically with analgesics, antipyretics, and antihistamines as needed. Severe or life-threatening CRS and/or IRR, such as hypotension, tachycardia, dyspnea, or chest discomfort, should be aggressively treated with supportive and resuscitation measures as directed, including high-dose corticosteroids, intravenous fluids, admission to the intensive care unit, and other supportive measures. Severe CRS may be associated with other clinical sequelae such as disseminated intravascular coagulation, capillary leak syndrome, or macrophage activation syndrome (MAS). The standard of care for severe or life-threatening CRS resulting from immunotherapy has not been established; case reports and recommendations on the use of anti-cytokine therapies (such as tocilizumab) have been published (Teachey et al., Blood, 121:5154-5157, 2013; Lee et al., Blood, 124:188-195, 2014; Maude et al., New Engl J Med, 371:1507-1517, 2014).

B. Pretreatment or management of CRS-related symptoms with tocilizumab

CRS is associated with high IL-6 levels (Panelli et al., J Transl Med, 2:17, 2004; Lee et al., Blood, 124:188-195, 2014; Doessegger and Banholzer, Clin Transl Immunology, 4:e39, 2015), and IL-6 is associated with the severity of CRS, with patients experiencing severe or life-threatening CRS (NCI CTCAE grade 4 or 5) having much higher IL-6 levels compared to patients who did not experience CRS or experienced a mild CRS response (NCI CTCAE grade 0-3) (Chen et al., J Immunol Methods, 434:1-8, 2016).

Tocilizumab is a recombinant humanized anti-human monoclonal antibody against soluble and membrane-bound IL-6R, which inhibits IL-6-mediated signaling (see, for example, WO 1992/019579, which is incorporated herein by reference in its entirety). Tocilizumab has been approved by the U.S. Food and Drug Administration for the treatment of severe or life-threatening CAR-T cell-induced CRS in adults and pediatric patients aged 2 years and older. Initial clinical data (Locke et al., Blood, 130:1547, 2017) suggest that tocilizumab prophylaxis can reduce the severity of CAR-T cell-induced CRS by blocking IL-6 receptor signaling prior to cytokine release. Therefore, tocilizumab prodrugation may also reduce the frequency or severity of CRS associated with bispecific antibody therapy. Other anti-IL-6R antibodies that can be used in combination with tocilizumab include sarilumab, vobarilizumab (ALX-0061), SA-237 and its variants.

In other respects, an effective amount of tocilizumab is administered as a prodrug, for example, before administration of an anti-CD20/anti-CD3 bispecific antibody to the subject. Administration of tocilizumab as a prodrug can reduce the frequency or severity of CRS. In some respects, tocilizumab is administered as a prodrug in cycle 1, for example, before the first dose (C1D1), second dose (C1D2), and/or third dose (C1D3) of the anti-CD20/anti-CD3 bispecific antibody. In some respects, tocilizumab is administered intravenously to the subject in a single dose of about 1 mg/kg to about 15 mg/kg (e.g., about 4 mg/kg to about 10 mg/kg, for example, about 6 mg/kg to about 10 mg/kg, for example, about 8 mg/kg). In some respects, tocilizumab is administered intravenously to the subject in a single dose of about 8 mg/kg. Other anti-IL-6R antibodies that can be used in combination with tocilizumab include sarilumab, vobarilizumab (ALX-0061), SA-237 and its variants.

For example, in one instance, co-administration of anti-CD20/anti-CD3 bispecific antibody and tocilizumab, wherein tocilizumab is first administered to the subject and then the bispecific antibody is administered alone (e.g., the subject is pre-treated with tocilizumab).

On the other hand, in subjects treated with an anti-CD20/anti-CD3 bispecific antibody, tocilizumab is administered to treat or alleviate symptoms associated with CRS. If a subject has grade 2 or higher CRS events with extensive comorbidities following administration of the anti-CD20/anti-CD3 bispecific antibody, the method may further include administering a first dose of an IL-6R antagonist (e.g., an anti-IL-6R antibody, such as tocilizumab) to the subject to manage grade 2 or higher CRS events while discontinuing treatment with the anti-CD20/anti-CD3 bispecific antibody. In some cases, the first dose of tocilizumab is administered intravenously to the subject at a dose of approximately 8 mg/kg. Other anti-IL-6R antibodies that can be used in combination with tocilizumab include sarilumab, vobarilizumab (ALX-0061), SA-237, and its variants. In some cases, if a grade 2 CRS event resolves to a grade ≤1 CRS event within two weeks, the method further includes restarting treatment with a reduced dose of an anti-CD20/anti-CD3 bispecific antibody. In some cases, if the event occurs during or within 24 hours of infusion, a smaller dose is administered at 50% of the initial infusion rate of the previous cycle. On the other hand, if a grade 2 or higher CRS event does not resolve or worsens to a grade ≥3 CRS event within 24 hours of treatment for the grade 2 or higher CRS event, the method may further include administering one or more (e.g., one, two, three, four, or five or more) additional doses of an IL-6R antagonist (e.g., an anti-IL-6R antibody, such as tocilizumab) to the subject to manage the grade 2 or ≥3 CRS event. In certain specific cases, if a grade 2 or higher CRS event does not resolve or worsens to a grade ≥3 CRS event within 24 hours of treatment for the grade 2 or higher CRS event, the method may further include administering one or more additional doses of tocilizumab to the subject to manage the grade 2 or ≥3 CRS event. In some cases, one or more additional doses of tocilizumab may be administered intravenously to the subject at a dose of about 1 mg/kg to about 15 mg/kg (e.g., about 4 mg/kg to about 10 mg/kg, for example, about 6 mg/kg to about 10 mg/kg, for example, about 8 mg/kg).

C. Other preventative treatments for CRS risk reduction

In one embodiment, the treatment regimen provided herein further includes administering a prophylactic medication prior to the administration of the anti-CD20/anti-CD3 bispecific antibody. In one embodiment, the prophylactic medication includes a corticosteroid (such as, for example, prednisolone, dexamethasone, or methylprednisolone), acetaminophen/paracetamol, and/or an antihistamine (such as, for example, diphenhydramine). In one embodiment, the prophylactic medication is administered at least 60 minutes (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours, or longer) prior to the administration of the anti-CD20/anti-CD3 bispecific antibody. In one embodiment, the treatment regimen further includes administering a prophylactic medication prior to the administration of glimepiride. In this embodiment, the prophylactic medication includes a corticosteroid (such as, for example, prednisolone, dexamethasone, or methylprednisolone), an antipyretic (such as, for example, acetaminophen/paracetamol), and/or an antihistamine (such as, for example, diphenhydramine). In one embodiment, the subject receives a corticosteroid prodrug prior to the anti-CD20/anti-CD3 bispecific antibody. It has been demonstrated that, compared to methylprednisolone, the use of a dexamethasone prodrug reduces the levels of glimetuzumab-induced cytokines in mice pretreated with dexamethasone. Therefore, in one embodiment, the corticosteroid is dexamethasone. In one embodiment, the prodrug is administered at least 60 minutes prior to glimetuzumab administration (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or longer). In another embodiment, the prodrug is administered at least 60 minutes prior to each administration of glimetuzumab (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or longer). In another embodiment, a prophylactic dose of corticosteroids is administered before the first dose (C1D1) of the first cycle and the second dose (C1D2) of the first cycle, and before the first dose (C2D1) of the second cycle and the first dose (C3D1) of the third cycle, and this prophylactic dose may be optional for subsequent cycles in which the target dose has been reached and tolerated by two doses for patients who did not have CRS in the previous cycles.

In one embodiment, a prophylactic drug is administered at least 60 minutes (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48 hours or longer) prior to the administration of pretreatment with an anti-CD20 antibody (particularly olibutuzumab).

In one embodiment, corticosteroids are administered to manage any associated adverse events following administration of an anti-CD20/anti-CD3 bispecific antibody (e.g., glucentumab).

(vi) Administration of anti-CD20/anti-CD3 bispecific antibodies

The method may involve administering an anti-CD20/anti-CD3 bispecific antibody (and/or any additional therapeutic agent) by any suitable means, including parenteral, intrapulmonary, and intranasal administration, and, if local treatment is required, intralesional administration. Parenteral infusion includes intravenous, subcutaneous, intramuscular, intra-arterial, and intraperitoneal routes. In some embodiments, the anti-CD20/anti-CD3 bispecific antibody is administered via intravenous infusion.

In one embodiment, the infusion time of the anti-CD20/anti-CD3 bispecific antibody (particularly glimetuzumab) is at least 4 hours (e.g., about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, or about 6 hours). In a particular embodiment, the infusion duration of glimetuzumab is about 4 hours. In one embodiment, the infusion time of the anti-CD20/anti-CD3 bispecific antibody may be reduced or prolonged. In one embodiment (e.g., in the absence of infusion-related adverse events), the infusion time of glimetuzumab in subsequent cycles is reduced to 2 hours ± 15 minutes. In one embodiment, the infusion time is increased to a maximum of 8 hours (e.g., about 4 hours, about 5 hours, about 6 hours, about 7 hours, or about 8 hours) (e.g., for subjects at high risk of experiencing CRS). In one embodiment, for example, for patients at potentially increased risk of CRS, patients who have experienced IRR or CRS with their previous dose of glimetuzumab, or patients at increased risk of recurrence of IRR/CRS at subsequent doses, the infusion time of glimetuzumab is prolonged to a maximum of 8 hours.

For all methods described herein, the anti-CD20/anti-CD3 bispecific antibody will be formulated, administered, and applied in accordance with good medical practice. Factors to be considered in this context include the specific disease being treated, the specific mammal being treated, the individual subject's clinical condition, the cause of the disease, the site of delivery, the method of administration, the administration regimen, and other factors known to the physician. The anti-CD20/anti-CD3 bispecific antibody does not necessarily, but optionally, need to be formulated with one or more agents currently used for the prevention or treatment of the disease in question. The effective amount of such other agents depends on the amount of anti-CD20/anti-CD3 bispecific antibody present in the formulation, the type of disease or treatment, and the other factors mentioned above. The anti-CD20/anti-CD3 bispecific antibody may be appropriately administered to the subject in a series of treatments.

Another aspect of the present invention relates to the invention described above.

Example

Some embodiments of the technology described herein can be defined according to any of the following numbered embodiments:

1. A method of treating a subject with a CD20-positive proliferative disorder, the method comprising administering an effective amount of the drug to the subject in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle:

(a) Bispecific antibodies that bind to CD20 and CD3;

(b) Anti-CD20 antibody; and

(c) One or more chemotherapeutic agents selected from ifosfamide, carboplatin and/or etoposide.

2. The method according to Example 1, wherein the subject is 18 years of age or older.

3. The method according to Example 2, wherein the subject is 31 years of age or older.

4. The method according to any one of Examples 1 to 3, wherein

The first dosing cycle includes a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody, wherein the C1D1 of the bispecific antibody is approximately 2.5 mg and the C1D2 of the bispecific antibody is approximately 10 mg; and

The second dosing cycle includes a single dose (C2D1) of the bispecific antibody, wherein the C2D1 of the bispecific antibody is about 10 mg, about 16 mg, or about 30 mg.

5. The method according to Example 4, wherein the C2D1 of the bispecific antibody is about 30 mg.

6. The method according to Example 4 or 5, wherein the C1D1 and the C1D2 of the bispecific antibody are administered to the subject on day 8 and day 15 of the first dosing cycle, respectively.

7. The method according to any one of Examples 4 to 6, wherein the C2D1 of the bispecific antibody is administered to the subject on day 8 of the second dosing cycle.

8. The method according to any one of Examples 1 to 7, wherein the anti-CD20 antibody is olibutuzumab and/or rituximab.

9. The method according to Example 8, wherein the first dosing cycle comprises a single dose of olibutuzumab (C1D1); and the second dosing cycle comprises a single dose of rituximab (C2D1).

10. The method according to Example 9, wherein the C1D1 of olibutuzumab is about 1000 mg and the C2D1 of rituximab is about 375 mg/ ^m² .

11. The method according to Example 9 or 10, wherein the anti-CD20 antibody is administered in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein the first dosing cycle comprises administering the C1D1 of olibutuzumab to the subject on day 1; and the second dosing cycle comprises administering the C2D1 of rituximab to the subject on day 1.

12. The method according to any one of Examples 1 to 11, wherein the method comprises administering ifosfamide, carboplatin and etoposide to the subject.

13. The method according to Example 12, wherein the first dosing cycle comprises a single dose of ifosfamide (C1D1); a single dose of carboplatin (C1D1); and a first dose of etoposide (C1D1), a second dose of etoposide (C1D2), and a third dose of etoposide (C1D3); and the second cycle comprises a single dose of ifosfamide (C2D1); a single dose of carboplatin (C2D1); and a first dose of etoposide (C2D1), a second dose of etoposide (C2D2), and a third dose of etoposide (C2D3).

14. The method according to Example 13, wherein ifosfamide is administered at a dose of about 5000 mg/ ^m² , about 4000 mg/ ^m² , or about 1666 mg/ ^m² , carboplatin is administered at a dose of about 5 mg/mL/min, wherein the maximum dose is about 750 mg, and etoposide is administered at a dose of about 100 mg/ ^m² or about 75 mg/ ^m² for each dose of etoposide.

15. The method according to Example 14, wherein ifosfamide is administered at a dose of about 5000 mg/ ^m² , carboplatin is administered at a dose of about 750 mg, which is the maximum of the target area under the curve (AUC) of about 5 mg/mL/min, and etoposide is administered at a dose of about 100 mg/ ^m² for each dose of etoposide.

16. The method according to Example 13, wherein carboplatin is administered at a dose of about 5 × (25 + creatinine clearance (CrCl)) mg, with a maximum dose of about 750 mg.

17. The method according to Example 16, wherein

(a) The subject is male, and CrCl is calculated using the formula CrCl = ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]); or

(b) The subject was female, and CrCl was calculated using the formula CrCl = 0.85 × ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]).

18. The method according to any one of Examples 13 to 17, wherein ifosfamide and carboplatin are administered on the second day of the first and second administration cycles, and the C1D1 to C1D3 and C2D1 to C2D3 of etoposide are administered on the first, second and third days of the first and second administration cycles, respectively.

19. The method according to any one of Examples 1 to 18, wherein the first dosing cycle and the second dosing cycle are each a 21-day dosing cycle.

20. The method according to any one of Examples 1 to 19, wherein the dosing regimen includes one or more additional dosing cycles.

21. The method according to Example 20, wherein each of the one or more additional dosing cycles is a 21-day dosing cycle.

22. The method according to Example 20 or 21, wherein the dosing regimen comprises a total of three dosing cycles.

23. The method according to any one of Examples 20 to 22, wherein each of the one or more additional dosing cycles comprises:

(a) An additional single dose of a bispecific antibody that binds to both CD20 and CD3.

(b) An additional single dose of anti-CD20 antibody, and

(c) Additional single doses of ifosfamide, additional single doses of carboplatin, and additional first, second, and third doses of etoposide.

24. The method according to Example 23, wherein the additional single dose of the bispecific antibody is about 30 mg.

25. The method according to Example 23 or 24, wherein the additional single dose of the bispecific antibody is administered to the subject on day 8 of each of the one or more additional dosing cycles.

26. The method according to any one of Examples 23 to 25, wherein the anti-CD20 antibody is rituximab.

27. The method according to Example 26, wherein the additional single dose of rituximab is approximately 375 mg/ ^m² .

28. The method according to Example 26 or 26, wherein the additional single dose of rituximab is administered on day 1 of each of the one or more additional dosing cycles.

29. The method according to any one of Examples 23 to 27, wherein the additional single dose of ifosfamide is about 5000 mg/ ^m² , about 4000 mg/ ^m² , or about 1666 mg/ ^m² , the additional single dose of carboplatin is about 5 mg/mL/min, wherein the maximum dose of the target area under the curve (AUC) is about 750 mg, and the additional first dose, the additional second dose, and the additional third dose of etoposide are each about 100 mg/ ^m² or about 75 mg/ ^m² .

30. The method according to Example 29, wherein ifosfamide is administered at a dose of about 5000 mg/ ^m² , carboplatin is administered at a dose of about 750 mg, which is the maximum of the target area under the curve (AUC) of about 5 mg/mL/min, and etoposide is administered at a dose of about 100 mg/ ^m² for each dose of etoposide.

31. The method according to any one of Examples 23 to 27, wherein the additional single dose of carboplatin is about 5 × (25 + creatinine clearance (CrCl)) mg, wherein the maximum dose is about 750 mg.

32. The method according to embodiment 31, wherein

(a) The subject is male, and CrCl is calculated using the formula CrCl = ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]); or

(b) The subject was female, and CrCl was calculated using the formula CrCl = 0.85 × ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]).

33. The method according to any one of Examples 23 to 32, wherein ifosfamide and carboplatin are administered on day 2 of each of the one or more additional dosing cycles, and the additional first dose, the additional second dose, and the additional third dose of etoposide are administered on day 1, day 2, and day 3 of each of the one or more additional dosing cycles, respectively.

34. The method according to any one of Examples 1 to 33, wherein the method further comprises administering one or more additional therapeutic agents to the subject.

35. The method according to Example 34, wherein the one or more additional therapeutic agents are tocilizumab.

36. The method according to Example 35, wherein the subject weighs more than or equal to about 30 kg and tocilizumab is administered at a dose of about 8 mg/kg, or the subject weighs less than 30 kg and tocilizumab is administered at a dose of about 12 mg/kg, and wherein the maximum dose is about 800 mg.

37. The method according to Example 34, wherein the one or more additional therapeutic agents are corticosteroids.

38. The method according to Example 37, wherein the corticosteroid comprises prednisone, prednisolone, methylprednisolone, or dexamethasone.

39. The method according to Example 38, wherein the corticosteroid is dexamethasone.

40. The method according to Example 39, wherein dexamethasone is administered intravenously at a dose of about 20 mg at least one hour prior to the administration of any dose of the bispecific antibody.

41. The method according to Example 39, wherein dexamethasone is administered intravenously at a dose of about 20 mg at least one hour prior to the administration of any dose of olibutuzumab.

42. The method according to Example 38, wherein the corticosteroid is methylprednisolone.

43. The method according to Example 42, wherein methylprednisolone is administered intravenously at a dose of about 80 mg at least one hour prior to the administration of any dose of the bispecific antibody.

44. The method according to Example 42, wherein methylprednisolone is administered intravenously at a dose of about 80 mg at least one hour prior to the administration of any dose of olibutuzumab.

45. The method according to Example 38, wherein the corticosteroid is prednisone.

46. The method according to Example 45, wherein prednisone is administered orally at a dose of about 100 mg at least one hour prior to the administration of any dose of the bispecific antibody.

47. The method according to Example 38, wherein the corticosteroid is prednisolone.

48. The method according to Example 47, wherein prednisolone is administered intravenously at a dose of about 100 mg at least one hour prior to the administration of any dose of the bispecific antibody.

49. The method according to Example 34, wherein the one or more additional therapeutic agents are antihistamines.

50. The method according to Example 49, wherein the antihistamine is diphenhydramine.

51. The method according to Example 50, wherein diphenhydramine is administered orally or intravenously at a dose of about 50 mg at least 30 minutes prior to the administration of any dose of the bispecific antibody.

52. The method according to Example 34, wherein the one or more additional therapeutic agents comprise granulocyte colony-stimulating factor (G-CSF).

53. The method according to Example 52, wherein G-CSF is administered between approximately one and approximately two days after administration of any dose of rituximab, ifosfamide, carboplatin and/or etoposide.

54. The method according to Example 34, wherein the one or more additional therapeutic agents are antipyretics.

55. The method according to Example 54, wherein the antipyretic is acetaminophen or paracetamol.

56. The method according to Example 55, wherein acetaminophen or paracetamol is administered orally at a dose between about 500 mg and about 1000 mg at least about 30 minutes prior to the administration of any dose of the bispecific antibody.

57. The method according to Example 55, wherein acetaminophen or paracetamol is administered orally at a dose between about 500 mg and about 1000 mg at least about 30 minutes prior to the administration of any dose of olibutuzumab.

58. The method according to Example 34, wherein the one or more additional therapeutic agents are mesna.

59. The method according to Example 58, wherein mesna is administered intravenously at a dose of about 5000 mg/ ^m² , about 4000 mg/ ^m² , or about 1666 mg/ ^m² .

60. The method according to Example 59, wherein mesna is administered via continuous infusion over approximately 24 hours on the second day of each dosing cycle.

61. The method according to Example 59 or 60, wherein mesna is administered simultaneously with any dose of ifosfamide.

62. A method for treating a subject aged 6 months to 17 years with a CD20-positive proliferative disorder, the method comprising administering an effective amount to the subject in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle:

(a) Bispecific antibodies that bind to CD20 and CD3;

(b) Anti-CD20 antibody; and

(c) One or more chemotherapeutic agents selected from ifosfamide, carboplatin and/or etoposide.

63. The method according to embodiment 62, wherein

The first dosing cycle includes a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody, wherein the C1D1 of the bispecific antibody is approximately 0.03 mg/kg, approximately 0.04 mg/kg, or approximately 2.5 mg, and the C1D2 of the bispecific antibody is approximately 0.15 mg/kg or approximately 10 mg; and

The second dosing cycle includes a single dose (C2D1) of the bispecific antibody, wherein the C2D1 of the bispecific antibody is about 0.4 mg/kg, about 0.5 mg/kg, or about 30 mg.

64. The method according to embodiment 63, wherein:

(a) The subject's weight is greater than or equal to about 7.5 kg and less than about 13 kg, and the C1D1 of the bispecific antibody is about 0.04 mg/kg, the C1D2 of the bispecific antibody is about 0.15 mg/kg, and the C2D1 of the bispecific antibody is about 0.5 mg/kg;

(b) The subject's weight is greater than or equal to about 13 kg and less than about 45 kg, and the C1D1 of the bispecific antibody is about 0.03 mg/kg, the C1D2 of the bispecific antibody is about 0.15 mg/kg, and the C2D1 of the bispecific antibody is about 0.4 mg/kg; or

(c) The subject's weight is greater than or equal to about 45 kg, and the C1D1 of the bispecific antibody is about 2.5 mg, the C1D2 of the bispecific antibody is about 10 mg, and the C2D1 of the bispecific antibody is about 30 mg.

65. The method according to Example 63 or 64, wherein the C1D1 and the C1D2 of the bispecific antibody are administered to the subject on day 8 and day 15 of the first dosing cycle, respectively.

66. The method according to any one of Examples 63 to 65, wherein the C2D1 of the bispecific antibody is administered to the subject on day 1 of the second dosing cycle.

67. The method according to any one of Examples 62 to 66, wherein the anti-CD20 antibody is olibutuzumab and/or rituximab.

68. The method according to Example 67, wherein the first dosing cycle includes a first dose (C1D1) of olibutuzumab and a second dose (C1D2) of olibutuzumab.

69. The method according to embodiment 68, wherein:

(a) The subject's weight is greater than or equal to about 7.5 kg and less than about 13 kg, and the sum of the C1D1 and C1D2 of olibutuzumab is about 38 mg/kg;

(b) The subject weighs more than or equal to about 13 kg and less than about 20 kg, and the sum of the C1D1 and C1D2 of olibutuzumab is about 28 mg/kg;

(c) The subject's weight is greater than or equal to about 20 kg and less than about 32 kg, and the sum of the C1D1 and C1D2 of olibutuzumab is about 23 mg/kg;

(d) The subject's weight is greater than or equal to about 32 kg and less than about 45 kg, and the sum of the C1D1 and C1D2 of olibutrazumab is about 20 mg/kg; or

(e) The subject weighs more than or equal to about 45 kg, and the sum of the C1D1 and C1D2 of olibutuzumab is about 1000 mg.

70. The method according to Example 68 or 69, wherein the C1D1 of olibutuzumab is about one-tenth of the sum of the C1D1 and the C1D2 of olibutuzumab, and the C1D2 of olibutuzumab is about nine-tenths of the sum of the C1D1 and the C1D2 of olibutuzumab.

71. The method according to any one of Examples 68 to 70, wherein:

(a) The subject's weight is greater than or equal to about 7.5 kg and less than about 13 kg, and the C1D1 of olibutuzumab is about 3.8 mg/kg and the C1D2 of olibutuzumab is about 34.2 mg/kg;

(b) The subject's weight is greater than or equal to about 13 kg and less than about 20 kg, and the C1D1 of olibutuzumab is about 2.8 mg/kg and the C1D2 of olibutuzumab is about 35.2 mg/kg;

(c) The subject's weight is greater than or equal to about 20 kg and less than about 32 kg, and the C1D1 of olibutuzumab is about 2.3 mg/kg and the C1D2 of olibutuzumab is about 35.7 mg/kg;

(d) The subject's weight is greater than or equal to about 32 kg and less than about 45 kg, and the C1D1 of olibutuzumab is about 2.0 mg/kg and the C1D2 of olibutuzumab is about 36.0 mg/kg; or

(e) The subject weighs more than or equal to about 45 kg, and the C1D1 of olibutuzumab is about 100 mg and the C1D2 of olibutuzumab is about 900 mg.

72. The method according to any one of Examples 68 to 71, wherein the subject is administered C1D1 of oxetuzumab on day 1 of the first dosing cycle, and the subject is administered C1D2 of oxetuzumab on day 2 of the first dosing cycle.

73. The method according to Example 67, wherein the second dosing cycle comprises a single dose of rituximab (C2D1).

74. The method according to Example 73, wherein the C2D1 of rituximab is about 375 mg/ ^m² .

75. The method according to Example 73 or 74, wherein rituximab is administered to the subject on day 5 of the second dosing cycle.

76. The method according to any one of Examples 62 to 75, wherein the method comprises administering ifosfamide, carboplatin and etoposide to the subject.

77. The method according to Example 76, wherein the first dosing cycle includes:

(a) The first dose of ifosfamide (C1D1), the second dose of ifosfamide (C1D2), and the third dose of ifosfamide (C1D3);

(b) A single dose of carboplatin (C1D1); and

(c) The first dose of etoposide (C1D1), the second dose of etoposide (C1D2), and the third dose of etoposide (C1D3);

And the second cycle includes:

(a) The first dose of ifosfamide (C2D1), the second dose of ifosfamide (C2D2), and the third dose of ifosfamide (C2D3);

(b) A single dose of carboplatin (C2D1); and

(c) The first dose of etoposide (C2D1), the second dose of etoposide (C2D2), and the third dose of etoposide (C2D3).

78. The method as described in claim 77, wherein ifosfamide is administered at a dose of about 3000 mg/ ^m² for each dose of ifosfamide, at a dose of about 635 mg/ ^m² , and carboplatin is administered at a dose of about 100 mg/ ^m² for each dose of etoposide.

79. The method according to embodiment 77 or 78, wherein:

(a) On days 3, 4 and 5 of the first dosing cycle, respectively, the C1D1, C1D2 and C1D3 of ifosfamide were administered;

(b) Administer carboplatin C1D1 on day 3 of the first dosing cycle;

(c) Etoposide C1D1, C1D2 and C1D3 were administered on days 3, 4 and 5 of the first dosing cycle, respectively;

(d) On days 6, 7 and 8 of the second dosing cycle, the C2D1, C2D2 and C2D3 of ifosfamide were administered respectively;

(e) Administer carboplatin C2D1 on day 6 of the second dosing cycle; and

(f) Etoposide C2D1, C2D2 and C2D3 were administered on days 6, 7 and 8 of the second dosing cycle, respectively.

80. The method according to any one of Examples 62 to 79, wherein the first dosing cycle and the second dosing cycle are each a 21-day dosing cycle.

81. The method according to any one of Examples 62 to 80, wherein the dosing regimen includes one or more additional dosing cycles.

82. The method according to Example 81, wherein each of the one or more additional dosing cycles is a 21-day dosing cycle.

83. The method according to Example 81 or 82, wherein the dosing regimen comprises a total of three dosing cycles.

84. The method according to any one of Examples 81 to 83, wherein each of the one or more additional dosing cycles comprises:

(a) An additional single dose of a bispecific antibody that binds to both CD20 and CD3.

(b) An additional single dose of anti-CD20 antibody, and

(c) Additional first, second and third doses of ifosfamide; additional single dose of carboplatin; and additional first, second and third doses of etoposide.

85. The method according to Example 84, wherein:

(a) The subject's weight is greater than or equal to about 7.5 kg and less than about 13 kg, and the additional single dose of the bispecific antibody is about 0.5 mg/kg;

(b) The subject's weight is greater than or equal to about 13 kg and less than about 45 kg, and the additional single dose of the bispecific antibody is about 0.4 mg/kg; or

(c) The subject weighs more than or equal to about 45 kg, and the additional single dose of the bispecific antibody is about 30 mg.

86. The method according to Example 84 or 85, wherein the additional single dose of the bispecific antibody is administered to the subject on day 1 of each of the one or more additional dosing cycles.

87. The method according to any one of Examples 84 to 86, wherein the anti-CD20 antibody is rituximab.

88. The method according to Example 87, wherein the additional single dose of rituximab is approximately 375 mg/ ^m² .

89. The method according to Example 87 or 88, wherein the additional single dose of rituximab is administered on day 5 of each of the one or more additional dosing cycles.

90. The method according to any one of Examples 81 to 89, wherein the additional first dose, the additional second dose, and the additional third dose of ifosfamide are each about 3000 mg/ ^m² , the additional single dose of carboplatin is about 635 mg/ ^m² , and the additional first dose, the additional second dose, and the additional third dose of etoposide are each about 100 mg/ ^m² .

91. The method according to any one of Examples 81 to 90, wherein:

(a) The subject is given the additional first dose, the additional second dose, and the additional third dose of ifosfamide on day 6, day 7, and day 8 of each of the one or more additional dosing cycles, respectively;

(b) Administer the additional single dose of carboplatin on day 6 of each of the one or more additional dosing cycles; and

(c) The subject is given an additional first dose, an additional second dose, and an additional third dose of etoposide on days 6, 7, and 8 of each of the one or more additional dosing cycles.

92. The method according to any one of Examples 62 to 91, wherein the method further comprises administering one or more additional therapeutic agents to the subject.

93. The method according to Example 92, wherein the one or more additional therapeutic agents are tocilizumab.

94. The method according to Example 93, wherein the subject weighs more than or equal to about 30 kg and tocilizumab is administered at a dose of about 8 mg/kg, or the subject weighs less than 30 kg and tocilizumab is administered at a dose of about 12 mg/kg, and wherein the maximum dose is about 800 mg.

95. The method according to Example 92, wherein the one or more additional therapeutic agents are corticosteroids.

96. The method according to Example 95, wherein the corticosteroid comprises prednisone, prednisolone, methylprednisolone, or dexamethasone.

97. The method according to Example 96, wherein the corticosteroid is dexamethasone.

98. The method according to Example 97, wherein dexamethasone is administered intravenously at a dose between about 0.15 mg/kg and about 0.5 mg/kg at least one hour prior to the administration of any dose of the bispecific antibody, and wherein the maximum daily dose is 10 mg.

99. The method according to Example 97, wherein dexamethasone is administered intravenously at a dose between about 0.15 mg/kg and about 0.5 mg/kg at least one hour prior to administration of any dose of olibutuzumab, and wherein the maximum daily dose is 10 mg.

100. The method according to Example 96, wherein the corticosteroid is methylprednisolone.

101. The method according to Example 100, wherein methylprednisolone is administered intravenously at a dose between about 1 mg/kg and about 2 mg/kg at least one hour prior to the administration of any dose of the bispecific antibody.

102. The method according to Example 100, wherein methylprednisolone is administered intravenously at a dose between about 1 mg/kg and about 2 mg/kg at least one hour prior to the administration of any dose of olibutuzumab.

103. The method according to Example 96, wherein the corticosteroid is prednisone or prednisolone.

104. The method according to Example 103, wherein prednisone or prednisolone is administered intravenously at a dose of about 100 mg or about 2 mg/kg at least one hour prior to the administration of any dose of the bispecific antibody.

105. The method according to Example 103, wherein prednisone or prednisolone is administered intravenously at a dose of about 100 mg or about 2 mg/kg at least one hour prior to the administration of any dose of olibutuzumab.

106. The method according to Example 92, wherein the one or more additional therapeutic agents are antihistamines.

107. The method according to Example 106, wherein the antihistamine is diphenhydramine.

108. The method according to Example 107, wherein the subject is between 2 and 17 years old, and wherein diphenhydramine is administered intravenously at a dose between about 10 mg and 20 mg, wherein the maximum single dose is about 1.25 mg/kg.

109. The method according to Example 107, wherein the subject is less than two years old, and wherein diphenhydramine is administered rectally at a dose of about 20 mg.

110. The method according to Example 108 or 109, wherein diphenhydramine is administered at least about 30 minutes prior to the administration of any dose of the bispecific antibody and/or anti-CD20 antibody.

111. The method according to Example 92, wherein the one or more additional therapeutic agents comprise granulocyte colony-stimulating factor (G-CSF).

112. The method according to Example 111, wherein G-CSF is administered between approximately one and approximately two days after administration of any dose of rituximab, ifosfamide, carboplatin and/or etoposide.

113. The method according to Example 112, wherein G-CSF is administered intravenously or subcutaneously at a dose of about 5 μg/kg/day or about 10 μg/kg/day.

114. The method according to Example 113, wherein G-CSF is administered at a dose of about 5 μg/kg/day in the first dosing cycle and at a dose of about 10 μg/kg/day in the second dosing cycle and/or each additional dosing cycle.

115. The method according to Example 92, wherein the one or more additional therapeutic agents are antipyretics.

116. The method according to Example 115, wherein the antipyretic is acetaminophen or paracetamol.

117. The method according to Example 116, wherein acetaminophen or paracetamol is administered orally or intravenously at a dose between about 500 mg and about 1000 mg.

118. The method according to Example 117, wherein acetaminophen or paracetamol is administered at least about 30 minutes prior to the administration of any dose of the bispecific antibody and/or anti-CD20 antibody.

119. The method according to Example 92, wherein the one or more additional therapeutic agents are mesna.

120. The method according to Example 119, wherein mesna is administered intravenously daily in five doses totaling 3000 mg/ ^m² .

121. The method according to Example 120, wherein mesna is administered intravenously at a first dose of about 600 mg/ ^m² and four repeated doses of about 600 mg/ ^m² prior to the administration of any dose of ifosfamide, the repeated doses being administered at about three hours, about six hours and about 12 hours after the first dose of ifosfamide, respectively.

122. The method according to Example 120 or 121, wherein the subject is given mesna daily on days 3, 4 and 5 of the first dosing cycle, days 6, 7 and 8 of the second dosing cycle and/or on days 6, 7 and 8 of each additional dosing cycle.

123. A method for treating a subject aged 18 to 30 years with a CD20-positive proliferative disorder, the method comprising administering to the subject an effective amount of: a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

(a) Bispecific antibodies that bind to CD20 and CD3;

(b) Anti-CD20 antibody; and

(c) One or more chemotherapeutic agents selected from ifosfamide, carboplatin and/or etoposide.

124. The method according to embodiment 123, wherein

The first dosing cycle includes a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody, wherein the C1D1 of the bispecific antibody is approximately 2.5 mg and the C1D2 of the bispecific antibody is approximately 10 mg; and

The second dosing cycle includes a single dose (C2D1) of the bispecific antibody, wherein the C2D1 of the bispecific antibody is approximately 30 mg.

125. The method according to Example 124, wherein the subject is administered the C1D1 and the C1D2 of the bispecific antibody on day 8 and day 15 of the first dosing cycle, respectively.

126. The method according to Example 124 or 125, wherein the C2D1 of the bispecific antibody is administered to the subject on day 1 of the second dosing cycle.

127. The method according to any one of Examples 123 to 126, wherein the anti-CD20 antibody is olibutuzumab and/or rituximab.

128. The method according to Example 127, wherein the first dosing cycle includes a first dose (C1D1) of olibutuzumab and a second dose (C1D2) of olibutuzumab.

129. The method according to Example 128, wherein the sum of the C1D1 and the C1D2 of olibutuzumab is about 1000 mg.

130. The method according to Example 128 or 129, wherein the C1D1 of olibutuzumab is about one-tenth the sum of the C1D1 and the C1D2 of olibutuzumab, and the C1D2 of olibutuzumab is about nine-tenths the sum of the C1D1 and the C1D2 of olibutuzumab.

131. The method according to any one of Examples 128 to 130, wherein the C1D1 of olibutuzumab is about 100 mg and the C1D2 of olibutuzumab is about 900 mg.

132. The method according to any one of Examples 128 to 131, wherein the subject is administered C1D1 of oxetuzumab on day 1 of the first dosing cycle and the subject is administered C1D2 of oxetuzumab on day 2 of the first dosing cycle.

133. The method according to Example 127, wherein the second dosing cycle comprises a single dose of rituximab (C2D1).

134. The method according to Example 133, wherein the C2D1 of rituximab is about 375 mg/ ^m² .

135. The method according to Example 133 or 134, wherein the C2D1 of rituximab is administered to the subject on day 5 of the second dosing cycle.

136. The method according to any one of Examples 133 to 135, wherein the method comprises administering ifosfamide, carboplatin and etoposide to the subject.

137. The method according to Example 136, wherein the first dosing cycle includes:

(a) A single dose of ifosfamide (C1D1);

(b) A single dose of carboplatin (C1D1); and

(c) The first dose of etoposide (C1D1), the second dose of etoposide (C1D2), and the third dose of etoposide (C1D3);

And the second cycle includes:

(a) A single dose of ifosfamide (C2D1);

(b) A single dose of carboplatin (C2D1); and

(c) The first dose of etoposide (C2D1), the second dose of etoposide (C2D2), and the third dose of etoposide (C2D3).

138. The method according to Example 137, wherein ifosfamide is administered at a dose of about 5000 mg/ ^m² , carboplatin is administered at a dose of about 5 × (25 + creatinine clearance (CrCl)) mg, wherein the maximum dose is about 750 mg, and etoposide is administered at a dose of about 100 mg/ ^m² for each dose of etoposide.

139. The method according to Example 138, wherein:

(a) The subject is male, and CrCl is calculated using the formula CrCl = ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]); or

(b) The subject was female, and CrCl was calculated using the formula CrCl = 0.85 × ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]).

140. The method according to embodiment 138 or 139, wherein:

(a) The subject had CrCl levels <60 mL/min, and each single dose of ifosfamide was reduced to 4000 mg/ ^m² ; and/or

(b) The subject had CrCl < 50 mL/min, and each dose of etoposide was reduced to 75 mg/ ^m² .

141. The method according to any one of embodiments 137 to 140, wherein:

(a) Administer C1D1 of ifosfamide on day 3 of the first dosing cycle;

(b) Administer carboplatin C1D1 on day 3 of the first dosing cycle;

(c) Etoposide C1D1, C1D2 and C1D3 were administered on days 3, 4 and 5 of the first dosing cycle, respectively;

(d) Administer C2D1 of ifosfamide on day 6 of the second dosing cycle;

(e) Administer carboplatin C2D1 on day 6 of the second dosing cycle; and

(f) Etoposide C2D1, C2D2 and C2D3 were administered on days 6, 7 and 8 of the second dosing cycle, respectively.

142. The method according to any one of Examples 123 to 141, wherein the first administration cycle and the second administration cycle are each a 21-day administration cycle.

143. The method according to any one of Examples 123 to 142, wherein the dosing regimen includes one or more additional dosing cycles.

144. The method according to Example 143, wherein each of the one or more additional dosing cycles is a 21-day dosing cycle.

145. The method according to Example 143 or 144, wherein the dosing regimen comprises a total of three dosing cycles.

146. The method according to any one of Examples 143 to 145, wherein each of the one or more additional dosing cycles comprises:

(a) An additional single dose of a bispecific antibody that binds to both CD20 and CD3.

(b) An additional single dose of anti-CD20 antibody, and

(c) Additional single doses of ifosfamide; additional single doses of carboplatin; and additional first, second and third doses of etoposide.

147. The method according to Example 146, wherein the additional single dose of the bispecific antibody is about 30 mg.

148. The method according to Example 146 or 147, wherein the additional single dose of the bispecific antibody is administered to the subject on day 1 of each of the one or more additional dosing cycles.

149. The method according to any one of Examples 146 to 148, wherein the anti-CD20 antibody is rituximab.

150. The method according to Example 149, wherein the additional single dose of rituximab is approximately 375 mg/ ^m² .

151. The method according to Example 149 or 150, wherein the additional single dose of rituximab is administered on day 5 of each of the one or more additional dosing cycles.

152. The method according to any one of Examples 146 to 151, wherein the additional single dose of ifosfamide is about 5000 mg/ ^m² , the additional single dose of carboplatin is about 5 × (25 + creatinine clearance (CrCl)) mg, wherein the maximum dose is about 750 mg, and the additional first dose, the additional second dose, and the additional third dose of etoposide are each about 100 mg/ ^m² .

153. The method according to Example 152, wherein:

(a) The subject is male, and CrCl is calculated using the formula CrCl = ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]); or

(b) The subject was female, and CrCl was calculated using the formula CrCl = 0.85 × ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]).

154. The method according to embodiment 152 or 153, wherein:

(a) The subject had CrCl levels <60 mL/min, and the additional single dose of ifosfamide was reduced to 4000 mg/ ^m² ; and/or

(b) The subject had CrCl < 50 mL/min, and each additional dose of etoposide was reduced to 75 mg/ ^m² .

155. The method according to any one of Examples 146 to 154, wherein:

(a) Administer the additional single dose of ifosfamide on day 6 of each of the one or more additional dosing cycles;

(b) Administer the additional single dose of carboplatin on day 6 of each of the one or more additional dosing cycles; and

(c) The subject is given an additional first dose, an additional second dose, and an additional third dose of etoposide on days 6, 7, and 8 of each of the one or more additional dosing cycles.

156. The method according to any one of Examples 123 to 155, wherein the method further comprises administering one or more additional therapeutic agents to the subject.

157. The method according to Example 156, wherein the one or more additional therapeutic agents are tocilizumab.

158. The method according to Example 157, wherein the subject weighs more than or equal to about 30 kg and tocilizumab is administered at a dose of about 8 mg/kg, or the subject weighs less than 30 kg and tocilizumab is administered at a dose of about 12 mg/kg, and wherein the maximum dose is about 800 mg.

159. The method according to Example 156, wherein the one or more additional therapeutic agents are corticosteroids.

160. The method according to Example 159, wherein the corticosteroid comprises prednisone, prednisolone, methylprednisolone, or dexamethasone.

161. The method according to Example 160, wherein the corticosteroid is dexamethasone.

162. The method according to Example 161, wherein dexamethasone is administered intravenously at a dose between about 0.15 mg/kg and about 0.5 mg/kg at least one hour prior to the administration of any dose of the bispecific antibody, and wherein the maximum daily dose is 10 mg.

163. The method according to Example 161, wherein dexamethasone is administered intravenously at a dose between about 0.15 mg/kg and about 0.5 mg/kg at least one hour prior to administration of any dose of olibutuzumab, and wherein the maximum daily dose is 10 mg.

164. The method according to Example 160, wherein the corticosteroid is methylprednisolone.

165. The method according to Example 164, wherein methylprednisolone is administered intravenously at a dose between about 1 mg/kg and about 2 mg/kg at least one hour prior to the administration of any dose of the bispecific antibody.

166. The method according to Example 164, wherein methylprednisolone is administered intravenously at a dose between about 1 mg/kg and about 2 mg/kg at least one hour prior to the administration of any dose of olibutuzumab.

167. The method according to Example 160, wherein the corticosteroid is prednisone or prednisolone.

168. The method according to Example 167, wherein prednisone or prednisolone is administered intravenously at a dose of about 100 mg or about 2 mg/kg at least one hour prior to the administration of any dose of the bispecific antibody.

169. The method according to Example 167, wherein prednisone or prednisolone is administered intravenously at a dose of about 100 mg or about 2 mg/kg at least one hour prior to the administration of any dose of olibutuzumab.

170. The method according to Example 156, wherein the one or more additional therapeutic agents are antihistamines.

171. The method according to Example 170, wherein the antihistamine is diphenhydramine.

172. The method according to Example 171, wherein diphenhydramine is administered orally or intravenously at a dose of about 50 mg.

173. The method according to Example 172, wherein diphenhydramine is administered at least about 30 minutes prior to the administration of any dose of the bispecific antibody and/or anti-CD20 antibody.

174. The method according to Example 156, wherein the one or more additional therapeutic agents comprise granulocyte colony-stimulating factor (G-CSF).

175. The method according to Example 174, wherein G-CSF is administered between approximately one and approximately two days after administration of any dose of rituximab, ifosfamide, carboplatin and/or etoposide.

176. The method according to Example 175, wherein G-CSF is administered intravenously or subcutaneously at a dose of about 5 μg/kg/day or about 10 μg/kg/day.

177. The method according to Example 176, wherein G-CSF is administered at a dose of about 5 μg/kg/day in the first dosing cycle and at a dose of about 10 μg/kg/day in the second dosing cycle and/or each additional dosing cycle.

178. The method according to Example 152, wherein the one or more additional therapeutic agents are antipyretics.

179. The method according to Example 178, wherein the antipyretic is acetaminophen or paracetamol.

180. The method according to Example 179, wherein acetaminophen or paracetamol is administered orally or intravenously at a dose between about 500 mg and about 1000 mg.

181. The method according to Example 180, wherein acetaminophen or paracetamol is administered at least about 30 minutes prior to the administration of any dose of the bispecific antibody and/or anti-CD20 antibody.

182. The method according to Example 156, wherein the one or more additional therapeutic agents are mesna.

183. The method according to Example 182, wherein mesna is administered intravenously at a dose of about 5000 mg/ ^m² .

184. The method according to Example 183, wherein mesna is administered via continuous infusion over approximately 24 hours on day 3 of the first dosing cycle, day 6 of the second dosing cycle, and/or day 6 of each additional dosing cycle.

185. The method according to Example 183 or 184, wherein mesna is administered simultaneously with any dose of ifosfamide.

186. The method according to any one of Examples 1 to 185, wherein the bispecific antibody comprises at least one Fab molecule that specifically binds to CD20, the Fab molecule comprising the following six hypervariable regions (HVRs):

(i)HVR-H1, which contains the amino acid sequence of YSWIN (SEQ ID NO:1);

(ii) HVR-H2, which contains the amino acid sequence RIFPGDGDTDYNGKFKG (SEQ ID NO:2);

(iii) HVR-H3, which contains the amino acid sequence NVFDGYWLVY (SEQ ID NO:3);

(iv) HVR-L1, which contains the amino acid sequence RSSKSLLHSNGITYLY (SEQ ID NO:4);

(v)HVR-L2, which contains the amino acid sequence of QMSNLVS (SEQ ID NO:5); and

(vi)HVR-L3, which contains the amino acid sequence of AQNLELPYT (SEQ ID NO:6).

187. The method according to any one of Examples 1 to 186, wherein the bispecific antibody comprises at least one Fab molecule that specifically binds to CD20, the Fab molecule comprising: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:7; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:8; or (c) the VH domain as in (a) and the VL domain as in (b).

188. The method according to Example 187, wherein the Fab molecule specifically binding to CD20 comprises: (a) a VH domain comprising the amino acid sequence of SEQ ID NO:7; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:8.

189. The method according to any one of Examples 1 to 188, wherein the bispecific antibody comprises at least one Fab molecule that specifically binds to CD3, the Fab molecule comprising the following six HVRs:

(i)HVR-H1, which contains the amino acid sequence of TYAMN (SEQ ID NO:9);

(ii) HVR-H2, which contains the amino acid sequence RIRSKYNNYATYYADSVKG (SEQ ID NO:10);

(iii) HVR-H3, which contains the amino acid sequence HGNFGNSYVSWFAY (SEQ ID NO:11);

(iv) HVR-L1, which contains the amino acid sequence GSSTGAVTTSNYAN (SEQ ID NO:12);

(v)HVR-L2, which contains the amino acid sequence of GTNKRAP (SEQ ID NO: 13); and

(vi)HVR-L3, which contains the amino acid sequence of ALWYSNLWV (SEQ ID NO:14).

190. The method according to any one of Examples 1 to 189, wherein the bispecific antibody comprises at least one Fab molecule that specifically binds to CD3, the Fab molecule comprising: (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 15; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 16; or (c) the VH domain as in (a) and the VL domain as in (b).

191. The method according to Example 190, wherein the Fab molecule that specifically binds to CD3 comprises: (a) a VH domain comprising the amino acid sequence of SEQ ID NO:15; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:16.

192. The method according to any one of Examples 1 to 191, wherein the bispecific antibody is divalent to CD20 and monovalent to CD3.

193. The method according to any one of Examples 1 to 192, wherein the bispecific antibody comprises two Fab molecules that specifically bind to CD20 and one Fab molecule that specifically binds to CD3.

194. The method according to any one of Examples 1 to 193, wherein the bispecific antibody is a humanized antibody.

195. The method according to any one of Examples 1 to 194, wherein the bispecific antibody is glimetuzumab.

196. The method according to any one of Examples 1 to 195, wherein the bispecific antibody is administered intravenously.

197. The method according to any one of Examples 1 to 196, wherein the anti-CD20 antibody is administered intravenously.

198. The method according to any one of Examples 1 to 197, wherein ifosfamide, carboplatin and/or etoposide are administered intravenously.

199. The method according to any one of Examples 1 to 198, wherein the CD20-positive cell proliferative disorder is a B-cell proliferative disorder.

200. The method according to Example 199, wherein the B-cell proliferative disorder is non-Hodgkin's lymphoma (NHL) or central nervous system lymphoma (CNSL).

201. The method according to Example 200, wherein the NHL is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), high-grade B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma (PMLBCL), diffuse B-cell lymphoma, or small lymphocytic lymphoma.

202. The method according to Example 200, wherein the NHL is Burkitt lymphoma (BL) or Burkitt leukemia (BAL).

203. The method according to any one of Examples 200 to 202, wherein the NHL is recurrent and/or refractory.

204. The method according to any one of Examples 200 to 203, wherein the NHL is invasive and/or mature.

205. The method according to Example 200, wherein the B-cell proliferative disorder is relapsed and/or refractory mature B-cell NHL.

206. The method according to Example 203, wherein the subject has received a prior systemic therapy.

207. The method according to Example 206, wherein the subject has received no more than one prior systemic therapy.

208. The method according to Example 206 or 207, wherein the prior systemic therapy comprises an anti-CD20 antibody and anthracycline.

209. The method according to any one of Examples 1 to 208, wherein the subject is a human being.

210. The method according to any one of Examples 1 to 209, wherein the subject meets the criteria for transplantation or CAR-T cell therapy.

211. The method according to Example 210, wherein the subject undergoes autologous stem cell transplantation (ASCT) after completing the dosing regimen according to any one of Examples 1 to 209.

212. The method according to Example 211, wherein the ASCT is an autologous hematopoietic stem cell transplantation.

213. The method according to Example 210, wherein the subject receives allogeneic hematopoietic stem cell transplantation after completing the dosing regimen according to any one of Examples 1 to 209.

214. The method according to Example 210, wherein the subject receives CAR-T cell therapy after completing the dosing regimen according to any one of Examples 1 to 209.

215. A method of treating a subject with a CD20-positive proliferative disorder, the method comprising administering to the subject an effective amount of glibenclamide, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein:

(a) This first dosing cycle comprises administering a first dose (C1D1) of glimetuzumab on day 8 and a second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is approximately 2.5 mg and the C1D2 of glimetuzumab is approximately 10 mg; and

(b) The second dosing cycle includes a single dose (C2D1) of glimetuzumab administered on day 8, wherein the C2D1 of glimetuzumab is approximately 30 mg.

216. A method of treating a subject with a CD20-positive proliferative disorder, the method comprising administering to the subject effective amounts of glimepiride, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle, wherein:

(a) The first dosing cycle includes administering a first dose (C1D1) of glimetuzumab on day 8 and a second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg and the C1D2 of glimetuzumab is about 10 mg.

(b) This second dosing cycle includes a single dose (C2D1) of glimetuzumab administered on day 8, wherein the C2D1 of glimetuzumab is approximately 30 mg; and

(c) The third dosing cycle includes a single dose (C3D1) of glimetuzumab administered on day 8, wherein the C3D1 of glimetuzumab is approximately 30 mg.

217. A method of treating a subject with a CD20-positive proliferative disorder, the method comprising administering to the subject an effective amount of glibenclamide, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein:

(a) The first dosing cycle includes:

(i) The first dose (C1D1) of glimetuzumab was administered on day 8 and the second dose (C1D2) of glimetuzumab was administered on day 15, wherein the C1D1 of glimetuzumab was about 2.5 mg and the C1D2 of glimetuzumab was about 10 mg.

(ii) Administer the first dose (C1D1) of olibutuzumab on day 1, wherein the C1D1 of olibutuzumab is approximately 1000 mg;

(iii) A single dose (C1D1) of ifosfamide was administered on day 2, wherein the C1D1 of ifosfamide was approximately 5000 mg/ ^m2 and the maximum dose was approximately 800 mg;

(iv) A single dose (C1D1) of carboplatin was administered on day 2, wherein the C1D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C1D1) on day 1, the second dose of etoposide (C1D2) on day 2, and the third dose of etoposide (C1D3) on day 3, wherein each of the three doses of etoposide (C1D1, C1D2, and C1D3) is approximately 100 mg/ ^m² ; and

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab was administered on day 8, wherein the C2D1 of glimetuzumab was approximately 30 mg;

(ii) Administer the first dose (C2D1) of rituximab on day 1, wherein the C2D1 of rituximab is approximately 375 mg/ ^m² .

(iii) A single dose (C2D1) of ifosfamide was administered on day 2, wherein the C2D1 of ifosfamide was approximately 5000 mg/ ^m2 and the maximum dose was approximately 800 mg;

(iv) A single dose (C2D1) of carboplatin was administered on day 2, wherein the C2D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose of etoposide (C2D1) was administered on day 1, the second dose of etoposide (C2D2) was administered on day 2, and the third dose of etoposide (C2D3) was administered on day 3, wherein each of the C2D1, C2D2 and C2D3 of etoposide was approximately 100 mg/ ^m2 .

218. A method of treating a subject with a CD20-positive proliferative disorder, the method comprising administering to the subject effective amounts of glimepiride, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle, wherein:

(a) The first dosing cycle includes:

(i) The first dose (C1D1) of glimetuzumab was administered on day 8 and the second dose (C1D2) of glimetuzumab was administered on day 15, wherein the C1D1 of glimetuzumab was about 2.5 mg and the C1D2 of glimetuzumab was about 10 mg.

(ii) Administer the first dose (C1D1) of olibutuzumab on day 1, wherein the C1D1 of olibutuzumab is approximately 1000 mg;

(iii) A single dose (C1D1) of ifosfamide was administered on day 2, wherein the C1D1 of ifosfamide was approximately 5000 mg/ ^m2 and the maximum dose was approximately 800 mg;

(iv) A single dose (C1D1) of carboplatin was administered on day 2, wherein the C1D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose of etoposide (C1D1) was administered on day 1, the second dose of etoposide (C1D2) was administered on day 2, and the third dose of etoposide (C1D3) was administered on day 3, wherein the C1D1, C1D2 and C1D3 of etoposide were each approximately 100 mg/ ^m2 .

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab was administered on day 8, wherein the C2D1 of glimetuzumab was approximately 30 mg;

(ii) Administer the first dose (C2D1) of rituximab on day 1, wherein the C2D1 of rituximab is approximately 375 mg/ ^m² .

(iii) A single dose (C2D1) of ifosfamide was administered on day 2, wherein the C2D1 of ifosfamide was approximately 5000 mg/ ^m2 and the maximum dose was approximately 800 mg;

(iv) A single dose (C2D1) of carboplatin was administered on day 2, wherein the C2D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C2D1) on day 1, the second dose of etoposide (C2D2) on day 2, and the third dose of etoposide (C2D3) on day 3, wherein each of the three doses of etoposide (C2D1, C2D2, and C2D3) is approximately 100 mg/ ^m² ; and

(c) The third dosing cycle includes:

(i) A single dose (C3D1) of glimetuzumab was administered on day 8, wherein the C3D1 of glimetuzumab was approximately 30 mg;

(ii) Administer the first dose (C3D1) of rituximab on day 1, wherein the C3D1 of rituximab is approximately 375 mg/ ^m² .

(iii) A single dose (C3D1) of ifosfamide was administered on day 2, wherein the C3D1 of ifosfamide was approximately 5000 mg/ ^m2 and the maximum dose was approximately 800 mg;

(iv) A single dose of carboplatin (C3D1) was administered on day 2, wherein the C3D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose of etoposide (C3D1) was administered on day 1, the second dose of etoposide (C3D2) was administered on day 2, and the third dose of etoposide (C3D3) was administered on day 3, wherein each of the C3D1, C3D2 and C3D3 of etoposide was approximately 100 mg/ ^m2 .

219. The method according to any one of Examples 215 to 218, wherein mesna is administered simultaneously with any dose of ifosfamide.

220. The method according to Example 219, wherein mesna is administered intravenously at a dose of about 5000 mg/ ^m² .

221. The method according to Example 220, wherein mesna is administered via continuous infusion over approximately 24 hours on the second day of each dosing cycle.

222. A method for treating a subject aged 6 months to 17 years with CD20-positive proliferative disorders, the method comprising administering to the subject effective amounts of glimepiride, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein:

(a) The first dosing cycle comprises administering a first dose (C1D1) of glimetuzumab on day 8 and a second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is approximately 0.03 mg/kg, approximately 0.04 mg/kg, or approximately 2.5 mg, and the C1D2 of glimetuzumab is approximately 0.15 mg/kg or approximately 10 mg; and

(b) The second dosing cycle includes a single dose (C2D1) of glimetuzumab administered on day 8, wherein the C2D1 of glimetuzumab is approximately 0.4 mg/kg, approximately 0.5 mg/kg, or approximately 30 mg.

223. A method for treating a subject aged 6 months to 17 years with CD20-positive proliferative disorders, the method comprising administering to the subject effective amounts of glibenclamide, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle, wherein:

(a) The first dosing cycle includes administering a first dose (C1D1) of glimetuzumab on day 8 and a second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is about 0.03 mg/kg, about 0.04 mg/kg or about 2.5 mg, and the C1D2 of glimetuzumab is about 0.15 mg/kg or about 10 mg;

(b) This second dosing cycle includes a single dose (C2D1) of glimetuzumab administered on day 8, wherein the C2D1 of glimetuzumab is approximately 0.4 mg/kg, approximately 0.5 mg/kg, or approximately 30 mg; and

(c) The third dosing cycle includes a single dose (C3D1) of glimetuzumab administered on day 8, wherein the C3D1 of glimetuzumab is approximately 0.4 mg/kg, approximately 0.5 mg/kg or approximately 30 mg.

224. A method for treating a subject aged 6 months to 17 years with CD20-positive proliferative disorders, the method comprising administering to the subject an effective amount of glibenclamide, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein:

(a) The first dosing cycle includes:

(i) Administer the first dose (C1D1) of glimetuzumab on day 8 and the second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is about 0.03 mg/kg, about 0.04 mg/kg or about 2.5 mg, and the C1D2 of glimetuzumab is about 0.15 mg/kg or about 10 mg;

(ii) Administering a first dose (C1D1) of olibutuzumab on day 1 and a second dose (C1D2) of olibutuzumab on day 2, wherein the C1D1 of olibutuzumab is approximately one-tenth of the sum of the C1D1 and C1D2 of olibutuzumab, and the C1D2 of olibutuzumab is approximately nine-tenths of the sum of the C1D1 and C1D2 of olibutuzumab, and wherein the sum of the C1D1 and C1D2 of olibutuzumab is approximately 38 mg/kg, approximately 28 mg/kg, approximately 23 mg/kg, approximately 20 mg/kg, or approximately 1000 mg;

(iii) Administer the first dose (C1D1) of ifosfamide on day 3, the second dose (C1D2) of ifosfamide on day 4, and the third dose (C1D3) of ifosfamide on day 5, wherein the C1D1, C1D2 and C1D3 of ifosfamide are each about 3000 mg/ ^m2 ;

(iv) A single dose of carboplatin (C1D1) was administered on day 3, wherein the C1D1 of carboplatin was approximately 635 mg/ ^m² ; and

(v) Administer the first dose of etoposide (C1D1) on day 3, the second dose of etoposide (C1D2) on day 4, and the third dose of etoposide (C1D3) on day 5, wherein each of the three doses of etoposide (C1D1, C1D2, and C1D3) is approximately 100 mg/ ^m² ; and

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab is administered on day 1, wherein the C2D1 of glimetuzumab is approximately 0.4 mg/kg, approximately 0.5 mg/kg or approximately 30 mg;

(ii) Administer the first dose (C2D1) of rituximab on day 5, wherein the C2D1 of rituximab is approximately 375 mg/ ^m² .

(iii) Administer the first dose (C2D1) of ifosfamide on day 6, the second dose (C2D2) of ifosfamide on day 7, and the third dose (C2D3) of ifosfamide on day 8, wherein each of the C2D1, C2D2 and C2D3 of ifosfamide is approximately 3000 mg/ ^m2 ;

(iv) A single dose (C2D1) of carboplatin was administered on day 6, wherein the C2D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose of etoposide (C2D1) was administered on day 6, the second dose of etoposide (C2D2) was administered on day 7, and the third dose of etoposide (C2D3) was administered on day 8, wherein each of the C2D1, C2D2 and C2D3 of etoposide was approximately 100 mg/ ^m2 .

225. A method for treating a subject aged 6 months to 17 years with CD20-positive proliferative disorders, the method comprising administering to the subject effective amounts of glimepiride, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle, wherein:

(a) The first dosing cycle includes:

(i) Administer the first dose (C1D1) of glimetuzumab on day 8 and the second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is about 0.03 mg/kg, about 0.04 mg/kg or about 2.5 mg, and the C1D2 of glimetuzumab is about 0.15 mg/kg or about 10 mg;

(ii) Administering a first dose (C1D1) of olibutuzumab on day 1 and a second dose (C1D2) of olibutuzumab on day 2, wherein the C1D1 of olibutuzumab is approximately one-tenth of the sum of the C1D1 and C1D2 of olibutuzumab, and the C1D2 of olibutuzumab is approximately nine-tenths of the sum of the C1D1 and C1D2 of olibutuzumab, and wherein the sum of the C1D1 and C1D2 of olibutuzumab is approximately 38 mg/kg, approximately 28 mg/kg, approximately 23 mg/kg, approximately 20 mg/kg, or approximately 1000 mg;

(iii) Administer the first dose (C1D1) of ifosfamide on day 3, the second dose (C1D2) of ifosfamide on day 4, and the third dose (C1D3) of ifosfamide on day 5, wherein the C1D1, C1D2 and C1D3 of ifosfamide are each about 3000 mg/ ^m2 ;

(iv) A single dose of carboplatin (C1D1) was administered on day 3, wherein the C1D1 of carboplatin was approximately 635 mg/ ^m² ; and

(v) The first dose of etoposide (C1D1) was administered on day 3, the second dose of etoposide (C1D2) was administered on day 4, and the third dose of etoposide (C1D3) was administered on day 5, wherein the C1D1, C1D2 and C1D3 of etoposide were each approximately 100 mg/ ^m2 .

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab is administered on day 1, wherein the C2D1 of glimetuzumab is approximately 0.4 mg/kg, approximately 0.5 mg/kg or approximately 30 mg;

(ii) Administer the first dose (C2D1) of rituximab on day 5, wherein the C2D1 of rituximab is approximately 375 mg/ ^m² .

(iii) Administer the first dose (C2D1) of ifosfamide on day 6, the second dose (C2D2) of ifosfamide on day 7, and the third dose (C2D3) of ifosfamide on day 8, wherein each of the C2D1, C2D2 and C2D3 of ifosfamide is approximately 3000 mg/ ^m2 ;

(iv) A single dose (C2D1) of carboplatin was administered on day 6, wherein the C2D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose of etoposide (C2D1) was administered on day 6, the second dose (C2D2) on day 7, and the third dose (C2D3) on day 8, wherein each of the three doses of etoposide (C2D1, C2D2, and C2D3) was approximately 100 mg/ ^m² ; and

(c) The third dosing cycle includes:

(i) A single dose (C3D1) of glimetuzumab is administered on day 1, wherein the C3D1 of glimetuzumab is approximately 0.4 mg/kg, approximately 0.5 mg/kg or approximately 30 mg;

(ii) Administer the first dose (C3D1) of rituximab on day 5, wherein the C3D1 of rituximab is approximately 375 mg/ ^m² .

(iii) Administer the first dose (C3D1) of ifosfamide on day 6, the second dose (C3D2) of ifosfamide on day 7, and the third dose (C3D3) of ifosfamide on day 8, wherein the C3D1, the C3D2 and the C3D3 of ifosfamide are each about 3000 mg/ ^m2 ;

(iv) A single dose of carboplatin (C3D1) was administered on day 6, wherein the C3D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose of etoposide (C3D1) was administered on day 6, the second dose of etoposide (C3D2) was administered on day 7, and the third dose of etoposide (C3D3) was administered on day 8, wherein each of the C3D1, C3D2 and C3D3 of etoposide was approximately 100 mg/ ^m2 .

226. The method according to any one of Examples 222 to 225, wherein the subject is administered mesna on days 3, 4 and 5 of the first dosing cycle, days 6, 7 and 8 of the second dosing cycle and/or on days 6, 7 and 8 of each additional dosing cycle.

227. The method according to Example 226, wherein mesna is administered intravenously daily at five doses totaling 3000 mg/ ^m² .

228. The method according to Example 227, wherein mesna is administered intravenously at a first dose of about 600 mg/ ^m² and four repeated doses of about 600 mg/ ^m² prior to the administration of any dose of ifosfamide, each repeated dose being administered about three hours, about six hours, and about 12 hours after the first dose of ifosfamide.

229. A method for treating a subject aged 18 to 30 years with a CD20-positive proliferative disorder, the method comprising administering to the subject an effective amount of glibenclamide, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein:

(a) This first dosing cycle comprises administering a first dose (C1D1) of glimetuzumab on day 8 and a second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is approximately 2.5 mg and the C1D2 of glimetuzumab is approximately 10 mg; and

(b) The second dosing cycle includes a single dose (C2D1) of glimetuzumab administered on day 1, wherein the C2D1 of glimetuzumab is approximately 30 mg.

230. A method for treating a subject aged 18 to 30 years with a CD20-positive proliferative disorder, the method comprising administering to the subject effective amounts of glimepiride, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle, wherein:

(a) The first dosing cycle includes administering a first dose (C1D1) of glimetuzumab on day 8 and a second dose (C1D2) of glimetuzumab on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg and the C1D2 of glimetuzumab is about 10 mg.

(b) This second dosing cycle includes a single dose (C2D1) of glimetuzumab administered on day 1, wherein the C2D1 of glimetuzumab is approximately 30 mg; and

(c) The third dosing cycle includes a single dose (C3D1) of glimetuzumab administered on day 1, wherein the C3D1 of glimetuzumab is approximately 30 mg.

231. A method for treating a subject aged 18 to 30 years with a CD20-positive proliferative disorder, the method comprising administering to the subject an effective amount of glibenclamide, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein:

(a) The first dosing cycle includes:

(i) The first dose (C1D1) of glimetuzumab was administered on day 8 and the second dose (C1D2) of glimetuzumab was administered on day 15, wherein the C1D1 of glimetuzumab was about 2.5 mg and the C1D2 of glimetuzumab was about 10 mg.

(ii) Administer a first dose (C1D1) of olibutuzumab on day 1 and a second dose (C1D2) of olibutuzumab on day 2, wherein the C1D1 of olibutuzumab is approximately one-tenth of the sum of the C1D1 and C1D2 of olibutuzumab, and the C1D2 of olibutuzumab is approximately nine-tenths of the sum of the C1D1 and C1D2 of olibutuzumab, and wherein the sum of the C1D1 and C1D2 of olibutuzumab is approximately 1000 mg;

(iii) A single dose (C1D1) of ifosfamide was administered on day 3, wherein the C1D1 of ifosfamide was approximately 5000 mg/ ^m² , and the maximum dose was approximately 800 mg.

(iv) A single dose of carboplatin (C1D1) was administered on day 3, wherein the C1D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) Administer the first dose of etoposide (C1D1) on day 3, the second dose of etoposide (C1D2) on day 4, and the third dose of etoposide (C1D3) on day 5, wherein each of the three doses of etoposide (C1D1, C1D2, and C1D3) is approximately 100 mg/ ^m² ; and

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab was administered on day 1, wherein the C2D1 of glimetuzumab was approximately 30 mg;

(ii) Administer the first dose (C2D1) of rituximab on day 5, wherein the C2D1 of rituximab is approximately 375 mg/ ^m² .

(iii) A single dose (C2D1) of ifosfamide was administered on day 6, wherein the C2D1 of ifosfamide was approximately 5000 mg/ ^m² , and the maximum dose was approximately 800 mg;

(iv) A single dose (C2D1) of carboplatin was administered on day 6, wherein the C2D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose of etoposide (C2D1) was administered on day 6, the second dose of etoposide (C2D2) was administered on day 7, and the third dose of etoposide (C2D3) was administered on day 8, wherein each of the C2D1, C2D2 and C2D3 of etoposide was approximately 100 mg/ ^m2 .

232. A method for treating a subject aged 18 to 30 years with a CD20-positive proliferative disorder, the method comprising administering to the subject effective amounts of glibenclamide, olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle, wherein:

(a) The first dosing cycle includes:

(i) The first dose (C1D1) of glimetuzumab was administered on day 8 and the second dose (C1D2) of glimetuzumab was administered on day 15, wherein the C1D1 of glimetuzumab was about 2.5 mg and the C1D2 of glimetuzumab was about 10 mg.

(ii) Administer a first dose (C1D1) of olibutuzumab on day 1 and a second dose (C1D2) of olibutuzumab on day 2, wherein the C1D1 of olibutuzumab is approximately one-tenth of the sum of the C1D1 and C1D2 of olibutuzumab, and the C1D2 of olibutuzumab is approximately nine-tenths of the sum of the C1D1 and C1D2 of olibutuzumab, and wherein the sum of the C1D1 and C1D2 of olibutuzumab is approximately 1000 mg;

(iii) A single dose (C1D1) of ifosfamide was administered on day 3, wherein the C1D1 of ifosfamide was approximately 5000 mg/ ^m² , and the maximum dose was approximately 800 mg.

(iv) A single dose of carboplatin (C1D1) was administered on day 3, wherein the C1D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose of etoposide (C1D1) was administered on day 3, the second dose of etoposide (C1D2) was administered on day 4, and the third dose of etoposide (C1D3) was administered on day 5, wherein the C1D1, C1D2 and C1D3 of etoposide were each approximately 100 mg/ ^m2 .

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab was administered on day 1, wherein the C2D1 of glimetuzumab was approximately 30 mg;

(ii) Administer the first dose (C2D1) of rituximab on day 5, wherein the C2D1 of rituximab is approximately 375 mg/ ^m² .

(iii) A single dose (C2D1) of ifosfamide was administered on day 6, wherein the C2D1 of ifosfamide was approximately 5000 mg/ ^m² , and the maximum dose was approximately 800 mg;

(iv) A single dose (C2D1) of carboplatin was administered on day 6, wherein the C2D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose of etoposide (C2D1) was administered on day 6, the second dose (C2D2) on day 7, and the third dose (C2D3) on day 8, wherein each of the three doses of etoposide (C2D1, C2D2, and C2D3) was approximately 100 mg/ ^m² ; and

(c) The third dosing cycle includes:

(i) A single dose (C3D1) of glimetuzumab was administered on day 1, wherein the C3D1 of glimetuzumab was approximately 30 mg;

(ii) Administer the first dose of rituximab (C3D1) on day 5, wherein the C3D1 of rituximab is approximately 375 mg/ ^m² .

(iii) A single dose (C3D1) of ifosfamide was administered on day 6, wherein the C3D1 of ifosfamide was approximately 5000 mg/ ^m2 and the maximum dose was approximately 800 mg;

(iv) A single dose of carboplatin (C3D1) was administered on day 6, wherein the C3D1 of carboplatin was approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose of etoposide (C3D1) was administered on day 6, the second dose of etoposide (C3D2) was administered on day 7, and the third dose of etoposide (C3D3) was administered on day 8, wherein each of the C3D1, C3D2 and C3D3 of etoposide was approximately 100 mg/ ^m2 .

233. The method according to any one of Examples 229 to 232, wherein mesna is administered simultaneously with any dose of ifosfamide.

234. The method according to Example 233, wherein mesna is administered intravenously at a dose of about 5000 mg/ ^m² .

235. The method according to Example 234, wherein mesna is administered via continuous infusion over approximately 24 hours on day 3 of the first dosing cycle, day 6 of the second dosing cycle, and/or day 6 of each additional dosing cycle.

236. The method according to any one of Examples 215 to 221, wherein the CD20-positive cell proliferative disorder is relapsed and/or refractory DLBCL.

237. The method according to any one of Examples 222 to 235, wherein the CD20-positive cell proliferative disorder is relapsed and/or refractory mature B-cell NHL.

238. A bispecific antibody that binds to CD20 and CD3, used in a method of treating a subject with a CD20-positive proliferative disorder, wherein the bispecific antibody that binds to CD20 and CD3 is administered in combination with an anti-CD20 antibody and one or more chemotherapeutic agents selected from ifosfamide, carboplatin, and/or etoposide, in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

239. Use of a bispecific antibody that binds to CD20 and CD3 in the manufacture of a medicament for treating a subject with a CD20-positive proliferative disorder, wherein, in said treatment, the bispecific antibody that binds to CD20 and CD3 is administered in combination with an anti-CD20 antibody and one or more chemotherapeutic agents selected from ifosfamide, carboplatin, and/or etoposide, in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

240. Use of a bispecific antibody that binds to CD20 and CD3 for the treatment of a subject with a CD20-positive proliferative disorder, wherein the bispecific antibody that binds to CD20 and CD3 is administered in combination with an anti-CD20 antibody and one or more chemotherapeutic agents selected from ifosfamide, carboplatin and/or etoposide, in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

241. The bispecific antibody or use provided according to any one of Examples 238 to 240, wherein the subject is 18 years of age or older.

242. The bispecific antibody or use provided according to Example 241, wherein the subject is 31 years of age or older.

243. The bispecific antibody or use according to any one of Examples 238 to 242, wherein the first dosing cycle comprises a first dose (C1D1) of the bispecific antibody and a second dose (C1D2) of the bispecific antibody, wherein the C1D1 of the bispecific antibody is about 2.5 mg and the C1D2 of the bispecific antibody is about 10 mg; and

The second dosing cycle includes a single dose (C2D1) of the bispecific antibody, wherein the C2D1 of the bispecific antibody is about 10 mg, about 16 mg, or about 30 mg.

244. The bispecific antibody or use according to Example 243, wherein the C2D1 of the bispecific antibody is about 30 mg.

245. The bispecific antibody or use according to Example 243 or 244, wherein the C1D1 and the C1D2 of the bispecific antibody are administered to the subject on day 8 and day 15 of the first dosing cycle, respectively.

246. The bispecific antibody or use according to any one of Examples 243 to 245, wherein the C2D1 of the bispecific antibody is to be administered to the subject on day 8 of the second dosing cycle.

247. The bispecific antibody or use according to any one of Examples 238 to 246, wherein the anti-CD20 antibody is olibutuzumab or rituximab.

248. The bispecific antibody or use according to Example 247, wherein the first dosing cycle comprises a single dose of olibutuzumab (C1D1); and the second dosing cycle comprises a single dose of rituximab (C2D1).

249. The bispecific antibody or use provided according to Example 248, wherein the C1D1 of olibutuzumab is about 1000 mg and the C2D1 of rituximab is about 375 mg/ ^m² .

250. The bispecific antibody or use according to Example 248 or 249, wherein the anti-CD20 antibody is to be administered in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein the first dosing cycle comprises C1D1 of olibutuzumab to be administered to the subject on day 1; and the second dosing cycle comprises C2D1 of rituximab to be administered to the subject on day 1.

251. The bispecific antibody or use according to any one of Examples 238 to 250, wherein the bispecific antibody binding to CD20 and CD3 is to be administered in combination with an anti-CD20 antibody, ifosfamide, carboplatin and etoposide.

252. The bispecific antibody or use according to Example 251, wherein the first dosing cycle comprises a single dose of ifosfamide (C1D1); a single dose of carboplatin (C1D1); and a first dose of etoposide (C1D1), a second dose of etoposide (C1D2), and a third dose of etoposide (C1D3); and the second cycle comprises a single dose of ifosfamide (C2D1); a single dose of carboplatin (C2D1); and a first dose of etoposide (C2D1), a second dose of etoposide (C2D2), and a third dose of etoposide (C2D3).

253. The bispecific antibody or use according to Example 251 or 252, wherein ifosfamide is to be administered at a dose of about 5000 mg/ ^m² , about 4000 mg/ ^m² , or about 1666 mg/ ^m² , carboplatin is to be administered at a dose of about 750 mg, which is the maximum of the target area under the curve (AUC) of about 5 mg/mL/min, and etoposide is to be administered at a dose of about 100 mg/ ^m² or about 75 mg/ ^m² .

254. The bispecific antibody or use according to Example 253, wherein ifosfamide is to be administered at a dose of about 5000 mg/ ^m² , carboplatin is to be administered at a dose of about 750 mg, which is the maximum dose of the target area under the curve (AUC) of about 5 mg/mL/min, and etoposide is to be administered at a dose of about ¹⁰⁰ mg/m².

255. The bispecific antibody or use according to Example 251, wherein carboplatin is to be administered at a dose of about 5 × (25 + creatinine clearance (CrCl)) mg, wherein the maximum dose is about 750 mg.

256. The bispecific antibody or use according to Example 255, wherein...

(a) The subject is male, and CrCl is calculated using the formula CrCl = ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]); or

(b) The subject was female, and CrCl was calculated using the formula CrCl = 0.85 × ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]).

257. The bispecific antibody or use according to any one of Examples 252 to 256, wherein ifosfamide and carboplatin are to be administered on day 2 of the first and second dosing cycles, and the C1D1 to C1D3 and C2D1 to C2D3 of etoposide are to be administered on day 1, day 2 and day 3 of the first and second dosing cycles, respectively.

258. The bispecific antibody or use according to any one of Examples 238 to 257, wherein the first and second dosing cycles are each 21-day dosing cycles.

259. The bispecific antibody or use according to any one of Examples 238 to 258, wherein the dosing regimen includes one or more additional dosing cycles.

260. The bispecific antibody or use provided according to Example 259, wherein each of the one or more additional dosing cycles is a 21-day dosing cycle.

261. The bispecific antibody or use provided according to Example 259 or 260, wherein the dosing regimen comprises a total of three dosing cycles.

262. The bispecific antibody or use according to any one of Examples 259 to 261, wherein each of the one or more additional dosing cycles comprises:

(a) An additional single dose of a bispecific antibody that binds to both CD20 and CD3.

(b) An additional single dose of anti-CD20 antibody, and

(c) Additional single doses of ifosfamide, additional single doses of carboplatin, and additional first, second, and third doses of etoposide.

263. The bispecific antibody or use provided according to Example 262, wherein the additional single dose of the bispecific antibody is about 30 mg.

264. The bispecific antibody or use provided according to Example 262 or 263, wherein the additional single dose of the bispecific antibody is to be administered to the subject on day 8 of each of the one or more additional dosing cycles.

265. The bispecific antibody or use according to any one of Examples 262 to 264, wherein the anti-CD20 antibody is rituximab.

266. The bispecific antibody or use provided according to Example 265, wherein the additional single dose of rituximab is approximately 375 mg/ ^m² .

267. The bispecific antibody or use provided according to Example 265 or 266, wherein the additional single dose of rituximab is to be administered on day 1 of each of the one or more additional dosing cycles.

268. The bispecific antibody or use according to any one of Examples 262 to 267, wherein the additional single dose of ifosfamide is about 5000 mg/ ^m² , about 4000 mg/ ^m² , or about 666 mg/ ^m² , the additional single dose of carboplatin is up to 5 mg/mL/min, wherein the maximum dose is about 750 mg, and the additional first dose, the additional second dose, and the additional third dose of etoposide are each about 100 mg/ ^m² or about 75 mg/ ^m² .

269. The bispecific antibody or use according to Example 268, wherein ifosfamide is to be administered at a dose of about 5000 mg/ ^m² , carboplatin is to be administered at a dose of about 750 mg, wherein the maximum dose of the target area under the curve (AUC) is up to 5 mg/mL/min, and etoposide is to be administered at a dose of about 100 mg/ ^m² .

270. The bispecific antibody or use according to any one of Examples 262 to 267, wherein the additional single dose of carboplatin is about 5 × (25 + creatinine clearance (CrCl)) mg, wherein the maximum dose is about 750 mg.

271. The bispecific antibody or use according to Example 270, wherein...

(a) The subject is male, and CrCl is calculated using the formula CrCl = ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]); or

(b) The subject was female, and CrCl was calculated using the formula CrCl = 0.85 × ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]).

272. The bispecific antibody or use according to any one of Examples 259 to 271, wherein ifosfamide and carboplatin are to be administered on day 2 of each of the one or more additional dosing cycles, and the additional first dose, the additional second dose and the additional third dose of etoposide are to be administered on day 1, day 2 and day 3 of each of the one or more additional dosing cycles, respectively.

273. The bispecific antibody or use according to any one of Examples 238 to 272, wherein the bispecific antibody binding to CD20 and CD3 is to be administered in combination with one or more additional therapeutic agents.

274. The bispecific antibody or use provided according to Example 273, wherein the one or more additional therapeutic agents are tocilizumab.

275. The bispecific antibody or use according to Example 274, wherein the subject weighs more than or equal to about 30 kg and is to be administered tocilizumab at a dose of about 8 mg/kg, or the subject weighs less than 30 kg and is to be administered tocilizumab at a dose of about 12 mg/kg, and wherein the maximum dose is about 800 mg.

276. The bispecific antibody or use provided according to Example 273, wherein the one or more additional therapeutic agents are corticosteroids.

277. The bispecific antibody or use provided according to Example 276, wherein the corticosteroid comprises prednisone, prednisolone, methylprednisolone, or dexamethasone.

278. The bispecific antibody or use provided according to Example 277, wherein the corticosteroid is dexamethasone.

279. The bispecific antibody or use according to Example 278, wherein dexamethasone is administered intravenously at a dose of about 20 mg at least one hour prior to the administration of any dose of the bispecific antibody.

280. The bispecific antibody or use provided according to Example 279, wherein dexamethasone is administered intravenously at a dose of about 20 mg or about 80 mg at least one hour prior to administration of any dose of olibutuzumab.

281. The bispecific antibody or use provided according to Example 277, wherein the corticosteroid is methylprednisolone.

282. The bispecific antibody or use according to Example 281, wherein methylprednisolone is administered intravenously at a dose of about 80 mg at least one hour prior to the administration of any dose of the bispecific antibody.

283. The bispecific antibody or use according to Example 281, wherein methylprednisolone is administered intravenously at a dose of about 80 mg at least one hour prior to administration of any dose of olibutuzumab.

284. The bispecific antibody or use provided according to Example 277, wherein the corticosteroid is prednisone.

285. The bispecific antibody or use according to Example 284, wherein prednisone is administered orally at a dose of about 100 mg at least one hour prior to the administration of any dose of the bispecific antibody.

286. The bispecific antibody or use provided according to Example 277, wherein the corticosteroid is prednisolone.

287. The bispecific antibody or use according to Example 286, wherein prednisolone is administered intravenously at a dose of about 100 mg at least one hour prior to the administration of any dose of the bispecific antibody.

288. The bispecific antibody or use provided according to Example 273, wherein the one or more additional therapeutic agents are antihistamines.

289. The bispecific antibody or use provided according to Example 288, wherein the antihistamine is diphenhydramine.

290. The bispecific antibody or use according to Example 289, wherein diphenhydramine is administered orally or intravenously at a dose of about 50 mg at least 30 minutes prior to the administration of any dose of the bispecific antibody.

291. The bispecific antibody or use provided according to Example 273, wherein the one or more additional therapeutic agents comprise G-CSF.

292. The bispecific antibody or use according to Example 291, wherein G-CSF is administered between about one and about two days after administration of any dose of rituximab, ifosfamide, carboplatin and/or etoposide.

293. The bispecific antibody or use provided according to Example 273, wherein the one or more additional therapeutic agents are antipyretics.

294. The bispecific antibody or use provided according to Example 293, wherein the antipyretic is acetaminophen or paracetamol.

295. The bispecific antibody or use according to Example 294, wherein acetaminophen or paracetamol is administered orally or intravenously at a dose between about 500 mg and about 1000 mg at least about 30 minutes prior to the administration of any dose of the bispecific antibody.

296. The bispecific antibody or use according to Example 294, wherein acetaminophen or paracetamol is administered orally or intravenously at a dose between about 500 mg and about 1000 mg at least about 30 minutes prior to administration of any dose of olibutuzumab.

297. The bispecific antibody or use provided according to Example 273, wherein the one or more additional therapeutic agents are mesna.

298. The bispecific antibody or use according to Example 297, wherein mesna is to be administered intravenously at a dose of about 5000 mg/ ^m² , about 4000 mg/ ^m² , or about 1666 mg/ ^m² .

299. The bispecific antibody or use according to Example 298, wherein mesna is administered via continuous infusion over approximately 24 hours on the second day of each dosing cycle.

300. The bispecific antibody or use provided according to Example 298 or 299, wherein mesna is to be administered simultaneously with any dose of ifosfamide.

301. A bispecific antibody that binds to CD20 and CD3, used in a method of treating a subject aged between 6 months and 17 years with a CD20-positive proliferative disorder, wherein the bispecific antibody that binds to CD20 and CD3 is administered in combination with an anti-CD20 antibody and one or more chemotherapeutic agents selected from ifosfamide, carboplatin, and/or etoposide, in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

302. Use of a bispecific antibody that binds to CD20 and CD3 in the manufacture of a medicament for treating a subject aged between 6 months and 17 years with a CD20-positive proliferative disorder, wherein in the treatment, the bispecific antibody that binds to CD20 and CD3 is administered in combination with an anti-CD20 antibody and one or more chemotherapeutic agents selected from ifosfamide, carboplatin, and/or etoposide, in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

303. Use of a bispecific antibody that binds to CD20 and CD3 for the treatment of a subject aged between 6 months and 17 years with CD20-positive proliferative disorders, wherein the bispecific antibody that binds to CD20 and CD3 is administered in combination with an anti-CD20 antibody and one or more chemotherapeutic agents selected from ifosfamide, carboplatin, and/or etoposide, in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

304. The bispecific antibody or use according to any one of Examples 301 to 303, wherein

The first dosing cycle includes a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody, wherein the C1D1 of the bispecific antibody is approximately 0.03 mg/kg, approximately 0.04 mg/kg, or approximately 2.5 mg, and the C1D2 of the bispecific antibody is approximately 0.15 mg/kg or approximately 10 mg; and

The second dosing cycle includes a single dose (C2D1) of the bispecific antibody, wherein the C2D1 of the bispecific antibody is about 0.4 mg/kg, about 0.5 mg/kg, or about 30 mg.

305. The bispecific antibody or use according to Example 304, wherein:

(a) The subject's weight is greater than or equal to about 7.5 kg and less than about 13 kg, and the C1D1 of the bispecific antibody is about 0.04 mg/kg, the C1D2 of the bispecific antibody is about 0.15 mg/kg, and the C2D1 of the bispecific antibody is about 0.5 mg/kg;

(b) The subject's weight is greater than or equal to about 13 kg and less than about 45 kg, and the C1D1 of the bispecific antibody is about 0.03 mg/kg, the C1D2 of the bispecific antibody is about 0.15 mg/kg, and the C2D1 of the bispecific antibody is about 0.4 mg/kg; or

(c) The subject's weight is greater than or equal to about 45 kg, and the C1D1 of the bispecific antibody is about 2.5 mg, the C1D2 of the bispecific antibody is about 10 mg, and the C2D1 of the bispecific antibody is about 30 mg.

306. The bispecific antibody or use according to Example 304 or 305, wherein the C1D1 and the C1D2 of the bispecific antibody are administered to the subject on day 8 and day 15 of the first dosing cycle, respectively.

307. The bispecific antibody or use according to any one of Examples 304 to 306, wherein the C2D1 of the bispecific antibody is to be administered to the subject on day 1 of the second dosing cycle.

308. The bispecific antibody or use according to any one of Examples 301 to 307, wherein the anti-CD20 antibody is olibutuzumab or rituximab.

309. The bispecific antibody or use according to Example 308, wherein the first dosing cycle comprises a first dose (C1D1) of olibutuzumab and a second dose (C1D2) of olibutuzumab.

310. The bispecific antibody or use according to Example 309, wherein:

(a) The subject's weight is greater than or equal to about 7.5 kg and less than about 13 kg, and the sum of the C1D1 and C1D2 of olibutuzumab is about 38 mg/kg;

(b) The subject weighs more than or equal to about 13 kg and less than about 20 kg, and the sum of the C1D1 and C1D2 of olibutuzumab is about 28 mg/kg;

(c) The subject weighs more than or equal to about 20 kg and less than about 32 kg, and the sum of the C1D1 and C1D2 of olibutuzumab is about 23 mg/kg;

(d) The subject's weight is greater than or equal to about 32 kg and less than about 45 kg, and the sum of the C1D1 and C1D2 of olibutrazumab is about 20 mg/kg; or

(e) The subject weighs more than or equal to about 45 kg, and the sum of the C1D1 and C1D2 of olibutuzumab is about 1000 mg.

311. The bispecific antibody or use according to Example 309 or 310, wherein the C1D1 of olibutuzumab is about one-tenth the sum of the C1D1 and the C1D2 of olibutuzumab, and the C1D2 of olibutuzumab is about nine-tenths the sum of the C1D1 and the C1D2 of olibutuzumab.

312. The bispecific antibody or use according to any one of Examples 309 to 311, wherein:

(a) The subject's weight is greater than or equal to about 7.5 kg and less than about 13 kg, and the C1D1 of olibutuzumab is about 3.8 mg/kg and the C1D2 of olibutuzumab is about 34.2 mg/kg;

(b) The subject's weight is greater than or equal to about 13 kg and less than about 20 kg, and the C1D1 of olibutuzumab is about 2.8 mg/kg and the C1D2 of olibutuzumab is about 35.2 mg/kg;

(c) The subject's weight is greater than or equal to about 20 kg and less than about 32 kg, and the C1D1 of olibutuzumab is about 2.3 mg/kg and the C1D2 of olibutuzumab is about 35.7 mg/kg;

(d) The subject's weight is greater than or equal to about 32 kg and less than about 45 kg, and the C1D1 of olibutuzumab is about 2.0 mg/kg and the C1D2 of olibutuzumab is about 36.0 mg/kg; or

(e) The subject weighs more than or equal to about 45 kg, and the C1D1 of olibutuzumab is about 100 mg and the C1D2 of olibutuzumab is about 900 mg.

313. The bispecific antibody or use according to any one of Examples 309 to 312, wherein the C1D1 of olibutuzumab is administered to the subject on day 1 of the first dosing cycle, and the C1D2 of olibutuzumab is administered to the subject on day 2 of the first dosing cycle.

314. The bispecific antibody or use provided according to Example 309, wherein the second dosing cycle comprises a single dose of rituximab (C2D1).

315. The bispecific antibody or use provided according to Example 314, wherein the C2D1 of rituximab is about 375 mg/ ^m² .

316. The bispecific antibody or use according to Example 314 or 315, wherein the C2D1 of rituximab is to be administered to the subject on day 5 of the second dosing cycle.

317. The bispecific antibody or use according to any one of Examples 291 to 304, wherein the bispecific antibody binding to CD20 and CD3 is to be administered in combination with an anti-CD20 antibody, ifosfamide, carboplatin and etoposide.

318. The bispecific antibody or use according to Example 317, wherein the first dosing cycle comprises:

(a) The first dose of ifosfamide (C1D1), the second dose of ifosfamide (C1D2), and the third dose of ifosfamide (C1D3);

(b) A single dose of carboplatin (C1D1); and

(c) The first dose of etoposide (C1D1), the second dose of etoposide (C1D2), and the third dose of etoposide (C1D3);

And the second cycle includes:

(a) The first dose of ifosfamide (C2D1), the second dose of ifosfamide (C2D2), and the third dose of ifosfamide (C2D3);

(b) A single dose of carboplatin (C2D1); and

(c) The first dose of etoposide (C2D1), the second dose of etoposide (C2D2), and the third dose of etoposide (C2D3).

319. The bispecific antibody or use according to Example 317 or 318, wherein ifosfamide is to be administered at a dose of about ³⁰⁰⁰ mg/m² for each dose of ifosfamide, carboplatin is to be administered at a dose of about 635 mg/ ^m² , and etoposide is to be administered at a dose of about 100 mg/ ^m² for each dose of etoposide.

320. The bispecific antibody or use provided according to Example 318 or 319, wherein:

(a) The C1D1, C1D2 and C1D3 of ifosfamide to be administered on days 3, 4 and 5 of the first dosing cycle, respectively;

(b) Administer carboplatin C1D1 on day 3 of the first dosing cycle;

(c) Etoposide C1D1, C1D2 and C1D3 were administered on days 3, 4 and 5 of the first dosing cycle, respectively;

(d) The C2D1, C2D2 and C2D3 of ifosfamide shall be administered on days 6, 7 and 8 of the second dosing cycle, respectively;

(e) Administer carboplatin C2D1 on day 6 of the second dosing cycle; and

(f) Etoposide C2D1, C2D2 and C2D3 will be administered on days 6, 7 and 8 of the second dosing cycle, respectively.

321. The bispecific antibody or use according to any one of Examples 301 to 320, wherein the first dosing cycle and the second dosing cycle are each a 21-day dosing cycle.

322. The bispecific antibody or use according to any one of Examples 301 to 321, wherein the dosing regimen includes one or more additional dosing cycles.

323. The bispecific antibody or use provided according to Example 322, wherein each of the one or more additional dosing cycles is a 21-day dosing cycle.

324. The bispecific antibody or use provided according to Example 322 or 323, wherein the dosing regimen comprises a total of three dosing cycles.

325. The bispecific antibody or use according to any one of Examples 322 to 324, wherein each of the one or more additional dosing cycles comprises:

(a) An additional single dose of a bispecific antibody that binds to both CD20 and CD3.

(b) An additional single dose of anti-CD20 antibody, and

(c) Additional first, second and third doses of ifosfamide; additional single dose of carboplatin; and additional first, second and third doses of etoposide.

326. The bispecific antibody or use according to Example 325, wherein:

(a) The subject's weight is greater than or equal to about 7.5 kg and less than about 13 kg, and the additional single dose of the bispecific antibody is about 0.5 mg/kg;

(b) The subject's weight is greater than or equal to about 13 kg and less than about 45 kg, and the additional single dose of the bispecific antibody is about 0.4 mg/kg; or

(c) The subject weighs more than or equal to about 45 kg, and the additional single dose of the bispecific antibody is about 30 mg.

327. The bispecific antibody or use as described in Example 325 or 326, wherein the additional single dose of the bispecific antibody is to be administered to the subject on day 1 of each of the one or more additional dosing cycles.

328. The bispecific antibody or use according to any one of Examples 325 to 327, wherein the anti-CD20 antibody is rituximab.

329. The bispecific antibody or use provided according to Example 328, wherein the additional single dose of rituximab is approximately 375 mg/ ^m² .

330. The bispecific antibody or use provided according to Example 328 or 329, wherein the additional single dose of rituximab is to be administered on day 5 of each of the one or more additional dosing cycles.

331. The bispecific antibody or use according to any one of Examples 322 to 330, wherein the additional first dose, the additional second dose and the additional third dose of ifosfamide are each about 3000 mg/ ^m² , the additional single dose of carboplatin is about 635 mg/ ^m² , and the additional first dose, the additional second dose and the additional third dose of etoposide are each about 100 mg/ ^m² .

332. The bispecific antibody or use according to any one of Examples 322 to 331, wherein:

(a) The subject shall be given the additional first dose, the additional second dose and the additional third dose of ifosfamide on day 6, day 7 and day 8 of each of the one or more additional dosing cycles;

(b) Administer an additional single dose of carboplatin on day 6 of each of the one or more additional dosing cycles; and

(c) The subject shall be given an additional first dose, an additional second dose, and an additional third dose of etoposide on days 6, 7, and 8 of each of the one or more additional dosing cycles.

333. The bispecific antibody or use according to any one of Examples 301 to 332, wherein the bispecific antibody binding to CD20 and CD3 is to be administered in combination with one or more additional therapeutic agents.

334. The bispecific antibody or use provided according to Example 333, wherein the one or more additional therapeutic agents are tocilizumab.

335. The bispecific antibody or use according to Example 334, wherein the subject weighs more than or equal to about 30 kg and is to be administered tocilizumab at a dose of about 8 mg/kg, or the subject weighs less than 30 kg and is to be administered tocilizumab at a dose of about 12 mg/kg, and wherein the maximum dose is about 800 mg.

336. The bispecific antibody or use provided according to Example 333, wherein the one or more additional therapeutic agents are corticosteroids.

337. The bispecific antibody or use provided according to Example 336, wherein the corticosteroid comprises prednisone, prednisolone, methylprednisolone, or dexamethasone.

338. The bispecific antibody or use provided according to Example 337, wherein the corticosteroid is dexamethasone.

339. The bispecific antibody or use according to Example 338, wherein dexamethasone is administered intravenously at a dose between about 0.15 mg/kg and about 0.5 mg/kg at least one hour prior to the administration of any dose of the bispecific antibody, and wherein the maximum daily dose is 10 mg.

340. The bispecific antibody or use according to Example 338, wherein dexamethasone is administered intravenously at a dose between about 0.15 mg/kg and about 0.5 mg/kg at least about one hour prior to administration of any dose of olibutuzumab, and wherein the maximum daily dose is 10 mg.

341. The bispecific antibody or use provided according to Example 337, wherein the corticosteroid is methylprednisolone.

342. The bispecific antibody or use according to Example 341, wherein methylprednisolone is administered intravenously at a dose between about 1 mg/kg and about 2 mg/kg at least one hour prior to the administration of any dose of the bispecific antibody.

343. The bispecific antibody or use provided according to Example 341, wherein methylprednisolone is administered intravenously at a dose between about 1 mg/kg and about 2 mg/kg at least one hour prior to administration of any dose of omethoate.

344. The bispecific antibody or use provided according to Example 337, wherein the corticosteroid is prednisone or prednisolone.

345. The bispecific antibody or use according to Example 344, wherein prednisone or prednisolone is administered intravenously at a dose of about 100 mg or about 2 mg/kg at least one hour prior to the administration of any dose of the bispecific antibody.

346. The bispecific antibody or use provided according to Example 344, wherein prednisone or prednisolone is administered intravenously at a dose of about 100 mg or about 2 mg/kg at least one hour prior to administration of any dose of olibutuzumab.

347. The bispecific antibody or use provided according to Example 333, wherein the one or more additional therapeutic agents are antihistamines.

348. The bispecific antibody or use provided according to Example 347, wherein the antihistamine is diphenhydramine.

349. The bispecific antibody or use according to Example 348, wherein the subject is between 2 and 17 years old, and wherein diphenhydramine is to be administered intravenously at a dose between about 10 mg and 20 mg, wherein the maximum single dose is about 1.25 mg/kg.

350. The bispecific antibody or use provided according to Example 348, wherein the subject is less than two years old, and wherein diphenhydramine is to be administered rectally at a dose of about 20 mg.

351. The bispecific antibody or use provided according to Example 349 or 350, wherein diphenhydramine is administered at least about 30 minutes prior to the administration of any dose of the bispecific antibody and/or anti-CD20 antibody.

352. The bispecific antibody or use provided according to Example 333, wherein the one or more additional therapeutic agents comprise G-CSF.

353. The bispecific antibody or use according to Example 352, wherein G-CSF is administered between about one and about two days after administration of any dose of rituximab, ifosfamide, carboplatin and/or etoposide.

354. The bispecific antibody or use according to Example 353, wherein G-CSF is to be administered intravenously or subcutaneously at a dose of about 5 μg/kg/day or about 10 μg/kg/day.

355. The bispecific antibody or use according to Example 354, wherein G-CSF is to be administered at a dose of about 5 μg/kg/day in the first dosing cycle and at a dose of about 10 μg/kg/day in the second dosing cycle and/or each additional dosing cycle.

356. The bispecific antibody or use provided according to Example 333, wherein the one or more additional therapeutic agents are antipyretics.

357. The bispecific antibody or use provided according to Example 356, wherein the antipyretic is acetaminophen or paracetamol.

358. The bispecific antibody or use according to Example 357, wherein acetaminophen or paracetamol is to be administered orally or intravenously at a dose between about 500 mg and about 1000 mg.

359. The bispecific antibody or use according to Example 358, wherein acetaminophen or paracetamol is administered at least about 30 minutes prior to the administration of any dose of the bispecific antibody and/or anti-CD20 antibody.

360. The bispecific antibody or use provided according to Example 333, wherein the one or more additional therapeutic agents are mesna.

361. The bispecific antibody or use according to Example 360, wherein mesna is to be administered intravenously daily in five doses totaling 3000 mg/ ^m² .

362. The bispecific antibody or use according to Example 361, wherein mesna is administered intravenously at a first dose of about 600 mg/ ^m² and four repeated doses of about 600 mg/ ^m² prior to administration of any dose of ifosfamide, each repeated dose being administered about three hours, about six hours, and about 12 hours after the first dose of ifosfamide.

363. The bispecific antibody or use according to Example 361 or 362, wherein mesna is administered to the subject daily on days 3, 4 and 5 of the first dosing cycle, days 6, 7 and 8 of the second dosing cycle and/or on days 6, 7 and 8 of each additional dosing cycle.

364. A bispecific antibody that binds to CD20 and CD3, used in a method for treating a subject aged 18 to 30 years with a CD20-positive proliferative disorder, wherein the bispecific antibody that binds to CD20 and CD3 is administered in combination with an anti-CD20 antibody and one or more chemotherapeutic agents selected from ifosfamide, carboplatin, and/or etoposide, in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

365. Use of a bispecific antibody binding to CD20 and CD3 in the manufacture of a medicament for treating a subject aged 18 to 30 years with a CD20-positive proliferative disorder, wherein, in the treatment, the bispecific antibody binding to CD20 and CD3 is administered in combination with an anti-CD20 antibody and one or more chemotherapeutic agents selected from ifosfamide, carboplatin, and/or etoposide, according to a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

366. Use of a bispecific antibody that binds to CD20 and CD3 for the treatment of a subject aged between 18 and 30 years with a CD20-positive proliferative disorder, wherein the bispecific antibody that binds to CD20 and CD3 is administered in combination with an anti-CD20 antibody and one or more chemotherapeutic agents selected from ifosfamide, carboplatin, and/or etoposide, in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

367. The bispecific antibody or use according to any one of Examples 364 to 366, wherein

The first dosing cycle includes a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody, wherein the C1D1 of the bispecific antibody is approximately 2.5 mg and the C1D2 of the bispecific antibody is approximately 10 mg; and

The second dosing cycle includes a single dose (C2D1) of the bispecific antibody, wherein the C2D1 of the bispecific antibody is approximately 30 mg.

368. The bispecific antibody or use according to Example 367, wherein the C1D1 and the C1D2 of the bispecific antibody are administered to the subject on day 8 and day 15 of the first dosing cycle, respectively.

369. The bispecific antibody or use according to Example 367 or 368, wherein the C2D1 of the bispecific antibody is to be administered to the subject on day 1 of the second dosing cycle.

370. The bispecific antibody or use according to any one of Examples 364 to 369, wherein the anti-CD20 antibody is olibutuzumab or rituximab.

371. The bispecific antibody or use according to Example 370, wherein the first dosing cycle comprises a first dose (C1D1) of olibutuzumab and a second dose (C1D2) of olibutuzumab.

372. The sum of C1D1 and C1D2 of the olibutuzumab for use or application as described in Example 371 is about 1000 mg.

373. The bispecific antibody or use according to Example 371 or 372, wherein the C1D1 of olibutuzumab is about one-tenth the sum of the C1D1 and the C1D2 of olibutuzumab, and the C1D2 of olibutuzumab is about nine-tenths the sum of the C1D1 and the C1D2 of olibutuzumab.

374. The bispecific antibody or use according to any one of Examples 371 to 373, wherein the C1D1 of olibutuzumab is about 100 mg and the C1D2 of olibutuzumab is about 900 mg.

375. The bispecific antibody or use according to any one of Examples 371 to 374, wherein the C1D1 of olibutuzumab is administered to the subject on day 1 of the first dosing cycle, and the C1D2 of olibutuzumab is administered to the subject on day 2 of the first dosing cycle.

376. The bispecific antibody or use provided according to Example 370, wherein the second dosing cycle comprises a single dose of rituximab (C2D1).

377. The bispecific antibody or use provided according to Example 376, wherein the C2D1 of rituximab is about 375 mg/ ^m² .

378. The bispecific antibody or use according to Example 376 or 377, wherein the C2D1 of rituximab is to be administered to the subject on day 5 of the second dosing cycle.

379. The bispecific antibody or use according to any one of Examples 364 to 378, wherein the bispecific antibody binding to CD20 and CD3 is to be administered in combination with an anti-CD20 antibody, ifosfamide, carboplatin and etoposide.

380. The bispecific antibody or use according to Example 379, wherein the first dosing cycle comprises:

(a) A single dose of ifosfamide (C1D1);

(b) A single dose of carboplatin (C1D1); and

(c) The first dose of etoposide (C1D1), the second dose of etoposide (C1D2), and the third dose of etoposide (C1D3);

And the second cycle includes:

(a) A single dose of ifosfamide (C2D1);

(b) A single dose of carboplatin (C2D1); and

(c) The first dose of etoposide (C2D1), the second dose of etoposide (C2D2), and the third dose of etoposide (C2D3).

381. The bispecific antibody or use according to Example 379 or 380, wherein ifosfamide is to be administered at a dose of about 5000 mg/ ^m² , carboplatin is to be administered at a dose of about 5 × (25 + creatinine clearance (CrCl)) mg, wherein the maximum dose is about 750 mg, and etoposide is to be administered at a dose of about 100 mg/ ^m² for each dose of etoposide.

382. The bispecific antibody or use according to Example 381, wherein:

(a) The subject is male, and CrCl is calculated using the formula CrCl = ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]); or

(b) The subject was female, and CrCl was calculated using the formula CrCl = 0.85 × ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]).

383. The bispecific antibody or use provided according to Example 381 or 382, wherein:

(a) The subject had CrCl levels <60 mL/min, and each single dose of ifosfamide was reduced to 4000 mg/ ^m² ; and/or

(b) The subject had CrCl < 50 mL/min, and each dose of etoposide was reduced to 75 mg/ ^m² .

384. The bispecific antibody or use according to any one of Examples 380 to 383, wherein:

(a) The C1D1 of ifosfamide will be administered on day 3 of the first dosing cycle;

(b) Administer carboplatin C1D1 on day 3 of the first dosing cycle;

(c) Etoposide C1D1, C1D2 and C1D3 were administered on days 3, 4 and 5 of the first dosing cycle, respectively;

(d) Administer C2D1 of ifosfamide on day 6 of the second dosing cycle;

(e) Administer carboplatin C2D1 on day 6 of the second dosing cycle; and

(f) Etoposide C2D1, C2D2 and C2D3 will be administered on days 6, 7 and 8 of the second dosing cycle, respectively.

385. The bispecific antibody or use according to any one of Examples 364 to 384, wherein the first dosing cycle and the second dosing cycle are each a 21-day dosing cycle.

386. The bispecific antibody or use according to any one of Examples 364 to 385, wherein the dosing regimen includes one or more additional dosing cycles.

387. The bispecific antibody or use provided according to Example 386, wherein each of the one or more additional dosing cycles is a 21-day dosing cycle.

388. The bispecific antibody or use provided according to Example 386 or 387, wherein the dosing regimen comprises a total of three dosing cycles.

389. The bispecific antibody or use according to any one of Examples 386 to 388, wherein each of the one or more additional dosing cycles comprises:

(a) An additional single dose of a bispecific antibody that binds to both CD20 and CD3.

(b) An additional single dose of anti-CD20 antibody, and

(c) Additional single doses of ifosfamide, additional single doses of carboplatin, and additional first, second, and third doses of etoposide.

390. The bispecific antibody or use provided according to Example 389, wherein the additional single dose of the bispecific antibody is about 30 mg.

391. The bispecific antibody or use according to Example 390, wherein the additional single dose of the bispecific antibody is to be administered to the subject on day 1 of each of the one or more additional dosing cycles.

392. The bispecific antibody or use according to any one of Examples 389 to 391, wherein the anti-CD20 antibody is rituximab.

393. The bispecific antibody or use provided according to Example 392, wherein the additional single dose of rituximab is approximately 375 mg/ ^m² .

394. The bispecific antibody or use provided according to Example 392 or 393, wherein the additional single dose of rituximab is to be administered on day 5 of each of the one or more additional dosing cycles.

395. The bispecific antibody or use according to any one of Examples 375 to 380, wherein the additional single dose of ifosfamide is about 5000 mg/ ^m² , the additional single dose of carboplatin is about 5 × (25 + creatinine clearance (CrCl)) mg, wherein the maximum dose is about 750 mg, and the additional first dose, the additional second dose, and the additional third dose of etoposide are each about 100 mg/ ^m² .

396. The bispecific antibody or use according to Example 395, wherein:

(a) The subject is male, and CrCl is calculated using the formula CrCl = ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]); or

(b) The subject was female, and CrCl was calculated using the formula CrCl = 0.85 × ([140 – age] × [weight (kg)]) / (72 × [serum creatinine (mg/dL)]).

397. The bispecific antibody or use according to Example 395 or 396, wherein:

(a) The subject had CrCl levels <60 mL/min, and the additional single dose of ifosfamide was reduced to 4000 mg/ ^m² ; and/or

(b) The subject had CrCl < 50 mL/min, and each additional dose of etoposide was reduced to 75 mg/ ^m² .

398. The bispecific antibody or use according to any one of Examples 389 to 397, wherein:

(a) The additional single dose of ifosfamide shall be administered on day 6 of each of the one or more additional dosing cycles;

(b) Administer an additional single dose of carboplatin on day 6 of each of the one or more additional dosing cycles; and

(c) The subject shall be given an additional first dose, an additional second dose, and an additional third dose of etoposide on days 6, 7, and 8 of each of the one or more additional dosing cycles.

399. The bispecific antibody or use according to any one of Examples 364 to 398, wherein the bispecific antibody binding to CD20 and CD3 is to be administered in combination with one or more additional therapeutic agents.

400. The bispecific antibody or use provided according to Example 399, wherein the one or more additional therapeutic agents are tocilizumab.

401. The bispecific antibody or use according to Example 400, wherein the subject weighs more than or equal to about 30 kg and is to be administered tocilizumab at a dose of about 8 mg/kg, or the subject weighs less than 30 kg and is to be administered tocilizumab at a dose of about 12 mg/kg, and wherein the maximum dose is about 800 mg.

402. The bispecific antibody or use provided according to Example 399, wherein the one or more additional therapeutic agents are corticosteroids.

403. The bispecific antibody or use provided according to Example 402, wherein the corticosteroid comprises prednisone, prednisolone, methylprednisolone, or dexamethasone.

404. The bispecific antibody or use provided according to Example 403, wherein the corticosteroid is dexamethasone.

405. The bispecific antibody or use according to Example 404, wherein dexamethasone is administered intravenously at a dose between about 0.15 mg/kg and about 0.5 mg/kg at least one hour prior to the administration of any dose of the bispecific antibody, and wherein the maximum daily dose is 10 mg.

406. The bispecific antibody or use according to Example 404, wherein dexamethasone is administered intravenously at a dose between about 0.15 mg/kg and about 0.5 mg/kg at least one hour prior to administration of any dose of olibutuzumab, and wherein the maximum daily dose is 10 mg.

407. The bispecific antibody or use provided according to Example 403, wherein the corticosteroid is methylprednisolone.

408. The bispecific antibody or use according to Example 407, wherein methylprednisolone is administered intravenously at a dose between about 1 mg/kg and about 2 mg/kg at least one hour prior to the administration of any dose of the bispecific antibody.

409. The bispecific antibody or use according to Example 407, wherein methylprednisolone is administered intravenously at a dose between about 1 mg/kg and about 2 mg/kg at least about one hour prior to administration of any dose of omethoate.

410. The bispecific antibody or use provided according to Example 399, wherein the one or more additional therapeutic agents are antihistamines.

411. The bispecific antibody or use provided according to Example 410, wherein the antihistamine is diphenhydramine.

412. The bispecific antibody or use according to Example 411, wherein diphenhydramine is to be administered orally or intravenously at a dose of about 50 mg.

413. The bispecific antibody or use according to Example 412, wherein diphenhydramine is administered at least about 30 minutes prior to the administration of any dose of the bispecific antibody and/or anti-CD20 antibody.

414. The bispecific antibody or use provided according to Example 399, wherein the one or more additional therapeutic agents comprise G-CSF.

415. The bispecific antibody or use according to Example 414, wherein G-CSF is administered between about one and about two days after administration of any dose of rituximab, ifosfamide, carboplatin and/or etoposide.

416. The bispecific antibody or use according to Example 415, wherein G-CSF is to be administered intravenously or subcutaneously at a dose of about 5 μg/kg/day or about 10 μg/kg/day.

417. The bispecific antibody or use according to Example 415, wherein G-CSF is to be administered at a dose of about 5 μg/kg/day in the first dosing cycle and at a dose of about 10 μg/kg/day in the second dosing cycle and/or each additional dosing cycle.

418. The bispecific antibody or use provided according to Example 399, wherein the one or more additional therapeutic agents are antipyretics.

419. The bispecific antibody or use according to Example 418, wherein the antipyretic is acetaminophen or paracetamol.

420. The bispecific antibody or use according to Example 419, wherein acetaminophen or paracetamol is to be administered orally or intravenously at a dose between about 500 mg and about 1000 mg.

421. The bispecific antibody or use according to Example 420, wherein acetaminophen or paracetamol is administered at least about 30 minutes prior to the administration of any dose of the bispecific antibody and/or anti-CD20 antibody.

422. The bispecific antibody or use provided according to Example 399, wherein the one or more additional therapeutic agents are mesna.

423. The bispecific antibody or use according to Example 422, wherein mesna is to be administered intravenously at a dose of about 5000 mg/ ^m² .

424. The bispecific antibody or use according to Example 423, wherein mesna is administered via continuous infusion over approximately 24 hours on day 3 of the first dosing cycle, day 6 of the second dosing cycle, and/or day 6 of each additional dosing cycle.

425. The bispecific antibody or use provided according to Example 423 or 424, wherein mesna is to be administered simultaneously with any dose of ifosfamide.

426. The bispecific antibody or use according to any one of Examples 238 to 425, wherein the bispecific antibody comprises at least one Fab molecule that specifically binds to CD20, the Fab molecule comprising the following six hypervariable regions (HVRs):

(i)HVR-H1, which contains the amino acid sequence of YSWIN (SEQ ID NO:1);

(ii) HVR-H2, which contains the amino acid sequence RIFPGDGDTDYNGKFKG (SEQ ID NO:2);

(iii) HVR-H3, which contains the amino acid sequence NVFDGYWLVY (SEQ ID NO:3);

(iv) HVR-L1, which contains the amino acid sequence RSSKSLLHSNGITYLY (SEQ ID NO:4);

(v)HVR-L2, which contains the amino acid sequence of QMSNLVS (SEQ ID NO:5); and

(vi)HVR-L3, which contains the amino acid sequence of AQNLELPYT (SEQ ID NO:6).

427. A bispecific antibody or use according to any one of Examples 238 to 412, wherein the bispecific antibody comprises at least one Fab molecule that specifically binds to CD20, the Fab molecule comprising: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:7; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:8; or (c) the VH domain as in (a) and the VL domain as in (b).

428. The bispecific antibody or use according to Example 427, wherein the Fab molecule specifically binding to CD20 comprises: (a) a VH domain comprising the amino acid sequence of SEQ ID NO:7; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:8.

429. A bispecific antibody or use according to any one of Examples 238 to 428, wherein the bispecific antibody comprises at least one Fab molecule that specifically binds to CD3, the Fab molecule comprising the following six HVRs:

(i)HVR-H1, which contains the amino acid sequence of TYAMN (SEQ ID NO:9);

(ii) HVR-H2, which contains the amino acid sequence RIRSKYNNYATYYADSVKG (SEQ ID NO:10);

(iii) HVR-H3, which contains the amino acid sequence HGNFGNSYVSWFAY (SEQ ID NO:11);

(iv) HVR-L1, which contains the amino acid sequence GSSTGAVTTSNYAN (SEQ ID NO:12);

(v)HVR-L2, which contains the amino acid sequence of GTNKRAP (SEQ ID NO: 13); and

(vi)HVR-L3, which contains the amino acid sequence of ALWYSNLWV (SEQ ID NO:14).

430. A bispecific antibody or use according to any one of Examples 238 to 429, wherein the bispecific antibody comprises at least one Fab molecule that specifically binds to CD3, the Fab molecule comprising: (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 15; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 16; or (c) the VH domain as in (a) and the VL domain as in (b).

431. The bispecific antibody or use according to Example 430, wherein the Fab molecule specifically binding to CD3 comprises: (a) a VH domain comprising the amino acid sequence of SEQ ID NO:15; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:16.

432. The bispecific antibody or use according to any one of Examples 238 to 431, wherein the bispecific antibody is divalent to CD20 and monovalent to CD3.

433. The bispecific antibody or use according to any one of Examples 238 to 432, wherein the bispecific antibody comprises two Fab molecules that specifically bind to CD20 and one Fab molecule that specifically binds to CD3.

434. The bispecific antibody or use according to any one of Examples 238 to 433, wherein the bispecific antibody is a humanized antibody.

435. The bispecific antibody or use according to any one of Examples 238 to 434, wherein the bispecific antibody is glimetuzumab.

436. The bispecific antibody or use according to any one of Examples 238 to 435, wherein the bispecific antibody is to be administered intravenously.

437. The bispecific antibody or use according to any one of Examples 238 to 436, wherein the anti-CD20 antibody is administered intravenously.

438. The bispecific antibody or use according to any one of Examples 238 to 437, wherein ifosfamide, carboplatin and/or etoposide are administered intravenously.

439. The bispecific antibody or use according to any one of Examples 238 to 438, wherein the CD20-positive proliferative disorder is a B-cell proliferative disorder.

440. The bispecific antibody or use according to Example 439, wherein the B-cell proliferative disorder is non-Hodgkin's lymphoma (NHL) or central nervous system lymphoma (CNSL).

441. The bispecific antibody or use according to Example 440, wherein the NHL is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), high-grade B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma (PMLBCL), diffuse B-cell lymphoma, or small lymphocytic lymphoma.

442. The bispecific antibody or use according to Example 440, wherein the NHL is Burkitt lymphoma (BL) or Burkitt leukemia (BAL).

443. The bispecific antibody or use according to any one of Examples 440 to 442, wherein the NHL is relapsed and/or refractory.

444. The bispecific antibody or use according to any one of Examples 440 to 443, wherein the NHL is invasive and/or mature.

445. The bispecific antibody or use according to Example 439, wherein the B-cell proliferative disorder is relapsed and/or refractory mature B-cell NHL.

446. The bispecific antibody or use provided according to Example 443, wherein the subject has received a prior systemic therapy.

447. The bispecific antibody or use provided according to Example 446, wherein the subject has received no more than one prior systemic therapy.

448. The bispecific antibody or use provided according to Example 446 or 447, wherein the prior systemic therapy comprises an anti-CD20 antibody and anthracycline.

449. The bispecific antibody or use provided according to any one of Examples 238 to 448, wherein the subject is a human.

450. The bispecific antibody or use according to any one of Examples 238 to 449, wherein the subject meets the criteria for transplantation or CAR-T cell therapy.

451. The bispecific antibody or use according to Example 450, wherein the subject undergoes autologous stem cell transplantation (ASCT) after completing the dosing regimen according to any one of Examples 238 to 449.

452. The bispecific antibody or use provided according to Example 451, wherein the ASCT is autologous hematopoietic stem cell transplantation.

453. The bispecific antibody or use according to Example 450, wherein the subject receives allogeneic hematopoietic stem cell transplantation after completing the dosing regimen according to any one of Examples 237 to 448.

454. The bispecific antibody or use according to Example 450, wherein the subject receives CAR-T cell therapy after completing the dosing regimen according to any one of Examples 238 to 449.

455. Glimetuzumab used in a method for treating subjects with CD20-positive proliferative disorders, wherein glimetuzumab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

(a) This first dosing cycle comprises a first dose (C1D1) of glimetuzumab to be administered on day 8 and a second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is approximately 2.5 mg and the C1D2 of glimetuzumab is approximately 10 mg; and

(b) The second dosing cycle includes a single dose (C2D1) of glimetuzumab to be administered on day 8, wherein the C2D1 of glimetuzumab is approximately 30 mg.

456. Use of glimetuzumab in the manufacture of a medicament for the treatment of a subject with a CD20-positive proliferative disorder, wherein, in this treatment, glimetuzumab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein...

(a) This first dosing cycle comprises a first dose (C1D1) of glimetuzumab to be administered on day 8 and a second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is approximately 2.5 mg and the C1D2 of glimetuzumab is approximately 10 mg; and

(b) The second dosing cycle includes a single dose (C2D1) of glimetuzumab to be administered on day 8, wherein the C2D1 of glimetuzumab is approximately 30 mg.

457. Use of glimetuzumab for the treatment of subjects with CD20-positive proliferative disorders, wherein glimetuzumab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

(a) This first dosing cycle comprises a first dose (C1D1) of glimetuzumab to be administered on day 8 and a second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is approximately 2.5 mg and the C1D2 of glimetuzumab is approximately 10 mg; and

(b) The second dosing cycle includes a single dose (C2D1) of glimetuzumab to be administered on day 8, wherein the C2D1 of glimetuzumab is approximately 30 mg.

458. Glimetuzumab used in a method of treating subjects with CD20-positive proliferative disorders, wherein glimetuzumab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle.

(a) The first dosing cycle includes a first dose (C1D1) of glimetuzumab to be administered on day 8 and a second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg and the C1D2 of glimetuzumab is about 10 mg.

(b) This second dosing cycle includes a single dose (C2D1) of glimetuzumab to be administered on day 8, wherein the C2D1 of glimetuzumab is approximately 30 mg; and

(c) The third dosing cycle includes a single dose (C3D1) of glimetuzumab to be administered on day 8, wherein the C3D1 of glimetuzumab is approximately 30 mg.

459. Use of glimetuzumab in the manufacture of a medicament for the treatment of a subject with a CD20-positive proliferative disorder, wherein, in this treatment, glimetuzumab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle.

(a) The first dosing cycle includes a first dose (C1D1) of glimetuzumab to be administered on day 8 and a second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg and the C1D2 of glimetuzumab is about 10 mg.

(b) This second dosing cycle includes a single dose (C2D1) of glimetuzumab to be administered on day 8, wherein the C2D1 of glimetuzumab is approximately 30 mg; and

(c) The third dosing cycle includes a single dose (C3D1) of glimetuzumab to be administered on day 8, wherein the C3D1 of glimetuzumab is approximately 30 mg.

460. Use of glimetuzumab in the treatment of subjects with CD20-positive proliferative disorders, wherein glimetuzumab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first, second, and third dosing cycle.

(a) The first dosing cycle includes a first dose (C1D1) of glimetuzumab to be administered on day 8 and a second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg and the C1D2 of glimetuzumab is about 10 mg.

(b) This second dosing cycle includes a single dose (C2D1) of glimetuzumab to be administered on day 8, wherein the C2D1 of glimetuzumab is approximately 30 mg; and

(c) The third dosing cycle includes a single dose (C3D1) of glimetuzumab to be administered on day 8, wherein the C3D1 of glimetuzumab is approximately 30 mg.

461. Glimetuzumab used in a method of treating subjects with CD20-positive proliferative disorders, wherein glimetuzumab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

(a) The first dosing cycle includes:

(i) The first dose (C1D1) of glimetuzumab to be administered on day 8 and the second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg and the C1D2 of glimetuzumab is about 10 mg.

(ii) The first dose (C1D1) of olibutuzumab to be administered on day 1, wherein the C1D1 of olibutuzumab is approximately 1000 mg;

(iii) A single dose (C1D1) of ifosfamide to be administered on day 2, wherein the C1D1 of ifosfamide is about 5000 mg/ ^m2 and the maximum dose is about 800 mg;

(iv) A single dose (C1D1) of carboplatin to be administered on day 2, wherein the C1D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C1D1) of etoposide to be administered on day 1, the second dose (C1D2) of etoposide to be administered on day 2, and the third dose (C1D3) of etoposide to be administered on day 3, wherein each of the three doses of etoposide is approximately 100 mg/ ^m² ; and

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab to be administered on day 8, wherein the C2D1 of glimetuzumab is approximately 30 mg;

(ii) The first dose (C2D1) of rituximab to be administered on day 1, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 ;

(iii) A single dose (C2D1) of ifosfamide to be administered on day 2, wherein the C2D1 of ifosfamide is about 5000 mg/ ^m2 and the maximum dose is about 800 mg;

(iv) A single dose (C2D1) of carboplatin to be administered on day 2, wherein the C2D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose of etoposide (C2D1) to be administered on day 1, the second dose of etoposide (C2D2) to be administered on day 2, and the third dose of etoposide (C1D3) to be administered on day 3, wherein each of the C2D1, C2D2 and C2D3 of etoposide is approximately 100 mg/ ^m2 .

462. Use of glimetuzumab in the manufacture of a medicament for the treatment of a subject with a CD20-positive proliferative disorder, wherein, in this treatment, glimetuzumab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein...

(a) The first dosing cycle includes:

(i) The first dose (C1D1) of glimetuzumab to be administered on day 8 and the second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg and the C1D2 of glimetuzumab is about 10 mg.

(ii) The first dose (C1D1) of olibutuzumab to be administered on day 1, wherein the C1D1 of olibutuzumab is approximately 1000 mg;

(iii) A single dose (C1D1) of ifosfamide to be administered on day 2, wherein the C1D1 of ifosfamide is about 5000 mg/ ^m2 and the maximum dose is about 800 mg;

(iv) A single dose (C1D1) of carboplatin to be administered on day 2, wherein the C1D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C1D1) of etoposide to be administered on day 1, the second dose (C1D2) of etoposide to be administered on day 2, and the third dose (C1D3) of etoposide to be administered on day 3, wherein each of the three doses of etoposide is approximately 100 mg/ ^m² ; and

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab to be administered on day 8, wherein the C2D1 of glimetuzumab is approximately 30 mg;

(ii) The first dose (C2D1) of rituximab to be administered on day 1, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 ;

(iii) A single dose (C2D1) of ifosfamide to be administered on day 2, wherein the C2D1 of ifosfamide is about 5000 mg/ ^m2 and the maximum dose is about 800 mg;

(iv) A single dose (C2D1) of carboplatin to be administered on day 2, wherein the C2D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose of etoposide (C2D1) to be administered on day 1, the second dose of etoposide (C2D2) to be administered on day 2, and the third dose of etoposide (C1D3) to be administered on day 3, wherein each of the C2D1, C2D2 and C2D3 of etoposide is approximately 100 mg/ ^m2 .

463. Use of glimetuzumab for the treatment of subjects with CD20-positive proliferative disorders, wherein glimetuzumab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

(a) The first dosing cycle includes:

(i) The first dose (C1D1) of glimetuzumab to be administered on day 8 and the second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg and the C1D2 of glimetuzumab is about 10 mg.

(ii) The first dose (C1D1) of olibutuzumab to be administered on day 1, wherein the C1D1 of olibutuzumab is approximately 1000 mg;

(iii) A single dose (C1D1) of ifosfamide to be administered on day 2, wherein the C1D1 of ifosfamide is about 5000 mg/ ^m2 and the maximum dose is about 800 mg;

(iv) A single dose (C1D1) of carboplatin to be administered on day 2, wherein the C1D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C1D1) of etoposide to be administered on day 1, the second dose (C1D2) of etoposide to be administered on day 2, and the third dose (C1D3) of etoposide to be administered on day 3, wherein each of the three doses of etoposide is approximately 100 mg/ ^m² ; and

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab to be administered on day 8, wherein the C2D1 of glimetuzumab is approximately 30 mg;

(ii) The first dose (C2D1) of rituximab to be administered on day 1, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 ;

(iii) A single dose (C2D1) of ifosfamide to be administered on day 2, wherein the C2D1 of ifosfamide is about 5000 mg/ ^m2 and the maximum dose is about 800 mg;

(iv) A single dose (C2D1) of carboplatin to be administered on day 2, wherein the C2D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose of etoposide (C2D1) to be administered on day 1, the second dose of etoposide (C2D2) to be administered on day 2, and the third dose of etoposide (C1D3) to be administered on day 3, wherein each of the C2D1, C2D2 and C2D3 of etoposide is approximately 100 mg/ ^m2 .

464. Glimetuzumab used in a method of treating subjects with CD20-positive proliferative disorders, wherein glimetuzumab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle.

(a) The first dosing cycle includes:

(i) The first dose (C1D1) of glimetuzumab to be administered on day 8 and the second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg and the C1D2 of glimetuzumab is about 10 mg.

(ii) The first dose (C1D1) of olibutuzumab to be administered on day 1, wherein the C1D1 of olibutuzumab is approximately 1000 mg;

(iii) A single dose (C1D1) of ifosfamide to be administered on day 2, wherein the C1D1 of ifosfamide is about 5000 mg/ ^m2 and the maximum dose is about 800 mg;

(iv) A single dose (C1D1) of carboplatin to be administered on day 2, wherein the C1D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C1D1) of etoposide to be administered on day 1, the second dose (C1D2) of etoposide to be administered on day 2, and the third dose (C1D3) of etoposide to be administered on day 3, wherein each of the C1D1, C1D2 and C1D3 of etoposide is approximately 100 mg/ ^m2 .

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab to be administered on day 8, wherein the C2D1 of glimetuzumab is approximately 30 mg;

(ii) The first dose (C2D1) of rituximab to be administered on day 1, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 ;

(iii) A single dose (C2D1) of ifosfamide to be administered on day 2, wherein the C2D1 of ifosfamide is about 5000 mg/ ^m2 and the maximum dose is about 800 mg;

(iv) A single dose (C2D1) of carboplatin to be administered on day 2, wherein the C2D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C2D1) of etoposide to be administered on day 1, the second dose (C2D2) of etoposide to be administered on day 2, and the third dose (C2D3) of etoposide to be administered on day 3, wherein each of the three doses of etoposide (C2D1, C2D2, and C2D3) is approximately 100 mg/ ^m² ; and

(c) The third dosing cycle includes:

(i) A single dose (C3D1) of glimetuzumab to be administered on day 8, wherein the C3D1 of glimetuzumab is approximately 30 mg;

(ii) The first dose (C3D1) of rituximab to be administered on day 1, wherein the C3D1 of rituximab is approximately 375 mg/ ^m2 ;

(iii) A single dose (C3D1) of ifosfamide to be administered on day 2, wherein the C3D1 of ifosfamide is about 5000 mg/ ^m2 and the maximum dose is about 800 mg;

(iv) A single dose (C3D1) of carboplatin to be administered on day 2, wherein the C3D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C3D1) of etoposide to be administered on day 1, the second dose (C3D2) of etoposide to be administered on day 2, and the third dose (C3D3) of etoposide to be administered on day 3, wherein each of the C3D1, C3D2 and C3D3 of etoposide is approximately 100 mg/ ^m2 .

465. Use of glimetuzumab in the manufacture of a medicament for the treatment of a subject with a CD20-positive proliferative disorder, wherein, in this treatment, glimetuzumab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle.

(a) The first dosing cycle includes:

(i) The first dose (C1D1) of glimetuzumab to be administered on day 8 and the second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg and the C1D2 of glimetuzumab is about 10 mg.

(ii) The first dose (C1D1) of olibutuzumab to be administered on day 1, wherein the C1D1 of olibutuzumab is approximately 1000 mg;

(iii) A single dose (C1D1) of ifosfamide to be administered on day 2, wherein the C1D1 of ifosfamide is about 5000 mg/ ^m2 and the maximum dose is about 800 mg;

(iv) A single dose (C1D1) of carboplatin to be administered on day 2, wherein the C1D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C1D1) of etoposide to be administered on day 1, the second dose (C1D2) of etoposide to be administered on day 2, and the third dose (C1D3) of etoposide to be administered on day 3, wherein each of the C1D1, C1D2 and C1D3 of etoposide is approximately 100 mg/ ^m2 .

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab to be administered on day 8, wherein the C2D1 of glimetuzumab is approximately 30 mg;

(ii) The first dose (C2D1) of rituximab to be administered on day 1, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 ;

(iii) A single dose (C2D1) of ifosfamide to be administered on day 2, wherein the C2D1 of ifosfamide is about 5000 mg/ ^m2 and the maximum dose is about 800 mg;

(iv) A single dose (C2D1) of carboplatin to be administered on day 2, wherein the C2D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C2D1) of etoposide to be administered on day 1, the second dose (C2D2) of etoposide to be administered on day 2, and the third dose (C2D3) of etoposide to be administered on day 3, wherein each of the three doses of etoposide (C2D1, C2D2, and C2D3) is approximately 100 mg/ ^m² ; and

(c) The third dosing cycle includes:

(i) A single dose (C3D1) of glimetuzumab to be administered on day 8, wherein the C3D1 of glimetuzumab is approximately 30 mg;

(ii) The first dose (C3D1) of rituximab to be administered on day 1, wherein the C3D1 of rituximab is approximately 375 mg/ ^m2 ;

(iii) A single dose (C3D1) of ifosfamide to be administered on day 2, wherein the C3D1 of ifosfamide is about 5000 mg/ ^m2 and the maximum dose is about 800 mg;

(iv) A single dose (C3D1) of carboplatin to be administered on day 2, wherein the C3D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C3D1) of etoposide to be administered on day 1, the second dose (C3D2) of etoposide to be administered on day 2, and the third dose (C3D3) of etoposide to be administered on day 3, wherein each of the C3D1, C3D2 and C3D3 of etoposide is approximately 100 mg/ ^m2 .

466. Use of glimetuzumab for the treatment of subjects with CD20-positive proliferative disorders, wherein glimetuzumab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first, second, and third dosing cycle.

(a) The first dosing cycle includes:

(i) The first dose (C1D1) of glimetuzumab to be administered on day 8 and the second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg and the C1D2 of glimetuzumab is about 10 mg.

(ii) The first dose (C1D1) of olibutuzumab to be administered on day 1, wherein the C1D1 of olibutuzumab is approximately 1000 mg;

(iii) A single dose (C1D1) of ifosfamide to be administered on day 2, wherein the C1D1 of ifosfamide is about 5000 mg/ ^m2 and the maximum dose is about 800 mg;

(iv) A single dose (C1D1) of carboplatin to be administered on day 2, wherein the C1D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C1D1) of etoposide to be administered on day 1, the second dose (C1D2) of etoposide to be administered on day 2, and the third dose (C1D3) of etoposide to be administered on day 3, wherein each of the C1D1, C1D2 and C1D3 of etoposide is approximately 100 mg/ ^m2 .

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab to be administered on day 8, wherein the C2D1 of glimetuzumab is approximately 30 mg;

(ii) The first dose (C2D1) of rituximab to be administered on day 1, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 ;

(iii) A single dose (C2D1) of ifosfamide to be administered on day 2, wherein the C2D1 of ifosfamide is about 5000 mg/ ^m2 and the maximum dose is about 800 mg;

(iv) A single dose (C2D1) of carboplatin to be administered on day 2, wherein the C2D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C2D1) of etoposide to be administered on day 1, the second dose (C2D2) of etoposide to be administered on day 2, and the third dose (C2D3) of etoposide to be administered on day 3, wherein each of the three doses of etoposide (C2D1, C2D2, and C2D3) is approximately 100 mg/ ^m² ; and

(c) The third dosing cycle includes:

(i) A single dose (C3D1) of glimetuzumab to be administered on day 8, wherein the C3D1 of glimetuzumab is approximately 30 mg;

(ii) The first dose (C3D1) of rituximab to be administered on day 1, wherein the C3D1 of rituximab is approximately 375 mg/ ^m2 ;

(iii) A single dose (C3D1) of ifosfamide to be administered on day 2, wherein the C3D1 of ifosfamide is about 5000 mg/ ^m2 and the maximum dose is about 800 mg;

(iv) A single dose (C3D1) of carboplatin to be administered on day 2, wherein the C3D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C3D1) of etoposide to be administered on day 1, the second dose (C3D2) of etoposide to be administered on day 2, and the third dose (C3D3) of etoposide to be administered on day 3, wherein each of the C3D1, C3D2 and C3D3 of etoposide is approximately 100 mg/ ^m2 .

467. Glucophage for use or intended use according to any one of Examples 455 to 466, wherein mesna is to be administered concurrently with any dose of ifosfamide.

468. The glucantuzumab for use or intended use as described in Example 467, wherein mesna is to be administered intravenously at a dose of about 5000 mg/ ^m² .

469. The glucantuzumab for use or intended use as described in Example 468, wherein mesna is administered via continuous infusion over approximately 24 hours on the second day of each dosing cycle.

470. Griffithomab used in a method for treating subjects aged 6 months to 17 years with CD20-positive proliferative disorders, wherein griffithomab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

(a) This first dosing cycle comprises a first dose (C1D1) of glimetuzumab to be administered on day 8 and a second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is approximately 0.03 mg/kg, approximately 0.04 mg/kg, or approximately 2.5 mg, and the C1D2 of glimetuzumab is approximately 0.15 mg/kg or approximately 10 mg; and

(b) The second dosing cycle includes a single dose (C2D1) of glimetuzumab to be administered on day 8, wherein the C2D1 of glimetuzumab is about 0.4 mg/kg, about 0.5 mg/kg or about 30 mg.

471. Use of glimetuzumab in the manufacture of a medicament for the treatment of subjects aged between 6 months and 17 years with CD20-positive proliferative disorders, wherein in this treatment, glimetuzumab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

(a) This first dosing cycle comprises a first dose (C1D1) of glimetuzumab to be administered on day 8 and a second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is approximately 0.03 mg/kg, approximately 0.04 mg/kg, or approximately 2.5 mg, and the C1D2 of glimetuzumab is approximately 0.15 mg/kg or approximately 10 mg; and

(b) The second dosing cycle includes a single dose (C2D1) of glimetuzumab to be administered on day 8, wherein the C2D1 of glimetuzumab is about 0.4 mg/kg, about 0.5 mg/kg or about 30 mg.

472. Use of glimetuzumab for the treatment of subjects aged 6 months to 17 years with CD20-positive proliferative disorders, wherein glimetuzumab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

(a) This first dosing cycle comprises a first dose (C1D1) of glimetuzumab to be administered on day 8 and a second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is approximately 0.03 mg/kg, approximately 0.04 mg/kg, or approximately 2.5 mg, and the C1D2 of glimetuzumab is approximately 0.15 mg/kg or approximately 10 mg; and

(b) The second dosing cycle includes a single dose (C2D1) of glimetuzumab to be administered on day 8, wherein the C2D1 of glimetuzumab is about 0.4 mg/kg, about 0.5 mg/kg or about 30 mg.

473. Glimetuzumab used in a method for treating subjects aged 6 months to 17 years with CD20-positive proliferative disorders, wherein glimetuzumab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first, second, and third dosing cycle.

(a) The first dosing cycle comprises a first dose (C1D1) of glimetuzumab to be administered on day 8 and a second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is about 0.03 mg/kg, about 0.04 mg/kg or about 2.5 mg, and the C1D2 of glimetuzumab is about 0.15 mg/kg or about 10 mg;

(b) This second dosing cycle includes a single dose (C2D1) of glimetuzumab to be administered on day 8, wherein the C2D1 of glimetuzumab is approximately 0.4 mg/kg, approximately 0.5 mg/kg, or approximately 30 mg; and

(c) The third dosing cycle includes a single dose (C3D1) of glimetuzumab to be administered on day 8, wherein the C3D1 of glimetuzumab is about 0.4 mg/kg, about 0.5 mg/kg or about 30 mg.

474. Use of glimetuzumab in the manufacture of a medicine for the treatment of subjects aged 6 months to 17 years with CD20-positive proliferative disorders, wherein in this treatment, glimetuzumab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle.

(a) The first dosing cycle comprises a first dose (C1D1) of glimetuzumab to be administered on day 8 and a second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is about 0.03 mg/kg, about 0.04 mg/kg or about 2.5 mg, and the C1D2 of glimetuzumab is about 0.15 mg/kg or about 10 mg;

(b) This second dosing cycle includes a single dose (C2D1) of glimetuzumab to be administered on day 8, wherein the C2D1 of glimetuzumab is approximately 0.4 mg/kg, approximately 0.5 mg/kg, or approximately 30 mg; and

(c) The third dosing cycle includes a single dose (C3D1) of glimetuzumab to be administered on day 8, wherein the C3D1 of glimetuzumab is about 0.4 mg/kg, about 0.5 mg/kg or about 30 mg.

475. Use of glimetuzumab for the treatment of subjects aged 6 months to 17 years with CD20-positive proliferative disorders, wherein glimetuzumab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first, second, and third dosing cycle.

(a) The first dosing cycle comprises a first dose (C1D1) of glimetuzumab to be administered on day 8 and a second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is about 0.03 mg/kg, about 0.04 mg/kg or about 2.5 mg, and the C1D2 of glimetuzumab is about 0.15 mg/kg or about 10 mg;

(b) This second dosing cycle includes a single dose (C2D1) of glimetuzumab to be administered on day 8, wherein the C2D1 of glimetuzumab is approximately 0.4 mg/kg, approximately 0.5 mg/kg, or approximately 30 mg; and

(c) The third dosing cycle includes a single dose (C3D1) of glimetuzumab to be administered on day 8, wherein the C3D1 of glimetuzumab is about 0.4 mg/kg, about 0.5 mg/kg or about 30 mg.

476. Griffithomab used in a method for treating subjects aged 6 months to 17 years with CD20-positive proliferative disorders, wherein griffithomab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

(a) The first dosing cycle includes:

(i) The first dose (C1D1) of glimetuzumab to be administered on day 8 and the second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is about 0.03 mg/kg, about 0.04 mg/kg or about 2.5 mg, and the C1D2 of glimetuzumab is about 0.15 mg/kg or about 10 mg;

(ii) A first dose (C1D1) of olibutuzumab to be administered on day 1 and a second dose (C1D2) of olibutuzumab to be administered on day 2, wherein the C1D1 of olibutuzumab is about one-tenth of the sum of the C1D1 and the C1D2 of olibutuzumab, and the C1D2 of olibutuzumab is about nine-tenths of the sum of the C1D1 and the C1D2 of olibutuzumab, and wherein the sum of the C1D1 and the C1D2 of olibutuzumab is about 38 mg/kg, about 28 mg/kg, about 23 mg/kg, about 20 mg/kg or about 1000 mg;

(iii) The first dose (C1D1) of ifosfamide to be administered on day 3, the second dose (C1D2) of ifosfamide to be administered on day 4, and the third dose (C1D3) of ifosfamide to be administered on day 5, wherein each of the C1D1, C1D2 and C1D3 of ifosfamide is about 3000 mg/ ^m2 ;

(iv) A single dose (C1D1) of carboplatin to be administered on day 3, wherein the C1D1 of carboplatin is approximately 635 mg/ ^m² ; and

(v) The first dose (C1D1) of etoposide to be administered on day 3, the second dose (C1D2) of etoposide to be administered on day 4, and the third dose (C1D3) of etoposide to be administered on day 5, wherein each of the three doses of etoposide (C1D1, C1D2, and C1D3) is approximately 100 mg/ ^m² ; and

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab to be administered on day 1, wherein the C2D1 of glimetuzumab is about 0.4 mg/kg, about 0.5 mg/kg or about 30 mg;

(ii) The first dose (C2D1) of rituximab to be administered on day 5, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 ;

(iii) The first dose (C2D1) of ifosfamide to be administered on day 6, the second dose (C2D2) of ifosfamide to be administered on day 7, and the third dose (C2D3) of ifosfamide to be administered on day 8, wherein each of the C2D1, the C2D2 and the C2D3 of ifosfamide is about 3000 mg/ ^m2 ;

(iv) A single dose (C2D1) of carboplatin to be administered on day 6, wherein the C2D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C2D1) of etoposide to be administered on day 6, the second dose (C2D2) of etoposide to be administered on day 7, and the third dose (C2D3) of etoposide to be administered on day 8, wherein each of the C2D1, C2D2 and C2D3 of etoposide is approximately 100 mg/ ^m2 .

477. Use of glimetuzumab in the manufacture of a medicine for the treatment of subjects aged between 6 months and 17 years with CD20-positive proliferative disorders, wherein in this treatment, glimetuzumab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

(a) The first dosing cycle includes:

(i) The first dose (C1D1) of glimetuzumab to be administered on day 8 and the second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is about 0.03 mg/kg, about 0.04 mg/kg or about 2.5 mg, and the C1D2 of glimetuzumab is about 0.15 mg/kg or about 10 mg;

(ii) A first dose (C1D1) of olibutuzumab to be administered on day 1 and a second dose (C1D2) of olibutuzumab to be administered on day 2, wherein the C1D1 of olibutuzumab is about one-tenth of the sum of the C1D1 and the C1D2 of olibutuzumab, and the C1D2 of olibutuzumab is about nine-tenths of the sum of the C1D1 and the C1D2 of olibutuzumab, and wherein the sum of the C1D1 and the C1D2 of olibutuzumab is about 38 mg/kg, about 28 mg/kg, about 23 mg/kg, about 20 mg/kg or about 1000 mg;

(iii) The first dose (C1D1) of ifosfamide to be administered on day 3, the second dose (C1D2) of ifosfamide to be administered on day 4, and the third dose (C1D3) of ifosfamide to be administered on day 5, wherein each of the C1D1, C1D2 and C1D3 of ifosfamide is about 3000 mg/ ^m2 ;

(iv) A single dose (C1D1) of carboplatin to be administered on day 3, wherein the C1D1 of carboplatin is approximately 635 mg/ ^m² ; and

(v) The first dose (C1D1) of etoposide to be administered on day 3, the second dose (C1D2) of etoposide to be administered on day 4, and the third dose (C1D3) of etoposide to be administered on day 5, wherein each of the three doses of etoposide (C1D1, C1D2, and C1D3) is approximately 100 mg/ ^m² ; and

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab to be administered on day 1, wherein the C2D1 of glimetuzumab is about 0.4 mg/kg, about 0.5 mg/kg or about 30 mg;

(ii) The first dose (C2D1) of rituximab to be administered on day 5, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 ;

(iii) The first dose (C2D1) of ifosfamide to be administered on day 6, the second dose (C2D2) of ifosfamide to be administered on day 7, and the third dose (C2D3) of ifosfamide to be administered on day 8, wherein each of the C2D1, the C2D2 and the C2D3 of ifosfamide is about 3000 mg/ ^m2 ;

(iv) A single dose (C2D1) of carboplatin to be administered on day 6, wherein the C2D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C2D1) of etoposide to be administered on day 6, the second dose (C2D2) of etoposide to be administered on day 7, and the third dose (C2D3) of etoposide to be administered on day 8, wherein each of the C2D1, C2D2 and C2D3 of etoposide is approximately 100 mg/ ^m2 .

478. Use of glimetuzumab for the treatment of subjects aged 6 months to 17 years with CD20-positive proliferative disorders, wherein glimetuzumab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide, comprising a dosing regimen including at least a first dosing cycle and a second dosing cycle.

(a) The first dosing cycle includes:

(i) The first dose (C1D1) of glimetuzumab to be administered on day 8 and the second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is about 0.03 mg/kg, about 0.04 mg/kg or about 2.5 mg, and the C1D2 of glimetuzumab is about 0.15 mg/kg or about 10 mg;

(ii) A first dose (C1D1) of olibutuzumab to be administered on day 1 and a second dose (C1D2) of olibutuzumab to be administered on day 2, wherein the C1D1 of olibutuzumab is about one-tenth of the sum of the C1D1 and the C1D2 of olibutuzumab, and the C1D2 of olibutuzumab is about nine-tenths of the sum of the C1D1 and the C1D2 of olibutuzumab, and wherein the sum of the C1D1 and the C1D2 of olibutuzumab is about 38 mg/kg, about 28 mg/kg, about 23 mg/kg, about 20 mg/kg or about 1000 mg;

(iii) The first dose (C1D1) of ifosfamide to be administered on day 3, the second dose (C1D2) of ifosfamide to be administered on day 4, and the third dose (C1D3) of ifosfamide to be administered on day 5, wherein each of the C1D1, C1D2 and C1D3 of ifosfamide is about 3000 mg/ ^m2 ;

(iv) A single dose (C1D1) of carboplatin to be administered on day 3, wherein the C1D1 of carboplatin is approximately 635 mg/ ^m² ; and

(v) The first dose (C1D1) of etoposide to be administered on day 3, the second dose (C1D2) of etoposide to be administered on day 4, and the third dose (C1D3) of etoposide to be administered on day 5, wherein each of the three doses of etoposide (C1D1, C1D2, and C1D3) is approximately 100 mg/ ^m² ; and

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab to be administered on day 1, wherein the C2D1 of glimetuzumab is about 0.4 mg/kg, about 0.5 mg/kg or about 30 mg;

(ii) The first dose (C2D1) of rituximab to be administered on day 5, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 ;

(iii) The first dose (C2D1) of ifosfamide to be administered on day 6, the second dose (C2D2) of ifosfamide to be administered on day 7, and the third dose (C2D3) of ifosfamide to be administered on day 8, wherein each of the C2D1, the C2D2 and the C2D3 of ifosfamide is about 3000 mg/ ^m2 ;

(iv) A single dose (C2D1) of carboplatin to be administered on day 6, wherein the C2D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C2D1) of etoposide to be administered on day 6, the second dose (C2D2) of etoposide to be administered on day 7, and the third dose (C2D3) of etoposide to be administered on day 8, wherein each of the C2D1, C2D2 and C2D3 of etoposide is approximately 100 mg/ ^m2 .

479. Griffithomab used in a method for treating subjects aged 6 months to 17 years with CD20-positive proliferative disorders, wherein griffithomab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first, second, and third dosing cycle.

(a) The first dosing cycle includes:

(i) The first dose (C1D1) of glimetuzumab to be administered on day 8 and the second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is about 0.03 mg/kg, about 0.04 mg/kg or about 2.5 mg, and the C1D2 of glimetuzumab is about 0.15 mg/kg or about 10 mg;

(ii) A first dose (C1D1) of olibutuzumab to be administered on day 1 and a second dose (C1D2) of olibutuzumab to be administered on day 2, wherein the C1D1 of olibutuzumab is about one-tenth of the sum of the C1D1 and the C1D2 of olibutuzumab, and the C1D2 of olibutuzumab is about nine-tenths of the sum of the C1D1 and the C1D2 of olibutuzumab, and wherein the sum of the C1D1 and the C1D2 of olibutuzumab is about 38 mg/kg, about 28 mg/kg, about 23 mg/kg, about 20 mg/kg or about 1000 mg;

(iii) The first dose (C1D1) of ifosfamide to be administered on day 3, the second dose (C1D2) of ifosfamide to be administered on day 4, and the third dose (C1D3) of ifosfamide to be administered on day 5, wherein each of the C1D1, C1D2 and C1D3 of ifosfamide is about 3000 mg/ ^m2 ;

(iv) A single dose (C1D1) of carboplatin to be administered on day 3, wherein the C1D1 of carboplatin is approximately 635 mg/ ^m² ; and

(v) The first dose (C1D1) of etoposide to be administered on day 3, the second dose (C1D2) of etoposide to be administered on day 4, and the third dose (C1D3) of etoposide to be administered on day 5, wherein each of the C1D1, C1D2 and C1D3 of etoposide is approximately 100 mg/ ^m2 .

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab to be administered on day 1, wherein the C2D1 of glimetuzumab is about 0.4 mg/kg, about 0.5 mg/kg or about 30 mg;

(ii) The first dose (C2D1) of rituximab to be administered on day 5, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 ;

(iii) The first dose (C2D1) of ifosfamide to be administered on day 6, the second dose (C2D2) of ifosfamide to be administered on day 7, and the third dose (C2D3) of ifosfamide to be administered on day 8, wherein each of the C2D1, the C2D2 and the C2D3 of ifosfamide is about 3000 mg/ ^m2 ;

(iv) A single dose (C2D1) of carboplatin to be administered on day 6, wherein the C2D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C2D1) of etoposide to be administered on day 6, the second dose (C2D2) of etoposide to be administered on day 7, and the third dose (C2D3) of etoposide to be administered on day 8, wherein each of the three doses of etoposide (C2D1, C2D2, and C2D3) is approximately 100 mg/ ^m² ; and

(c) The third dosing cycle includes:

(i) A single dose (C3D1) of glimetuzumab to be administered on day 1, wherein the C3D1 of glimetuzumab is about 0.4 mg/kg, about 0.5 mg/kg or about 30 mg;

(ii) The first dose (C3D1) of rituximab to be administered on day 5, wherein the C3D1 of rituximab is approximately 375 mg/ ^m2 ;

(iii) The first dose (C3D1) of ifosfamide to be administered on day 6, the second dose (C3D2) of ifosfamide to be administered on day 7, and the third dose (C3D3) of ifosfamide to be administered on day 8, wherein each of the C3D1, the C3D2 and the C3D3 of ifosfamide is approximately 3000 mg/ ^m2 ;

(iv) A single dose (C3D1) of carboplatin to be administered on day 6, wherein the C3D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C3D1) of etoposide to be administered on day 6, the second dose (C3D2) of etoposide to be administered on day 7, and the third dose (C3D3) of etoposide to be administered on day 8, wherein each of the C3D1, C3D2 and C3D3 of etoposide is approximately 100 mg/ ^m2 .

480. Use of glimetuzumab in the manufacture of a medicine for the treatment of subjects aged 6 months to 17 years with CD20-positive proliferative disorders, wherein in this treatment, glimetuzumab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle.

(a) The first dosing cycle includes:

(i) The first dose (C1D1) of glimetuzumab to be administered on day 8 and the second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is about 0.03 mg/kg, about 0.04 mg/kg or about 2.5 mg, and the C1D2 of glimetuzumab is about 0.15 mg/kg or about 10 mg;

(ii) A first dose (C1D1) of olibutuzumab to be administered on day 1 and a second dose (C1D2) of olibutuzumab to be administered on day 2, wherein the C1D1 of olibutuzumab is about one-tenth of the sum of the C1D1 and the C1D2 of olibutuzumab, and the C1D2 of olibutuzumab is about nine-tenths of the sum of the C1D1 and the C1D2 of olibutuzumab, and wherein the sum of the C1D1 and the C1D2 of olibutuzumab is about 38 mg/kg, about 28 mg/kg, about 23 mg/kg, about 20 mg/kg or about 1000 mg;

(iii) The first dose (C1D1) of ifosfamide to be administered on day 3, the second dose (C1D2) of ifosfamide to be administered on day 4, and the third dose (C1D3) of ifosfamide to be administered on day 5, wherein each of the C1D1, C1D2 and C1D3 of ifosfamide is about 3000 mg/ ^m2 ;

(iv) A single dose (C1D1) of carboplatin to be administered on day 3, wherein the C1D1 of carboplatin is approximately 635 mg/ ^m² ; and

(v) The first dose (C1D1) of etoposide to be administered on day 3, the second dose (C1D2) of etoposide to be administered on day 4, and the third dose (C1D3) of etoposide to be administered on day 5, wherein each of the C1D1, C1D2 and C1D3 of etoposide is approximately 100 mg/ ^m2 .

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab to be administered on day 1, wherein the C2D1 of glimetuzumab is about 0.4 mg/kg, about 0.5 mg/kg or about 30 mg;

(ii) The first dose (C2D1) of rituximab to be administered on day 5, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 ;

(iii) The first dose (C2D1) of ifosfamide to be administered on day 6, the second dose (C2D2) of ifosfamide to be administered on day 7, and the third dose (C2D3) of ifosfamide to be administered on day 8, wherein each of the C2D1, the C2D2 and the C2D3 of ifosfamide is about 3000 mg/ ^m2 ;

(iv) A single dose (C2D1) of carboplatin to be administered on day 6, wherein the C2D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C2D1) of etoposide to be administered on day 6, the second dose (C2D2) of etoposide to be administered on day 7, and the third dose (C2D3) of etoposide to be administered on day 8, wherein each of the three doses of etoposide (C2D1, C2D2, and C2D3) is approximately 100 mg/ ^m² ; and

(c) The third dosing cycle includes:

(i) A single dose (C3D1) of glimetuzumab to be administered on day 1, wherein the C3D1 of glimetuzumab is about 0.4 mg/kg, about 0.5 mg/kg or about 30 mg;

(ii) The first dose (C3D1) of rituximab to be administered on day 5, wherein the C3D1 of rituximab is approximately 375 mg/ ^m2 ;

(iii) The first dose (C3D1) of ifosfamide to be administered on day 6, the second dose (C3D2) of ifosfamide to be administered on day 7, and the third dose (C3D3) of ifosfamide to be administered on day 8, wherein each of the C3D1, the C3D2 and the C3D3 of ifosfamide is approximately 3000 mg/ ^m2 ;

(iv) A single dose (C3D1) of carboplatin to be administered on day 6, wherein the C3D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C3D1) of etoposide to be administered on day 6, the second dose (C3D2) of etoposide to be administered on day 7, and the third dose (C3D3) of etoposide to be administered on day 8, wherein each of the C3D1, C3D2 and C3D3 of etoposide is approximately 100 mg/ ^m2 .

481. Use of glimetuzumab for the treatment of subjects aged 6 months to 17 years with CD20-positive proliferative disorders, wherein glimetuzumab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first, second, and third dosing cycle.

(a) The first dosing cycle includes:

(i) The first dose (C1D1) of glimetuzumab to be administered on day 8 and the second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is about 0.03 mg/kg, about 0.04 mg/kg or about 2.5 mg, and the C1D2 of glimetuzumab is about 0.15 mg/kg or about 10 mg;

(ii) A first dose (C1D1) of olibutuzumab to be administered on day 1 and a second dose (C1D2) of olibutuzumab to be administered on day 2, wherein the C1D1 of olibutuzumab is about one-tenth of the sum of the C1D1 and the C1D2 of olibutuzumab, and the C1D2 of olibutuzumab is about nine-tenths of the sum of the C1D1 and the C1D2 of olibutuzumab, and wherein the sum of the C1D1 and the C1D2 of olibutuzumab is about 38 mg/kg, about 28 mg/kg, about 23 mg/kg, about 20 mg/kg or about 1000 mg;

(iii) The first dose (C1D1) of ifosfamide to be administered on day 3, the second dose (C1D2) of ifosfamide to be administered on day 4, and the third dose (C1D3) of ifosfamide to be administered on day 5, wherein each of the C1D1, C1D2 and C1D3 of ifosfamide is about 3000 mg/ ^m2 ;

(iv) A single dose (C1D1) of carboplatin to be administered on day 3, wherein the C1D1 of carboplatin is approximately 635 mg/ ^m² ; and

(v) The first dose (C1D1) of etoposide to be administered on day 3, the second dose (C1D2) of etoposide to be administered on day 4, and the third dose (C1D3) of etoposide to be administered on day 5, wherein each of the C1D1, C1D2 and C1D3 of etoposide is approximately 100 mg/ ^m2 .

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab to be administered on day 1, wherein the C2D1 of glimetuzumab is about 0.4 mg/kg, about 0.5 mg/kg or about 30 mg;

(ii) The first dose (C2D1) of rituximab to be administered on day 5, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 ;

(iii) The first dose (C2D1) of ifosfamide to be administered on day 6, the second dose (C2D2) of ifosfamide to be administered on day 7, and the third dose (C2D3) of ifosfamide to be administered on day 8, wherein each of the C2D1, the C2D2 and the C2D3 of ifosfamide is about 3000 mg/ ^m2 ;

(iv) A single dose (C2D1) of carboplatin to be administered on day 6, wherein the C2D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C2D1) of etoposide to be administered on day 6, the second dose (C2D2) of etoposide to be administered on day 7, and the third dose (C2D3) of etoposide to be administered on day 8, wherein each of the three doses of etoposide (C2D1, C2D2, and C2D3) is approximately 100 mg/ ^m² ; and

(c) The third dosing cycle includes:

(i) A single dose (C3D1) of glimetuzumab to be administered on day 1, wherein the C3D1 of glimetuzumab is about 0.4 mg/kg, about 0.5 mg/kg or about 30 mg;

(ii) The first dose (C3D1) of rituximab to be administered on day 5, wherein the C3D1 of rituximab is approximately 375 mg/ ^m2 ;

(iii) The first dose (C3D1) of ifosfamide to be administered on day 6, the second dose (C3D2) of ifosfamide to be administered on day 7, and the third dose (C3D3) of ifosfamide to be administered on day 8, wherein each of the C3D1, the C3D2 and the C3D3 of ifosfamide is approximately 3000 mg/ ^m2 ;

(iv) A single dose (C3D1) of carboplatin to be administered on day 6, wherein the C3D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C3D1) of etoposide to be administered on day 6, the second dose (C3D2) of etoposide to be administered on day 7, and the third dose (C3D3) of etoposide to be administered on day 8, wherein each of the C3D1, C3D2 and C3D3 of etoposide is approximately 100 mg/ ^m2 .

482. The glucantuzumab for use or intended use according to any one of Examples 470 to 481, wherein mesna is administered to the subject daily on days 3, 4 and 5 of the first dosing cycle, days 6, 7 and 8 of the second dosing cycle and/or on days 6, 7 and 8 of each additional dosing cycle.

483. The glucantuzumab for use or intended use as described in Example 482, wherein mesna is administered intravenously daily at five doses totaling 3000 mg/ ^m² .

484. Glucophage for use or intended use as described in Example 483, wherein mesna is administered intravenously at a first dose of about 600 mg/ ^m² and four repeated doses of about 600 mg/ ^m² prior to administration of any dose of ifosfamide, each repeated dose being administered about three hours, about six hours, and about 12 hours after the first dose of ifosfamide.

485. Glimetuzumab used in a method for treating subjects aged 18 to 30 years with CD20-positive proliferative disorders, wherein glimetuzumab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

(a) This first dosing cycle comprises a first dose (C1D1) of glimetuzumab to be administered on day 8 and a second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is approximately 2.5 mg and the C1D2 of glimetuzumab is approximately 10 mg; and

(b) The second dosing cycle includes a single dose (C2D1) of glimetuzumab to be administered on day 1, wherein the C2D1 of glimetuzumab is approximately 30 mg.

486. Use of glimetuzumab in the manufacture of a medicament for the treatment of subjects aged 18 to 30 years with CD20-positive proliferative disorders, wherein in this treatment, glimetuzumab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

(a) This first dosing cycle comprises a first dose (C1D1) of glimetuzumab to be administered on day 8 and a second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is approximately 2.5 mg and the C1D2 of glimetuzumab is approximately 10 mg; and

(b) The second dosing cycle includes a single dose (C2D1) of glimetuzumab to be administered on day 1, wherein the C2D1 of glimetuzumab is approximately 30 mg.

487. Use of glimetuzumab for the treatment of subjects aged 18 to 30 years with CD20-positive proliferative disorders, wherein glimetuzumab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide, in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

(a) This first dosing cycle comprises a first dose (C1D1) of glimetuzumab to be administered on day 8 and a second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is approximately 2.5 mg and the C1D2 of glimetuzumab is approximately 10 mg; and

(b) The second dosing cycle includes a single dose (C2D1) of glimetuzumab to be administered on day 1, wherein the C2D1 of glimetuzumab is approximately 30 mg.

488. Griffithomab used in a method for treating subjects aged 18 to 30 years with CD20-positive proliferative disorders, wherein griffithomab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first, second, and third dosing cycle.

(a) The first dosing cycle includes a first dose (C1D1) of glimetuzumab to be administered on day 8 and a second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg and the C1D2 of glimetuzumab is about 10 mg.

(b) This second dosing cycle includes a single dose (C2D1) of glimetuzumab to be administered on day 1, wherein the C2D1 of glimetuzumab is approximately 30 mg; and

(c) The third dosing cycle includes a single dose (C3D1) of glimetuzumab to be administered on day 1, wherein the C3D1 of glimetuzumab is approximately 30 mg.

489. Use of glimetuzumab in the manufacture of a medicine for the treatment of subjects aged 18 to 30 years with CD20-positive proliferative disorders, wherein in this treatment, glimetuzumab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle.

(a) The first dosing cycle includes a first dose (C1D1) of glimetuzumab to be administered on day 8 and a second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg and the C1D2 of glimetuzumab is about 10 mg.

(b) This second dosing cycle includes a single dose (C2D1) of glimetuzumab to be administered on day 1, wherein the C2D1 of glimetuzumab is approximately 30 mg; and

(c) The third dosing cycle includes a single dose (C3D1) of glimetuzumab to be administered on day 1, wherein the C3D1 of glimetuzumab is approximately 30 mg.

490. Use of glimetuzumab for the treatment of subjects aged 18 to 30 years with CD20-positive proliferative disorders, wherein glimetuzumab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first, second, and third dosing cycle.

(a) The first dosing cycle includes a first dose (C1D1) of glimetuzumab to be administered on day 8 and a second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg and the C1D2 of glimetuzumab is about 10 mg.

(b) This second dosing cycle includes a single dose (C2D1) of glimetuzumab to be administered on day 1, wherein the C2D1 of glimetuzumab is approximately 30 mg; and

(c) The third dosing cycle includes a single dose (C3D1) of glimetuzumab to be administered on day 1, wherein the C3D1 of glimetuzumab is approximately 30 mg.

491. Griffithomab used in a method for treating subjects aged 18 to 30 years with CD20-positive proliferative disorders, wherein griffithomab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

(a) The first dosing cycle includes:

(i) The first dose (C1D1) of glimetuzumab to be administered on day 8 and the second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg and the C1D2 of glimetuzumab is about 10 mg.

(ii) The first dose (C1D1) of olibutuzumab to be administered on day 1 and the second dose (C1D2) of olibutuzumab to be administered on day 2, wherein the C1D1 of olibutuzumab is about one-tenth of the sum of the C1D1 and the C1D2 of olibutuzumab, and the C1D2 of olibutuzumab is about nine-tenths of the sum of the C1D1 and the C1D2 of olibutuzumab, and wherein the sum of the C1D1 and the C1D2 of olibutuzumab is about 1000 mg;

(iii) A single dose (C1D1) of ifosfamide to be administered on day 3, wherein the C1D1 of ifosfamide is about 5000 mg/ ^m2 and the maximum dose is about 800 mg;

(iv) A single dose (C1D1) of carboplatin to be administered on day 3, wherein the C1D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C1D1) of etoposide to be administered on day 3, the second dose (C1D2) of etoposide to be administered on day 4, and the third dose (C1D3) of etoposide to be administered on day 5, wherein each of the three doses of etoposide (C1D1, C1D2, and C1D3) is approximately 100 mg/ ^m² ; and

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab to be administered on day 1, wherein the C2D1 of glimetuzumab is approximately 30 mg;

(ii) The first dose (C2D1) of rituximab to be administered on day 5, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 ;

(iii) A single dose (C2D1) of ifosfamide to be administered on day 6, wherein the C2D1 of ifosfamide is about 5000 mg/ ^m2 and the maximum dose is about 800 mg;

(iv) A single dose (C2D1) of carboplatin to be administered on day 6, wherein the C2D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C2D1) of etoposide to be administered on day 6, the second dose (C2D2) of etoposide to be administered on day 7, and the third dose (C2D3) of etoposide to be administered on day 8, wherein each of the C2D1, C2D2 and C2D3 of etoposide is approximately 100 mg/ ^m2 .

492. Use of glimetuzumab in the manufacture of a medicament for the treatment of subjects aged 18 to 30 years with CD20-positive proliferative disorders, wherein in this treatment, glimetuzumab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

(a) The first dosing cycle includes:

(i) The first dose (C1D1) of glimetuzumab to be administered on day 8 and the second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg and the C1D2 of glimetuzumab is about 10 mg.

(ii) The first dose (C1D1) of olibutuzumab to be administered on day 1 and the second dose (C1D2) of olibutuzumab to be administered on day 2, wherein the C1D1 of olibutuzumab is about one-tenth of the sum of the C1D1 and the C1D2 of olibutuzumab, and the C1D2 of olibutuzumab is about nine-tenths of the sum of the C1D1 and the C1D2 of olibutuzumab, and wherein the sum of the C1D1 and the C1D2 of olibutuzumab is about 1000 mg;

(iii) A single dose (C1D1) of ifosfamide to be administered on day 3, wherein the C1D1 of ifosfamide is about 5000 mg/ ^m2 and the maximum dose is about 800 mg;

(iv) A single dose (C1D1) of carboplatin to be administered on day 3, wherein the C1D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C1D1) of etoposide to be administered on day 3, the second dose (C1D2) of etoposide to be administered on day 4, and the third dose (C1D3) of etoposide to be administered on day 5, wherein each of the three doses of etoposide (C1D1, C1D2, and C1D3) is approximately 100 mg/ ^m² ; and

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab to be administered on day 1, wherein the C2D1 of glimetuzumab is approximately 30 mg;

(ii) The first dose (C2D1) of rituximab to be administered on day 5, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 ;

(iii) A single dose (C2D1) of ifosfamide to be administered on day 6, wherein the C2D1 of ifosfamide is about 5000 mg/ ^m2 and the maximum dose is about 800 mg;

(iv) A single dose (C2D1) of carboplatin to be administered on day 6, wherein the C2D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C2D1) of etoposide to be administered on day 6, the second dose (C2D2) of etoposide to be administered on day 7, and the third dose (C2D3) of etoposide to be administered on day 8, wherein each of the C2D1, C2D2 and C2D3 of etoposide is approximately 100 mg/ ^m2 .

493. Use of glimetuzumab for the treatment of subjects aged 18 to 30 years with CD20-positive proliferative disorders, wherein glimetuzumab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide, in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle.

(a) The first dosing cycle includes:

(i) The first dose (C1D1) of glimetuzumab to be administered on day 8 and the second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg and the C1D2 of glimetuzumab is about 10 mg.

(ii) The first dose (C1D1) of olibutuzumab to be administered on day 1 and the second dose (C1D2) of olibutuzumab to be administered on day 2, wherein the C1D1 of olibutuzumab is about one-tenth of the sum of the C1D1 and the C1D2 of olibutuzumab, and the C1D2 of olibutuzumab is about nine-tenths of the sum of the C1D1 and the C1D2 of olibutuzumab, and wherein the sum of the C1D1 and the C1D2 of olibutuzumab is about 1000 mg;

(iii) A single dose (C1D1) of ifosfamide to be administered on day 3, wherein the C1D1 of ifosfamide is about 5000 mg/ ^m2 and the maximum dose is about 800 mg;

(iv) A single dose (C1D1) of carboplatin to be administered on day 3, wherein the C1D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C1D1) of etoposide to be administered on day 3, the second dose (C1D2) of etoposide to be administered on day 4, and the third dose (C1D3) of etoposide to be administered on day 5, wherein each of the three doses of etoposide (C1D1, C1D2, and C1D3) is approximately 100 mg/ ^m² ; and

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab to be administered on day 1, wherein the C2D1 of glimetuzumab is approximately 30 mg;

(ii) The first dose (C2D1) of rituximab to be administered on day 5, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 ;

(iii) A single dose (C2D1) of ifosfamide to be administered on day 6, wherein the C2D1 of ifosfamide is about 5000 mg/ ^m2 and the maximum dose is about 800 mg;

(iv) A single dose (C2D1) of carboplatin to be administered on day 6, wherein the C2D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C2D1) of etoposide to be administered on day 6, the second dose (C2D2) of etoposide to be administered on day 7, and the third dose (C2D3) of etoposide to be administered on day 8, wherein each of the C2D1, C2D2 and C2D3 of etoposide is approximately 100 mg/ ^m2 .

494. Griffithomab used in a method for treating subjects aged 18 to 30 years with CD20-positive proliferative disorders, wherein griffithomab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first, second, and third dosing cycle.

(a) The first dosing cycle includes:

(i) The first dose (C1D1) of glimetuzumab to be administered on day 8 and the second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg and the C1D2 of glimetuzumab is about 10 mg.

(ii) The first dose (C1D1) of olibutuzumab to be administered on day 1 and the second dose (C1D2) of olibutuzumab to be administered on day 2, wherein the C1D1 of olibutuzumab is about one-tenth of the sum of the C1D1 and the C1D2 of olibutuzumab, and the C1D2 of olibutuzumab is about nine-tenths of the sum of the C1D1 and the C1D2 of olibutuzumab, and wherein the sum of the C1D1 and the C1D2 of olibutuzumab is about 1000 mg;

(iii) A single dose (C1D1) of ifosfamide to be administered on day 3, wherein the C1D1 of ifosfamide is about 5000 mg/ ^m2 and the maximum dose is about 800 mg;

(iv) A single dose (C1D1) of carboplatin to be administered on day 3, wherein the C1D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C1D1) of etoposide to be administered on day 3, the second dose (C1D2) of etoposide to be administered on day 4, and the third dose (C1D3) of etoposide to be administered on day 5, wherein each of the C1D1, C1D2 and C1D3 of etoposide is approximately 100 mg/ ^m2 .

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab to be administered on day 1, wherein the C2D1 of glimetuzumab is approximately 30 mg;

(ii) The first dose (C2D1) of rituximab to be administered on day 5, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 ;

(iii) A single dose (C2D1) of ifosfamide to be administered on day 6, wherein the C2D1 of ifosfamide is about 5000 mg/ ^m2 and the maximum dose is about 800 mg;

(iv) A single dose (C2D1) of carboplatin to be administered on day 6, wherein the C2D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C2D1) of etoposide to be administered on day 6, the second dose (C2D2) of etoposide to be administered on day 7, and the third dose (C2D3) of etoposide to be administered on day 8, wherein each of the three doses of etoposide (C2D1, C2D2, and C2D3) is approximately 100 mg/ ^m² ; and

(c) The third dosing cycle includes:

(i) A single dose (C3D1) of glimetuzumab to be administered on day 1, wherein the C3D1 of glimetuzumab is approximately 30 mg;

(ii) The first dose (C3D1) of rituximab to be administered on day 5, wherein the C3D1 of rituximab is approximately 375 mg/ ^m2 ;

(iii) A single dose (C3D1) of ifosfamide to be administered on day 6, wherein the C3D1 of ifosfamide is about 5000 mg/ ^m2 and the maximum dose is about 800 mg;

(iv) A single dose (C3D1) of carboplatin to be administered on day 6, wherein the C3D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C3D1) of etoposide to be administered on day 6, the second dose (C3D2) of etoposide to be administered on day 7, and the third dose (C3D3) of etoposide to be administered on day 8, wherein each of the C3D1, C3D2 and C3D3 of etoposide is approximately 100 mg/ ^m2 .

495. Use of glimetuzumab in the manufacture of a medicine for the treatment of subjects aged 18 to 30 years with CD20-positive proliferative disorders, wherein in this treatment, glimetuzumab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first dosing cycle, a second dosing cycle, and a third dosing cycle.

(a) The first dosing cycle includes:

(i) The first dose (C1D1) of glimetuzumab to be administered on day 8 and the second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg and the C1D2 of glimetuzumab is about 10 mg.

(ii) The first dose (C1D1) of olibutuzumab to be administered on day 1 and the second dose (C1D2) of olibutuzumab to be administered on day 2, wherein the C1D1 of olibutuzumab is about one-tenth of the sum of the C1D1 and the C1D2 of olibutuzumab, and the C1D2 of olibutuzumab is about nine-tenths of the sum of the C1D1 and the C1D2 of olibutuzumab, and wherein the sum of the C1D1 and the C1D2 of olibutuzumab is about 1000 mg;

(iii) A single dose (C1D1) of ifosfamide to be administered on day 3, wherein the C1D1 of ifosfamide is about 5000 mg/ ^m2 and the maximum dose is about 800 mg;

(iv) A single dose (C1D1) of carboplatin to be administered on day 3, wherein the C1D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C1D1) of etoposide to be administered on day 3, the second dose (C1D2) of etoposide to be administered on day 4, and the third dose (C1D3) of etoposide to be administered on day 5, wherein each of the C1D1, C1D2 and C1D3 of etoposide is approximately 100 mg/ ^m2 .

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab to be administered on day 1, wherein the C2D1 of glimetuzumab is approximately 30 mg;

(ii) The first dose (C2D1) of rituximab to be administered on day 5, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 ;

(iii) A single dose (C2D1) of ifosfamide to be administered on day 6, wherein the C2D1 of ifosfamide is about 5000 mg/ ^m2 and the maximum dose is about 800 mg;

(iv) A single dose (C2D1) of carboplatin to be administered on day 6, wherein the C2D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C2D1) of etoposide to be administered on day 6, the second dose (C2D2) of etoposide to be administered on day 7, and the third dose (C2D3) of etoposide to be administered on day 8, wherein each of the three doses of etoposide (C2D1, C2D2, and C2D3) is approximately 100 mg/ ^m² ; and

(c) The third dosing cycle includes:

(i) A single dose (C3D1) of glimetuzumab to be administered on day 1, wherein the C3D1 of glimetuzumab is approximately 30 mg;

(ii) The first dose (C3D1) of rituximab to be administered on day 5, wherein the C3D1 of rituximab is approximately 375 mg/ ^m2 ;

(iii) A single dose (C3D1) of ifosfamide to be administered on day 6, wherein the C3D1 of ifosfamide is about 5000 mg/ ^m2 and the maximum dose is about 800 mg;

(iv) A single dose (C3D1) of carboplatin to be administered on day 6, wherein the C3D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C3D1) of etoposide to be administered on day 6, the second dose (C3D2) of etoposide to be administered on day 7, and the third dose (C3D3) of etoposide to be administered on day 8, wherein each of the C3D1, C3D2 and C3D3 of etoposide is approximately 100 mg/ ^m2 .

496. Use of glimetuzumab for the treatment of subjects aged 18 to 30 years with CD20-positive proliferative disorders, wherein glimetuzumab is administered in combination with olibutuzumab, rituximab, ifosfamide, carboplatin, and etoposide in a dosing regimen comprising a first, second, and third dosing cycle.

(a) The first dosing cycle includes:

(i) The first dose (C1D1) of glimetuzumab to be administered on day 8 and the second dose (C1D2) of glimetuzumab to be administered on day 15, wherein the C1D1 of glimetuzumab is about 2.5 mg and the C1D2 of glimetuzumab is about 10 mg.

(ii) The first dose (C1D1) of olibutuzumab to be administered on day 1 and the second dose (C1D2) of olibutuzumab to be administered on day 2, wherein the C1D1 of olibutuzumab is about one-tenth of the sum of the C1D1 and the C1D2 of olibutuzumab, and the C1D2 of olibutuzumab is about nine-tenths of the sum of the C1D1 and the C1D2 of olibutuzumab, and wherein the sum of the C1D1 and the C1D2 of olibutuzumab is about 1000 mg;

(iii) A single dose (C1D1) of ifosfamide to be administered on day 3, wherein the C1D1 of ifosfamide is about 5000 mg/ ^m2 and the maximum dose is about 800 mg;

(iv) A single dose (C1D1) of carboplatin to be administered on day 3, wherein the C1D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C1D1) of etoposide to be administered on day 3, the second dose (C1D2) of etoposide to be administered on day 4, and the third dose (C1D3) of etoposide to be administered on day 5, wherein each of the C1D1, C1D2 and C1D3 of etoposide is approximately 100 mg/ ^m2 .

(b) The second dosing cycle includes:

(i) A single dose (C2D1) of glimetuzumab to be administered on day 1, wherein the C2D1 of glimetuzumab is approximately 30 mg;

(ii) The first dose (C2D1) of rituximab to be administered on day 5, wherein the C2D1 of rituximab is approximately 375 mg/ ^m2 ;

(iii) A single dose (C2D1) of ifosfamide to be administered on day 6, wherein the C2D1 of ifosfamide is about 5000 mg/ ^m2 and the maximum dose is about 800 mg;

(iv) A single dose (C2D1) of carboplatin to be administered on day 6, wherein the C2D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C2D1) of etoposide to be administered on day 6, the second dose (C2D2) of etoposide to be administered on day 7, and the third dose (C2D3) of etoposide to be administered on day 8, wherein each of the three doses of etoposide (C2D1, C2D2, and C2D3) is approximately 100 mg/ ^m² ; and

(c) The third dosing cycle includes:

(i) A single dose (C3D1) of glimetuzumab to be administered on day 1, wherein the C3D1 of glimetuzumab is approximately 30 mg;

(ii) The first dose (C3D1) of rituximab to be administered on day 5, wherein the C3D1 of rituximab is approximately 375 mg/ ^m2 ;

(iii) A single dose (C3D1) of ifosfamide to be administered on day 6, wherein the C3D1 of ifosfamide is about 5000 mg/ ^m2 and the maximum dose is about 800 mg;

(iv) A single dose (C3D1) of carboplatin to be administered on day 6, wherein the C3D1 of carboplatin is approximately 5 × (25 + creatinine clearance) mg; and

(v) The first dose (C3D1) of etoposide to be administered on day 6, the second dose (C3D2) of etoposide to be administered on day 7, and the third dose (C3D3) of etoposide to be administered on day 8, wherein each of the C3D1, C3D2 and C3D3 of etoposide is approximately 100 mg/ ^m2 .

497. Glucophage for use or intended use according to any one of Examples 485 to 496, wherein mesna is to be administered concurrently with any dose of ifosfamide.

498. The glucantuzumab for use or intended use as described in Example 497, wherein mesna is to be administered intravenously at a dose of about 5000 mg/ ^m² .

499. The glucantuzumab for use or intended use as described in Example 498, wherein mesna is administered via continuous infusion over approximately 24 hours on day 3 of the first dosing cycle, day 6 of the second dosing cycle, and/or day 6 of each additional dosing cycle.

500. Glimetoumab for use or intended use according to any one of Examples 455 to 469, wherein the CD20-positive proliferative disorder is relapsed and/or refractory DLBCL.

501. The glimetuzumab for use or intended use according to any one of Examples 470 to 499, wherein the CD20-positive proliferative disorder is relapsed and/or refractory mature B-cell NHL.

502. The present invention as described above.

Example

The following are examples of the methods and compositions of the present invention. It should be understood that various other embodiments may be practiced given the general description provided above.

Example 1. A Phase IB, open-label, multicenter, single-arm study evaluating the preliminary efficacy, safety, and pharmacokinetics of glimetuzumab combined with rituximab plus ifosfamide, carboplatin, and etoposide phosphate in patients with relapsed/refractory diffuse B-cell lymphoma who are eligible for transplantation or CAR-T therapy.

Research rationale

The aim of this study was to evaluate the preliminary efficacy, safety, and pharmacokinetics of glofit in combination with rituximab plus ifosfamide, carboplatin, and etoposide (R-ICE) in participants with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who had failed first-line therapy including anti-differentiation cluster (CD)20 antibody (i.e., rituximab) and anthracycline and were eligible for transplantation or CAR-T therapy (defined as being medically eligible for intensified platinum-based salvage therapy followed by autologous stem cell transplantation (ASCT) or CAR-T therapy).

Purpose

The primary objective of this study was to evaluate the preliminary efficacy, safety, and pharmacokinetics of the combination of glimetuzumab and R-ICE in participants with R/RDLBCL who had previously failed first-line therapy including an anti-CD20 antibody (i.e., rituximab) and anthracycline and were eligible for transplantation or CAR-T therapy.

In this protocol, "study treatment" refers to the combination of treatments (i.e., glimetuzumab and R-ICE) allocated to participants as part of this study. Table 6 below outlines the specific objectives and corresponding endpoints of the study.

Table 6. Goals and Endpoints

ADA = Anti-drug antibody; CAR-T = Chimeric antigen receptor T cells; CR = Complete response; CTCAE = Common Terminology Standard for Adverse Events; ctDNA = Circulating tumor DNA; DOCR = Duration of complete response; DOR = Duration of response; EFS = Event-free survival; glofit = Glucophage; MARR = Mobilization-adjusted response rate; ORR = Objective response rate; OS = Overall survival; PFS = Progression-free survival; PK = Pharmacokinetics; PR = Partial response; R-ICE = Rituximab plus ifosfamide, carboplatin, and etoposide; NCI CTCAE = Common Terminology Standard for Adverse Events. Overall Study Design

This is a phase Ib, open-label, multicenter, single-arm trial for patients with R/R DLBCL who have failed first-line therapy including anti-CD20 antibody (i.e., rituximab) and anthracycline and are eligible for transplantation (defined as being medically eligible for intensive platinum-based salvage therapy followed by ASCT or CAR-T therapy).

Potential participants will undergo eligibility screening during a 28-day screening period. Approximately 40 participants will be recruited via an Interactive Voice or Internet-based Response System (IxRS) to receive up to three 21-day cycles of glofit-R-ICE. During cycle 1, participants will receive olibutuzumab pretreatment (Gpt) on day 1, followed by ICE from day 1 to day 3, then glimetuzumab 2.5 mg on day 8 and 10 mg on day 15 in escalating doses. During cycles 2 and 3, participants will receive R-ICE from day 1 to day 3 and glimetuzumab 30 mg on day 8.

Participants' remission was assessed after two to three cycles of glofit-R-ICE, depending on institutional criteria regarding the number of cycles. Participants without evidence of disease progression after two cycles may receive a third cycle of glofit-R-ICE at the investigator's discretion. Participants experiencing disease progression at any point in time will discontinue study therapy.

Participants who achieve CR or partial remission after completing the study therapy using glofit-R-ICE will continue ASCT or CAR-T therapy according to specific pre-treatment protocols and care plans defined by institutional standards. Participants whose disease stabilizes or progresses will receive further therapy as defined by their attending physician. Survival will be followed regardless of whether participants undergo transplantation, CAR-T therapy, or begin a new anti-lymphoma therapy.

The study protocol is provided in Figure 3, and the dosing protocol is shown in Figure 4.

Research on treatment

The investigational drugs (IMPs) in this study were glofit (RO7082859), olibutuzumab (RO5072759), and tocilizumab (RO4877533).

Glucetuzumab

Glucophage is a bispecific antibody that binds to CD20 and CD3. It comprises two Fab molecules that specifically bind to CD20, each containing six hypervariable regions (HVRs): HVR-H1: YSWIN (SEQ ID NO:1); HVR-H2: RIFPGDGDTDYNGKFKG (SEQ ID NO:2); HVR-H3: NVFDGYWLVY (SEQ ID NO:3); HVR-L1: RSSKSLLHSNGITYLY (SEQ ID NO:4); HVR-L2: QMSNLVS (SEQ ID NO:5); and HVR-L3: AQNLELPYT (SEQ ID NO:5). O:6); and at least one Fab molecule that specifically binds to CD3, the Fab molecule comprising the amino acid sequences of the following six hypervariable regions (HVR): HVR-H1: TYAMN (SEQ ID NO:9); HVR-H2: RIRSKYNNYATYYADSVKG (SEQ ID NO:10); HVR-H3: HGNFGNSYVSWFAY (SEQ ID NO:11); HVR-L1: GSSTGAVTTSNYAN (SEQ ID NO:12); HVR-L2: GTNKRAP (SEQ ID NO:13); and HVR-L3: ALWYSNLWV (SEQ ID NO:14).

Intravenous administration of glimetuzumab was performed using an escalating dosing regimen, starting with 2.5 mg on day 8 of cycle 1, increasing to 10 mg on day 15 of cycle 1, and then increasing to 30 mg on day 8 of cycles 2 and 3.

Glimetrozine should be administered to well-hydrated participants. A prophylactic dose of dexamethasone 20 mg IV is required and should be administered 1 hour before the administration of glimetrozine; oral acetaminophen or paracetamol (500 mg or 1000 mg) and an antihistamine such as diphenhydramine (50 mg) should be administered approximately 30 minutes before the start of the infusion.

Initially, glimetuzumab was administered to participants over 4 hours (±15 minutes) on days 8 and 15 of cycle 1, and on day 8 of cycles 2 and 3. For participants at potentially increased risk of CRS, or those who experienced CRS at previous glimetuzumab doses or, in the investigator's judgment, had an increased risk of recurrent CRS at subsequent doses, the infusion time could be extended to a maximum of 8 hours. In the absence of infusion-related adverse events caused by rituximab or olibutuzumab administration, or CRS caused by glimetuzumab, the infusion time of glimetuzumab in cycle 3 could be reduced to 2 hours (±15 minutes) in the investigator's judgment.

Obin eutozumab

Obinutuzumab pretreatment was administered to all participants via intravenous infusion at an absolute (fixed) dose of 1000 mg on day 1 of cycle 1. Participants who were adequately hydrated should receive oxetuzumab.

Pre-treatment with dexamethasone 20 mg IV or methylprednisolone 80 mg IV is required and should be administered 1 hour before olibutuzumab administration; oral acetaminophen or paracetamol (500 mg or 1000 mg) and antihistamines such as diphenhydramine (50 mg) should be administered approximately 30 minutes before the start of infusion.

If a participant has an increased risk of infusion-related response (IRR) (e.g., due to high tumor burden, high peripheral lymphocyte count) or experiences adverse events during infusion, the olibutuzumab infusion can be administered over 2 days.

When dexamethasone is required in the regimen, methylprednisolone, prednisolone, or prednisolone may be used if dexamethasone is unavailable or the participant is intolerant to it. For a 20 mg IV dose of dexamethasone, an equivalent dose of 80 mg IV methylprednisolone, 100 mg PO prednisolone, or 100 mg prednisolone via IV infusion may be used.

Tocilizumab

Tocilizumab may be administered as a salvage clinical trial drug (IMP) to participants experiencing CRS events when necessary. Tocilizumab is administered at a dose of 8 mg/kg to participants ≥30 kg and at a dose of 12 mg/kg to participants <30 kg. A dose exceeding 800 mg per infusion is not recommended.

Rituximab

Rituximab was administered intravenously at a dose of 375 mg/ ^m² along with ICE on day 1 of cycles 2 and 3. If a participant completed all 3 cycles, they received a total of 2 doses of rituximab; if they completed only 2 cycles, they received 1 dose of rituximab.

Rituximab preparation and administration were performed according to local prescribing information, including prophylactic medication. Subcutaneous administration of rituximab was not permitted in this study. The use of locally approved standard-of-care biosimilar rituximab was permitted.

If a participant has an increased risk of infusion-related response (IRR) (high tumor burden or high peripheral lymphocyte count), rituximab infusion can be administered over two days.

ICE chemotherapy (ifosfamide, carboplatin, and etoposide (including mesna))

ICE chemotherapy consists of ifosfamide, carboplatin, and etoposide. Hospitalization or outpatient administration is permitted at the investigator's discretion. Etoposide phosphate can be used as an alternative to the same dose of etoposide. Ifosfamide, carboplatin, and etoposide chemotherapy will be administered starting on day 1 of cycle 1, continuing for two or three 21-day cycles, as described below:

● Etoposide: 100 mg/ ^m² , administered IV daily on days 1, 2, and 3 of each cycle.

Participants with a creatinine clearance (CrCl) of <50 mL/min should reduce their dose to 75% of the planned dose (or reduce it according to institutional standards).

●Carboplatin: Dosage in mg = 5 mg/mL/min × (25 + CrCl), with an upper limit of 750 mg.

IV infusion on day 2 of each cycle

○ The Cockcroft-Gault equation should be used to calculate CrCl in mL/min:

Male: CrCl (mL/min) = [(140 - age) × (weight (kg))] / [72 × serum creatinine (mg/dL)]

Female: CrCl (mL/min) = 0.85 × CrCl (Male)

Weight adjustment is permitted for overweight/obese participants (BMI ≥ 25) or participants with abnormally low creatinine levels, according to institutional standards.

●Ifosfamide (inpatient administration): Mix 5000 mg/ ^m² with 5000 mg/ ^m² of mesna and administer via IV infusion over 24 hours, starting on day 2 of each cycle and ending on day 3 of each cycle. Following the infusion, mesna should be administered IV or orally according to institutional standards.

Participants with CrCl concentrations <60 mL/min should reduce their dose to 80% of the planned dose (or reduce it according to institutional standards).

○ Alternative dosage in outpatient settings: If R-ICE is used in an outpatient setting, if if cyclophosphamide 1666 mg/ ^m² mixed with mesna 1666 mg/ ^m² may be administered intravenously on days 1, 2 and 3 of each cycle (Hertzberg et al. 2006, Ann Oncol 17, IV 25-30).

In Cycle 1, oxetuzumab should be administered before ICE. Initiation of ICE (Cycle 1) may be delayed by one day to facilitate completion of oxetuzumab administration.

For cycles 2 and 3, rituximab should be administered before ICE. If rituximab is administered 1 day before ICE according to institutional standards, or if an adverse event occurs, the initiation of ICE (cycles 2 and 3) may be delayed by 1 day.

Drug administration and drug-related toxicities (e.g., allergic reactions, hemorrhagic cystitis, and neurotoxicity) should be monitored according to institutional standards.

Granulocyte colony-stimulating factor

All participants received granulocyte colony-stimulating factor (G-CSF). G-CSF should be started 1 to 2 days after the completion of R-ICE administration. The dosage of G-CSF should follow the institutional standards of each research center.

Basis for primary endpoint selection

Given that this study is a Phase Ib trial evaluating the preliminary efficacy of glofit-R-ICE in participants eligible for ASCT or CAR-T therapy, the decision to proceed with transplantation depends on whether the participant's disease responds to the glofit-R-ICE combination and on the observation of superior outcomes with CAR-T therapy in patients with lower disease burden. Therefore, the objective response rate (ORR) is a clinically meaningful endpoint for assessing the preliminary activity of glofit-R-ICE. ORR is defined as the proportion of participants who achieve CR or PR within three cycles of glofit-R-ICE, as determined by the investigator according to the Lugano criteria.

Basis for selecting secondary endpoints

Secondary endpoints included standard endpoints used in DLBCL to assess long-term survival-based endpoints (including EFS, PFS, and OS) and the duration of overall and complete remission. Additionally, the mobilization-adjusted response rate (MARR) endpoint was included to assess the percentage of patients achieving an objective response and mobilization of a target dose of 2,000,000 CD34+ hematopoietic stem cells/kg (typically considered the minimum requirement for ASCT). The MARR definition used in this study was consistent with the study endpoints in the CORAL study (Gisselbrecht et al. 2010, J Clin Oncol 28, 4184-90). Although no minimum dose of CD34+ hematopoietic stem cells is defined for ASCT, the American Society of Blood and Marrow Transplantation practice guidelines state that a dose of 2,000,000 CD34+ hematopoietic stem cells/kg is the “generally accepted minimum” number of stem cells required for ASCT (Duong et al. 2014, Biol Bone Marrow Transplant 20, 1262-73).

Study duration

The total duration of each individual's participation in the study is expected to be approximately 2 years and 6 months.

research group

Approximately 40 participants with DLBCL who have failed a previous line of therapy (including anti-CD20 antibody and anthracycline) and are eligible for transplantation or CAR-T will be enrolled in this study. This study will allow up to 20 participants diagnosed with primary relapsed/relapsed DLBCL within one year of their initial diagnosis.

Prospective approval of deviations from recruitment and inclusion criteria is not permitted; this is referred to as a protocol exemption or waiver.

Inclusion criteria

Participants are eligible to be included in the study only if they meet all of the following criteria:

● Participants aged 18 and above

●Life expectancy ≥ 12 weeks

● Histologically confirmed B-cell lymphomas, including one of the following diagnoses according to the 2016 WHO classification of lymphomas, which may be newly developed or evolved from indolent lymphomas:

–DLBCL, unless otherwise specified (NOS) (including Estée Lauder Virus [EBV]+)

DLBCL)

– High-grade B-cell lymphoma (HGBCL) with MYC and B-cell lymphoma 2 and/or B-cell lymphoma 6 rearrangements.

–HGBCL, NOS

● Received a prior line of systemic therapy, including an anti-CD20 monoclonal antibody (i.e., rituximab) and anthracycline.

●Relapsed or refractory disease after first-line chemoimmunotherapy

– Relapsed disease is defined as complete remission with first-line therapy followed by a biopsy-proven relapse.

– Refractory diseases are defined as those that fail to achieve complete remission with first-line therapy, including:

PD as the best response to first-line therapy

Disease stability (SD) is the best response following at least four cycles of first-line therapy (e.g., four cycles of R-CHOP).

PR is considered the best remission after at least 6 cycles and is accompanied by biopsy-proven residual disease or subsequent disease progression.

● Participants must be candidates for high-dose chemotherapy followed by ASCT or CAR-T therapy.

● At least one two-dimensional measurable (≥1.5cm) nodular lesion or one two-dimensional measurable (≥1)

Extranodal lesions (cm) as measured by CT scan

●ECOG fitness level is 0 or 1

●Adequate blood system function (unless attributable to an underlying disease, such as that determined by extensive bone marrow involvement or associated by the investigator with hypersplenism secondary to splenic involvement in DLBCL), is defined as follows:

– Hemoglobin ≥ 9.0 g/dL (≥ 90 g/L)

–ANC≥1.0×10 ⁹ /L(≥1000/μL)

Participants may include those with a history of benign familial neutropenia:

ANC≥0.75×10 ⁹ /L (≥750/μL).

– Platelet count ≥75× ^10⁹ /L (≥75,000/μL) and no blood transfusion within one week prior to starting study treatment.

●Sufficient renal function is defined as an estimated CrCl level of 45 mL/min.

Exclusion criteria

Participants will be excluded from the study if any of the following criteria are met:

● Participants had received more than one previous line of therapy for DLBCL.

Treatment using partial and complete first-line therapy regimens (i.e., rituximab, cyclophosphamide, vincristine, and prednisone, followed by R-CHOP) will be counted as one line of therapy.

Treatments that use steroid monotherapy as a bridge to final treatment will not be counted in the previous line of therapy.

Local therapies (i.e., radiation therapy) will not be considered as lines of treatment.

● Primary mediastinal B-cell lymphoma (PMBCL)

● A history of severe allergy or allergic reaction to humanized or murine monoclonal antibodies (or recombinant antibody-associated fusion proteins), or known sensitivity or allergy to rodent products.

● Contraindications for olibutuzumab, rituximab, ifosfamide, mesna, carboplatin, etoposide, or tocilizumab

●Previous treatment with glimepiride or other bispecific antibodies targeting both CD20 and CD3.

● Peripheral neuropathy classified as grade >1 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) v5.0 at enrollment.

●Having received radiation therapy, chemotherapy, immunotherapy, immunosuppressive therapy, or any investigational drug intended to treat cancer within 2 weeks prior to the first study treatment.

● Received monoclonal antibody therapy for cancer treatment within 4 weeks prior to the first study treatment.

● Patients with primary or secondary CNS lymphoma or a history of CNS lymphoma at the time of enrollment.

●Currently have or have a history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease.

- Participants with a history of stroke, who have not experienced a stroke or transient ischemic attack in the past 2 years, and who, in the investigator's judgment, do not have residual neurological deficits are eligible.

● Any of the following abnormal laboratory values are not considered, unless in the investigator's opinion, related to potential lymphoma:

–AST or ALT > 2.5 times the upper limit of normal (ULN)

–Total bilirubin ≥1.5 times ULN

– Patients with a documented history of Gilbert's disease and a total bilirubin level ≤ 3 times the ULN are eligible for enrollment.

– In the absence of therapeutic anticoagulation therapy, INR or PT > 1.5 times ULN

– In the absence of therapeutic anticoagulation or lupus anticoagulation therapy, PTT or aPTT > 1.5 times ULN

● Other malignant tumor history that may affect protocol adherence or outcome interpretation, except in the following cases:

Participants with a history of radical basal carcinoma of the skin, squamous cell carcinoma, or cervical carcinoma in situ at any time prior to enrollment are eligible.

Participants with low-grade, early-stage prostate cancer (Gleason score of 6 or below, stage 1 or 2) who did not require treatment at any time prior to enrollment were eligible.

Participants who have received appropriate treatment for a curative purpose and whose malignant tumor has been in remission for ≥2 years prior to enrollment, or any other malignant tumor, are eligible.

Participants who received adjuvant endocrine therapy for non-metastatic hormone receptor-positive breast cancer for ≥2 years prior to enrollment were eligible.

● Evidence of significant, uncontrolled comorbidities that may affect adherence to the protocol or interpretation of outcomes, including major cardiovascular disease (such as New York Heart Association class III or IV or objectively assessed class C or D heart disease, myocardial infarction within the previous 6 months, unstable arrhythmia, or unstable angina) or major lung disease (including obstructive pulmonary disease).

● Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infections (excluding nail bed fungal infections) at study enrollment, or any major infectious event (as assessed by the investigator) within 4 weeks prior to the first study treatment.

● Suspected or latent tuberculosis (e.g., confirmed by a positive interferon-gamma release assay)

● A positive test result for hepatitis B virus (HBV) infection (defined as serological positivity for hepatitis B surface antigen [HBsAg]).

– If HBV DNA cannot be detected, participants with occult or prior HBV infection (defined as HBsAg negative and hepatitis B core antibody [HBcAb] positive) may be included, provided they are willing to undergo DNA testing on day 1 of cycle 2 and cycle 3, and every three months for at least 12 months following the last study treatment cycle and appropriate antiviral therapy.

● Hepatitis C virus (HCV) antibody test result was positive.

- Only patients who are positive for HCV antibodies and whose polymerase chain reaction (PCR) is negative for HCV RNA are eligible.

● Known or suspected chronic active estabar virus infection (CAEBV)

CAEBV is defined as a chronic disease lasting at least 3 months with elevated EBV levels in tissues or blood and a lack of evidence of a known underlying immunodeficiency (Kimura and Cohen, 2017). Participants with EBV+DLBCL should not be excluded unless there is other evidence or medical history suggesting CAEBV.

●A known or suspected history of hemophagocytic lymphohistiocytosis (HLH)

● History of known progressive multifocal leukoencephalopathy

● Adverse events resulting from previous anticancer therapy have not resolved to Grade 1 or better (except for hair loss and anorexia or other conditions permitted by the inclusion criteria).

● Administer the live attenuated vaccine within 4 weeks prior to the first study treatment administration, or if the live attenuated vaccine is expected to be needed during the study.

●Previous solid organ transplant

●Previous allogeneic stem cell transplant

●Previous ASCT for lymphoma

● Previous autologous stem cell transplantation within 5 years of the start of study treatment for any indication other than lymphoma

● Active autoimmune diseases requiring treatment.

Participants with a history of autoimmune-related hypothyroidism requiring stable doses of thyroid replacement hormone are eligible.

Participants with type 1 diabetes who are on an insulin regimen are eligible for this study.

Participants with a history of autoimmune hepatitis, systemic lupus erythematosus, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, multiple sclerosis, or glomerulonephritis will be excluded.

Participants with a history of immune thrombocytopenic purpura, autoimmune hemolytic anemia, Guillain-Barré syndrome, myasthenia gravis, myositis, rheumatoid arthritis, vasculitis, or other autoimmune diseases will be excluded unless they have not required systemic therapy in the past 12 months.

● Received prior treatment with systemic immunosuppressive drugs (including but not limited to cyclophosphamide, methotrexate, thalidomide, and anti-tumor necrosis factor agents) within 4 days prior to the first dose of the study treatment.

● Continuous use of prednisone or its equivalent at >30 mg/day. Patients receiving prednisone or its equivalent at ≤30 mg/day prior to Day 1 of Cycle 1 must have a history of stable doses for at least 4 weeks. Patients may have already received a short (≤7 days) course of systemic steroids (≤100 mg prednisone equivalent daily) before initiating investigational therapy to control lymphoma-related symptoms.

– Inhaled corticosteroids are permitted.

– Mineral corticosteroids are permitted for the management of orthostatic hypotension.

– Allows the use of physiological doses of corticosteroids to manage adrenal insufficiency.

●In addition to diagnosis, have recently undergone major surgery (within 4 weeks prior to the initial study treatment).

●A clinically significant history of cirrhosis

● Any other disease, metabolic disorder, physical examination findings, or clinical laboratory findings that reasonably suggest a disease or condition, which contraindicates the use of the investigational drug or may affect the interpretation of the results or place the participant at high risk of treatment complications.

●Pregnant or breastfeeding, or planning to become pregnant during study treatment or within 18 months after the first dose of study treatment.

-Women of childbearing age must have a negative serum pregnancy test result within 7 days prior to starting the study treatment.

Example 2. A Phase I/II, open-label, single-arm, two-part trial evaluating the safety, tolerability, pharmacokinetics, and antitumor activity of glimetuzumab in combination with chemoimmunotherapy in pediatric and young adult patients with relapsed/refractory mature B-cell non-Hodgkin lymphoma.

Research rationale

The aim of this study was to evaluate the safety and efficacy of glimetuzumab (a novel CD20/CD3 bispecific antibody) as monotherapy and in combination with a standard second-line chemoimmunotherapy regimen (rituximab, ifosfamide, carboplatin, and etoposide (R-ICE)) in pediatric and young adult participants with relapsed and refractory (R/R) mature B-cell non-Hodgkin lymphoma (B-NHL). R/R B-NHL in children, adolescents, and young adults represents a highly unmet need, with current 1-year overall survival (OS) rates below 30%. T-cell conjugates have been identified as the class of medicines most likely to benefit the pediatric population. Combining glimetuzumab with R-ICE improved response rates to salvage chemoimmunotherapy and translated into a higher percentage of participants receiving final treatment with HSCT, and improved survival in that treatment setting.

Goals and End Points

This study evaluated the safety, tolerability, pharmacokinetics, and antitumor activity of glimetuzumab alone, as well as in combination with R-ICE induction and olibutuzumab pretreatment, in pediatric and young adult participants with R/R B-NHL. The specific objectives and corresponding endpoints of the study are summarized in Table 7 below.

Table 7. Goals and Endpoints

ADA = Anti-drug antibody; CR = Complete response; CTCAE = Common Terminology Standard for Adverse Events; DOCR = Duration of complete response; EFS = Event-free survival; HSCT = Hematopoietic stem cell transplantation; NCI = National Cancer Institute; NHL = Non-Hodgkin lymphoma; ORR = Objective response rate; OS = Overall survival; PFS = Progression-free survival; PK = Pharmacokinetics; PR = Partial response; R-ICE = Rituximab, ifosfamide, carboplatin, and etoposide.

International pediatric non-Hodgkin lymphoma response criteria: Sandlund JT, Guillerman RP, Perkins SL, et al. International pediatric non-Hodgkin lymphoma response criteria. J. Clin. Oncol. 33:2106-2111, 2015.

NCI CTCAE v5.0:cancer.gov

Overall Design

This is a phase I/II, two-part, sequential, open-label, single-arm, multicenter trial evaluating the safety, tolerability, pharmacokinetics, and antitumor activity of glucentumab in combination with chemoimmunotherapy in pediatric participants aged 6 months to <18 years with R/R mature B-NHL.

This study is divided into two parts (see Figure 5):

Part 1 – Security Import:

The study aimed to assess the safety, tolerability, and pharmacokinetics of the combination of glimetuzumab and R-ICE chemoimmunotherapy to determine the recommended pediatric dose of glimetuzumab, evaluate the early efficacy of glimetuzumab plus R-ICE chemoimmunotherapy in pediatric participants with R/R mature B-NHL aged 6 months to <18 years, and confirm the pediatric dose of olibutuzumab pretreatment. During this part of the study, between 10 and 15 participants aged 6 months to <18 years were enrolled. Prior to the commencement of Part 2 of the study, at least 10 participants were enrolled and early efficacy at the recommended pediatric dose was assessed.

Part 2 – Queue Expansion:

If the predefined extended efficacy criteria are met, and after evaluating safety and tolerability data at the recommended pediatric dose of glimetuzumab, at least 30 new pediatric participants <18 years of age will be enrolled to evaluate the efficacy of glimetuzumab plus R-ICE chemoimmunotherapy at the recommended pediatric dose of glimetuzumab. Part 2 of this study expands eligibility to younger adult participants aged 18 to 30 years, and an additional up to 10 younger adults are expected to be enrolled. A total of up to 40 participants will be enrolled in this part of the study.

In both Part 1 and Part 2, the longest treatment duration will be three cycles of glimetuzumab and R-ICE.

A summary of this study is shown in Figure 6.

Research on treatment

The investigational drugs (IMPs) in this study were olibutuzumab, glibenclamide, rituximab, ifosfamide, carboplatin, etoposide (ICE), and tocilizumab, all administered via intravenous infusion. Other pre-treatment and supportive care medications (i.e., mesna, G-CSF, dexamethasone, and intrathecal (IT) methotrexate, cytarabine, cortisol [or other equivalent doses of steroids]) were considered non-investigative drugs (NIMPs). Treatment was administered according to Figure 7 (pediatric patients aged 6 months to 17 years) and Figure 8 (young adult patients aged 18 to 30 years).

Obin eutozumab

In this study, all participants received a single full-dose olibutuzumab pretreatment, divided into two doses during Cycle 1 and before the initiation of glimetuzumab administration. The olibutuzumab pretreatment was administered only over 4 hours via IV (IV) infusion during the first dosing cycle (Cycle 1), with the dose adjusted according to weight for pediatric participants <18 years of age and a fixed dose of 1000 mg for participants aged 18 to 30 years. On Day 1 of Cycle 1 (i.e., the C1D1 dose) and Day 2 of Cycle 1 (i.e., the C1D2 dose), olibutuzumab was administered at one-tenth and nine-tenths of the total dose, respectively (i.e., 100 mg as the C1D1 dose and 900 mg as the C1D2 dose). The two doses (C1D1 and C1D2) were administered over 4 hours using the same infusion and prophylactic dosing guidelines. For pediatric participants <18 years of age, a weight-adjusted dose was used (see Table 8).

Table 9. Weight-adjusted doses of olibutuzumab and glimetuzumab for patients <18 years of age.

FD = Full dose; SUD = Incremental dose.

^The weight range is based on the CDC growth chart (cdc.gov, 2000).

^b. All participants aged ≥18 years should be given a recommended fixed dose independent of body weight.

^For the ≥45kg category, the dosage is based on the recommended adult stage II dosage.

Glucetuzumab

Glimetuzumab was administered via IV infusion on day 8 and day 15 of the first cycle in an escalating dosing regimen, followed by up to two subsequent full doses on day 1 of the second cycle (cycle 2) and day 1 of the third cycle (cycle 3).

Glimetrozine is administered to participants via IV infusion using a dedicated infusion line and administration catheter. The first dose of glimetrozine (day 8 of cycle 1) should be administered over 4 hours ± 15 minutes (see the pharmacy manual for details on infusion rates). Participants in the ascending dosing cohort should also receive the doses from day 15 of cycle 1 and day 1 of cycle 2 over at least 4 hours. In the absence of infusion-related adverse events, the infusion time of glimetrozine in subsequent cycles may be reduced to 2 hours ± 15 minutes at the investigator's discretion. For patients at potentially increased risk of CRS, those who have experienced infusion-related reactions (IRR) or cytokine release syndrome (CRS) at their previous dose of glimetrozine, or those at increased risk of recurrent IRR or CRS at subsequent doses, the infusion time may be extended to a maximum of 8 hours. All participants are required to undergo hospitalization from day 1 of each cycle.

For pediatric participants under 18 years of age, a weight-adjusted dose will be used (see Table 8). For participants aged 18 to 30 years, glimetuzumab will be administered at a weight-independent dose: starting at 2.5 mg on day 8 of cycle 1, increasing to 10 mg on day 15 of cycle 1, and then increasing to 30 mg on day 1 of cycles 2 and 3.

Gfinitusumab full-dose administration occurs on day 1 of cycle 2 and cycle 3 (with a maximum delay of 7 days) and does not begin until the absolute neutrophil count (ANC) is >1.00× ^10⁹ /L and the platelet count is >75× ^10⁹ /L.

Rituximab

Rituximab was administered to all participants at a dose of 375 mg/ ^m² on day 5 of cycles 2 and 3. Prophylactic administration of acetaminophen and diphenhydramine was recommended. In the treatment of pediatric B-NHL, instead of the established double-dose rituximab administered on days 1 and 3 of each R-ICE cycle, rituximab was administered only on day 5 of cycles 2 and 3 to prevent CD20 receptor overload by the three anti-CD20 antibodies, which could potentially reduce the efficacy of glimetuzumab.

Use acetaminophen and diphenhydramine as a prophylactic medication. If there is evidence of hepatitis B reactivation, postpone rituximab administration.

First bet:

– The infusion rate for the first hour should be 0.5 mg/kg/h, with a maximum rate of 50 mg/h for the first hour. If no infusion-related events are observed, the infusion rate may be increased in increments of 0.5 mg/kg/h (maximum increase of 50 mg/h). The rate may be increased every 30 minutes until the maximum infusion rate of 400 mg/h is reached.

– If any hypersensitivity reaction or other infusion-related symptoms occur, the infusion should be stopped. Additional diphenhydramine or other medications may be necessary to treat the event. Once the participant has improved and pulmonary infiltration and TLS have been ruled out by clinical and/or laboratory means as indicated clinically, the infusion may be restarted at 50% of the rate at which it occurred.

Subsequent bets:

– If symptoms occur during the first infusion, follow the “First Infusion” guidelines for subsequent infusions. If no symptoms occur, begin subsequent infusions at 1 mg/kg/h, with a maximum rate of 50 mg/h for the first hour. The rate can be increased by 1 mg/kg/h every 30 minutes (maximum increase of 50 mg/h) until a maximum infusion rate of 400 mg/h is reached.

As with the initial infusion, if any infusion-related events are observed, the infusion should be stopped. Once symptoms improve, the infusion can be restarted at half the previous rate.

Hypersensitivity to rituximab:

If a hypersensitivity reaction occurs to rituximab, additional doses of acetaminophen and diphenhydramine may be administered. Steroid therapy may be considered for the reaction, along with a prophylactic dose before subsequent administration. Due to the possibility of transient hypotension, antihypertensive medications should be withheld for 12 hours prior to rituximab administration.

Ifosfamide, carboplatin, and etoposide (ICE)

ICE chemotherapy consists of ifosfamide, carboplatin, and etoposide. Notably, during cycle 1, ICE (omitting rituximab) is administered between pre-treatment with olibutuzumab and the initial dose escalation of glimepiride as initial tumor-reducing therapy and an additional CRS response strategy. ICE administration begins on day 3 of cycle 1 and continues for two or three 21-day cycles, as described below:

●Ifosfamide

For participants under 18 years of age: 3 g/ ^m² /day, administered intravenously over 2 hours daily on days 3, 4, and 5 of cycle 1, and on days 6, 7, and 8 of cycles 2 and 3. See Table 10.

For participants ≥18 years of age: 5 g/ ^m² , administered via continuous IV infusion over 24 hours, starting on day 3 of cycle 1 and day 6 of cycles 2 and 3 (including mesna). Participants with a creatinine clearance (CrCl) <60 ml/min should have their dose reduced to 80% of the planned dose (or reduced according to institutional standards). See Table 11.

●Carboplatin

Participants <18 years of age: 635 mg/ ^m² (no maximum dose), administered intravenously over 1 hour on day 3 of cycle 1 and day 6 of cycles 2 and 3. See Table 10.

For participants aged ≥18 years: 5 mg/mL/min × (25 + CrCl), IV infusion on day 3 of cycle 1 and day 6 of cycles 2 and 3 (maximum 750 mg).

See Table 11.

● Etoposide

For participants under 18 years of age: 100 mg/ ^m² /day, administered intravenously over 1 hour on days 3, 4, and 5 of cycle 1, and on days 6, 7, and 8 of cycles 2 and 3. See Table 10.

For participants ≥18 years of age: 100 mg/ ^m² /day, administered IV over 1 hour on days 3, 4, and 5 of cycle 1, and on days 6, 7, and 8 of cycles 2 and 3. Participants with CrCl at a rate <50 mL/min should have their dose reduced to 75% of the planned dose (or reduced according to institutional standards). See Table 11.

Etoposide phosphate can replace the same dose of etoposide.

R-ICE chemoimmunotherapy (consisting of rituximab, ifosfamide, carboplatin, and etoposide) is administered at the doses specified in Tables 10 and 11 below. Mesna (sodium 2-mercaptoethanesulfonate) is administered as supportive therapy to reduce the risk of hemorrhagic cystitis known to be associated with ifosfamide.

Table 10. Dosage and schedule of R-ICE treatment regimen for participants <18 years of age

IV = Intravenous

Table 11. Dosage and schedule of R-ICE treatment regimen for participants aged ≥18 years

CrCl = Creatinine clearance rate; IV = intravenous, PO = oral; oral.

^CrCl should be calculated in mL/min using the Cockcroft-Gault equation:

– Male: CrCl (mL/min) = ([140 – age] × [weight (kg)]) / (72 × serum creatinine [mg/dL])

–For women: CrCl (mL/min) = 0.85 × CrCl (for men)

Weight adjustment is permitted for overweight/obese participants (BMI ≥ 25) or participants with abnormally low creatinine levels, according to institutional standards.

During the second and third dosing cycles, there should be at least a 4-day interval between the administration of glimetuzumab and the initiation of R-ICE. R-ICE should be administered on day 5 of the second and third dosing cycles, and no later than 34 days after the initiation of the previous R-ICE regimen, except for treatment delays due to infection, after consultation with a medical monitor.

Mesna

Administer mesna as described in Tables 10 and 11. The total daily dose of mesna is equal to 100% of the daily dose of ifosfamide. For patients under 18 years of age, oral mesna is not recommended as a substitute for IV formulations. In cases of microscopic or gross hematuria, the mesna dose should be administered via continuous 24-hour infusion.

Tocilizumab

Tocilizumab is administered as an investigational rescue drug (IMP) to participants experiencing cytokine release syndrome when necessary. Tocilizumab is administered intravenously at a dose of 8 mg/kg to participants ≥30 kg and at a dose of 12 mg/kg to participants <30 kg. If necessary, it may be repeated every 8 hours (up to four doses), with each dose not exceeding 800 mg.

Intrathecal (IT) chemotherapy

All intrathecal chemotherapy should be administered at least 24 hours before or 48 hours after any olibutuzumab or gifertuzumab infusion.

Participants with CNS disease (of any histological nature) received IT therapy on days 3, 10, and 17 of cycle 1, and on days 5, 12, and 19 of cycles 2 and 3. Participants with large B-cell lymphoma and a negative CNS presentation received IT therapy only on day 3 of cycle 1. Participants with Burkitt lymphoma (BL) and a negative CNS presentation received IT therapy on day 3 of cycle 1 and on day 5 of cycles 2 and 3. If a participant was given IT therapy during screening, the day 3 IT therapy in cycle 1 could be omitted.

IT therapy using methotrexate, cytarabine, and cortisol will be administered in age-dependent doses (see Table 12). According to local guidelines, IT cortisol can be replaced with an equivalent dose of another IT steroid (e.g., prednisolone).

Table 12. Dosage of methotrexate, cytarabine, and cortisol

Age (years) Methotrexate Cytarabine Hydrocortisone 0 to <1 8 mg 15mg 8mg 1 to <3 10mg 20mg 10mg 3 to <9 12mg 25mg 12mg ≥9 15mg 30mg 15mg

Additional medication

Because some participants may experience hypersensitivity or other IRRs to olibutuzumab or glimetuzumab, oral or IV acetaminophen (500 mg to 1000 mg) and prophylactic antihistamines such as diphenhydramine (10 to 20 mg single IV dose [for children ≥2 years of age, the maximum single IV dose is 1.25 mg/kg; for children <2 years of age, 20 mg is administered rectally]) must be administered at least 30 minutes before the start of each study drug infusion (unless contraindicated). The use of corticosteroids (0.15 mg/kg to 0.5 mg/kg dexamethasone IV [maximum daily dose 10 mg] or a single IV dose of methylprednisolone 1 mg/kg to 2 mg/kg, or an equivalent of prednisone (100 mg or about 2 mg/kg IV) or prednisolone (100 mg or about 2 mg/kg IV)) should be administered at least 60 minutes before olibutuzumab and glimetuzumab administration. For participants who have tolerated the escalating dose and two full doses of glimepiride without experiencing any grade of CRS, a corticosteroid prophylaxis in subsequent cycles will be optional, based on investigator assessment. However, if a participant experiences CRS, a steroid prophylaxis will be administered in subsequent cycles until no further CRS events are observed.

Changing this corticosteroid regimen requires medical evidence and can be implemented after consulting a medical supervisor. Corticosteroids should not be used as a prophylactic medication. See Table 13 for details.

All doses of olibutuzumab and glimetuzumab were administered to well-hydrated participants.

Table 13. Overview of pretreatment with olibutuzumab and prophylactic medications before glimetuzumab infusion

CrCl = Creatinine clearance rate; CRS = Cytokine release syndrome; IV = Intravenous; TLS = Tumor lysis syndrome.

^0.15-0.5 mg/kg IV dexamethasone (maximum 10 mg daily) or 1-2 mg/kg/day methylprednisolone or an equivalent dose of IV prednisone (100 mg); corticosteroids should not be used as they are not effective in reducing the rate of infusion response. Note: Dexamethasone is recommended as a pretreatment with glimepiride instead of other corticosteroids.

^b . For example, a single dose of 10 mg to 20 mg of IV diphenhydramine (for children >2 years of age: maximum single dose of 1.25 mg/kg IV diphenhydramine), unless contraindicated.

^c. For participants who have tolerated two target doses of glimetuzumab without experiencing CRS, this can be optional in subsequent cycles based on investigator assessment.

Granulocyte colony-stimulating factor (G-CSF)

G-CSF administration of growth factor support is mandatory and should begin 24 to 48 hours after the completion of ICE and/or R-ICE infusion, starting on day 6 or 7 of cycle 1 and day 9 or 10 of cycles 2 and 3. G-CSF will be administered until the absolute neutrophil count (ANC) recovers, reaching a minimum of ANC >1.50 × ^10⁹ /L twice or >5.00 × ^10⁹ /L once. The dose is 5 μg/kg/day IV or subcutaneously, unless peripheral blood stem cell (PBSC) collection is planned after cycle 2 or 3, in which case the dose will be increased to 10 μg/kg/day.

Treatment administration schedule

See Figure 7 for a summary of the treatment administration schedule for patients <18 years of age. See Figure 8 for a summary of the treatment administration schedule for patients between 18 and 30 years of age.

For cycles 2 and 3, glimepiride infusion occurs on day 1 and should not be initiated until an ANC ≥ 1.00 × ^10⁹ /L and a platelet count ≥ 75 × ^10⁹ /L. Participants achieving complete remission (CR) at the end of cycle 2 will proceed to hematopoietic stem cell transplantation (HSCT), if possible. These participants may also proceed to cycle 3 to compensate for a longer-than-expected HSCT preparation time. Participants who did not achieve CR at the end of cycle 2 (i.e., those achieving stable disease (SD) or partial remission (PR)) will proceed to cycle 3. All participants receiving cycle 3 will be reassessed at the end of cycle 3. Participants experiencing disease progression after cycle 2 or 3 will withdraw from the study. Subsequent HSCT for CR patients and potential subsequent treatment options for SD and PR patients will be determined according to institutional standards. Autologous stem cell harvesting will be considered during cycle 2 or 3 in the event of a planned autologous HSCT, following local guidelines.

Infection prevention

According to local/institutional guidelines, all participants are required to undergo anti-Pneumocystis pneumonia prophylaxis.

Participants with neutropenia require antifungal and antibacterial prophylaxis. Ciprofloxacin or other appropriate antibiotics are recommended for prophylaxis in participants with neutropenia and should be administered according to local/institutional guidelines until neutrophil counts recover or until treatment with IV antibiotics is initiated (whichever comes first).

Fungal prophylaxis is recommended for participants with neutropenia and should be administered according to institutional/local guidelines until neutrophil counts recover or therapeutic antifungal therapy is initiated. Fluconazole and echinocandins (e.g., caspofungin, micafungin) are permitted. Strong CYP3A inhibitors, including voriconazole and posaconazole, are permitted as prophylaxis.

Duration of participation

The total duration of each individual's participation in the study includes a maximum of approximately 9 weeks of treatment (up to three cycles), followed by a follow-up assessment at least 1 year after the end of treatment.

research group

This study included approximately 40 to 45 participants aged <18 years with first-time R/R mature B-NHL and up to 10 young adult participants aged 18 to 30 years to investigate the combination of glimetuzumab with R-ICE chemoimmunotherapy, and was to be conducted in pediatric and young adult participants with first-time R/R mature B-NHL.

Inclusion criteria:

● The age at which informed consent for Part 1 of the study was signed was 6 months to <18 years, and the age at which informed consent for Part 2 of the study was 6 months to ≤30 years.

● In cases of first-time R/R (relapsed and/or refractory) disease, the diagnosis of aggressive mature B-NHL (B-cell non-Hodgkin's lymphoma) expressing CD20 was reconfirmed histologically prior to enrollment in the study (reconfirmed by immunohistochemistry (IHC), including BL (Burkitt lymphoma), BAL (mature B-cell leukemia FAB L3 or Burkitt leukemia), DLBCL (diffuse large B-cell lymphoma), and PMBCL (primary medial large B-cell lymphoma).

● Refractory or relapsed disease following first-line standard chemoimmunotherapy

●Measurable diseases, defined as

○ At least one two-dimensional measurable nodular lesion (defined as the longest dimension > 1.5 cm) or at least one two-dimensional measurable extranodular lesion (defined as the longest dimension > 1.0 cm); or

○ Percentage of lymphoma cells involved in bone marrow as defined by cellular morphology analysis of bone marrow aspirates

● Appropriate physical condition as assessed by the Lansky or Karnofsky Performance Status Scale:

o Participants under 16 years of age: Lansky fitness level ≥50% (Lansky et al., Cancer. 60(7):1651-1656, 1987)

Participants aged ≥16 years: Karnofsky fitness level ≥50% (Karnofsky et al.)

Cancer. 1(4):634-656, 1948)

● Achieve adequate bone marrow function as defined by the following laboratory results within 7 days prior to starting the study drug:

○ Hemoglobin ≥ 8 g/dL (blood transfusion permitted)

○ Peripheral absolute neutrophil count (ANC) ≥ 0.75 × ^10⁹ /L and no granulocyte colony-stimulating factor (G-CSF) support for at least 24 hours.

○ Platelet count ≥75× ^10⁹ /L

Part 1 participants may be enrolled if their ANC is ≥0.5 × ^10⁹ /L and they have NHL with extensive bone marrow involvement and/or disease-related cytopenia (e.g., immune thrombocytopenic purpura). There is no minimum ANC requirement for Part 2 participants.

●Platelets: It is unknown whether platelet transfusion is refractory.

●Sufficient liver function:

o ALT (alanine aminotransferase) or AST (aspartate aminotransferase) ≤3 times the upper limit of normal (ULN) (or ≤5 times ULN for participants with concurrent liver infiltration or TLS)

○ Bilirubin ≤1.5 times the age-appropriate ULN (or ≤2.5 times the ULN for participants with concurrent liver infiltration)

■ Participants with a documented history of Gilbert's syndrome and elevated total bilirubin along with elevated indirect bilirubin are eligible.

○ International Normalized Ratio (INR) ≤ 1.5 times the corresponding age of ULN

○ Prothrombin time (PTT) or activated partial thromboplastin time (aPTT)

≤1.5 times the corresponding age ULN

●Adequate renal function: serum creatinine ≤1.5 times ULN; or, as determined by the investigator, for participants whose serum creatinine level does not adequately reflect renal function, creatinine clearance (CrCl) ≥50 mL/min (for participants ≥18 years of age, calculated according to the Cockcroft-Gault formula (Cockcroft and Gault, Nephron. 16(1):31-41, 1976); or for participants <18 years of age, calculated according to the Schwartz formula (Mian and Schwartz, Adv. Chronic Kidney Dis. 24(6):348-356), 2017).

● Negative serological or polymerase chain reaction (PCR) test results for acute or chronic hepatitis B virus (HBV) infection. Note: Participants whose HBV infection status cannot be determined by serological testing must have a negative HBV PCR result to be eligible for study participation.

● Negative Hepatitis C Virus (HCV) test result. Participants who are HCV antibody positive must be confirmed as HCV negative by PCR to meet the criteria for participating in the study.

● Negative HIV test result. Individuals who tested HIV positive at screening are eligible if they meet the following criteria: they are stable on antiretroviral therapy, have a CD4 count ≥200/μL, and have undetectable viral load.

Exclusion criteria (participants are excluded if they meet any of the following criteria):

● Isolated CNS diseases of mature B-NHL without systemic involvement and primary CNS lymphoma

● Received glimetuzumab prior to study enrollment.

●Persistent adverse events from previous anticancer therapies have not resolved to grade ≤1. Exceptions: alopecia and grade 2 peripheral neuropathy.

● Grade 3 or higher adverse events, excluding grade 3 endocrine disorders treated with replacement therapy.

●Previous solid organ transplant

●A known or suspected history of hemophagocytic lymphohistiocytosis (HLH)

● Known or suspected chronic active EBV infection. CAEBV is defined as a chronic condition lasting at least 3 months with elevated EBV levels in tissues or blood and a lack of evidence of a known underlying immunodeficiency (Kimura and Cohen, Front. Immunol. 8:1867 2017). Participants with EBV+ lymphoma should not be excluded if no other evidence or medical history suggests CAEBV.

● Active autoimmune diseases requiring treatment

○ Participants with a history of autoimmune-related hypothyroidism requiring stable doses of thyroid replacement hormone are eligible.

○ Participants with type 1 diabetes who are receiving an insulin regimen are eligible for this study.

Participants with a history of autoimmune hepatitis, systemic lupus erythematosus, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, multiple sclerosis, or glomerulonephritis will be excluded.

Participants with a history of immune thrombocytopenic purpura, autoimmune hemolytic anemia, Guillain-Barré syndrome, myasthenia gravis, myositis, rheumatoid arthritis, vasculitis, or other autoimmune diseases will be excluded unless they have not required systemic therapy in the past 12 months.

○ Participants with eczema, psoriasis, chronic simple lichen simplex, or vitiligo with only skin manifestations (e.g., excluding participants with psoriatic arthritis) are eligible for this study if they meet all of the following criteria:

■ The rash must cover less than 10% of the body surface area.

■ The disease is well controlled at baseline and only requires the use of ineffective topical corticosteroids.

■ No acute exacerbations of underlying diseases requiring psoralen plus UVA radiation, methotrexate, retinoids, biologics, oral calcineurin inhibitors or high-potency drugs or oral corticosteroids have occurred in the past 12 months.

● A history of severe allergy or anaphylactic reaction to monoclonal antibody therapy (or recombinant antibody-associated fusion protein), or known sensitivity or allergy to rodent products, unless the participant is able to safely tolerate the investigational drug after the first administration (consider consulting a medical monitor).

● Medical history of diagnosis of progressive multifocal leukoencephalopathy

● Current or past history of uncontrolled non-malignant CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease. Note: Participants with a history of stroke are allowed, provided they have not experienced a stroke or transient ischemic attack within the past 2 years and do not have residual neurological deficits in the investigator's judgment.

● Evidence of significant and uncontrolled comorbidities that could potentially affect protocol adherence or outcome interpretation.

● Underwent major surgery or had significant traumatic injury (excluding biopsy) within 28 days prior to olibutuzumab pretreatment infusion, or is expected to require major surgery during study treatment.

● Administer the attenuated vaccine within 4 weeks prior to the start of study treatment (olibutuzumab pretreatment), at any time during study treatment, or within 12 months after the end of study treatment.

● Participants with any other illness or symptom that reasonably raises suspicion of contraindication to the investigational drug, metabolic disorders, physical examination findings, or clinical laboratory findings.

●Pregnant or breastfeeding, or planning to become pregnant during the study. Female participants of childbearing age must have a negative serum pregnancy test result within 7 days prior to the start of study treatment.

● Receive any R-ICE chemoimmunotherapy prior to study enrollment. Systemic steroid therapy and intrathecal (IT) chemotherapy are permitted up to 14 days prior to the start of study treatment to control high tumor burden or CNS disease.

● Received more than one prior standard of care line of B-NHL chemoimmunotherapy

●Previous allogeneic or autologous SCT

Study endpoints

The final analysis will be based on participant data collected up to the end of the study. All analyses will be based on a population with assessable safety. All summaries will be presented according to the specified dose levels.

Primary endpoint

The primary efficacy endpoint is the investigator-assessed complete remission (CR) rate, defined as the proportion of participants in cohort A (both pediatric and young adult groups) whose best overall response is CR after a maximum of three treatment cycles. CR will be based on investigator assessments of PET/CT/MRI scans using the International Pediatric NHL Remission Criteria for pediatric participants <18 years of age and the Lugano Criteria for young adult participants ≥18 years of age and <30 years of age. This analysis will be based on the population for which efficacy is evaluable. Participants lacking or without a remission assessment will be classified as non-responders.

Secondary endpoint

ORR, defined as the proportion of participants with the best overall response of PR or CR, was assessed using the International Pediatric NHL Response Criteria for pediatric participants aged <18 years (Sandlund JT, Guillerman RP, Perkins SL et al. International pediatric non-Hodgkin lymphoma response criteria. J. Clin. Oncol. 33:2106-2111, 2015) and the Lugano Classification for younger adult participants aged ≥18 years and <30 years (Lugano Classification, Cheson et al. J Clin. Oncol. Sep 20; 32(27):3059–3067, 2014). ORR was assessed by investigators using PET-CT/-MRI scans after up to three treatment cycles.

Duration of complete remission (DOCR) is defined as the time from the first recorded occurrence of CR to the first recorded disease progression or death from any cause (whichever occurs first). DOCR is assessed by investigators using the International Pediatric NHL Remission Criteria for pediatric participants <18 years of age and the Lugano Classification for younger adult participants ≥18 years of age and <30 years of age.

Progression-free survival (PFS) is defined as the time from the first treatment of the study to the first occurrence of disease progression or death from any cause (whichever comes first). PFS is assessed by investigators using the International Pediatric NHL Remission Criteria for pediatric participants aged <18 years and the Lugano Classification for younger adult participants aged ≥18 years and <30 years.

Event-free survival (EFS) is defined as the time from the first treatment of the study to the first occurrence of disease progression, death from any cause, or initiation of a new anti-lymphoma therapy (excluding planned HSCT), whichever occurs first. EFS is assessed by the investigator using the International Pediatric NHL Remission Criteria for pediatric participants aged <18 years and the Lugano Classification for younger adult participants aged ≥18 years and <30 years.

OS is defined as the time from the first research treatment to the date of death from any cause.

The percentage of patients who undergo HSCT after a maximum of three treatment cycles.

First result

The first patient was treated in the study described in this article. A 14-year-old boy with first-time relapse of Burkitt lymphoma achieved complete remission after two cycles of chemoimmunotherapy with glimetuzumab and R-ICE and will undergo stem cell transplantation.

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Other embodiments

Although the invention has been described in considerable detail above by way of example and illustration for the purpose of clarity, such description and examples should not be construed as limiting the scope of the invention. All disclosures of patents and scientific literature cited herein are expressly incorporated herein by reference in their entirety.

Claims (94)

1. A method of treating a subject with a CD20-positive proliferative disorder, the method comprising administering an effective amount of the drug to the subject in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle: (a) Bispecific antibodies that bind to CD20 and CD3; (b) Anti-CD20 antibody; and (c) One or more chemotherapeutic agents selected from ifosfamide, carboplatin and/or etoposide. 2. The method according to claim 1, wherein The first dosing cycle includes a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody, wherein the C1D1 of the bispecific antibody is approximately 2.5 mg and the C1D2 of the bispecific antibody is approximately 10 mg; and The second dosing cycle includes a single dose (C2D1) of the bispecific antibody, wherein the C2D1 of the bispecific antibody is about 10 mg, about 16 mg, or about 30 mg. 3. The method of claim 2, wherein the C1D1 and the C1D2 of the bispecific antibody are administered to the subject on day 8 and day 15 of the first dosing cycle, respectively. 4. The method according to claim 2 or 3, wherein the C2D1 of the bispecific antibody is administered to the subject on day 8 of the second dosing cycle. 5. The method according to any one of claims 1 to 4, wherein the anti-CD20 antibody is olibutuzumab and/or rituximab. 6. The method of claim 5, wherein the first dosing cycle comprises a single dose of olibutuzumab (C1D1); and the second dosing cycle comprises a single dose of rituximab (C2D1). 7. The method of claim 6, wherein the C1D1 of olibutuzumab is about 1000 mg and the C2D1 of rituximab is about 375 mg/ ^m² . 8. The method of claim 6 or 7, wherein the anti-CD20 antibody is administered in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein the first dosing cycle comprises administering the C1D1 of olibutuzumab to the subject on day 1; and the second dosing cycle comprises administering the C2D1 of rituximab to the subject on day 1. 9. The method according to any one of claims 1 to 8, wherein the method comprises administering ifosfamide, carboplatin and etoposide to the subject. 10. The method of claim 9, wherein the first dosing cycle comprises a single dose of ifosfamide (C1D1); a single dose of carboplatin (C1D1); and a first dose of etoposide (C1D1), a second dose of etoposide (C1D2), and a third dose of etoposide (C1D3); and the second cycle comprises a single dose of ifosfamide (C2D1); a single dose of carboplatin (C2D1); and a first dose of etoposide (C2D1), a second dose of etoposide (C2D2), and a third dose of etoposide (C2D3). 11. The method of claim 10, wherein ifosfamide is administered at a dose of about 5000 mg/ ^m² , about 4000 mg/ ^m² , or about 1666 mg/ ^m² , carboplatin is administered at a dose of about 750 mg maximum dose with a target area under the curve (AUC) of about 5 mg/mL/min, and etoposide is administered at a dose of about 100 mg/ ^m² or about 75 mg/ ^m² for each dose of etoposide. 12. The method according to claim 10 or 11, wherein ifosfamide and carboplatin are administered on day 2 of the first and second administration cycles, and the C1D1 to C1D3 and C2D1 to C2D3 of etoposide are administered on days 1, 2 and 3 of the first and second administration cycles, respectively. 13. The method according to any one of claims 1 to 12, wherein the first administration cycle and the second administration cycle are each a 21-day administration cycle. 14. The method according to any one of claims 1 to 13, wherein the dosing regimen includes one or more additional dosing cycles. 15. The method of claim 14, wherein each of the one or more additional dosing cycles is a 21-day dosing cycle. 16. The method of claim 14 or 15, wherein the dosing regimen comprises a total of three dosing cycles. 17. The method according to any one of claims 14 to 16, wherein each of the one or more additional dosing cycles comprises: (a) An additional single dose of the bispecific antibody that binds to CD20 and CD3. (b) An additional single dose of the anti-CD20 antibody, and (c) Additional single doses of ifosfamide, additional single doses of carboplatin, and additional first, second, and third doses of etoposide. 18. The method of claim 17, wherein the additional single dose of the bispecific antibody is about 30 mg. 19. The method of claim 17 or 18, wherein the additional single dose of the bispecific antibody is administered to the subject on day 8 of each of the one or more additional dosing cycles. 20. The method according to any one of claims 17 to 19, wherein the anti-CD20 antibody is rituximab. 21. The method of claim 20, wherein the additional single dose of rituximab is about 375 mg/ ^m² . 22. The method of claim 20 or 21, wherein the additional single dose of rituximab is administered on day 1 of each of the one or more additional dosing cycles. 23. The method according to any one of claims 17 to 22, wherein the additional single dose of ifosfamide is about 5000 mg/ ^m² , about 4000 mg/ ^m² , or about 1666 mg/ ^m² , the additional single dose of carboplatin is a maximum dose of about 750 mg of the target area under the curve (AUC) of about 5 mg/mL/min, and the additional first dose, the additional second dose, and the additional third dose of etoposide are each about 100 mg/ ^m² or about 75 mg/ ^m² . 24. The method according to any one of claims 17 to 23, wherein ifosfamide and carboplatin are administered on day 2 of each of the one or more additional dosing cycles, and the additional first dose, the additional second dose, and the additional third dose of etoposide are administered on day 1, day 2, and day 3 of each of the one or more additional dosing cycles, respectively. 25. A method of treating a subject aged 6 months to 17 years with a CD20-positive proliferative disorder, the method comprising administering an effective amount to the subject in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle: (a) Bispecific antibodies that bind to CD20 and CD3; (b) Anti-CD20 antibody; and (c) One or more chemotherapeutic agents selected from ifosfamide, carboplatin and/or etoposide. 26. The method of claim 25, wherein The first dosing cycle includes a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody, wherein the C1D1 of the bispecific antibody is about 0.03 mg/kg, about 0.04 mg/kg, or about 2.5 mg, and the C1D2 of the bispecific antibody is about 0.15 mg/kg or about 10 mg; and The second dosing cycle includes a single dose (C2D1) of the bispecific antibody, wherein the C2D1 of the bispecific antibody is about 0.4 mg/kg, about 0.5 mg/kg, or about 30 mg. 27. The method according to claim 26, wherein: (a) The subject's weight is greater than or equal to about 7.5 kg and less than about 13 kg, and the C1D1 of the bispecific antibody is about 0.04 mg/kg, the C1D2 of the bispecific antibody is about 0.15 mg/kg, and the C2D1 of the bispecific antibody is about 0.5 mg/kg; (b) The subject's weight is greater than or equal to about 13 kg and less than about 45 kg, and the C1D1 of the bispecific antibody is about 0.03 mg/kg, the C1D2 of the bispecific antibody is about 0.15 mg/kg, and the C2D1 of the bispecific antibody is about 0.4 mg/kg; or (c) The subject's weight is greater than or equal to about 45 kg, and the C1D1 of the bispecific antibody is about 2.5 mg, the C1D2 of the bispecific antibody is about 10 mg, and the C2D1 of the bispecific antibody is about 30 mg. 28. The method of claim 26 or 27, wherein the C1D1 and the C1D2 of the bispecific antibody are administered to the subject on day 8 and day 15 of the first dosing cycle, respectively. 29. The method according to any one of claims 26 to 28, wherein the C2D1 of the bispecific antibody is administered to the subject on day 1 of the second dosing cycle. 30. The method according to any one of claims 25 to 29, wherein the anti-CD20 antibody is olibutuzumab and/or rituximab. 31. The method of claim 30, wherein the first dosing cycle comprises a first dose (C1D1) of olibutuzumab and a second dose (C1D2) of olibutuzumab. 32. The method according to claim 31, wherein: (a) The subject's weight is greater than or equal to about 7.5 kg and less than about 13 kg, and the sum of the C1D1 and the C1D2 of olibutuzumab is about 38 mg/kg; (b) The subject's weight is greater than or equal to about 13 kg and less than about 20 kg, and the sum of the C1D1 and the C1D2 of olibutuzumab is about 28 mg/kg; (c) The subject's weight is greater than or equal to about 20 kg and less than about 32 kg, and the sum of the C1D1 and the C1D2 of olibutuzumab is about 23 mg/kg; (d) The subject's weight is greater than or equal to about 32 kg and less than about 45 kg, and the sum of the C1D1 and C1D2 of olibutuzumab is about 20 mg/kg; or (e) The subject weighs more than or equal to about 45 kg, and the sum of the C1D1 and C1D2 of olibutuzumab is about 1000 mg. 33. The method according to claim 31 or 32, wherein the C1D1 of olibutuzumab is about one-tenth of the sum of the C1D1 and the C1D2 of olibutuzumab, and the C1D2 of olibutuzumab is about nine-tenths of the sum of the C1D1 and the C1D2 of olibutuzumab. 34. The method according to any one of claims 31 to 33, wherein the subject is given the C1D1 of oxetuzumab on day 1 of the first dosing cycle, and the subject is given the C1D2 of oxetuzumab on day 2 of the first dosing cycle. 35. The method of claim 34, wherein the second dosing cycle comprises a single dose of rituximab (C2D1). 36. The method of claim 35, wherein the C2D1 of rituximab is about 375 mg/ ^m² . 37. The method of claim 35 or 36, wherein rituximab is administered to the subject on day 5 of the second dosing cycle. 38. The method according to any one of claims 25 to 37, wherein the method comprises administering ifosfamide, carboplatin, and etoposide to the subject. 39. The method of claim 38, wherein the first dosing cycle comprises: (a) The first dose of ifosfamide (C1D1), the second dose of ifosfamide (C1D2), and the third dose of ifosfamide (C1D3); (b) A single dose of carboplatin (C1D1); and (c) The first dose of etoposide (C1D1), the second dose of etoposide (C1D2), and the third dose of etoposide (C1D3); And the second cycle includes: (a) The first dose of ifosfamide (C2D1), the second dose of ifosfamide (C2D2), and the third dose of ifosfamide (C2D3); (b) A single dose of carboplatin (C2D1); and (c) The first dose of etoposide (C2D1), the second dose of etoposide (C2D2), and the third dose of etoposide (C2D3). 40. The method of claim 39, wherein ifosfamide is administered at a dose of about 3000 mg/ ^m² for each dose of ifosfamide, carboplatin is administered at a dose of about 635 mg/ ^m² , and etoposide is administered at a dose of about 100 mg/ ^m² for each dose of etoposide. 41. The method according to claim 39 or 40, wherein: (a) The C1D1, C1D2 and C1D3 of ifosfamide were administered on days 3, 4 and 5 of the first dosing cycle, respectively; (b) Administer the C1D1 of carboplatin on day 3 of the first dosing cycle; (c) Etoposide C1D1, C1D2 and C1D3 were administered on days 3, 4 and 5 of the first dosing cycle, respectively; (d) The C2D1, C2D2 and C2D3 of ifosfamide were administered on days 6, 7 and 8 of the second dosing cycle, respectively; (e) Administer the C2D1 of carboplatin on day 6 of the second dosing cycle; and (f) Etoposide C2D1, C2D2 and C2D3 were administered on days 6, 7 and 8 of the second dosing cycle, respectively. 42. The method according to any one of claims 25 to 41, wherein the first administration cycle and the second administration cycle are each a 21-day administration cycle. 43. The method according to any one of claims 25 to 42, wherein the dosing regimen includes one or more additional dosing cycles. 44. The method of claim 43, wherein each of the one or more additional dosing cycles is a 21-day dosing cycle. 45. The method of claim 43 or 44, wherein the dosing regimen comprises a total of three dosing cycles. 46. The method according to any one of claims 43 to 45, wherein each of the one or more additional dosing cycles comprises: (a) An additional single dose of the bispecific antibody that binds to CD20 and CD3. (b) An additional single dose of the anti-CD20 antibody, and (c) Additional first, second and third doses of ifosfamide; additional single dose of carboplatin; and additional first, second and third doses of etoposide. 47. The method of claim 46, wherein: (a) The subject's weight is greater than or equal to about 7.5 kg and less than about 13 kg, and the additional single dose of the bispecific antibody is about 0.5 mg/kg; (b) The subject's weight is greater than or equal to about 13 kg and less than about 45 kg, and the additional single dose of the bispecific antibody is about 0.4 mg/kg; or (c) The subject weighs more than or equal to about 45 kg, and the additional single dose of the bispecific antibody is about 30 mg. 48. The method of claim 46 or 47, wherein the additional single dose of the bispecific antibody is administered to the subject on day 1 of each of the one or more additional dosing cycles. 49. The method according to any one of claims 46 to 48, wherein the anti-CD20 antibody is rituximab. 50. The method of claim 49, wherein the additional single dose of rituximab is about 375 mg/ ^m² . 51. The method of claim 49 or 50, wherein the additional single dose of rituximab is administered on day 5 of each of the one or more additional dosing cycles. 52. The method according to any one of claims 43 to 51, wherein the additional first dose, the additional second dose, and the additional third dose of ifosfamide are each about 3000 mg/ ^m² , the additional single dose of carboplatin is about 635 mg/ ^m² , and the additional first dose, the additional second dose, and the additional third dose of etoposide are each about 100 mg/ ^m² . 53. The method according to any one of claims 43 to 52, wherein: (a) The subject is given the additional first dose, the additional second dose, and the additional third dose of ifosfamide on days 6, 7, and 8 of each of the one or more additional dosing cycles; (b) Administer the additional single dose of carboplatin on day 6 of each of the one or more additional dosing cycles; and (c) The subject is given the additional first dose, the additional second dose, and the additional third dose of etoposide on days 6, 7, and 8 of each of the one or more additional dosing cycles. 54. A method for treating a subject aged 18 to 30 years with a CD20-positive proliferative disorder, the method comprising administering an effective amount to the subject in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle: (a) Bispecific antibodies that bind to CD20 and CD3; (b) Anti-CD20 antibody; and (c) One or more chemotherapeutic agents selected from ifosfamide, carboplatin and/or etoposide. 55. The method of claim 54, wherein The first dosing cycle includes a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody, wherein the C1D1 of the bispecific antibody is approximately 2.5 mg and the C1D2 of the bispecific antibody is approximately 10 mg; and The second dosing cycle includes a single dose (C2D1) of the bispecific antibody, wherein the C2D1 of the bispecific antibody is approximately 30 mg. 56. The method of claim 55, wherein the C1D1 and the C1D2 of the bispecific antibody are administered to the subject on day 8 and day 15 of the first dosing cycle, respectively. 57. The method of claim 55 or 56, wherein the C2D1 of the bispecific antibody is administered to the subject on day 1 of the second dosing cycle. 58. The method according to any one of claims 54 to 57, wherein the anti-CD20 antibody is olibutuzumab and/or rituximab. 59. The method of claim 58, wherein the first dosing cycle comprises a first dose (C1D1) of olibutuzumab and a second dose (C1D2) of olibutuzumab. 60. The method of claim 59, wherein the sum of the C1D1 and the C1D2 of olibutuzumab is about 1000 mg. 61. The method according to claim 59 or 60, wherein the C1D1 of olibutuzumab is about one-tenth the sum of the C1D1 and C1D2 of olibutuzumab, and the C1D2 of olibutuzumab is about nine-tenths the sum of the C1D1 and C1D2 of olibutuzumab. 62. The method according to any one of claims 59 to 61, wherein the C1D1 of olibutuzumab is about 100 mg and the C1D2 of olibutuzumab is about 900 mg. 63. The method according to any one of claims 59 to 62, wherein the subject is given the C1D1 of oxetuzumab on day 1 of the first dosing cycle, and the subject is given the C1D2 of oxetuzumab on day 2 of the first dosing cycle. 64. The method of claim 58, wherein the second dosing cycle comprises a single dose of rituximab (C2D1). 65. The method of claim 64, wherein the C2D1 of rituximab is about 375 mg/ ^m² . 66. The method of claim 64 or 65, wherein the C2D1 of rituximab is administered to the subject on day 5 of the second dosing cycle. 67. The method according to any one of claims 54 to 66, wherein the method comprises administering ifosfamide, carboplatin, and etoposide to the subject. 68. The method of claim 67, wherein the first dosing cycle comprises: (a) A single dose of ifosfamide (C1D1); (b) A single dose of carboplatin (C1D1); and (c) The first dose of etoposide (C1D1), the second dose of etoposide (C1D2), and the third dose of etoposide (C1D3); And the second cycle includes: (a) A single dose of ifosfamide (C2D1); (b) A single dose of carboplatin (C2D1); and (c) The first dose of etoposide (C2D1), the second dose of etoposide (C2D2), and the third dose of etoposide (C2D3). 69. The method of claim 68, wherein ifosfamide is administered at a dose of about 5000 mg/ ^m² , carboplatin is administered at a maximum dose of about 750 mg of about 5 × (25 + creatinine clearance (CrCl)) mg, and etoposide is administered at a dose of about 100 mg/ ^m² for each dose of etoposide. 70. The method according to claim 68 or 69, wherein: (a) Administering the C1D1 of ifosfamide on day 3 of the first dosing cycle; (b) Administer the C1D1 of carboplatin on day 3 of the first dosing cycle; (c) Etoposide C1D1, C1D2 and C1D3 were administered on days 3, 4 and 5 of the first dosing cycle, respectively; (d) Administer the C2D1 of ifosfamide on day 6 of the second dosing cycle; (e) Administer the C2D1 of carboplatin on day 6 of the second dosing cycle; and (f) Etoposide C2D1, C2D2 and C2D3 were administered on days 6, 7 and 8 of the second dosing cycle, respectively. 71. The method according to any one of claims 54 to 70, wherein the first administration cycle and the second administration cycle are each a 21-day administration cycle. 72. The method according to any one of claims 54 to 71, wherein the dosing regimen includes one or more additional dosing cycles. 73. The method of claim 72, wherein each of the one or more additional dosing cycles is a 21-day dosing cycle. 74. The method of claim 72 or 73, wherein the dosing regimen comprises a total of three dosing cycles. 75. The method according to any one of claims 72 to 74, wherein each of the one or more additional dosing cycles comprises: (a) An additional single dose of the bispecific antibody that binds to CD20 and CD3. (b) An additional single dose of the anti-CD20 antibody, and (c) Additional single doses of ifosfamide; additional single doses of carboplatin; and additional first, second and third doses of etoposide. 76. The method of claim 75, wherein the additional single dose of the bispecific antibody is about 30 mg. 77. The method of claim 75 or 76, wherein the additional single dose of the bispecific antibody is administered to the subject on day 1 of each of the one or more additional dosing cycles. 78. The method according to any one of claims 75 to 77, wherein the anti-CD20 antibody is rituximab. 79. The method of claim 78, wherein the additional single dose of rituximab is about 375 mg/ ^m² . 80. The method of claim 78 or 79, wherein the additional single dose of rituximab is administered on day 5 of each of the one or more additional dosing cycles. 81. The method according to any one of claims 75 to 80, wherein the additional single dose of ifosfamide is about 5000 mg/ ^m² , and the additional single dose of carboplatin is about 5 mg/m². The maximum dose is approximately 750 mg × (25 + creatinine clearance (CrCl)) mg, and the additional first dose, the additional second dose, and the additional third dose of etoposide are each approximately 100 mg/ ^m² . 82. The method according to any one of claims 75 to 81, wherein: (a) Administer the additional single dose of ifosfamide on day 6 of each of the one or more additional dosing cycles; (b) Administer the additional single dose of carboplatin on day 6 of each of the one or more additional dosing cycles; and (c) The subject is given the additional first dose, the additional second dose, and the additional third dose of etoposide on days 6, 7, and 8 of each of the one or more additional dosing cycles. 83. The method according to any one of claims 1 to 82, wherein the bispecific antibody comprises at least one Fab molecule that specifically binds to CD20, the Fab molecule comprising: (A) The following six high-variance zones (HVR): (i)HVR-H1, which contains the amino acid sequence of YSWIN (SEQ ID NO:1); (ii) HVR-H2, which contains the amino acid sequence RIFPGDGDTDYNGKFKG (SEQ ID NO:2); (iii) HVR-H3, which contains the amino acid sequence NVFDGYWLVY (SEQ ID NO:3); (iv) HVR-L1, which contains the amino acid sequence RSSKSLLHSNGITYLY (SEQ ID NO:4); (v)HVR-L2, which contains the amino acid sequence of QMSNLVS (SEQ ID NO:5); and (vi) HVR-L3, which contains the amino acid sequence of AQNLELPYT (SEQ ID NO: 6); and/or (B)(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:7; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:8; or (c) the VH domain as in (a) and the VL domain as in (b). 84. The method according to any one of claims 1 to 83, wherein the bispecific antibody comprises at least one Fab molecule that specifically binds to CD3, the Fab molecule comprising: (A) The following six HVRs: (i)HVR-H1, which contains the amino acid sequence of TYAMN (SEQ ID NO:9); (ii) HVR-H2, which contains the amino acid sequence RIRSKYNNYATYYADSVKG (SEQ ID NO:10); (iii) HVR-H3, which contains the amino acid sequence HGNFGNSYVSWFAY (SEQ ID NO:11); (iv) HVR-L1, which contains the amino acid sequence GSSTGAVTTSNYAN (SEQ ID NO:12); (v)HVR-L2, which contains the amino acid sequence of GTNKRAP (SEQ ID NO: 13); and (vi) HVR-L3, which contains the amino acid sequence of ALWYSNLWV (SEQ ID NO:14); and/or (B)(a) A VH domain containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:15; (b) A VL domain containing an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:16; or (c) the VH domain as in (a) and the VL domain as in (b). 85. The method according to any one of claims 1 to 84, wherein the bispecific antibody is glimetuzumab. 86. The method according to any one of claims 1 to 85, wherein the CD20-positive cell proliferative disorder is a B-cell proliferative disorder. 87. The method of claim 86, wherein the B-cell proliferative disorder is non-Hodgkin's lymphoma (NHL) or central nervous system lymphoma (CNSL). 88. A bispecific antibody that binds to CD20 and CD3, used in a method of treating a subject with a CD20-positive proliferative disorder, wherein the bispecific antibody that binds to CD20 and CD3 is administered in combination with an anti-CD20 antibody and one or more chemotherapeutic agents selected from ifosfamide, carboplatin, and/or etoposide, in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle. 89. Use of a bispecific antibody that binds to CD20 and CD3 in the manufacture of a medicament for treating a subject with a CD20-positive proliferative disorder, wherein, in said treatment, the bispecific antibody that binds to CD20 and CD3 is administered in combination with an anti-CD20 antibody and one or more chemotherapeutic agents selected from ifosfamide, carboplatin, and/or etoposide, in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle. 90. A bispecific antibody that binds to CD20 and CD3, used in a method of treating a subject aged between 6 months and 17 years with CD20-positive proliferative disorders, wherein the bispecific antibody that binds to CD20 and CD3 is administered in combination with an anti-CD20 antibody and one or more chemotherapeutic agents selected from ifosfamide, carboplatin, and/or etoposide, in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle. 91. Use of a bispecific antibody binding to CD20 and CD3 in the manufacture of a medicament for treating a subject aged between 6 months and 17 years with a CD20-positive proliferative disorder, wherein, in said treatment, the bispecific antibody binding to CD20 and CD3 is administered in combination with an anti-CD20 antibody and one or more chemotherapeutic agents selected from ifosfamide, carboplatin, and/or etoposide, in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle. 92. A bispecific antibody that binds to CD20 and CD3, used in a method of treating a subject aged 18 to 30 years with a CD20-positive proliferative disorder, wherein the bispecific antibody that binds to CD20 and CD3 is administered in combination with an anti-CD20 antibody and one or more chemotherapeutic agents selected from ifosfamide, carboplatin, and/or etoposide, in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle. 93. Use of a bispecific antibody binding to CD20 and CD3 in the manufacture of a medicament for treating a subject aged between 18 and 30 years with a CD20-positive proliferative disorder, wherein, in said treatment, the bispecific antibody binding to CD20 and CD3 is administered in combination with an anti-CD20 antibody and one or more chemotherapeutic agents selected from ifosfamide, carboplatin, and/or etoposide, in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle. 94. The present invention as described above.