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CN118557750A - Methods of treating diffuse large B-cell lymphoma using anti-CD79b immunoconjugates - Google Patents

Methods of treating diffuse large B-cell lymphoma using anti-CD79b immunoconjugates Download PDF

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CN118557750A
CN118557750A CN202410671437.1A CN202410671437A CN118557750A CN 118557750 A CN118557750 A CN 118557750A CN 202410671437 A CN202410671437 A CN 202410671437A CN 118557750 A CN118557750 A CN 118557750A
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immunoconjugate
gemcitabine
oxaliplatin
seq
amino acid
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J·E·埃尔南德斯·蒙塔尔沃
N·U·D·卡尤姆
J·H·平田
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F Hoffmann La Roche AG
Genentech Inc
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F Hoffmann La Roche AG
Genentech Inc
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Abstract

本发明提供了治疗B细胞增殖性疾患(诸如弥漫性大B细胞淋巴瘤(DLBCL))的方法，所述方法将包含抗CD79b抗体的免疫缀合物与抗CD20抗体(诸如利妥昔单抗)和一种或多种化疗剂(诸如吉西他滨和奥沙利铂)联合使用。

The invention provides methods of treating B cell proliferative disorders, such as diffuse large B cell lymphoma (DLBCL), using an immunoconjugate comprising an anti-CD79b antibody in combination with an anti-CD20 antibody, such as rituximab, and one or more chemotherapeutic agents, such as gemcitabine and oxaliplatin.

Description

Methods of treating diffuse large B-cell lymphomas using anti-CD 79B immunoconjugates
The application is a divisional application of China patent application with the application number 202080071134.6 (application day: 6/9/2020, title of application: method for treating diffuse large B-cell lymphoma using anti-CD 79B immunoconjugate).
Cross Reference to Related Applications
The present application claims the benefit of U.S. provisional application 62/923,359 filed on 10 months 18 in 2019, which is incorporated herein by reference in its entirety.
Technical Field
The present disclosure relates to methods of treating B cell proliferative disorders (e.g., diffuse Large B Cell Lymphoma (DLBCL)) by administering an immunoconjugate comprising an anti-CD 79B antibody in combination with an anti-CD 20 antibody (e.g., rituximab) and one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin (oxaliplatin)).
Submitting sequence list with ASCII text file
The contents of the following submitted ASCII text files are incorporated herein by reference in their entirety: computer Readable Format (CRF) of sequence Listing (filename: 14639909102 SEQLIST. TXT, recording date: month 6, 8 of 2020, size: 59 KB).
Background
Non-hodgkin lymphomas (NHL) are the most common hematological malignancy worldwide, and thirteenth among the total most common cancers (Bray et al, (2018) CA Cancer J Clin, 68:394-424). Diffuse large B-cell lymphoma (DLBCL) is an aggressive subtype of NHL, accounting for approximately 32.5% of all NHL cases. DLBCL originates from mature B cells and has a median survival of <1 year in untreated patients (Rovira et al, (2015) Ann Hematol, 378:1396-1407). Most DLBCL cells express CD20, a membrane antigen that is important for cell cycle initiation and differentiation (Anderson et al, (1984) Blood, 63:1424-1433).
First line treatment of DLBCL consisted of anti-CD 20 monoclonal antibody therapy in combination with multi-agent chemotherapy (National Comprehensive Cancer Network 2018; shen et al, (2018) Lancet vol 5, e 264). For patients not cured by first line therapy, autologous stem cell transplantation following high dose chemotherapy provides a second opportunity for long term remission. For recurrent/refractory (R/R) DLBCL patients who are unsuitable for stem cell transplantation due to age, co-disease or other factors, there are different treatment options, including various chemotherapies. However, these chemotherapies are used for the purpose of alleviating the condition rather than long-term survival. More recently approved treatments for the R/R DLBCL case include CAR-T therapy and poloxamer (polatuzumab) vedotin-piiq in combination with bendamustine (bendamustine) and rituximab.
About half of recurrent DLBCL patients fail to respond to secondary therapy because of a refractory disease (Gisselbrecht et al, (2010) J Clin Oncol, 28:4184-4190). Patients who relapse after stem cell transplantation or are unsuitable for stem cell transplantation because of refractory diseases or frailty have poor results. In addition, a large number of relapsed/refractory patients are unsuitable for active treatment due to age, co-disease or other factors. Although rescue therapy of recurrent or refractory DLBCL shows encouraging results in therapy response rate methods, the long-term survival of recurrent or refractory DLBCL patients remains limited (Lopez et al, (2007) European J of Haematology 80:127-32; gnaoui et al, (2007) Ann Oncol 18:1363-68; mounoier et al, (2013) Haemallogic 98 (11) 1726-31). Thus, there is a need in the art for new therapeutic methods for recurrent or refractory DLBCL patients.
All references, including patent applications and publications, cited herein are hereby incorporated by reference in their entirety.
Disclosure of Invention
In one aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of:
(a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin.
In certain embodiments, an anti-CD 79b antibody comprises (i) a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO:19, and (ii) a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, an anti-CD 79b antibody comprises (i) a heavy chain comprising the amino acid sequence of SEQ ID NO:36, and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 35. In certain embodiments, p is between 2 and 5. In certain embodiments, p is between 3 and 4. In certain embodiments, the immunoconjugate is a poloxamer vedotin-piiq.
In some embodiments, the anti-CD 79b antibody comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO. 37; and a light chain comprising the amino acid sequence of SEQ ID NO. 35. In some embodiments, the anti-CD 79b antibody comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO. 36; and a light chain comprising the amino acid sequence of SEQ ID NO. 38. In some embodiments, the immunoconjugate is Iladatuzumab vedotin. In certain embodiments, p is between 2 and 5. In certain embodiments, p is 2.
In some embodiments, the immunoconjugate is administered at a dose of about 1mg/kg to about 5 mg/kg. In some embodiments, the immunoconjugate is administered at a dose of about 1.2mg/kg, about 1.8mg/kg, about 2.4mg/kg, about 3.6mg/kg, or about 4.8 mg/kg. In some embodiments, the immunoconjugate is administered at a dose of about 1.8 mg/kg.
In some embodiments, which may be combined with any of the preceding embodiments, the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2. In certain embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for one or more 21-day periods. In certain embodiments, the immunoconjugate is administered at a dose of about 1.8mg/kg per cycle, rituximab is administered at a dose of about 375mg/m 2 per cycle, gemcitabine is administered at a dose of about 1000mg/m 2 per cycle, and oxaliplatin is administered at a dose of about 100mg/m 2 per cycle. In certain embodiments, the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, while gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle. In certain embodiments, rituximab is administered prior to the immunoconjugate. In certain embodiments, gemcitabine is administered prior to oxaliplatin. In certain embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for up to eight 21-day periods. In certain embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for eight 21-day periods.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of:
(a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) A heavy chain comprising the amino acid sequence of SEQ ID No. 36, and (ii) a light chain comprising the amino acid sequence of SEQ ID No. 35, and wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for up to eight 21-day cycles, wherein in each cycle the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; and wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein the gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of:
(a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) A heavy chain comprising the amino acid sequence of SEQ ID No. 36, and (ii) a light chain comprising the amino acid sequence of SEQ ID No. 35, and wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; and wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein the gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of:
(a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) A heavy chain comprising the amino acid sequence of SEQ ID No. 36, and (ii) a light chain comprising the amino acid sequence of SEQ ID No. 35, and wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for up to eight 21-day cycles, wherein in each cycle the immunoconjugate is administered at a dose of about 1.4mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; and wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein the gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of:
(a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) A heavy chain comprising the amino acid sequence of SEQ ID No. 36, and (ii) a light chain comprising the amino acid sequence of SEQ ID No. 35, and wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.4mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; and wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein the gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of:
(a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) A heavy chain comprising the amino acid sequence of SEQ ID No. 36, and (ii) a light chain comprising the amino acid sequence of SEQ ID No. 35, and wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for up to eight 21-day cycles, wherein in each cycle the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 75mg/m 2; and wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein the gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of:
(a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) A heavy chain comprising the amino acid sequence of SEQ ID No. 36, and (ii) a light chain comprising the amino acid sequence of SEQ ID No. 35, and wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 75mg/m 2; and wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein the gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of:
(a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) A heavy chain comprising the amino acid sequence of SEQ ID No. 36, and (ii) a light chain comprising the amino acid sequence of SEQ ID No. 35, and wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for up to eight 21-day cycles, wherein in each cycle the immunoconjugate is administered at a dose of about 1.4mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 75mg/m 2; and wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein the gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of:
(a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) A heavy chain comprising the amino acid sequence of SEQ ID No. 36, and (ii) a light chain comprising the amino acid sequence of SEQ ID No. 35, and wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.4mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 75mg/m 2; and wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein the gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle.
In some embodiments, which may be combined with any of the preceding embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for at least two, at least three, at least four, at least five, at least six, or at least seven 21-day periods. In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for eight 21-day periods. In some embodiments, rituximab is administered prior to the immunoconjugate. In some embodiments, gemcitabine is administered prior to oxaliplatin. In some embodiments, the immunoconjugate is a poloxamer vedotin-piiq.
In some embodiments, the human receives at least one prior therapy for DLBCL. In some embodiments, the human has received at least one prior systemic therapy for DLBCL. In some embodiments, the human receives at least two prior therapies for DLBCL. In certain embodiments, the DLBCL is a histologically confirmed DLBCL, is Not Otherwise Specified (NOS), or the human has a history of inert disease conversion to DLBCL. In certain embodiments, DLBCL is recurrent or refractory DLBCL. In certain embodiments, the human eastern tumor collaboration group (Eastern Cooperative Oncology Group (ECOG)) physical stamina is 0,1, or 2. In certain embodiments, the human is not scheduled for autologous or allogeneic Stem Cell Transplantation (SCT). In certain embodiments, the human is not undergoing prior therapy in combination with gemcitabine and a platinum-based agent. In certain embodiments, the person does not have a peripheral neuropathy of greater than grade 1 according to the U.S. national cancer institute adverse event generic term Version 5.0 (National Cancer Institute Common Terminology Criteria for ADVERSE EVENTS, version 5.0). In certain embodiments, the human is free of primary or secondary central nervous system lymphomas. In some embodiments, the human is not a candidate for Hematopoietic Stem Cell Transplantation (HSCT) prior to administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, the human is not a candidate for autologous Hematopoietic Stem Cell Transplantation (HSCT) prior to administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, the human receives at least two prior therapies for DLBCL. In some embodiments, the human has not received prior therapy with polotophyllizumab vedotin-piiq for DLBCL. In some embodiments, the human adult is. In some embodiments, the adult is otherwise afflicted with recurrent or refractory non-specific diffuse large B-cell lymphoma.
In certain embodiments, the human does not experience a grade 3 or higher peripheral neuropathy that does not regress to a grade 1 or lower within 14 days after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In certain embodiments, 33% or less of the individuals who receive the treatment develop a grade 3 or higher peripheral neuropathy that does not resolve to grade 1 or lower within 14 days after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In certain embodiments, 33% or less of the plurality of people who receive the treatment have peripheral neuropathy of grade 3 or higher that does not resolve to grade 1 or lower within 14 days after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not result in grade 3 or higher peripheral neuropathy that does not regress to grade 1 or lower within 14 days. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not result in grade 4 or higher peripheral neuropathy. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not result in a grade 4 or higher neurotoxicity. In some embodiments, the human does not experience a grade 4 or higher peripheral neuropathy after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, the human does not experience a grade 4 or higher neurotoxicity after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in 3 or more grade peripheral neuropathy that does not resolve to grade 1 or less within 14 days in 33% or less of the people in the plurality. In some embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in less than about 40% of the plurality of people developing peripheral neuropathy of grade 3 or higher that does not resolve to grade 1 or lower within 14 days. In some embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to the plurality of people results in less than about 8% of the plurality of people experiencing grade 3 or higher peripheral neuropathy. In some embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in less than about 6% of the plurality of people experiencing peripheral neuropathy that results in discontinuation of treatment with the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In certain embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day periods.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the human does not experience a grade 3 or higher peripheral neuropathy that does not regress to a grade 1 or lower within 14 days after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not result in a grade 3 or higher peripheral neuropathy that does not regress to a grade 1 or lower within 14 days in the human.
In certain embodiments, an anti-CD 79b antibody comprises (i) a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO:19, and (ii) a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, an anti-CD 79b antibody comprises (i) a heavy chain comprising the amino acid sequence of SEQ ID NO:36, and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 35. In certain embodiments, p is between 2 and 5. In certain embodiments, p is between 3 and 4. In certain embodiments, the immunoconjugate is a poloxamer vedotin-piiq.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein 33% or less of the plurality of persons who receive the treatment develop a grade 3 or higher peripheral neuropathy that does not resolve to grade 1 or lower within 14 days after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in 3 or more grade peripheral neuropathy that does not regress to grade 1 or less in 14 days in 33% or less of the people in the plurality.
In certain embodiments, an anti-CD 79b antibody comprises (i) a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO:19, and (ii) a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, an anti-CD 79b antibody comprises (i) a heavy chain comprising the amino acid sequence of SEQ ID NO:36, and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 35. In certain embodiments, p is between 2 and 5. In certain embodiments, p is between 3 and 4. In certain embodiments, the immunoconjugate is a poloxamer vedotin-piiq.
In some embodiments, which may be combined with any of the preceding embodiments, the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2. In certain embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for one or more 21-day periods. In certain embodiments, the immunoconjugate is administered at a dose of about 1.8mg/kg per cycle, rituximab is administered at a dose of about 375mg/m 2 per cycle, gemcitabine is administered at a dose of about 1000mg/m 2 per cycle, and oxaliplatin is administered at a dose of about 100mg/m 2 per cycle. In certain embodiments, the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, while gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle. In certain embodiments, rituximab is administered prior to the immunoconjugate. In certain embodiments, gemcitabine is administered prior to oxaliplatin. In certain embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for up to eight 21-day periods. In certain embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for eight 21-day periods.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) A heavy chain comprising the amino acid sequence of SEQ ID No. 36, and (ii) a light chain comprising the amino acid sequence of SEQ ID No. 35, and wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for up to eight 21-day cycles, wherein in each cycle the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle; and wherein the human does not experience a grade 3 or higher peripheral neuropathy that does not regress to a grade 1 or lower within 14 days after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) A heavy chain comprising the amino acid sequence of SEQ ID No. 36, and (ii) a light chain comprising the amino acid sequence of SEQ ID No. 35, and wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle; and wherein the human does not experience a grade 3 or higher peripheral neuropathy that does not regress to a grade 1 or lower within 14 days after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) A heavy chain comprising the amino acid sequence of SEQ ID No. 36, and (ii) a light chain comprising the amino acid sequence of SEQ ID No. 35, and wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for up to eight 21-day cycles, wherein in each cycle the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle; and wherein administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not result in a grade 3 or higher peripheral neuropathy that does not regress to a grade 1 or lower within 14 days in the human.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) A heavy chain comprising the amino acid sequence of SEQ ID No. 36, and (ii) a light chain comprising the amino acid sequence of SEQ ID No. 35, and wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle; and wherein administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not result in a grade 3 or higher peripheral neuropathy that does not regress to a grade 1 or lower within 14 days in the human.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) A heavy chain comprising the amino acid sequence of SEQ ID No. 36, and (ii) a light chain comprising the amino acid sequence of SEQ ID No. 35, and wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for up to eight 21-day cycles, wherein in each cycle the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle; and wherein 33% or less of the plurality of persons who receive the treatment after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have a peripheral neuropathy of grade 3 or higher that does not resolve to grade 1 or lower within 14 days.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) A heavy chain comprising the amino acid sequence of SEQ ID No. 36, and (ii) a light chain comprising the amino acid sequence of SEQ ID No. 35, and wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle; and wherein 33% or less of the plurality of persons who receive the treatment after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have a peripheral neuropathy of grade 3 or higher that does not resolve to grade 1 or lower within 14 days.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) A heavy chain comprising the amino acid sequence of SEQ ID No. 36, and (ii) a light chain comprising the amino acid sequence of SEQ ID No. 35, and wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for up to eight 21-day cycles, wherein in each cycle the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle; and wherein administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to the plurality of people results in 3 or more grade peripheral neuropathy that does not regress to grade 1 or less in 14 days in 33% or less of the plurality of people.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) A heavy chain comprising the amino acid sequence of SEQ ID No. 36, and (ii) a light chain comprising the amino acid sequence of SEQ ID No. 35, and wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle; and wherein administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to the plurality of people results in 3 or more grade peripheral neuropathy that does not regress to grade 1 or less in 14 days in 33% or less of the plurality of people.
In some embodiments, which may be combined with any of the preceding embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day periods.
In some embodiments, which may be combined with any of the preceding embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for at least two, at least three, at least four, at least five, at least six, or at least seven 21-day periods. In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for eight 21-day periods. In some embodiments, rituximab is administered prior to the immunoconjugate. In some embodiments, gemcitabine is administered prior to oxaliplatin.
In some embodiments, which can be combined with any of the preceding embodiments, the immunoconjugate is a poloxamer vedotin-piiq.
In some embodiments, which may be combined with any of the preceding embodiments, the anti-CD 79b antibody comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO. 37; and a light chain comprising the amino acid sequence of SEQ ID NO. 35. In some embodiments, the anti-CD 79b antibody comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO. 36; and a light chain comprising the amino acid sequence of SEQ ID NO. 38. In some embodiments, the immunoconjugate is Iladatuzumab vedotin. In certain embodiments, p is between 2 and 5. In certain embodiments, p is 2.
In some embodiments, the human receives at least one prior therapy for DLBCL. In some embodiments, the human has received at least one prior systemic therapy for DLBCL. In some embodiments, the human receives at least two prior therapies for DLBCL. In certain embodiments, the DLBCL is a histologically confirmed DLBCL, is Not Otherwise Specified (NOS), or the human has a history of inert disease conversion to DLBCL. In certain embodiments, DLBCL is recurrent or refractory DLBCL. In certain embodiments, the human eastern tumor collaboration group (Eastern Cooperative Oncology Group (ECOG)) physical stamina is 0,1, or 2. In certain embodiments, the human is not scheduled for autologous or allogeneic Stem Cell Transplantation (SCT). In certain embodiments, the human is not undergoing prior therapy in combination with gemcitabine and a platinum-based agent. In certain embodiments, the person does not have a peripheral neuropathy of greater than grade 1 according to the U.S. national cancer institute adverse event generic term Version 5.0 (National Cancer Institute Common Terminology Criteria for ADVERSE EVENTS, version 5.0). In certain embodiments, the human is free of primary or secondary central nervous system lymphomas. In some embodiments, the human is not a candidate for Hematopoietic Stem Cell Transplantation (HSCT) prior to administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, the human is not a candidate for autologous Hematopoietic Stem Cell Transplantation (HSCT) prior to administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, the human receives at least two prior therapies for DLBCL. In some embodiments, the human has not received prior therapy with polotophyllizumab vedotin-piiq for DLBCL. In some embodiments, the human adult is. In some embodiments, the adult is otherwise afflicted with recurrent or refractory non-specific diffuse large B-cell lymphoma.
In some embodiments, which may be combined with any of the preceding embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not result in grade 3 or higher peripheral neuropathy that does not regress to grade 1 or lower within 14 days. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not result in grade 4 or higher peripheral neuropathy. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not result in a grade 4 or higher neurotoxicity. In some embodiments, the human does not experience a grade 4 or higher peripheral neuropathy after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, the human does not experience a grade 4 or higher neurotoxicity after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in 3 or more grade peripheral neuropathy that does not resolve to grade 1 or less within 14 days in 33% or less of the people in the plurality. In some embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in less than about 40% of the plurality of people developing peripheral neuropathy of grade 3 or higher that does not resolve to grade 1 or lower within 14 days. In some embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to the plurality of people results in less than about 8% of the plurality of people experiencing grade 3 or higher peripheral neuropathy. In some embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in less than about 6% of the plurality of people experiencing peripheral neuropathy that results in discontinuation of treatment with the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day periods. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in complete remission in humans. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in partial remission in a human.
In some embodiments, which may be combined with any of the preceding embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in progression-free survival of the human. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in a progression free survival of the human of at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 24 months, or at least about 25 months after initiation of the treatment with the immunoconjugate, gemcitabine, and oxaliplatin. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in a progression free survival of the human of at least about 4 months after initiation of the treatment with the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in a progression free survival of the human of at least about 5 months after initiation of the treatment with the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in a progression free survival of the human of at least about 6 months after initiation of the treatment with the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in a progression free survival of the human of at least about 9.5 months after initiation of the treatment with the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in a progression free survival of the human of at least about 11 months after initiation of the treatment with the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in a progression free survival of the human of at least about 14 months after initiation of the treatment with the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in an increase in the progression free survival of the human as compared to administration of rituximab, gemcitabine, and oxaliplatin to a corresponding human. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of humans results in an increase in the progression free survival of these humans as compared to a plurality of corresponding humans administered rituximab, gemcitabine, and oxaliplatin.
In some embodiments, which may be combined with any of the preceding embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in event-free survival of the human. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in a human event-free survival of at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 24 months, or at least about 25 months after initiation of the treatment with the immunoconjugate, gemcitabine, and oxaliplatin. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in a human event-free survival of at least about 4 months after initiation of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin treatment. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in a human event-free survival of at least about 5 months after initiation of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin treatment. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in a no-event survival of the human of at least about 6 months after initiation of treatment with the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in a human event-free survival of at least about 9.5 months after initiation of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin treatment. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in a human event-free survival of at least about 11 months after initiation of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin treatment. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in a human event-free survival of at least about 14 months after initiation of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin treatment. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in an increase in the event-free survival of the human as compared to administration of rituximab, gemcitabine, and oxaliplatin to a corresponding human. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of humans results in an increase in the event-free survival of these humans as compared to a plurality of corresponding humans administered rituximab, gemcitabine, and oxaliplatin.
In some embodiments, which may be combined with any of the preceding embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in a survival of the human of at least about 10 months or more, at least about 11 months or more, at least about 12 months or more, at least about 13 months or more, at least about 14 months or more, or at least about 15 months or more after initiation of treatment with the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in a median total survival of the plurality of people after initiation of the treatment with the immunoconjugate, rituximab, gemcitabine, and oxaliplatin of at least about 10 months or more, at least about 11 months or more, at least about 12 months or more, at least about 13 months or more, at least about 14 months or more, or at least about 15 months or more. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in an increase in survival of the human compared to administration of rituximab, gemcitabine, and oxaliplatin to a corresponding human. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of humans results in an increase in the median overall survival of these humans as compared to a plurality of corresponding humans administered rituximab, gemcitabine, and oxaliplatin.
In some embodiments, which may be combined with any of the preceding embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin do not cause tumor lysis syndrome in the human. In some embodiments, the methods provided herein further comprise administering to the human a prophylactic treatment against tumor lysis syndrome before, during, and/or after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to the human.
In some embodiments, which may be combined with any of the preceding embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin do not cause an infection in the human. In some embodiments, the infection is a pneumosporoal infection or a herpes virus infection. In some embodiments, the methods provided herein further comprise administering to the human a prophylactic treatment against the infection before, during, and/or after the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered to the human.
In some embodiments, which may be combined with any of the preceding embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin do not result in neutropenia in the human. In some embodiments, the methods provided herein further comprise administering to the human a prophylactic treatment for neutropenia before, during, and/or after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to the human. In some embodiments, the prophylactic treatment for neutropenia comprises administering G-CSF to the human. In some embodiments, the methods provided herein further comprise discontinuing treatment with the immunoconjugate, rituximab, gemcitabine, and oxaliplatin if the human experiences grade 3 or grade 4 neutropenia following administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, the method further comprises resuming treatment with the immunoconjugate, rituximab, gemcitabine, and oxaliplatin if the Absolute Neutrophil Count (ANC) of the human increases to >1000/μl. In some embodiments, the method further comprises administering one or more growth factors to treat neutropenia. In some embodiments, the one or more growth factors comprise G-CSF. In some embodiments, the method further comprises, if the ANC of the human is restored to >1000/μl at or before day 7 of the 21 day cycle, restoring treatment with the immunoconjugate, rituximab, gemcitabine, and oxaliplatin without reducing the dose of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, the method further comprises, if the ANC of the human returns to >1000/μl after day 7 of the 21-day cycle, resuming treatment with the immunoconjugate, rituximab, gemcitabine, and oxaliplatin, wherein the dose of the immunoconjugate is reduced to 1.4mg/kg. In some embodiments, the method further comprises interrupting treatment with the immunoconjugate, rituximab, gemcitabine, and oxaliplatin if a dose reduction of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin has previously occurred.
In some embodiments, which may be combined with any of the preceding embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin do not result in reactivation of hepatitis b in the human. In some embodiments, the methods provided herein further comprise administering to the human a prophylactic treatment for hepatitis b reactivation prior to, during, and/or after administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to the human. In some embodiments, the methods provided herein further comprise administering an antiviral drug therapy to the human if reactivation of hepatitis b is detected in the human.
In some embodiments, which may be combined with any of the preceding embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not result in one or more adverse events selected from the group consisting of: drug-induced liver injury, progressive multifocal leukoencephalopathy, systemic hypersensitivity, anaphylaxis, anaphylactoid reactions, and secondary malignancy.
In some embodiments, which may be combined with any of the preceding embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of humans results in an increase in the rate of complete remission (CRR) compared to a plurality of corresponding humans administered rituximab, gemcitabine, and oxaliplatin.
In some embodiments, which may be combined with any of the preceding embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of humans results in an increase in the Objective Remission Rate (ORR) compared to a plurality of corresponding humans administered rituximab, gemcitabine, and oxaliplatin.
In some embodiments, which may be combined with any of the preceding embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of humans results in an increase in the optimal total remission rate (BOR) compared to a plurality of corresponding humans administered rituximab, gemcitabine, and oxaliplatin.
In some embodiments, which may be combined with any of the preceding embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of humans results in an increase in duration of remission (DOR) as compared to a plurality of corresponding humans administered rituximab, gemcitabine, and oxaliplatin.
In some embodiments, which may be combined with any of the preceding embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in a1 year progression free survival rate of at least about 30% or greater, at least about 40% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of these people. In some embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in a 2-year progression-free survival rate of at least about 63% or greater, at least about 65% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% for the plurality of people. In some embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in a 5-year progression-free survival rate of at least about 14% or greater, at least about 15% or greater, at least about 20% or greater, at least about 30% or greater, at least about 40% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of the plurality of people. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in an increase in progression free survival of these people for 1 year, 2 years, 3.5 years, or 5 years, as compared to a plurality of corresponding people administered rituximab, gemcitabine, and oxaliplatin.
In some embodiments, which may be combined with any of the preceding embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in a1 year overall survival rate of the plurality of people of at least about 42% or greater, at least about 45% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100%. In some embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in a total 2-year survival rate of the plurality of people of at least about 67% or more, at least about 70% or more, at least about 80% or more, at least about 90% or more, at least about 95% or more, or about 100%. In some embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in a 3.5 year overall survival rate of the plurality of people of at least about 38% or greater, at least about 40% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100%. In some embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in a 5-year overall survival rate of the plurality of people of at least about 15% or more, at least about 20% or more, at least about 30% or more, at least about 40% or more, at least about 50% or more, at least about 60% or more, at least about 70% or more, at least about 80% or more, at least about 90% or more, at least about 95% or more, or about 100%. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of humans results in an increase in the overall survival rate of these humans for 1 year, 2 years, 3.5 years, or 5 years, as compared to a plurality of corresponding humans administered rituximab, gemcitabine, and oxaliplatin.
In some embodiments, which may be combined with any of the preceding embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in a 2-year event-free survival rate of the plurality of people of at least about 44% or greater, at least about 45% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100%. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in an increase in event-free survival rate of 1 year, 2 years, 3.5 years, or 5 years for these people compared to a plurality of corresponding people administered rituximab, gemcitabine, and oxaliplatin.
In some embodiments, which may be combined with any of the preceding embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in an objective remission rate of the plurality of people of at least about 44% or more, at least about 45% or more, at least about 50% or more, at least about 60% or more, at least about 70% or more, at least about 80% or more, at least about 90% or more, at least about 95% or more, or about 100%.
In some embodiments, which may be combined with any of the preceding embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in a complete remission rate of the plurality of people of at least about 35% or greater, at least about 40% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100%.
In some embodiments, which may be combined with any of the preceding embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in a partial remission rate of the plurality of people of at least about 10% or greater, at least about 20% or greater, at least about 30% or greater, at least about 40% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100%. In some embodiments, which may be combined with any of the preceding embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of humans results in an increase in the rate of partial remission as compared to a plurality of corresponding humans administered rituximab, gemcitabine, and oxaliplatin.
In another aspect, provided herein is a kit comprising an immunoconjugate comprising the formula (la)
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8 for use in combination with rituximab, gemcitabine and oxaliplatin according to any of the preceding embodiments for the treatment of a human suffering from Diffuse Large B Cell Lymphoma (DLBCL) in need thereof.
In another aspect, provided herein is a kit comprising pototouzumab vedotin-piiq for use in combination with rituximab, gemcitabine, and oxaliplatin according to any of the preceding embodiments in treating a human in need thereof having diffuse large B-cell lymphoma (DLBCL).
In another aspect, provided herein is an immunoconjugate comprising formula (la)
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8 for use in a method for treating Diffuse Large B Cell Lymphoma (DLBCL) in combination with rituximab, gemcitabine and oxaliplatin according to any of the preceding embodiments.
In another aspect, provided herein is rituximab for use in a method for treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8.
In another aspect, provided herein is gemcitabine for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) in combination with an immunoconjugate, rituximab, and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8.
In another aspect, provided herein is oxaliplatin for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) according to any one of the preceding embodiments in combination with an immunoconjugate, gemcitabine and rituximab, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8.
In another aspect, provided herein is an immunoconjugate comprising formula (la)
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8 for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) according to any one of the preceding embodiments in combination with rituximab, gemcitabine and oxaliplatin; wherein the human does not experience a grade 3 or higher peripheral neuropathy that does not regress to a grade 1 or lower within 14 days after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin.
In another aspect, provided herein is an immunoconjugate comprising formula (la)
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8 for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) according to any one of the preceding embodiments in combination with rituximab, gemcitabine and oxaliplatin; wherein administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not result in a grade 3 or higher peripheral neuropathy that does not regress to a grade 1 or lower within 14 days in the human.
In another aspect, provided herein is an immunoconjugate comprising formula (la)
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8 for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) according to any one of the preceding embodiments in combination with rituximab, gemcitabine and oxaliplatin; wherein 33% or less of the plurality of persons who receive the treatment develop a grade 3 or higher peripheral neuropathy that does not resolve to grade 1 or lower within 14 days after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin.
In another aspect, provided herein is an immunoconjugate comprising formula (la)
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8 for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) according to any one of the preceding embodiments in combination with rituximab, gemcitabine and oxaliplatin; wherein administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in 3 or more grade peripheral neuropathy that does not regress to grade 1 or less in 14 days in 33% or less of the people in the plurality.
In another aspect, provided herein is rituximab for use in a method for treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8, wherein the human does not experience a grade 3 or higher peripheral neuropathy that does not regress to a grade 1 or lower within 14 days after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin.
In another aspect, provided herein is rituximab for use in a method for treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8, wherein administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not result in a grade 3 or higher peripheral neuropathy that does not regress to a grade 1 or lower within 14 days in the human.
In another aspect, provided herein is rituximab for use in a method for treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8, wherein in a plurality of people receiving treatment, 33% or less of the plurality of people have peripheral neuropathy of grade 3 or higher which does not resolve to grade 1 or lower within 14 days after administration of the immunoconjugate, rituximab, gemcitabine and oxaliplatin.
In another aspect, provided herein is rituximab for use in a method for treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8, wherein administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in 3 or more grade peripheral neuropathy that does not regress to grade 1 or less within 14 days in 33% or less of the people in the plurality of people.
In another aspect, provided herein is gemcitabine for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) in combination with an immunoconjugate, rituximab, and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8, wherein the human does not experience a grade 3 or higher peripheral neuropathy that does not regress to a grade 1 or lower within 14 days after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin.
In another aspect, provided herein is gemcitabine for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) in combination with an immunoconjugate, rituximab, and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8, wherein administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not result in a grade 3 or higher peripheral neuropathy that does not regress to a grade 1 or lower within 14 days in the human.
In another aspect, provided herein is gemcitabine for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) in combination with an immunoconjugate, rituximab, and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8, wherein in a plurality of people receiving treatment, 33% or less of the plurality of people have peripheral neuropathy of grade 3 or higher which does not resolve to grade 1 or lower within 14 days after administration of the immunoconjugate, rituximab, gemcitabine and oxaliplatin.
In another aspect, provided herein is gemcitabine for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) in combination with an immunoconjugate, rituximab, and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8, wherein administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in 3 or more grade peripheral neuropathy that does not regress to grade 1 or less within 14 days in 33% or less of the people in the plurality of people.
In another aspect, provided herein is oxaliplatin for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) according to any one of the preceding embodiments in combination with an immunoconjugate, gemcitabine and rituximab, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8, wherein the human does not experience a grade 3 or higher peripheral neuropathy that does not regress to a grade 1 or lower within 14 days after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin.
In another aspect, provided herein is oxaliplatin for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) according to any one of the preceding embodiments in combination with an immunoconjugate, gemcitabine and rituximab, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8, wherein administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not result in a grade 3 or higher peripheral neuropathy that does not regress to a grade 1 or lower within 14 days in the human.
In another aspect, provided herein is oxaliplatin for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) according to any one of the preceding embodiments in combination with an immunoconjugate, gemcitabine and rituximab, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8, wherein in a plurality of people receiving treatment, 33% or less of the plurality of people have peripheral neuropathy of grade 3 or higher which does not resolve to grade 1 or lower within 14 days after administration of the immunoconjugate, rituximab, gemcitabine and oxaliplatin.
In another aspect, provided herein is oxaliplatin for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) according to any one of the preceding embodiments in combination with an immunoconjugate, gemcitabine and rituximab, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8, wherein administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in 3 or more grade peripheral neuropathy that does not regress to grade 1 or less within 14 days in 33% or less of the people in the plurality of people.
In one aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of:
(a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8, (b) oxalizumab, (c) gemcitabine, and (d) oxaliplatin.
In certain embodiments, an anti-CD 79b antibody comprises (i) a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO:19, and (ii) a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, an anti-CD 79b antibody comprises (i) a heavy chain comprising the amino acid sequence of SEQ ID NO:36, and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 35. In certain embodiments, p is between 2 and 5. In certain embodiments, p is between 3 and 4. In certain embodiments, the immunoconjugate is a poloxamer vedotin-piiq.
In some embodiments, the anti-CD 79b antibody comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO. 37; and a light chain comprising the amino acid sequence of SEQ ID NO. 35. In some embodiments, the anti-CD 79b antibody comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO. 36; and a light chain comprising the amino acid sequence of SEQ ID NO. 38. In some embodiments, the immunoconjugate is Iladatuzumab vedotin. In certain embodiments, p is between 2 and 5. In certain embodiments, p is 2.
In some embodiments, which may be combined with any of the preceding embodiments, the immunoconjugate is administered at a dose of about 1.8mg/kg, the otophyllab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2. In certain embodiments, the immunoconjugate, omutazumab, gemcitabine, and oxaliplatin are administered for one or more 21-day periods. In certain embodiments, the immunoconjugate is administered at a dose of about 1.8mg/kg per cycle, the otophyllizumab is administered at a dose of about 1000mg per cycle, the gemcitabine is administered at a dose of about 1000mg/m 2 per cycle, and the oxaliplatin is administered at a dose of about 100mg/m 2 per cycle. In certain embodiments, the otophyllab is administered prior to the immunoconjugate. In certain embodiments, gemcitabine is administered prior to oxaliplatin. In certain embodiments, the immunoconjugate, the otophyllizumab, the gemcitabine, and the oxaliplatin are administered for up to eight 21-day periods. In certain embodiments, the immunoconjugate, omtuzumab, gemcitabine, and oxaliplatin are administered for eight 21-day periods.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of:
(a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) A heavy chain comprising the amino acid sequence of SEQ ID NO:36, and (ii) a light chain comprising the amino acid sequence of SEQ ID NO:35, and wherein p is between 2 and 5, (b) octuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin are administered for up to eight 21-day cycles, wherein in each cycle the immunoconjugate is administered at a dose of about 1.8mg/kg, the otophyllab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of:
(a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) A heavy chain comprising the amino acid sequence of SEQ ID NO:36, and (ii) a light chain comprising the amino acid sequence of SEQ ID NO:35, and wherein p is between 2 and 5, (b) octuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the otophyllab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of:
(a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) A heavy chain comprising the amino acid sequence of SEQ ID NO:36, and (ii) a light chain comprising the amino acid sequence of SEQ ID NO:35, and wherein p is between 2 and 5, (b) octuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin are administered for up to eight 21-day cycles, wherein in each cycle the immunoconjugate is administered at a dose of about 1.4mg/kg, the otophyllab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of:
(a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) A heavy chain comprising the amino acid sequence of SEQ ID NO:36, and (ii) a light chain comprising the amino acid sequence of SEQ ID NO:35, and wherein p is between 2 and 5, (b) octuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.4mg/kg, the otophyllab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of:
(a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) A heavy chain comprising the amino acid sequence of SEQ ID NO:36, and (ii) a light chain comprising the amino acid sequence of SEQ ID NO:35, and wherein p is between 2 and 5, (b) octuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin are administered for up to eight 21-day cycles, wherein in each cycle the immunoconjugate is administered at a dose of about 1.8mg/kg, the otophyllab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 75mg/m 2.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of:
(a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) A heavy chain comprising the amino acid sequence of SEQ ID NO:36, and (ii) a light chain comprising the amino acid sequence of SEQ ID NO:35, and wherein p is between 2 and 5, (b) octuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the otophyllab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 75mg/m 2.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of:
(a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) A heavy chain comprising the amino acid sequence of SEQ ID NO:36, and (ii) a light chain comprising the amino acid sequence of SEQ ID NO:35, and wherein p is between 2 and 5, (b) octuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin are administered for up to eight 21-day cycles, wherein in each cycle the immunoconjugate is administered at a dose of about 1.4mg/kg, the otophyllab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 75mg/m 2.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of:
(a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) A heavy chain comprising the amino acid sequence of SEQ ID NO:36, and (ii) a light chain comprising the amino acid sequence of SEQ ID NO:35, and wherein p is between 2 and 5, (b) octuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.4mg/kg, the otophyllab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 75mg/m 2.
In some embodiments, which may be combined with any of the preceding embodiments, the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin are administered for at least two, at least three, at least four, at least five, at least six, or at least seven 21-day periods. In some embodiments, the immunoconjugate, the otophyllizumab, the gemcitabine, and the oxaliplatin are administered for eight 21-day periods. In some embodiments, the otophyllab is administered prior to the immunoconjugate. In some embodiments, gemcitabine is administered prior to oxaliplatin. In some embodiments, the immunoconjugate is a poloxamer vedotin-piiq.
In some embodiments, the human receives at least one prior therapy for DLBCL. In some embodiments, the human has received at least one prior systemic therapy for DLBCL. In some embodiments, the human receives at least two prior therapies for DLBCL. In certain embodiments, the DLBCL is a histologically confirmed DLBCL, is Not Otherwise Specified (NOS), or the human has a history of inert disease conversion to DLBCL. In certain embodiments, DLBCL is recurrent or refractory DLBCL. In certain embodiments, the human eastern tumor collaboration group (Eastern Cooperative Oncology Group (ECOG)) physical stamina is 0,1, or 2. In certain embodiments, the human is not scheduled for autologous or allogeneic Stem Cell Transplantation (SCT). In certain embodiments, the human is not undergoing prior therapy in combination with gemcitabine and a platinum-based agent. In certain embodiments, the person does not have a peripheral neuropathy of greater than grade 1 according to the U.S. national cancer institute adverse event generic term Version 5.0 (National Cancer Institute Common Terminology Criteria for ADVERSE EVENTS, version 5.0). In certain embodiments, the human is free of primary or secondary central nervous system lymphomas. In some embodiments, the human is not a candidate for Hematopoietic Stem Cell Transplantation (HSCT) prior to administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin. In some embodiments, the human is not a candidate for autologous Hematopoietic Stem Cell Transplantation (HSCT) prior to administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin. In some embodiments, the human receives at least two prior therapies for DLBCL. In some embodiments, the human has not received prior therapy with polotophyllizumab vedotin-piiq for DLBCL. In some embodiments, the human adult is. In some embodiments, the adult is otherwise afflicted with recurrent or refractory non-specific diffuse large B-cell lymphoma.
In certain embodiments, the human does not experience a grade 3 or higher peripheral neuropathy that does not regress to a grade 1 or lower within 14 days after administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin. In certain embodiments, 33% or less of the individuals who receive the treatment develop a grade 3 or higher peripheral neuropathy that does not resolve to grade 1 or lower within 14 days after administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin. In certain embodiments, 33% or less of the plurality of people who receive the treatment have peripheral neuropathy of grade 3 or higher that does not resolve to grade 1 or lower within 14 days after administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin. In some embodiments, administration of the immunoconjugate, omtuzumab, gemcitabine, and oxaliplatin does not result in grade 3 or higher peripheral neuropathy that does not regress to grade 1 or lower within 14 days. In some embodiments, administration of the immunoconjugate, the otophyllizumab, the gemcitabine, and the oxaliplatin does not result in a grade 4 or higher peripheral neuropathy. In some embodiments, administration of the immunoconjugate, the otophyllizumab, the gemcitabine, and the oxaliplatin does not result in a grade 4 or higher neurotoxicity. In some embodiments, the human does not experience a grade 4 or higher peripheral neuropathy after administration of the immunoconjugate, the otophyllizumab, the gemcitabine, and the oxaliplatin. In some embodiments, the human does not experience a grade 4 or higher neurotoxicity after administration of the immunoconjugate, the otobulab, the gemcitabine, and the oxaliplatin. In some embodiments, administering the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin to the plurality of people results in 3 or more grade peripheral neuropathy in 33% or less of the plurality of people, which does not resolve to grade 1 or less within 14 days. In some embodiments, administering the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin to the plurality of people results in less than about 40% of the plurality of people developing peripheral neuropathy of grade 3 or higher, which does not resolve to grade 1 or lower within 14 days. In some embodiments, administering the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin to the plurality of people results in less than about 8% of the plurality of people experiencing grade 3 or higher peripheral neuropathy. In some embodiments, administering the immunoconjugate, the omutazumab, the gemcitabine, and the oxaliplatin to the plurality of people results in less than about 6% of the plurality of people experiencing peripheral neuropathy that results in discontinuation of treatment with the immunoconjugate, the omutazumab, the gemcitabine, and the oxaliplatin. In certain embodiments, the immunoconjugate, the otophyllizumab, the gemcitabine, and the oxaliplatin have been administered for at least four 21-day periods.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8, (b) octuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein the human does not experience a grade 3 or higher peripheral neuropathy that does not regress to a grade 1 or lower within 14 days after administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8, (b) octuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin does not result in a grade 3 or higher peripheral neuropathy that does not regress to a grade 1 or lower within 14 days in the human.
In certain embodiments, an anti-CD 79b antibody comprises (i) a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO:19, and (ii) a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, an anti-CD 79b antibody comprises (i) a heavy chain comprising the amino acid sequence of SEQ ID NO:36, and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 35. In certain embodiments, p is between 2 and 5. In certain embodiments, p is between 3 and 4. In certain embodiments, the immunoconjugate is a poloxamer vedotin-piiq.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8, (b) octuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein 33% or less of the plurality of persons who receive the treatment develop a grade 3 or higher peripheral neuropathy that does not resolve to grade 1 or lower within 14 days after administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8, (b) octuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein administration of the immunoconjugate, the octuzumab, the gemcitabine, and the oxaliplatin to a plurality of people results in 3 or more peripheral neuropathy in 33% or less of the plurality of people, the 3 or more peripheral neuropathy not regressing to 1 or less within 14 days.
In certain embodiments, an anti-CD 79b antibody comprises (i) a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO:19, and (ii) a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, an anti-CD 79b antibody comprises (i) a heavy chain comprising the amino acid sequence of SEQ ID NO:36, and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 35. In certain embodiments, p is between 2 and 5. In certain embodiments, p is between 3 and 4. In certain embodiments, the immunoconjugate is a poloxamer vedotin-piiq.
In some embodiments, which may be combined with any of the preceding embodiments, the immunoconjugate is administered at a dose of about 1.8mg/kg, the otophyllab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2. In certain embodiments, the immunoconjugate, omutazumab, gemcitabine, and oxaliplatin are administered for one or more 21-day periods. In certain embodiments, the immunoconjugate is administered at a dose of about 1.8mg/kg per cycle, the otophyllizumab is administered at a dose of about 1000mg per cycle, the gemcitabine is administered at a dose of about 1000mg/m 2 per cycle, and the oxaliplatin is administered at a dose of about 100mg/m 2 per cycle. In certain embodiments, the otophyllab is administered prior to the immunoconjugate. In certain embodiments, gemcitabine is administered prior to oxaliplatin. In certain embodiments, the immunoconjugate, the otophyllizumab, the gemcitabine, and the oxaliplatin are administered for up to eight 21-day periods. In certain embodiments, the immunoconjugate, omtuzumab, gemcitabine, and oxaliplatin are administered for eight 21-day periods.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) A heavy chain comprising the amino acid sequence of SEQ ID NO:36, and (ii) a light chain comprising the amino acid sequence of SEQ ID NO:35, and wherein p is between 2 and 5, (b) octuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin are administered for up to eight 21-day cycles, wherein in each cycle the immunoconjugate is administered at a dose of about 1.8mg/kg, the otophyllab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; and wherein the human does not experience a grade 3 or higher peripheral neuropathy that does not regress to a grade 1 or lower within 14 days after administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) A heavy chain comprising the amino acid sequence of SEQ ID NO:36, and (ii) a light chain comprising the amino acid sequence of SEQ ID NO:35, and wherein p is between 2 and 5, (b) octuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the otophyllab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; and wherein the human does not experience a grade 3 or higher peripheral neuropathy that does not regress to a grade 1 or lower within 14 days after administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) A heavy chain comprising the amino acid sequence of SEQ ID NO:36, and (ii) a light chain comprising the amino acid sequence of SEQ ID NO:35, and wherein p is between 2 and 5, (b) octuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin are administered for up to eight 21-day cycles, wherein in each cycle the immunoconjugate is administered at a dose of about 1.8mg/kg, the otophyllab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; and wherein administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin does not result in a grade 3 or higher peripheral neuropathy that does not regress to a grade 1 or lower within 14 days in the human.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) A heavy chain comprising the amino acid sequence of SEQ ID NO:36, and (ii) a light chain comprising the amino acid sequence of SEQ ID NO:35, and wherein p is between 2 and 5, (b) octuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the otophyllab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; and wherein administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin does not result in a grade 3 or higher peripheral neuropathy that does not regress to a grade 1 or lower within 14 days in the human.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) A heavy chain comprising the amino acid sequence of SEQ ID NO:36, and (ii) a light chain comprising the amino acid sequence of SEQ ID NO:35, and wherein p is between 2 and 5, (b) octuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin are administered for up to eight 21-day cycles, wherein in each cycle the immunoconjugate is administered at a dose of about 1.8mg/kg, the otophyllab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; and wherein 33% or less of the plurality of persons who receive the treatment develop peripheral neuropathy of grade 3 or higher that does not resolve to grade 1 or lower within 14 days after administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) A heavy chain comprising the amino acid sequence of SEQ ID NO:36, and (ii) a light chain comprising the amino acid sequence of SEQ ID NO:35, and wherein p is between 2 and 5, (b) octuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the otophyllab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; and wherein 33% or less of the plurality of persons who receive the treatment develop peripheral neuropathy of grade 3 or higher that does not resolve to grade 1 or lower within 14 days after administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) A heavy chain comprising the amino acid sequence of SEQ ID NO:36, and (ii) a light chain comprising the amino acid sequence of SEQ ID NO:35, and wherein p is between 2 and 5, (b) octuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin are administered for up to eight 21-day cycles, wherein in each cycle the immunoconjugate is administered at a dose of about 1.8mg/kg, the otophyllab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; and wherein administration of the immunoconjugate, the octuzumab, the gemcitabine, and the oxaliplatin to the plurality of people results in 3 or more peripheral neuropathy in 33% or less of the plurality of people, the 3 or more peripheral neuropathy not regressing to 1 or less within 14 days.
In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) A heavy chain comprising the amino acid sequence of SEQ ID NO:36, and (ii) a light chain comprising the amino acid sequence of SEQ ID NO:35, and wherein p is between 2 and 5, (b) octuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the otophyllab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; and wherein administration of the immunoconjugate, the octuzumab, the gemcitabine, and the oxaliplatin to the plurality of people results in 3 or more peripheral neuropathy in 33% or less of the plurality of people, the 3 or more peripheral neuropathy not regressing to 1 or less within 14 days.
In some embodiments, which may be combined with any of the preceding embodiments, the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin have been administered for at least four 21-day periods.
In some embodiments, which may be combined with any of the preceding embodiments, the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin are administered for at least two, at least three, at least four, at least five, at least six, or at least seven 21-day periods. In some embodiments, the immunoconjugate, the otophyllizumab, the gemcitabine, and the oxaliplatin are administered for eight 21-day periods. In some embodiments, the otophyllab is administered prior to the immunoconjugate. In some embodiments, gemcitabine is administered prior to oxaliplatin.
In some embodiments, which can be combined with any of the preceding embodiments, the immunoconjugate is a poloxamer vedotin-piiq.
In some embodiments, which may be combined with any of the preceding embodiments, the anti-CD 79b antibody comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO. 37; and a light chain comprising the amino acid sequence of SEQ ID NO. 35. In some embodiments, the anti-CD 79b antibody comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO. 36; and a light chain comprising the amino acid sequence of SEQ ID NO. 38. In some embodiments, the immunoconjugate is Iladatuzumab vedotin. In certain embodiments, p is between 2 and 5. In certain embodiments, p is 2.
In some embodiments, the human receives at least one prior therapy for DLBCL. In some embodiments, the human has received at least one prior systemic therapy for DLBCL. In some embodiments, the human receives at least two prior therapies for DLBCL. In certain embodiments, the DLBCL is a histologically confirmed DLBCL, is Not Otherwise Specified (NOS), or the human has a history of inert disease conversion to DLBCL. In certain embodiments, DLBCL is recurrent or refractory DLBCL. In certain embodiments, the human eastern tumor collaboration group (Eastern Cooperative Oncology Group (ECOG)) physical stamina is 0,1, or 2. In certain embodiments, the human is not scheduled for autologous or allogeneic Stem Cell Transplantation (SCT). In certain embodiments, the human is not undergoing prior therapy in combination with gemcitabine and a platinum-based agent. In certain embodiments, the person does not have a peripheral neuropathy of greater than grade 1 according to the U.S. national cancer institute adverse event generic term Version 5.0 (National Cancer Institute Common Terminology Criteria for ADVERSE EVENTS, version 5.0). In certain embodiments, the human is free of primary or secondary central nervous system lymphomas. In some embodiments, the human is not a candidate for Hematopoietic Stem Cell Transplantation (HSCT) prior to administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin. In some embodiments, the human is not a candidate for autologous Hematopoietic Stem Cell Transplantation (HSCT) prior to administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin. In some embodiments, the human receives at least two prior therapies for DLBCL. In some embodiments, the human has not received prior therapy with polotophyllizumab vedotin-piiq for DLBCL. In some embodiments, the human adult is. In some embodiments, the adult is otherwise afflicted with recurrent or refractory non-specific diffuse large B-cell lymphoma.
In some embodiments, which may be combined with any of the preceding embodiments, administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin does not result in grade 3 or higher peripheral neuropathy that does not regress to grade 1 or lower within 14 days. In some embodiments, administration of the immunoconjugate, the otophyllizumab, the gemcitabine, and the oxaliplatin does not result in a grade 4 or higher peripheral neuropathy. In some embodiments, administration of the immunoconjugate, the otophyllizumab, the gemcitabine, and the oxaliplatin does not result in a grade 4 or higher neurotoxicity. In some embodiments, the human does not experience a grade 4 or higher peripheral neuropathy after administration of the immunoconjugate, the otophyllizumab, the gemcitabine, and the oxaliplatin. In some embodiments, the human does not experience a grade 4 or higher neurotoxicity after administration of the immunoconjugate, the otobulab, the gemcitabine, and the oxaliplatin. In some embodiments, administering the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin to the plurality of people results in 3 or more grade peripheral neuropathy in 33% or less of the plurality of people, which does not resolve to grade 1 or less within 14 days. In some embodiments, administering the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin to the plurality of people results in less than about 40% of the plurality of people developing peripheral neuropathy of grade 3 or higher, which does not resolve to grade 1 or lower within 14 days. In some embodiments, administering the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin to the plurality of people results in less than about 8% of the plurality of people experiencing grade 3 or higher peripheral neuropathy. In some embodiments, administering the immunoconjugate, the omutazumab, the gemcitabine, and the oxaliplatin to the plurality of people results in less than about 6% of the plurality of people experiencing peripheral neuropathy that results in discontinuation of treatment with the immunoconjugate, the omutazumab, the gemcitabine, and the oxaliplatin. In some embodiments, the immunoconjugate, the otophyllizumab, the gemcitabine, and the oxaliplatin have been administered for at least four 21-day periods. In some embodiments, administration of the immunoconjugate, omtuzumab, gemcitabine, and oxaliplatin results in complete remission in the human. In some embodiments, administration of the immunoconjugate, omtuzumab, gemcitabine, and oxaliplatin results in partial remission in the human.
In some embodiments, which may be combined with any of the preceding embodiments, the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin results in progression-free survival of the human. In some embodiments, administration of the immunoconjugate, omtuzumab, gemcitabine, and oxaliplatin results in a progression free survival of the human of at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 24 months, or at least about 25 months after starting the treatment with the immunoconjugate, omtuzumab, gemcitabine, and oxaliplatin. In some embodiments, administration of the immunoconjugate, omtuzumab, gemcitabine, and oxaliplatin results in a progression free survival of the human of at least about 4 months after initiation of treatment with the immunoconjugate, omtuzumab, gemcitabine, and oxaliplatin. In some embodiments, administration of the immunoconjugate, omtuzumab, gemcitabine, and oxaliplatin results in a progression free survival of the human of at least about 5 months after initiation of treatment with the immunoconjugate, omtuzumab, gemcitabine, and oxaliplatin. In some embodiments, administration of the immunoconjugate, omtuzumab, gemcitabine, and oxaliplatin results in a progression free survival of the human of at least about 6 months after initiation of treatment with the immunoconjugate, omtuzumab, gemcitabine, and oxaliplatin. In some embodiments, administration of the immunoconjugate, omtuzumab, gemcitabine, and oxaliplatin results in a progression free survival of the human of at least about 9.5 months after initiation of treatment with the immunoconjugate, omtuzumab, gemcitabine, and oxaliplatin. In some embodiments, administration of the immunoconjugate, omtuzumab, gemcitabine, and oxaliplatin results in a progression free survival of the human of at least about 11 months after initiation of treatment with the immunoconjugate, omtuzumab, gemcitabine, and oxaliplatin. In some embodiments, administration of the immunoconjugate, omtuzumab, gemcitabine, and oxaliplatin results in a progression free survival of the human of at least about 14 months after initiation of treatment with the immunoconjugate, omtuzumab, gemcitabine, and oxaliplatin. In some embodiments, administration of the immunoconjugate, the otouzumab, the gemcitabine, and the oxaliplatin results in an increase in the progression free survival of the human as compared to administration of the otouzumab, the gemcitabine, and the oxaliplatin to a corresponding human. In some embodiments, administration of the immunoconjugate, the omtuzumab, the gemcitabine, and the oxaliplatin to a plurality of people results in an increase in the progression free survival of these people compared to a plurality of corresponding people administered the omtuzumab, the gemcitabine, and the oxaliplatin.
In some embodiments, which may be combined with any of the preceding embodiments, the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin results in event-free survival of the human. In some embodiments, administration of the immunoconjugate, omtuzumab, gemcitabine, and oxaliplatin results in an event-free survival of the human of at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 24 months, or at least about 25 months after initiation of treatment with the immunoconjugate, omtuzumab, gemcitabine, and oxaliplatin. In some embodiments, administration of the immunoconjugate, omtuzumab, gemcitabine, and oxaliplatin results in a no-event survival of the human of at least about 4 months after initiation of treatment with the immunoconjugate, omtuzumab, gemcitabine, and oxaliplatin. In some embodiments, administration of the immunoconjugate, omtuzumab, gemcitabine, and oxaliplatin results in a no-event survival of the human of at least about 5 months after initiation of treatment with the immunoconjugate, omtuzumab, gemcitabine, and oxaliplatin. In some embodiments, administration of the immunoconjugate, omtuzumab, gemcitabine, and oxaliplatin results in a no-event survival of the human of at least about 6 months after initiation of treatment with the immunoconjugate, omtuzumab, gemcitabine, and oxaliplatin. In some embodiments, administration of the immunoconjugate, omtuzumab, gemcitabine, and oxaliplatin results in a no-event survival of the human of at least about 9.5 months after initiation of treatment with the immunoconjugate, omtuzumab, gemcitabine, and oxaliplatin. In some embodiments, administration of the immunoconjugate, omtuzumab, gemcitabine, and oxaliplatin results in a no-event survival of the human of at least about 11 months after initiation of treatment with the immunoconjugate, omtuzumab, gemcitabine, and oxaliplatin. In some embodiments, administration of the immunoconjugate, omtuzumab, gemcitabine, and oxaliplatin results in a no-event survival of the human of at least about 14 months after initiation of treatment with the immunoconjugate, omtuzumab, gemcitabine, and oxaliplatin. In some embodiments, administration of the immunoconjugate, the otouzumab, the gemcitabine, and the oxaliplatin results in an increase in the event-free survival of the human as compared to administration of the otouzumab, the gemcitabine, and the oxaliplatin to a corresponding human. In some embodiments, administration of the immunoconjugate, the omtuzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase in the event-free survival of these humans as compared to a plurality of corresponding humans administered with the omtuzumab, the gemcitabine, and the oxaliplatin.
In some embodiments, which may be combined with any of the preceding embodiments, administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin results in a survival of the human of at least about 10 months or more, at least about 11 months or more, at least about 12 months or more, at least about 13 months or more, at least about 14 months or more, or at least about 15 months or more after initiation of treatment with the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin. In some embodiments, administration of the immunoconjugate, the omutazumab, the gemcitabine, and the oxaliplatin to a plurality of people results in a median total survival of these people of at least about 10 months or more, at least about 11 months or more, at least about 12 months or more, at least about 13 months or more, at least about 14 months or more, or at least about 15 months or more after initiation of treatment with the immunoconjugate, the omutazumab, the gemcitabine, and the oxaliplatin. In some embodiments, administration of the immunoconjugate, the otouzumab, the gemcitabine, and the oxaliplatin results in an increase in survival of the human as compared to administration of the otouzumab, the gemcitabine, and the oxaliplatin to a corresponding human. In some embodiments, administration of the immunoconjugate, the omtuzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase in the median overall survival of these humans as compared to a plurality of corresponding humans administered with the omtuzumab, the gemcitabine, and the oxaliplatin.
In some embodiments, which may be combined with any of the preceding embodiments, the immunoconjugate, the otophyllizumab, the gemcitabine, and the oxaliplatin do not cause tumor lysis syndrome in the human. In some embodiments, the methods provided herein further comprise administering to the human a prophylactic treatment against tumor lysis syndrome before, during, and/or after administering the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin to the human.
In some embodiments, which may be combined with any of the preceding embodiments, the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin do not cause an infection in the human. In some embodiments, the infection is a pneumosporoal infection or a herpes virus infection. In some embodiments, the methods provided herein further comprise administering to the human a prophylactic treatment against the infection before, during, and/or after the administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin to the human.
In some embodiments, which may be combined with any of the preceding embodiments, the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin do not result in neutropenia in the human. In some embodiments, the methods provided herein further comprise administering to the human a prophylactic treatment for neutropenia before, during, and/or after the administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin to the human. In some embodiments, the prophylactic treatment for neutropenia comprises administering G-CSF to the human. In some embodiments, the methods provided herein further comprise discontinuing treatment with the immunoconjugate, the octuzumab, the gemcitabine, and the oxaliplatin if the human experiences grade 3 or grade 4 neutropenia following administration of the immunoconjugate, the octuzumab, the gemcitabine, and the oxaliplatin. In some embodiments, the method further comprises resuming treatment with the immunoconjugate, the octuzumab, the gemcitabine, and the oxaliplatin if the Absolute Neutrophil Count (ANC) of the human increases to >1000/μl. In some embodiments, the method further comprises administering one or more growth factors to treat neutropenia. In some embodiments, the one or more growth factors comprise G-CSF. In some embodiments, the method further comprises, if the ANC of the human is restored to >1000/μl at or before day 7 of the 21 day cycle, restoring treatment with the immunoconjugate, the omuzumab, the gemcitabine, and the oxaliplatin without reducing the dose of the immunoconjugate, the omuzumab, the gemcitabine, and the oxaliplatin. In some embodiments, the method further comprises, if the ANC of the human returns to >1000/μl after day 7 of the 21-day cycle, resuming treatment with the immunoconjugate, the omutazumab, the gemcitabine, and the oxaliplatin, wherein the dose of the immunoconjugate is reduced to 1.4mg/kg. In some embodiments, the method further comprises interrupting treatment with the immunoconjugate, the octuzumab, the gemcitabine, and the oxaliplatin if a dose reduction of the immunoconjugate, the octuzumab, the gemcitabine, and the oxaliplatin has previously occurred.
In some embodiments, which may be combined with any of the preceding embodiments, the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin do not result in reactivation of hepatitis b in the human. In some embodiments, the methods provided herein further comprise administering to the human a prophylactic treatment for hepatitis b reactivation prior to, during, and/or after administering the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin to the human. In some embodiments, the methods provided herein further comprise administering an antiviral drug therapy to the human if reactivation of hepatitis b is detected in the human.
In some embodiments, which may be combined with any of the preceding embodiments, administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin does not result in one or more adverse events selected from the group consisting of: drug-induced liver injury, progressive multifocal leukoencephalopathy, systemic hypersensitivity, anaphylaxis, anaphylactoid reactions, and secondary malignancy.
In some embodiments, which may be combined with any of the preceding embodiments, administration of the immunoconjugate, the otouzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase in the rate of complete remission (CRR) as compared to a plurality of corresponding humans administered with the otouzumab, the gemcitabine, and the oxaliplatin.
In some embodiments, which may be combined with any of the preceding embodiments, administration of the immunoconjugate, the otouzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase in the Objective Remission Rate (ORR) as compared to a plurality of corresponding humans administered with the otouzumab, the gemcitabine, and the oxaliplatin.
In some embodiments, which may be combined with any of the preceding embodiments, administration of the immunoconjugate, the otouzumab, the gemcitabine, and the oxaliplatin to a plurality of people results in an increase in the optimal total remission rate (BOR) as compared to a plurality of corresponding people administered the otouzumab, the gemcitabine, and the oxaliplatin.
In some embodiments, which may be combined with any of the preceding embodiments, administration of the immunoconjugate, the otouzumab, the gemcitabine, and the oxaliplatin to a plurality of people results in an increase in duration of remission (DOR) as compared to a plurality of corresponding people administered the otouzumab, the gemcitabine, and the oxaliplatin.
In some embodiments, which may be combined with any of the preceding embodiments, administering the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin to a plurality of people results in a1 year progression-free survival rate of at least about 30% or greater, at least about 40% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of these people. In some embodiments, administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin to a plurality of people results in a 2-year progression-free survival rate of at least about 63% or greater, at least about 65% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of these people. In some embodiments, administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin to a plurality of people results in a 5-year progression-free survival rate of at least about 14% or greater, at least about 15% or greater, at least about 20% or greater, at least about 30% or greater, at least about 40% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or 100% of these people. In some embodiments, administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin to a plurality of people results in an increase in progression free survival of those people for 1 year, 2 years, 3.5 years, or 5 years, as compared to a plurality of corresponding people administered the otophyllab, the gemcitabine, and the oxaliplatin.
In some embodiments, which may be combined with any of the preceding embodiments, administering the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin to a plurality of people results in a total survival rate of at least about 42% or greater, at least about 45% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of these people for 1 year. In some embodiments, administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin to a plurality of people results in a 2-year progression-free survival rate of at least about 67% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of these people. In some embodiments, administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin to a plurality of people results in a 3.5 year overall survival rate of these people of at least about 38% or greater, at least about 40% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100%. In some embodiments, administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin to a plurality of people results in a 5-year overall survival rate of these people of at least about 15% or greater, at least about 20% or greater, at least about 30% or greater, at least about 40% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or 100%. In some embodiments, administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase in the overall survival rate of these humans for 1 year, 2 years, 3.5 years, or 5 years, as compared to a plurality of corresponding humans administered the otophyllab, the gemcitabine, and the oxaliplatin.
In some embodiments, which may be combined with any of the preceding embodiments, administering the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin to a plurality of people results in a 2-year event-free survival rate of at least about 44% or greater, at least about 45% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of these people. In some embodiments, administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin to a plurality of people results in an increase in event-free survival rate of 1 year, 2 years, 3.5 years, or 5 years for these people compared to a plurality of corresponding people administered the otophyllab, the gemcitabine, and the oxaliplatin.
In some embodiments, which may be combined with any of the preceding embodiments, administering the immunoconjugate, the otophyllizumab, the gemcitabine, and the oxaliplatin to a plurality of people results in an objective remission rate of at least about 44% or greater, at least about 45% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of these people.
In some embodiments, which may be combined with any of the preceding embodiments, administering the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin to a plurality of people results in a complete remission rate of at least about 35% or greater, at least about 40% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of these people.
In some embodiments, which may be combined with any of the preceding embodiments, administering the immunoconjugate, the otophyllizumab, the gemcitabine, and the oxaliplatin to a plurality of people results in a partial remission rate of at least about 10% or greater, at least about 20% or greater, at least about 30% or greater, at least about 40% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of these people. In some embodiments, which may be combined with any of the preceding embodiments, administration of the immunoconjugate, the otobulab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase in the rate of partial remission as compared to a plurality of corresponding humans administered with the otobulab, the gemcitabine, and the oxaliplatin.
In another aspect, provided herein is a kit comprising an immunoconjugate comprising the formula (la)
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8 for use in combination with octuzumab, gemcitabine and oxaliplatin according to any of the preceding embodiments for treating a human in need thereof having Diffuse Large B Cell Lymphoma (DLBCL).
In another aspect, provided herein is a kit comprising poluzumab vedotin-piiq for use in combination with octuzumab, gemcitabine, and oxaliplatin according to any of the preceding embodiments in treating a human in need thereof with diffuse large B-cell lymphoma (DLBCL).
In another aspect, provided herein is an immunoconjugate comprising formula (la)
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8 for use in a method for treating Diffuse Large B Cell Lymphoma (DLBCL) in combination with octuzumab, gemcitabine and oxaliplatin according to any of the preceding embodiments.
In another aspect, provided herein is an method of treating Diffuse Large B Cell Lymphoma (DLBCL) using an omutazumab in combination with an immunoconjugate, gemcitabine and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8.
In another aspect, provided herein is gemcitabine for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) in combination with an immunoconjugate, omutazumab, and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8.
In another aspect, provided herein is oxaliplatin for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine and otobulab according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8.
In another aspect, provided herein is an immunoconjugate comprising formula (la)
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8 for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) according to any one of the preceding embodiments in combination with octuzumab, gemcitabine and oxaliplatin; wherein the human does not experience a grade 3 or higher peripheral neuropathy that does not regress to a grade 1 or lower within 14 days after administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin.
In another aspect, provided herein is an immunoconjugate comprising formula (la)
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8 for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) according to any one of the preceding embodiments in combination with octuzumab, gemcitabine and oxaliplatin; wherein administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin does not result in a grade 3 or higher peripheral neuropathy that does not regress to a grade 1 or lower within 14 days in the human.
In another aspect, provided herein is an immunoconjugate comprising formula (la)
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8 for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) according to any one of the preceding embodiments in combination with octuzumab, gemcitabine and oxaliplatin; wherein 33% or less of the plurality of persons who receive the treatment develop a grade 3 or higher peripheral neuropathy that does not resolve to grade 1 or lower within 14 days after administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin.
In another aspect, provided herein is an immunoconjugate comprising formula (la)
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8 for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) according to any one of the preceding embodiments in combination with octuzumab, gemcitabine and oxaliplatin; wherein administration of the immunoconjugate, the octuzumab, the gemcitabine, and the oxaliplatin to a plurality of people results in 3 or more peripheral neuropathy in 33% or less of the plurality of people, the 3 or more peripheral neuropathy not regressing to 1 or less within 14 days.
In another aspect, provided herein is an method of treating Diffuse Large B Cell Lymphoma (DLBCL) using an omutazumab in combination with an immunoconjugate, gemcitabine and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8, wherein the human does not experience a grade 3 or higher peripheral neuropathy that does not regress to a grade 1 or lower within 14 days after administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin.
In another aspect, provided herein is an method of treating Diffuse Large B Cell Lymphoma (DLBCL) using an omutazumab in combination with an immunoconjugate, gemcitabine and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8, wherein administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin does not result in a grade 3 or higher peripheral neuropathy that does not regress to a grade 1 or lower within 14 days in the human.
In another aspect, provided herein is an method of treating Diffuse Large B Cell Lymphoma (DLBCL) using an omutazumab in combination with an immunoconjugate, gemcitabine and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8, wherein in a plurality of people receiving treatment, 33% or less of the plurality of people have peripheral neuropathy of grade 3 or higher which does not resolve to grade 1 or lower within 14 days after administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin.
In another aspect, provided herein is an method of treating Diffuse Large B Cell Lymphoma (DLBCL) using an omutazumab in combination with an immunoconjugate, gemcitabine and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8, wherein administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin to a plurality of people results in a grade 3 or higher peripheral neuropathy that does not regress to grade 1 or lower within 14 days in 33% or less of the people in the plurality of people.
In another aspect, provided herein is gemcitabine for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) in combination with an immunoconjugate, omutazumab, and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8, wherein the human does not experience a grade 3 or higher peripheral neuropathy that does not regress to a grade 1 or lower within 14 days after administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin.
In another aspect, provided herein is gemcitabine for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) in combination with an immunoconjugate, omutazumab, and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8, wherein administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin does not result in a grade 3 or higher peripheral neuropathy that does not regress to a grade 1 or lower within 14 days in the human.
In another aspect, provided herein is gemcitabine for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) in combination with an immunoconjugate, omutazumab, and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8, wherein in a plurality of people receiving treatment, 33% or less of the plurality of people have peripheral neuropathy of grade 3 or higher which does not resolve to grade 1 or lower within 14 days after administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin.
In another aspect, provided herein is gemcitabine for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) in combination with an immunoconjugate, omutazumab, and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8, wherein administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin to a plurality of people results in a grade 3 or higher peripheral neuropathy that does not regress to grade 1 or lower within 14 days in 33% or less of the people in the plurality of people.
In another aspect, provided herein is oxaliplatin for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine and otobulab according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8, wherein the human does not experience a grade 3 or higher peripheral neuropathy that does not regress to a grade 1 or lower within 14 days after administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin.
In another aspect, provided herein is oxaliplatin for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine and otobulab according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8, wherein administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin does not result in a grade 3 or higher peripheral neuropathy that does not regress to a grade 1 or lower within 14 days in the human.
In another aspect, provided herein is oxaliplatin for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine and otobulab according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8, wherein in a plurality of people receiving treatment, 33% or less of the plurality of people have peripheral neuropathy of grade 3 or higher which does not resolve to grade 1 or lower within 14 days after administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin.
In another aspect, provided herein is oxaliplatin for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine and otobulab according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and wherein p is between 1 and 8, wherein administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin to a plurality of people results in a grade 3 or higher peripheral neuropathy that does not regress to grade 1 or lower within 14 days in 33% or less of the people in the plurality of people.
In another aspect, provided herein is a method for treating recurrent or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human in need thereof, comprising administering to the human a 1.8mg/kg dose of pertuzumab vedotin-piiq, a 375mg/m 2 dose of rituximab, a 1000mg/m 2 dose of gemcitabine, and a 100mg/m 2 dose of oxaliplatin.
In another aspect, provided herein is a method for treating recurrent or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human in need thereof, comprising administering to the human a dose of 1.8mg/kg of pertuzumab vedotin-piiq, a dose of 375mg/m 2 of rituximab, a dose of 1000mg/m 2 of gemcitabine, and a dose of 100mg/m 2 of oxaliplatin, wherein the pertuzumab vedotin-piiq, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21 day period, wherein the pertuzumab vedotin-piiq and rituximab are administered intravenously on day 1 of each 21 day period, and wherein the gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21 day period.
In another aspect, provided herein is a method for treating recurrent or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human in need thereof, comprising administering to the human a dose of Iladatuzumab vedotin mg/kg, a dose of 375mg/m 2 rituximab, a dose of 1000mg/m 2 of gemcitabine, and a dose of 100mg/m 2 of oxaliplatin.
In another aspect, provided herein is a method for treating recurrent or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human in need thereof, comprising administering to the human a dose of Iladatuzumab vedotin mg/kg, a dose of 375mg/m 2 rituximab, a dose of 1000mg/m 2 of gemcitabine, and a dose of 100mg/m 2 of oxaliplatin.
In another aspect, provided herein is a method for treating recurrent or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human in need thereof, comprising administering to the human a dose of Iladatuzumab vedotin mg/kg, a dose of 375mg/m 2 rituximab, a dose of 1000mg/m 2 of gemcitabine, and a dose of 100mg/m 2 of oxaliplatin, wherein Iladatuzumab vedotin, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day period, wherein Iladatuzumab vedotin and rituximab are administered intravenously on day 1 of each 21-day period, and wherein gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day period.
In another aspect, provided herein is a method for treating recurrent or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human in need thereof, comprising administering to the human a dose of Iladatuzumab vedotin mg/kg, a dose of 375mg/m 2 rituximab, a dose of 1000mg/m 2 of gemcitabine, and a dose of 100mg/m 2 of oxaliplatin, wherein Iladatuzumab vedotin, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day period, wherein Iladatuzumab vedotin and rituximab are administered intravenously on day 1 of each 21-day period, and wherein gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day period.
In another aspect, provided herein is a method for treating recurrent or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human in need thereof, comprising administering to the human a dose of 1.8mg/kg of pertuzumab vedotin-piiq, a dose of 1000mg of octuzumab, a dose of 1000mg/m 2 of gemcitabine, and a dose of 100mg/m 2 of oxaliplatin.
In another aspect, provided herein is a method for treating recurrent or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human in need thereof, comprising administering to the human a dose of 1.8mg/kg of pertuzumab vedotin-piiq, a dose of 1000mg of octuzumab, a dose of 1000mg/m 2 of gemcitabine, and a dose of 100mg/m 2 of oxaliplatin, wherein the pertuzumab vedotin-piiq, the octuzumab, the gemcitabine, and the oxaliplatin are administered for at least one 21 day cycle, wherein the pertuzumab vedotin-piiq and the oxaliplatin are administered intravenously on day 1 of each 21 day cycle, and wherein the gemcitabine and the oxaliplatin are administered intravenously on day 2 of each 21 day cycle.
In another aspect, provided herein is a method for treating recurrent or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human in need thereof, comprising administering to the human a dose of Iladatuzumab vedotin, a dose of 1000mg of octuzumab, a dose of 1000mg/m 2 of gemcitabine, and a dose of 100mg/m 2 of oxaliplatin.
In another aspect, provided herein is a method for treating recurrent or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human in need thereof, comprising administering to the human a dose of Iladatuzumab vedotin, a dose of 1000mg of octuzumab, a dose of 1000mg/m 2 of gemcitabine, and a dose of 100mg/m 2 of oxaliplatin.
In another aspect, provided herein is a method for treating recurrent or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human in need thereof, comprising administering to the human a dose of Iladatuzumab vedotin mg/kg, a dose of 1000mg of octuzumab, a dose of 1000mg/m 2 of gemcitabine, and a dose of 100mg/m 2 of oxaliplatin, wherein Iladatuzumab vedotin, octuzumab, gemcitabine, and oxaliplatin are administered for at least one 21-day period, wherein Iladatuzumab vedotin and octuzumab are administered intravenously on day 1 of each 21-day period, and wherein gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day period.
In another aspect, provided herein is a method for treating recurrent or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human in need thereof, comprising administering to the human a dose of Iladatuzumab vedotin mg/kg, a dose of 1000mg of octuzumab, a dose of 1000mg/m 2 of gemcitabine, and a dose of 100mg/m 2 of oxaliplatin, wherein Iladatuzumab vedotin, octuzumab, gemcitabine, and oxaliplatin are administered for at least one 21-day period, wherein Iladatuzumab vedotin and octuzumab are administered intravenously on day 1 of each 21-day period, and wherein gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day period.
In another aspect, provided herein is an immunoconjugate comprising formula (la)
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID No. 26, and wherein p is between 1 and 8, for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) in accordance with any one of the preceding examples in combination with rituximab, gemcitabine and oxaliplatin, wherein the immunoconjugate, rituximab, gemcitabine and oxaliplatin are administered for at least one 21 day period, wherein during each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; and wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein the gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle.
In another aspect, provided herein is rituximab for use in a method for treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID No. 26, and wherein p is between 1 and 8, wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; and wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein the gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle.
In another aspect, provided herein is gemcitabine for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) in combination with an immunoconjugate, rituximab, and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID No. 26, and wherein p is between 1 and 8, wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; and wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein the gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle.
In another aspect, provided herein is oxaliplatin for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) according to any one of the preceding embodiments in combination with an immunoconjugate, gemcitabine and rituximab, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID No. 26, and wherein p is between 1 and 8, wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; and wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein the gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle.
In another aspect, provided herein is an immunoconjugate comprising formula (la)
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, for use in a method according to any one of the preceding examples in combination with rituximab, gemcitabine and oxaliplatin for treating Diffuse Large B Cell Lymphoma (DLBCL), wherein after administration of the immunoconjugate, rituximab, gemcitabine and oxaliplatin the human does not experience grade 3 or higher peripheral neuropathy that does not regress to grade 1 or lower within 14 days; and wherein the immunoconjugates rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; and wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein the gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle.
In another aspect, provided herein is an immunoconjugate comprising formula (la)
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, for use in a method according to any one of the preceding examples in combination with rituximab, gemcitabine and oxaliplatin for the treatment of Diffuse Large B Cell Lymphoma (DLBCL), wherein administration of the immunoconjugate, rituximab, gemcitabine and oxaliplatin does not result in grade 3 or higher peripheral neuropathy that does not regress to grade 1 or lower within 14 days in the human; and wherein the immunoconjugates rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; and wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein the gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle.
In another aspect, provided herein is an immunoconjugate comprising formula (la)
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, for use in a method according to any one of the preceding examples in combination with rituximab, gemcitabine, and oxaliplatin for treating Diffuse Large B Cell Lymphoma (DLBCL), wherein 33% or less of the plurality of people, after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin, do not regress to grade 3 or higher peripheral neuropathy below grade 1 or lower within 14 days in a plurality of people receiving the treatment; and wherein the immunoconjugates rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; and wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein the gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle.
In another aspect, provided herein is an immunoconjugate comprising formula (la)
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, for use in a method for treating Diffuse Large B Cell Lymphoma (DLBCL) in combination with rituximab, gemcitabine, and oxaliplatin according to any one of the preceding embodiments, wherein administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in 3 or more grade 3 peripheral neuropathy that does not regress to grade 1 or less in 14 days in 33% or less of the plurality of people; and wherein the immunoconjugates rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; and wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein the gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle.
In another aspect, provided herein is rituximab for use in a method for treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein upon administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin, the human does not experience grade 3 or higher peripheral neuropathy that does not regress to grade 1 or lower within 14 days; and wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; and wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein the gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle.
In another aspect, provided herein is rituximab for use in a method for treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not result in a grade 3 or higher peripheral neuropathy that does not regress to a grade 1 or lower within 14 days in the human; and wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; and wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein the gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle.
In another aspect, provided herein is rituximab for use in a method for treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein in a plurality of persons receiving treatment, 33% or less of the plurality of persons have peripheral neuropathy of grade 3 or higher which does not regress to grade 1 or lower within 14 days after administration of the immunoconjugate, rituximab, gemcitabine and oxaliplatin; and wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; and wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein the gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle.
In another aspect, provided herein is rituximab for use in a method for treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of humans results in 3 or higher peripheral neuropathy that does not resolve to 1 or lower stage within 14 days in 33% or less of the plurality of humans; and wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; and wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein the gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle.
In another aspect, provided herein is gemcitabine for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) in combination with an immunoconjugate, rituximab, and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein upon administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin, the human does not experience grade 3 or higher peripheral neuropathy that does not regress to grade 1 or lower within 14 days; and wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; and wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein the gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle.
In another aspect, provided herein is gemcitabine for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) in combination with an immunoconjugate, rituximab, and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not result in a grade 3 or higher peripheral neuropathy that does not regress to a grade 1 or lower within 14 days in the human; and wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; and wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein the gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle.
In another aspect, provided herein is gemcitabine for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) in combination with an immunoconjugate, rituximab, and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein in a plurality of persons receiving treatment, 33% or less of the plurality of persons have peripheral neuropathy of grade 3 or higher which does not regress to grade 1 or lower within 14 days after administration of the immunoconjugate, rituximab, gemcitabine and oxaliplatin; and wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; and wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein the gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle.
In another aspect, provided herein is gemcitabine for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) in combination with an immunoconjugate, rituximab, and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of humans results in 3 or higher peripheral neuropathy that does not resolve to 1 or lower stage within 14 days in 33% or less of the plurality of humans; and wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; and wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein the gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle.
In another aspect, provided herein is oxaliplatin for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) according to any one of the preceding embodiments in combination with an immunoconjugate, gemcitabine and rituximab, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein upon administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin, the human does not experience grade 3 or higher peripheral neuropathy that does not regress to grade 1 or lower within 14 days; and wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; and wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein the gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle.
In another aspect, provided herein is oxaliplatin for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) according to any one of the preceding embodiments in combination with an immunoconjugate, gemcitabine and rituximab, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not result in a grade 3 or higher peripheral neuropathy that does not regress to a grade 1 or lower within 14 days in the human; and wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; and wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein the gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle.
In another aspect, provided herein is oxaliplatin for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) according to any one of the preceding embodiments in combination with an immunoconjugate, gemcitabine and rituximab, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein in a plurality of persons receiving treatment, 33% or less of the plurality of persons have peripheral neuropathy of grade 3 or higher which does not regress to grade 1 or lower within 14 days after administration of the immunoconjugate, rituximab, gemcitabine and oxaliplatin; and wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; and wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein the gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle.
In another aspect, provided herein is oxaliplatin for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) according to any one of the preceding embodiments in combination with an immunoconjugate, gemcitabine and rituximab, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of humans results in 3 or higher peripheral neuropathy that does not resolve to 1 or lower stage within 14 days in 33% or less of the plurality of humans; and wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; and wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein the gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle.
In another aspect, provided herein is an immunoconjugate comprising formula (la)
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, for use in a method for treating Diffuse Large B Cell Lymphoma (DLBCL) in combination with octuzumab, gemcitabine, and oxaliplatin according to any of the preceding examples, wherein the immunoconjugate, the octuzumab, the gemcitabine, and the oxaliplatin are administered for at least one 21-day period, wherein during each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the octuzumab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2.
In another aspect, provided herein is an method of treating Diffuse Large B Cell Lymphoma (DLBCL) using an omutazumab in combination with an immunoconjugate, gemcitabine and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID No. 26, and wherein p is between 1 and 8, wherein the immunoconjugate, the otobulab, the gemcitabine, and the oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the otobulab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2.
In another aspect, provided herein is gemcitabine for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) in combination with an immunoconjugate, omutazumab, and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID No. 26, and wherein p is between 1 and 8, wherein the immunoconjugate, the otobulab, the gemcitabine, and the oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the otobulab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2.
In another aspect, provided herein is oxaliplatin for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine and otobulab according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID No. 26, and wherein p is between 1 and 8, wherein the immunoconjugate, the otobulab, the gemcitabine, and the oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the otobulab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2.
In another aspect, provided herein is an immunoconjugate comprising formula (la)
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, for use in a method according to any one of the preceding examples in combination with octuzumab, gemcitabine, and oxaliplatin for treating Diffuse Large B Cell Lymphoma (DLBCL), wherein upon administration of the immunoconjugate, the octuzumab, the gemcitabine, and the oxaliplatin, the human does not experience grade 3 or higher peripheral neuropathy that does not regress to grade 1 or lower within 14 days; and wherein the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the otophyllab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2.
In another aspect, provided herein is an immunoconjugate comprising formula (la)
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, for use in a method according to any one of the preceding examples in combination with omuzumab, gemcitabine, and oxaliplatin for the treatment of Diffuse Large B Cell Lymphoma (DLBCL), wherein administration of the immunoconjugate, omuzumab, gemcitabine, and oxaliplatin does not result in grade 3 or higher peripheral neuropathy that does not regress to grade 1 or lower within 14 days in the human; and wherein the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the otophyllab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2.
In another aspect, provided herein is an immunoconjugate comprising formula (la)
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID No. 26, and wherein p is between 1 and 8, for use in a method according to any one of the preceding examples in combination with omuzumab, gemcitabine, and oxaliplatin for treating Diffuse Large B Cell Lymphoma (DLBCL), wherein 33% or less of the plurality of people, after administration of the immunoconjugate, omuzumab, gemcitabine, and oxaliplatin, do not regress to grade 1 or less peripheral neuropathy in the 3 or more peripheral neuropathy within 14 days in the plurality of people receiving treatment; and wherein the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the otophyllab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2.
In another aspect, provided herein is an immunoconjugate comprising formula (la)
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, for use in a method for treating Diffuse Large B Cell Lymphoma (DLBCL) in combination with octuzumab, gemcitabine, and oxaliplatin according to any of the preceding examples, wherein administration of the immunoconjugate, the octuzumab, the gemcitabine, and the oxaliplatin to a plurality of people results in 33% or less of the plurality of people having peripheral neuropathy of grade 3 or higher that does not regress to grade 1 or lower within 14 days; and wherein the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the otophyllab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2.
In another aspect, provided herein is an method of treating Diffuse Large B Cell Lymphoma (DLBCL) using an omutazumab in combination with an immunoconjugate, gemcitabine and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein upon administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin, the human does not experience grade 3 or higher peripheral neuropathy that does not regress to grade 1 or lower within 14 days; and wherein the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the otophyllab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2.
In another aspect, provided herein is an method of treating Diffuse Large B Cell Lymphoma (DLBCL) using an omutazumab in combination with an immunoconjugate, gemcitabine and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin does not result in a grade 3 or higher peripheral neuropathy in the human that does not regress to a grade 1 or lower within 14 days; and wherein the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the otophyllab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2.
In another aspect, provided herein is an method of treating Diffuse Large B Cell Lymphoma (DLBCL) using an omutazumab in combination with an immunoconjugate, gemcitabine and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein in a plurality of persons receiving treatment, 33% or less of the plurality of persons have peripheral neuropathy of grade 3 or higher which does not regress to grade 1 or lower within 14 days after administration of the immunoconjugate, octuzumab, gemcitabine and oxaliplatin; and wherein the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the otophyllab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2.
In another aspect, provided herein is an method of treating Diffuse Large B Cell Lymphoma (DLBCL) using an omutazumab in combination with an immunoconjugate, gemcitabine and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID No. 26, and wherein p is between 1 and 8, wherein administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin to a plurality of humans results in 3 or higher peripheral neuropathy that does not resolve to 1 or lower in 14 days in 33% or less of the plurality of humans; and wherein the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the otophyllab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2.
In another aspect, provided herein is gemcitabine for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) in combination with an immunoconjugate, omutazumab, and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein upon administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin, the human does not experience grade 3 or higher peripheral neuropathy that does not regress to grade 1 or lower within 14 days; and wherein the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the otophyllab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2.
In another aspect, provided herein is gemcitabine for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) in combination with an immunoconjugate, omutazumab, and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin does not result in a grade 3 or higher peripheral neuropathy in the human that does not regress to a grade 1 or lower within 14 days; and wherein the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the otophyllab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2.
In another aspect, provided herein is gemcitabine for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) in combination with an immunoconjugate, omutazumab, and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein in a plurality of persons receiving treatment, 33% or less of the plurality of persons have peripheral neuropathy of grade 3 or higher which does not regress to grade 1 or lower within 14 days after administration of the immunoconjugate, octuzumab, gemcitabine and oxaliplatin; and wherein the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the otophyllab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2.
In another aspect, provided herein is gemcitabine for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) in combination with an immunoconjugate, omutazumab, and oxaliplatin according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID No. 26, and wherein p is between 1 and 8, wherein administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin to a plurality of humans results in 3 or higher peripheral neuropathy that does not resolve to 1 or lower in 14 days in 33% or less of the plurality of humans; and wherein the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the otophyllab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2.
In another aspect, provided herein is oxaliplatin for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine and otobulab according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID No. 26, and wherein p is between 1 and 8, wherein after administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin, the human does not experience grade 3 or higher peripheral neuropathy that does not regress to grade 1 or lower within 14 days; and wherein the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the otophyllab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2.
In another aspect, provided herein is oxaliplatin for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine and otobulab according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID No. 26, and wherein p is between 1 and 8, wherein administration of the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin does not result in the human experiencing a grade 3 or higher peripheral neuropathy that does not regress to grade 1 or lower within 14 days; and wherein the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the otophyllab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2.
In another aspect, provided herein is oxaliplatin for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine and otobulab according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein in a plurality of persons receiving treatment, 33% or less of the plurality of persons have peripheral neuropathy of grade 3 or higher which does not regress to grade 1 or lower within 14 days after administration of the immunoconjugate, octuzumab, gemcitabine and oxaliplatin; and wherein the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the otophyllab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2.
In another aspect, provided herein is oxaliplatin for use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine and otobulab according to any one of the preceding embodiments, wherein the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein administration of the immunoconjugate, the octuzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in 3 or higher peripheral neuropathy that does not resolve to 1 or lower in 14 days in 33% or less of the plurality of humans; and wherein the immunoconjugate, the otophyllab, the gemcitabine, and the oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the otophyllab is administered at a dose of about 1000mg, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2.
Drawings
Fig. 1 is a schematic diagram of the overall design of the study described in example 1. Pola = polotophyllizumab vedotin; rand = randomization; R-GemOx = rituximab plus gemcitabine plus oxaliplatin; R/R DLBCL = recurrent or refractory diffuse large B-cell lymphoma.
Fig. 2 is a schematic diagram of stage 1 (safety lead-in period) of the study described in example 1. EOT = end of treatment; RCT = random control (phase 2).
Figures 3A-3B show experimental and control treatment regimens for the study described in example 1. FIG. 3A is a schematic representation of the experimental treatment regimen (Pola-R-GemOx) studied as described in example 1. Diamonds indicate the dose of rituximab (375 mg/m 2); circles represent the dose of the polotophyllizumab vedotin (1.8 mg/kg); the thin arrow represents the dose of gemcitabine (1000 mg/m 2); the broad arrow represents the dose of oxaliplatin (100 mg/m 2);a rituximab administered before the polozolomide vedotin; b gemcitabine administered before the oxaliplatin fig. 3B is a schematic of the control treatment regimen (R-GemOx) of the study described in example 1, diamond indicates the dose of rituximab (375 mg/m 2), the thin arrow represents the dose of gemcitabine (1000 mg/m 2), the broad arrow represents the dose of oxaliplatin (100 mg/m 2);a gemcitabine administered before the oxaliplatin. In fig. 3A-3B, c=cycle (21 days for 1 cycle); d=day; and iv=intravenous.
Detailed Description
As used herein, the term "poloxamer (Polatuzumab) vedotin-piiq" refers to an anti-CD 79b immunoconjugate having iuphas/BPS number 8404, KEGG number D10761, or CAS accession number 1313206-42-6. Polotuzumab vedotin-piiq is also interchangeably referred to as "Polotuzumab (Polatuzumab) vedotin", "huMA79bv28-MC-vc-PAB-MMAE", "DCDS4501A" or "RG7596".
Provided herein are methods for treating or slowing the progression of diffuse large B-cell lymphoma (DLBCL, e.g., relapsed/refractory DLBCL) in an individual (e.g., a human) comprising administering to the individual an effective amount of an anti-CD 79B immunoconjugate (e.g., polo-toxazumab vedotin-piiq), an anti-CD 20 agent (e.g., an anti-CD 20 antibody, such as rituximab), and one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin).
In some embodiments, the method comprises a method of treating an individual with diffuse large B-cell lymphoma (DLBCL) (e.g., recurrent/refractory DLBCL) by: administering to the individual (a) an immunoconjugate comprising formula (la)
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising amino acid sequence GYTFSSYWIE (SEQ ID NO: 21); (ii) HVR-H2 comprising amino acid sequence GEILPGGGDTNYNEIFKG (SEQ ID NO: 22); (iii) HVR-H3 comprising amino acid sequence TRRVPIRLDY (SEQ ID NO: 23); (iv) HVR-L1 comprising amino acid sequence KASQSVDYEGDSFLN (SEQ ID NO: 24); (v) HVR-L2 comprising amino acid sequence AASNLES (SEQ ID NO: 25); and (vi) HVR-L3 comprising the amino acid sequence of QQSNEDPLT (SEQ ID NO: 26), and wherein p is between 1 and 8 (e.g., between 2 and 5, or between 3 and 4); (b) an anti-CD 20 agent (e.g., rituximab); and (c) one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin). In some embodiments, the immunoconjugate is administered at a dose of between about 1.4mg/kg and about 1.8mg/kg, the anti-CD 20 agent (e.g., rituximab) is administered at a dose of about 375mg/m 2, gemcitabine is administered at a dose of about 1000mg/m 2, and oxaliplatin is administered at a dose of about 100mg/m 2.
I. general technique
The practice of the present invention will employ, unless otherwise indicated, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry and immunology, which are within the skill of the art. Such techniques are fully explained in the following documents, such as "Molecular Cloning: A Laboratory Manual", 2 nd edition (Sambrook et al, 1989); "Oligonucleotide Synthesis" (M.J.Gait, 1984); "ANIMAL CELL Culture" (R.I. Freshney, inc. ,1987);"Methods in Enzymology"(Academic Press,Inc.);"Current Protocols in Molecular Biology"(F.M.Ausubel et al, 1987, and periodic updates); "PCR The Polymerase Chain Reaction" (Mullis et al, code ,1994);"A Practical Guide to Molecular Cloning"(Perbal Bernard V.,1988);"Phage Display:A Laboratory Manual",Barbas et al, 2001).
II. Definition of
Before describing the present invention in detail, it is to be understood that this invention is not limited to particular compositions or biological systems, which may, of course, vary. In addition, it is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
As used in this specification and the appended claims, the singular forms "a," "an," "the," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a molecule" optionally includes a combination of two or more such molecules, and the like.
The term "about" as used herein refers to a common error range for the corresponding value as readily known to those skilled in the art. References herein to "about" a value or parameter include (and describe) embodiments that relate to the value or parameter itself.
It is to be understood that the aspects and embodiments of the invention described herein include aspects and embodiments referred to as "comprising," consisting of, "and" consisting essentially of.
The term "CD79b" as used herein refers to any natural CD79b from any vertebrate source, including mammals such as primates (e.g., humans, cynomolgus ("cyno")) and rodents (e.g., mice and rats), unless otherwise indicated. Human CD79B is also referred to herein as "igβ", "B29", "DNA225786" or "PRO36249". An exemplary CD79b sequence comprising a signal sequence is shown in SEQ ID NO. 1. An exemplary CD79b sequence without a signal sequence is shown in SEQ ID NO. 2. The term "CD79b" encompasses "full length" unprocessed CD79b, as well as any form of CD79b produced by processing in a cell. The term also encompasses naturally occurring variants of CD79b, such as splice variants, allelic variants, and isoforms. The CD79b polypeptides described herein may be isolated from a variety of sources, such as from human tissue types or other sources, or produced by recombinant or synthetic methods. "native sequence CD79b polypeptides" comprise polypeptides having the same amino acid sequence as the corresponding CD79b polypeptide from nature. Such native sequence CD79b polypeptides may be isolated from nature or may be produced recombinantly or synthetically. The term "native sequence CD79b polypeptide" specifically encompasses naturally occurring truncated or secreted forms (e.g., extracellular domain sequences), naturally occurring variant forms (e.g., alternatively spliced forms) of a particular CD79b polypeptide, and naturally occurring allelic variants of the polypeptide.
As used herein, "CD20" refers to the human B lymphocyte antigen CD20 (also known as CD20, B lymphocyte surface antigen B1, leu-16, bp35, BM5, and LF5; the sequence is characterized by SwissProt database entry P11836), which is a hydrophobic transmembrane protein of about 35kD molecular weight located on pre-B and mature B lymphocytes. (Valentine, M.A. et al, J.biol. Chem.264 (19) (1989 11282-11287; tedder, T.F. et al, proc. Natl. Acad. Sci. U.S. A.85 (1988) 208-12; stamekovic, I. Et al, J.exp. Med.167 (1988) 1975-80; einfeld, D.A. et al, EMBO J.7 (1988) 711-7; tedder, T.F. et al, J.Immunol.142 (1989) 2560-8.) the corresponding human gene is a transmembrane 4 domain, subfamily A member 1, also known as member of the family of genes encoding transmembrane 4A genes, members of the nascent protein family being characterized by common structural features and similar intronic/exon boundaries, and exhibiting a unique expression pattern in hematopoietic cells and non-lymphoid tissues, the B cell surface of the genes encoding the gene being a variant of the gene in the same family of genes encoding the two cell-specific gene clusters in the cell-surface of the cell-envelope 11, and the B-cell-envelope of the gene producing the variant of the gene in the same gene family in the cell-envelope 11.
The terms "CD20" and "CD20 antigen" are used interchangeably herein and include any variant, isoform, and species homolog of human CD20 that is naturally expressed by a cell or expressed on a cell transfected with the CD20 gene. Binding of the antibodies of the invention to CD20 antigen mediates killing of CD20 expressing cells (e.g., tumor cells) by inactivating CD 20. Killing of cells expressing CD20 may occur through one or more of the following mechanisms: cell death/apoptosis induction, ADCC and CDC. As recognized in the art, the aliases for CD20 include the B lymphocyte antigen CD20, the B lymphocyte surface antigen B1, leu-16, bp35, BM5 and LF5.
The term "expression of CD20 antigen" is intended to mean the expression of a significant level of CD20 antigen in a cell (e.g., a T cell or B cell). In one embodiment, a patient to be treated according to the methods of the invention expresses significant levels of CD20 on a B cell tumor or cancer. Patients with "CD20 expressing cancers" can be determined by standard assays known in the art. For example, CD20 antigen expression is measured using Immunohistochemical (IHC) detection, FACS, or by detection of the corresponding mRNA based on PCR.
"Affinity" refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). As used herein, "binding affinity" refers to an intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (such as antibodies and antigens), unless otherwise specified. The affinity of a molecule X for its partner Y can generally be expressed by a dissociation constant (Kd). Affinity can be measured by conventional methods known in the art, including those described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described below.
An "affinity matured" antibody refers to an antibody having one or more alterations in one or more hypervariable regions (HVRs) that result in an improvement in the affinity of the antibody for an antigen as compared to a parent antibody that does not have such alterations.
The term "antibody" is used herein in its broadest sense and includes a variety of antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired antigen-binding activity.
An "antibody fragment" refers to a molecule other than an intact antibody that comprises a portion of the intact antibody and binds to an antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to Fv, fab, fab ', fab ' -SH, F (ab ') 2; a diabody antibody; a linear antibody; single chain antibody molecules (e.g., scFv); and multispecific antibodies formed from antibody fragments.
By "antibody that binds to the same epitope" as the reference antibody is meant an antibody that blocks the binding of the reference antibody to its antigen by 50% or more in a competition assay, whereas the reference antibody blocks the binding of the antibody to its antigen by 50% or more in a competition assay. An exemplary competition assay is provided herein.
The term "epitope" refers to a specific site on an antigen molecule to which an antibody binds.
The term "chimeric" antibody refers to an antibody in which a portion of the heavy and/or light chains are derived from a particular source or species, while the remainder of the heavy and/or light chains are derived from a different source or species.
The "class" of antibodies refers to the type of constant domain or constant region that the heavy chain of an antibody has. There are five main classes of antibodies: igA, igD, igE, igG and IgM, and some of them can be further divided into subclasses (isotypes), such as IgG 1、IgG2、IgG3、IgG4、IgA1, and IgA 2. The heavy chain constant domains corresponding to the different classes of immunoglobulins are called α, δ, ε, γ and μ, respectively.
The terms "anti-CD 79b antibody" and "antibody that binds CD79 b" refer to antibodies that are capable of binding CD79b with sufficient affinity such that the antibodies are useful as diagnostic and/or therapeutic agents that target CD79 b. Preferably, the anti-CD 79b antibody binds to an unrelated non-CD 79b protein to less than about 10% of the binding of the antibody to CD79b, as measured, for example, by a Radioimmunoassay (RIA). In certain embodiments, antibodies that bind CD79b have a dissociation constant (Kd) of 1. Mu.M, 100nM, 10nM, 1nM or 0.1 nM. In certain embodiments, the anti-CD 79b antibody binds to an epitope of CD79b that is conserved among CD79b from different species.
The term "anti-CD 20 antibody" according to the invention refers to an antibody that is capable of binding CD20 with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent for targeting CD 20. Preferably, the anti-CD 20 antibody binds to an unrelated non-CD 20 protein to less than about 10% of the binding of the antibody to CD20, as measured, for example, by a Radioimmunoassay (RIA). In certain embodiments, antibodies that bind CD20 have a dissociation constant (Kd) of 1. Mu.M, 100nM, 10nM, 1nM or 0.1 nM. In certain embodiments, the anti-CD 20 antibody binds to an epitope of CD20 that is conserved among CD20 from different species.
An "isolated" antibody is an antibody that has been isolated from a component of its natural environment. In some embodiments, the antibodies are purified to greater than 95% or 99% purity as determined by, for example, electrophoresis (e.g., SDS-PAGE, isoelectric focusing (isoelectric focusing, IEF), capillary electrophoresis), or chromatography (e.g., ion exchange or reverse phase HPLC). For a review of methods of assessing antibody purity, see, for example: flatman et al, J.chromatogr.B 848:79-87 (2007). "variable region" or "variable domain" of an antibody refers to the amino-terminal domain of the heavy or light chain of the antibody. The variable domain of the heavy chain may be referred to as "VH". The variable domain of the light chain may be referred to as "VL". These domains are typically the most variable parts of an antibody and comprise antigen binding sites.
"Isolated nucleic acid encoding an anti-CD 79b antibody" refers to one or more nucleic acid molecules encoding the heavy and light chains of the antibody (or fragments thereof), including such nucleic acid molecules in a single vector or in separate vectors, as well as such nucleic acid molecules present at one or more positions in a host cell.
As used herein, the term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., the individual antibodies comprising the population are identical and/or bind to the same epitope except for possible variant antibodies (e.g., containing naturally occurring mutations or produced during production of a monoclonal antibody preparation, such variants typically being present in minor amounts). In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody in a monoclonal antibody preparation is directed against a single determinant on the antigen. Thus, the modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies for use in accordance with the present 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 is not conjugated to a heterologous moiety (e.g., a cytotoxic moiety) or radiolabeled. The naked antibody may be present in a pharmaceutical formulation.
"Natural antibody" refers to naturally occurring immunoglobulin molecules having different structures. For example, a natural IgG antibody is a heterotetrameric glycoprotein of about 150,000 daltons, consisting of two identical light chains and two identical heavy chains that are disulfide-bonded. From the N-terminus to the C-terminus, each heavy chain has a variable region (VH), also known as a variable heavy chain domain or heavy chain variable domain, followed by three constant domains (CH 1, CH2 and CH 3). Similarly, from N-terminal to C-terminal, each light chain has a variable region (VL), also known as a variable light chain domain or light chain variable domain, followed by a constant light Chain (CL) domain. The light chain of an antibody can be assigned to one of two types, called kappa (kappa) and lambda (lambda), based on the amino acid sequence of its constant domain.
The term "Fc region" is used herein to define the C-terminal region of an immunoglobulin heavy chain, which comprises at least a portion of a constant region. The term includes native sequence Fc regions and variant Fc regions. In one embodiment, the human IgG heavy chain Fc region extends from Cys226 or from Pro230 to the carboxy terminus of the heavy chain. However, the C-terminal lysine (Lys 447) of the Fc region may or may not be present. Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also known as the EU index, as described in Kabat et al, sequences of Proteins of Immunological Interest, 5 th edition, public HEALTH SERVICE, national Institutes of Health, bethesda, MD, 1991.
"Framework" or "FR" refers to variable domain residues other than hypervariable region (HVR) residues. The FR of the variable domain typically consists of four FR domains: FR1, FR2, FR3 and FR4. Thus, HVR and FR sequences typically occur in VH (or VL) with the following sequences: FR1-H1 (L1) -FR2-H2 (L2) -FR3-H3 (L3) -FR4.
For purposes herein, a "recipient human framework" is a framework comprising an amino acid sequence derived from a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework of a human immunoglobulin framework or a human consensus framework as defined below. The recipient human framework "derived from" a human immunoglobulin framework or human consensus framework may comprise the same amino acid sequence as the human immunoglobulin framework or human consensus framework, or it may comprise amino acid sequence changes. In some embodiments, the number of amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, the VL acceptor human framework is identical in sequence to the VL human immunoglobulin framework sequence or the human consensus framework sequence.
The terms "full length antibody", "whole antibody" and "whole antibody" are used interchangeably herein to refer to an antibody having a structure substantially similar to the structure of a natural antibody or having a heavy chain comprising an Fc region as defined herein.
The terms "host cell", "host cell line", and "host cell culture" are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include "transformants" and "transformed cells" which include primary transformed cells and progeny derived from such primary transformed cells, regardless of the number of passages. The progeny may not be completely identical to the nucleic acid content of the parent cell, but may contain mutations. Included herein are mutant progeny that have the same function or biological activity as screened or selected in the original transformed cell.
A "human antibody" is an antibody having an amino acid sequence that corresponds to the amino acid sequence of an antibody produced by a human or human cell, or an amino acid sequence derived from a non-human antibody that utilizes the coding sequence of a human antibody library or other human antibody. This definition of human antibodies specifically excludes humanized antibodies that comprise non-human antigen binding residues.
A "human consensus framework" is a framework that represents the amino acid residues that are most commonly present in the selection of human immunoglobulin VL or VH framework sequences. In general, the selection of human immunoglobulin VL or VH sequences is from a subset of variable domain sequences. In general, a subset of sequences is as described in Kabat et al Sequences of Proteins of Immunological Interest, 5 th 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 (supra).
"Humanized" antibody refers to chimeric antibodies that comprise amino acid residues from a non-human HVR and amino acid residues from a human FR. In certain embodiments, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the HVRs (e.g., CDRs) correspond to those of a non-human antibody and all or substantially all of the FRs correspond to those of a human antibody. The humanized antibody optionally may comprise at least a portion of an antibody constant region derived from a human antibody. An antibody in a "humanized form", e.g., a non-human antibody, refers to an antibody that has been humanized.
The term "hypervariable region" or "HVR" as used herein refers to each region of an antibody variable domain that is hypervariable in sequence and/or forms a structurally defined loop ("hypervariable loop"). Typically, a natural four-chain antibody comprises six HVRs: three in VH (H1, H2, H3) and three in VL (L1, L2, L3). HVRs typically comprise amino acid residues from hypervariable loops and/or from "complementarity determining regions" (CDRs) that have the highest sequence variability and/or are involved in antigen recognition. Exemplary hypervariable loops occur at 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)) exemplary CDRs (CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3) occur at amino acid residues 24-34 of L1, amino acid residues 50-56 of L2, amino acid residues 89-97 of L3, amino acid residues 50-65 of amino acid residues 31-35B, H of H1 and amino acid residues 95-102 of H3. (Kabat et al Sequences of Proteins of Immunological Interest, 5 th edition, U.S. department of health and public service, national institutes of health, bethesda, MD (1991)) in addition to CDR1 in VH, the CDRs typically comprise amino acid residues that form hypervariable loops. CDRs also contain "specificity determining residues" or "SDRs," which are residues that contact an antigen. SDR is contained within CDR regions known as shortened CDRs or a-CDRs. Exemplary a-CDRs (a-CDR-L1, a-CDR-L2, a-CDR-L3, a-CDR-H1, a-CDR-H2 and a-CDR-H3) occur at amino acid residues 31-34 of L1, amino acid residues 50-55 of L2, amino acid residues 89-96 of L3, amino acid residues 31-35B, H of H1, amino acid residues 50-58 of H3 and amino acid residues 95-102. (see Almagro and Franson, front. Biosci.13:1619-1633 (2008)) unless otherwise indicated, HVR residues and other residues in the variable domains (e.g., FR residues) are numbered herein according to Kabat et al, supra.
The term "variable region" or "variable domain" refers to the domain of an antibody heavy or light chain that is involved in binding an antibody to an antigen. The variable domains of the heavy and light chains of natural antibodies (VH and VL, respectively) generally have similar structures, with each domain comprising four conserved Framework Regions (FR) and three hypervariable regions (HVR). (see, e.g., kindt et al, kuby Immunology, 6 th edition, w.h. freeman and co., page 91 (2007)) a single VH or VL domain may be sufficient to confer antigen binding specificity. In addition, antibodies that bind a particular antigen can be isolated using VH or VL domains, respectively, from antibodies that bind that antigen to screen libraries of complementary VL or VH domains. See, for example: portolano et al, J.Immunol.150:880-887 (1993); clarkson et al Nature 352:624-628 (1991).
"Effector functions" refer to those biological activities attributable to the Fc region of an antibody that vary with the variation of the antibody isotype. Examples of antibody effector functions include: c1q binding and Complement Dependent Cytotoxicity (CDC); fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down-regulation of cell surface receptors (e.g., B cell receptors); b cell activation.
By "CD79b polypeptide variant" is meant a CD79b polypeptide as defined herein (preferably an active CD79b polypeptide) that has at least about 80% amino acid sequence identity to a full-length native sequence CD79b polypeptide sequence disclosed herein, a CD79b polypeptide lacking a signal peptide as disclosed herein, an extracellular domain of a CD79b polypeptide comprising or not comprising a signal peptide as disclosed herein, or any other fragment of a full-length CD79b polypeptide sequence as disclosed herein, such as those encoded by a nucleic acid that occupies only a portion of the complete coding sequence of a full-length CD79b polypeptide. Such CD79b polypeptide variants include, for example, CD79b polypeptides in which one or more amino acid residues are added or deleted at the N-terminus or C-terminus of the full length native amino acid sequence. Typically, a CD79b polypeptide variant will have at least about 80% amino acid sequence identity, alternatively at least about 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% amino acid sequence identity, to a full length native sequence CD79b polypeptide sequence as disclosed herein, a CD79b polypeptide lacking a signal peptide as disclosed herein, an extracellular domain of a CD79b polypeptide comprising or not comprising a signal peptide as disclosed herein, or any other fragment of a full length CD79b polypeptide sequence as disclosed herein. Typically, the CD79b variant polypeptide is at least about 10 amino acids in length, alternatively at least about 20、30、40、50、60、70、80、90、100、110、120、130、140、150、160、170、180、190、200、210、220、230、240、250、260、270、280、290、300、310、320、330、340、350、360、370、380、390、400、410、420、430、440、450、460、470、480、490、500、510、520、530、540、550、560、570、580、590、600 amino acids or more in length. Optionally, a CD79b variant polypeptide will have no more than one conservative amino acid substitution compared to the native CD79b polypeptide sequence, alternatively will comprise no more than 2, 3,4, 5, 6, 7, 8, 9, or 10 conservative amino acid substitutions compared to the native CD79b polypeptide sequence.
"Percent (%) amino acid sequence identity" with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in the candidate sequence that are identical to amino acid residues in the reference polypeptide sequence after aligning the candidate sequence to the reference polypeptide sequence and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and without regard to any conservative substitutions as part of the sequence identity. The alignment used to determine the percent amino acid sequence identity can be accomplished in a variety of ways within the skill of the art, for example using publicly available computer software such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. One skilled in the art can determine the appropriate parameters for aligning sequences, including any algorithms needed to achieve maximum alignment over the full length of the sequences compared. However, for purposes herein, the sequence comparison computer program ALIGN-2 was used to generate values for% amino acid sequence identity. ALIGN-2 sequence comparison computer programs were written by Genntech, inc., and the source code had been submitted with the user document to U.S. Copyright Office, washington D.C.,20559, where it was registered with U.S. copyright accession number TXU 510087. ALIGN-2 programs are publicly available from Genntech, inc. (Inc., south San Francisco, california) or may be compiled from the source code. The ALIGN-2 program should be compiled for use on a UNIX operating system, including the digital UNIX V4.0D. All sequence comparison parameters were set by the ALIGN-2 program and were unchanged.
In the case of amino acid sequence comparison using ALIGN-2, the amino acid sequence identity of a given amino acid sequence A with a given amino acid sequence B (which may alternatively be expressed as having or comprising some amino acid sequence identity with a given amino acid sequence B) is calculated as follows:
100 times the fraction X/Y
Wherein X is the number of amino acid residues scored as identical matches in the program alignment of A and B by the sequence alignment program ALIGN-2, and wherein Y is the total number of amino acid residues in B. It will be appreciated that in the case where the length of amino acid sequence a is not equal to the length of amino acid sequence B, the% amino acid sequence identity of a to B will not be equal to the% amino acid sequence identity of B to a. All values of% amino acid sequence identity as used herein are obtained using the ALIGN-2 computer program as described in the previous paragraph, unless specifically indicated otherwise.
The term "vector" as used herein refers to a nucleic acid molecule capable of carrying another nucleic acid linked thereto. The term includes vectors that are self-replicating nucleic acid structures, as well as vectors that are incorporated into the genome of a host cell into which they have been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operably linked. Such vectors are referred to herein as "expression vectors".
An "immunoconjugate" is an antibody conjugated to one or more heterologous molecules, including but not limited to a cytotoxic agent.
In the context of the formulas provided herein, "p" refers to the average number of drug moieties per antibody, which may range, for example, from about 1 to about 20 drug moieties per antibody, and in certain embodiments, from 1 to about 8 drug moieties per antibody. The invention includes a composition comprising a mixture of antibody-drug compounds of formula I, wherein the average drug load of each antibody is from about 2 to about 5, or from about 3 to about 4 (e.g., about 3.5).
As used herein, the term "cytotoxic agent" refers to a substance that inhibits or prevents cellular function and/or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioisotopes (e.g., At211、I131、I125、Y90、Re186、Re188、Sm153、Bi212、P32、Pb212 and radioactive isotopes of Lu); chemotherapeutic agents or drugs (e.g., methotrexate, doxorubicin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin, or other intercalating agents); a growth inhibitor; enzymes and fragments thereof such as nucleolytic enzymes; an antibiotic; toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof; and various antitumor or anticancer agents disclosed below.
The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is often characterized by uncontrolled cell growth. Examples of cancers include, but are not limited to: b-cell lymphomas (including mild/follicular non-hodgkin's lymphoma (NHL), small Lymphocytic (SL) NHL, moderate/follicular NHL, moderate diffuse NHL, hyperimmune blast NHL, high lymphocytic NHL, high small non-nucleated cell NHL, giant tumor NHL, mantle cell lymphoma, AIDS-related lymphoma, waldenstrom's macroglobulinemia (Waldenstrom's Macroglobulinemia)); chronic Lymphocytic Leukemia (CLL); acute Lymphoblastic Leukemia (ALL); hairy cell leukemia; chronic granulocytic leukemia; and post-transplant lymphoproliferative disorder (PTLD); and abnormal vascular proliferation associated with mole-type hamartoma, oedema (such as a disease associated with brain tumors), mergers syndrome. More specific examples include, but are not limited to: recurrent or refractory NHL, stage III/IV NHL, chemotherapy-resistant NHL, precursor B-lymphoblastic leukemia and/or lymphoma, small lymphocytic lymphoma, B-cell chronic lymphocytic leukemia and/or pre-and/or small lymphocytic lymphoma, B-cell pre-lymphocytic lymphoma, immunocytoma and/or lymphoplasmacytic lymphoma, marginal zone B-cell lymphoma, splenic marginal zone lymphoma, extra-nodal marginal zone-MALT lymphoma, lymph node marginal zone lymphoma, hairy cell leukemia, plasmacytoma and/or plasma cell myeloma, low grade/follicular lymphoma, medium grade/follicular NHL, mantle cell lymphoma, follicular central lymphoma (follicular), follicular lymphoma (e.g., recurrent/refractory follicular lymphoma), moderate diffuse NHL, diffuse large B-cell lymphoma (DLBCL), recurrent DLBCL, refractory DLBCL, recurrent/refractory DLBCL, invasive NHL (including invasive anterior NHL and invasive recurrent NHL), recurrent or refractory NHL after autologous stem cell transplantation, primary mediastinum large B-cell lymphoma, primary lymphoma, hyperimmune blast NHL, highly lymphocytic NHL, highly non-nucleated small cell NHL, megaloblastic NHL, burkitt's lymphoma, precursor (peripheral) large granular lymphocytic leukemia, mycosis fungoides and/or Sezary syndrome, cutaneous (skin-affecting) lymphomas, anaplastic large cell lymphomas, angiocentric lymphomas.
An "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., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the individual or subject is a human.
An "effective amount" of an agent (e.g., a pharmaceutical formulation) refers to an amount effective to achieve a desired therapeutic or prophylactic result at the necessary dosage and time period.
The term "pharmaceutical formulation" refers to a formulation that is in a form that allows for the biological activity of the active ingredient contained therein to be effective, and that is free of additional components that have unacceptable toxicity to the subject to whom the formulation is to be administered.
"Pharmaceutically acceptable carrier" refers to ingredients of the pharmaceutical formulation that are non-toxic to the subject, except for the active ingredient. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.
As used herein, "treatment" (and grammatical variations thereof, such as "treatment" or "treatment") refers to a clinical intervention that attempts to alter the natural course of the treated individual, and may be performed for prophylaxis or in the course of clinical pathology. Desirable effects of treatment include, but are not limited to, reducing free light chains, preventing the occurrence or recurrence of disease, alleviating symptoms, attenuating any direct or indirect pathological consequences of disease, reducing the rate of disease progression, improving or alleviating the disease state, and alleviating or improving prognosis. In some embodiments, the antibodies described herein are used to delay the progression of a disease or slow the progression of a disease.
The term "CD79b positive cells" refers to cancers that comprise cells that express CD79b on their surface. In some embodiments, the expression of CD79b on the cell surface is determined, for example, using antibodies to CD79b in a method such as immunohistochemistry, FACS, and the like. Alternatively, CD79b mRNA expression is considered to be related to CD79b expression on the cell surface and may be determined by a method selected from in situ hybridization and RT-PCR (including quantitative RT-PCR).
As used herein, "in combination with … …" or "in combination with … …" refers to administration of one therapeutic modality in addition to another therapeutic modality. Thus, "in combination with … …" or "in combination with … …" refers to the administration of one therapeutic modality prior to, during, or after the administration of another therapeutic modality to an individual.
"Chemotherapeutic agents" are chemical compounds useful in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib @Gene tek (Genentech)/OSI pharmaceutical company, osipharm @), bortezomib @Qiannium pharmaceutical Co (Millennium pharm), disulfiram, epigallocatechin gallate, halosporide A, carfilzomib, 17-AAG (geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant @Aspirin (AstraZeneca)), sunitinib @, andThe Pfizer/Sugen and letrozoleNovartis (Novartis)), imatinib mesylateNorhua, phenacetinNorhua, oxaliplatin @Cynophenanthrene (Sanofi)), 5-FU (5-fluorouracil), folinic acid, rapamycin (sirolimus,Hui's (Wyeth)), lapatinib @, andGSK572016, glaxo SMITH KLINE, luo Nafa m Lonafamib (SCH 66336), sorafenib @Bayer Labs (Bayer Labs)), gefitinib @Aliskir), AG1478; alkylating agents such as thiotepa andCyclophosphamide; alkyl sulfonates such as busulfan, imperoshu and piposhu; aziridines such as benzotepa (benzodopa), carboquinone, metutinib (meturedopa), and uredept (uredopa); ethylimines and methyl melamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphamide, and trimethylol melamine; annonaceous acetogenins (especially bullatacin) and bullatacin (bullatacinone)); camptothecins (including topotecan and irinotecan); Bryostatin; calistatin (callystatin); CC-1065 (including adorinone (adozelesin), carbozelesin (carzelesin) and bizelesin (bizelesin) synthetic analogues thereof); nostoc (cryptophycin) (in particular, nostoc 1 and nostoc 8); corticosteroids (including prednisone and prednisolone); cyproterone acetate; 5-reductase (including finasteride and dutasteride); vorinostat, romidepsin, ubibetastat, valproic acid, mo Xisi he (mocetinostat), dolastatin (dolastatin); Aldi interleukin, talc, du Kamei elements (including synthetic analogues KW-2189 and CB1-TM 1); eleutherobin (eleutherobin); a podophylline; the stoichiometriol (sarcodictyin); sponge chalone; nitrogen mustards such as chlorambucil, chlorpheniramine, cyclophosphamide, estramustine, ifosfamide, mechlorethamine hydrochloride, melphalan, mechlorethamine (novembichin), mechlorethamine cholesterol, prednisone mustard, qu Luolin amine (trofosfamide), uratemustine (uracil mustard); Nitrosoureas such as carmustine, chlorourea, fotemustine, lomustine, nimustine and ranimustine; antibiotics such as enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gamma 1I and calicheamicin omega 1I (Angew chem. Intl. Ed. Engl. 1994. 33: 183-186)), dactinomycin (dynemicin), including dactinomycin A, bisphosphonates such as chlorophosphonate, ai Simi stars, and new oncostatin (neocarzinostatin) chromophores and related chromophores of chromoprotein enediyne antibiotics; Aclacinomycin (aclacinomysin), actinomycin (actinomycin), anthramycin (authramycin), azoserine (azaserine), bleomycin, actinomycin (calinanomycin), cartrubicin (carabicin), carminomycin (caminomycin), carcinophilin (carzinophilin), chromomycin (chromomycinis), dactinomycin, daunomycin, dithiin (detorubicin), 6-azido-5-oxo-L-norleucine,(Doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrroline-doxorubicin and deoxydoxorubicin, epirubicin, isorubicin, everolimus (everolimus), sotrataurin, idarubicin, maramycin (marcellomycin); mitomycin, such as mitomycin C, mycophenolic acid, norgamycin, olivomycin, percomycin, methylmitomycin, puromycin, doxorubicin (quelamycin), rodobicin (rodorubicin), streptozotocin, tuberculin, ubenimex, clean statin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-Fu); folic acid analogs such as, for example, dimethylfolic acid (denopterin), methotrexate, pterin (pteropterin), and methotrexate; purine analogs such as fludarabine, 6-mercaptopurine, thioadenine (thiamiprine), thioguanine; pyrimidine analogs such as ambcitabine, azacytidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enotabine, fluorouridine; androgens such as carbosterone, drotasone propionate, cyclothiolane, emasculan, and testosterone; anti-adrenergic agents such as aminoglutethimide, mitotane, qu Luosi; folic acid supplements such as folinic acid; acetoglucurolactone; aldehyde phosphoramide glycosides; aminolevulinic acid; enuracil; amsacrine; double Qu Buxi (bestrabucil); a specific group; edatroxas (edatraxate); ground phosphoramide (defofamine); colchicine; imine quinone; -irinotecan (elfomithine); ammonium elegance; epothilones; an ethyleneoxy pyridine; gallium nitrate; hydroxyurea; lentinan; lonidamine (lonidainine); a maytansinoid, which is selected from the group consisting of, such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mo Pai darol (mopidamnol); diamine nitroacridine (nitraerine); prastatin; egg ammonia nitrogen mustard (phenamet); pirarubicin; losoxantrone (losoxantrone); podophylloic acid; 2-ethyl hydrazine; methyl benzyl hydrazine; Polysaccharide complex (JHS natural products company (JHS Natural Products, eugene, oreg.)) in Eugene, oregon, usa; carrying out a process of preparing the raw materials; rhizomycin (rhizoxin); schizophyllan (sizofuran); germanium spiroamine; tenuazonic acid; triiminoquinone; 2,2',2 "-trichlorotriethylamine; trichothecene toxins (especially T-2 toxin, verakulin A (verracurin A), plaque a, and serpentine hormone (anguidine)); a urethane; vindesine; dacarbazine; mannitol nitrogen mustard; dibromomannitol; dibromodulcitol; pipobromine; ganciclovir (gacytosine); arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxanes, such as TAXOL (Bristol-Myers Squibb Oncology, princeton, n.j.), beta.mexican cancer specialty (Bristol, n.j.) (Without hydrogenated castor oil), albumin engineered nanoparticle formulations of paclitaxel (american pharmaceutical partner company (American Pharmaceutical Partners, schaumberg, ill.)) and (Shao Bake, illinois)(Docetaxel, celecoxib-avantis (Sanofi-Aventis)); chlorambucil; (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; (vinorelbine); nortrilon (novantrone); teniposide; edatrase; daunomycin; aminopterin; capecitabine Ibandronate; CPT-11; topoisomerase inhibitor RFS2000; difluoromethyl ornithine (DMFO); retinoids such as retinoic acid; pharmaceutically acceptable salts, acids and derivatives of any of the above; and combinations of two or more of the foregoing, such as CHOP (abbreviation for cyclophosphamide, doxorubicin, vincristine, and prednisolone combination therapy) and FOLFOX (abbreviation for oxaliplatin (ELOXATIN TM) in combination with treatment regimen of 5-FU and folinic acid). Other examples of chemotherapeutic agents include bendamustine (or bendamustine hydrochloride)Ibrutinib (ibrutinib), lenalidomide and/or alilapril (idelalisib) (GS-1101).
Other examples of chemotherapeutic agents include anti-hormonal agents that are used to modulate, reduce, block or inhibit the action of growth hormone that may promote cancer, and are typically in the form of systemic or systemic therapies. They may be hormones themselves. Examples include: antiestrogens and Selective Estrogen Receptor Modulators (SERMs) including, for example, tamoxifen (includingTamoxifen, raloxifeneDroloxifene, 4-hydroxy tamoxifen, trawoxifene, raloxifene, LY117018, onapristone and toremifeneAntiprogestin; estrogen receptor down-regulation (ERD); estrogen receptor antagonists, such as fulvestrantDrugs acting on ovarian suppression or closure, e.g. Luteinizing Hormone Releasing Hormone (LHRH) antagonists, such as leuprolide acetate @, e.gAnd) Goserelin acetate (goserelin acetate), buserelin acetate (buserelin acetate) and triptorelin (tripterelin); antiandrogens such as flutamide, nilutamide, and bicalutamide; and aromatase inhibitors which inhibit aromatase and thereby regulate estrogen production in the adrenal gland, e.g. 4 (5) -imidazoles, aminoglutethimide, megestrol acetateExemestaneFumesteine (formestanie), fatrozole (fadrozole), and FucloxazoleLetrozoleAnd anastrozoleFurthermore, the definition of such chemotherapeutic agents includes: bisphosphonates, such as chlorophosphonate (e.g.Or (b)) Etidronate saltsNE-58095, zoledronic acid/zoledronateAlendronatePamidronate saltTilofosinate saltOr risedronateTroxacitabine (1, 3-dioxolane cytosine nucleoside analog); antisense oligonucleotides, particularly those that inhibit the expression of genes in signaling pathways involved in abnormal cell proliferation, such as PKC- α, ralf, H-Ras, and epidermal growth factor receptor (EGF-R); vaccines, such asVaccines and gene therapy vaccines (e.gVaccine(s),Vaccine and method for producing the sameA vaccine.
In some embodiments, the chemotherapeutic agent comprises a topoisomerase 1 inhibitor (e.g.,) ; Antiestrogens such as fulvestrant; kit inhibitors, such as imatinib or EXEL-0862 (a tyrosine kinase inhibitor); EGFR inhibitors such as erlotinib or cetuximab; anti-VEGF inhibitors, such as bevacizumab; arinotecan; rmRH (e.g.,) ; Lapatinib and lapatinib ditosylate (an ErbB-2 and EGFR dual tyrosine kinase small molecule inhibitor, also known as GW 572016); 17AAG (geldanamycin derivatives as heat shock protein (Hsp) 90 poisons), and pharmaceutically acceptable salts, acids and derivatives of any of the above.
Chemotherapeutic agents also include antibodies such as alemtuzumab (Campath), bevacizumab @Gene tek) ; Cetuximab Panitumumab @Amantadine (Amgen)), rituximab @Gene Talcr/Baijian Aidi (Biogen Idec)), pertuzumab @2C4, gene tek), trastuzumab @Gene tek), tositumomab (Bexxar, corixia) and antibody drug conjugate gemtuzumab ozagrel @Wheatstone (Wyeth)). Other humanized monoclonal antibodies of therapeutic potential in combination with the compounds include: abelmoschus antibody (apolizumab), abelmoschus antibody, abilmosome, barbituzumab, mo Bi valuzumab (bivatuzumab mertansine), mo Kantuo valuzumab (cantuzumab mertansine), cetrimab (cedelizumab), cetuzumab (certolizumab pegol), cetuximab (cidfusituzumab), cetuximab (cidtuzumab), Daclizumab, eculizumab (ecalizumab), efalizumab (efalizumab), epratuzumab (epratuzumab), erlivizumab erlizumab, pantoprizumab (felvizumab), rituximab (fontolizumab), gemtuzumab octopamicin, oxuzumab (inotuzumab ozogamicin), ipilimumab, pull Bei Zhushan (labetuzumab), rituximab, matuzumab, mepaniamab, mevaluzumab, Mo Tuowei Belizumab (motovizumab), natalizumab, nituzumab, nor Luo Weizhu Belizumab (nolovizumab), nu Ma Weizhu Belizumab (numavizumab), orelizumab (ocrelizumab), omalizumab, panizumab, pacololizumab (pascolizumab), pefuxib (pecfusituzumab), hillside Bemamab (pectuzumab), pekezumab (pexelizumab), ralizumab (ralivizumab), Raney monoclonal antibody, ralividizumab (reslivizumab), ralizumab (reslizumab), ralizumab (resyvizumab), luo Weizhu monoclonal antibody (rovelizumab), lu Lizhu monoclonal antibody (ruplizumab), cetrimizumab, pinocembrizumab (Sontuzumab), tiuzumab (tacatuzumab tetraxetan), talizumab (tadocizumab), talizumab, tifeizumab (tefibazumab), Tozucchini, tolizumab (toralizumab), cetrimizumab (tucotuzumab celmoleukin), tukuxizucchini (tucusituzumab), wu Mawei zucchini (umavizumab), wu Zhushan, uteukinumab (ustekinumab), utezucchini and interleukin-12 (ABT-874/J695, wheatstone research and Atbang laboratories) are anti-interleukin-12, a recombinant human specific sequence full length IgG1 lambda antibody genetically modified to recognize interleukin-12 p40 protein.
The term "package insert" is used to refer to instructions generally included in commercial packages of therapeutic products that contain information concerning the indication, usage, dosage, administration, combination therapy, contraindications and/or warnings concerning the use of such therapeutic products.
"Alkyl" is a C 1-C18 hydrocarbon containing a normal, secondary, tertiary, or cyclic carbon atom. examples are methyl (Me, -CH 3), ethyl (Et, -CH 2CH3), 1-propyl (n-Pr, n-propyl, -CH 2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH (CH 3)2), 1-butyl (n-Bu, n-butyl, -CH 2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH 2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH (CH 3)CH2CH3), 2-methyl-2-propyl (t-Bu), t-butyl, -C (CH 3)3), 1-pentyl (n-pentyl, -CH 2CH2CH2CH2CH3), 2-pentyl (-CH (CH 3)CH2CH2CH3), 3-pentyl (-CH (CH 2CH3)2)), a catalyst, 2-methyl-2-butyl (-C (CH 3)2CH2CH3), 3-methyl-2-butyl (-CH (CH 3)CH(CH3)2), 3-methyl-1-butyl (-CH 2CH2CH(CH3)2), 2-methyl-1-butyl (-CH 2CH(CH3)CH2CH3), 1-hexyl (-CH 2CH2CH2CH2CH2CH3), 2-hexyl (-CH (CH 3)CH2CH2CH2CH3), 3-hexyl (-CH (CH 2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C (CH 3)2CH2CH2CH3)), a catalyst, 3-methyl-2-pentyl (-CH (CH 3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH (CH 3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C (CH 3)(CH2CH3)2), 2-methyl-3-pentyl (-CH (CH 2CH3)CH(CH3)2)), a catalyst for the preparation of a pharmaceutical composition, 2, 3-dimethyl-2-butyl (-C (CH 3)2CH(CH3)2), 3-dimethyl-2-butyl (-CH (CH 3)C(CH3)3).
The term "C 1-C8 alkyl" as used herein refers to straight or branched, saturated or unsaturated hydrocarbons having from 1 to 8 carbon atoms. Representative "C 1-C8 alkyl" groups include, but are not limited to, methyl, -ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl; and branched C 1-C8 alkyl includes, but is not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, unsaturated C 1-C8 alkyl includes, but is not limited to, -vinyl, -allyl, -1-butenyl, -2-butenyl, -isobutenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl, -2, 3-dimethyl-2-butenyl, 1-hexyl, 2-hexyl, 3-hexyl, -ethynyl, -propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl-1-butynyl. The C1-C8 alkyl groups may be unsubstituted or substituted with one or more groups including, but not limited to: -C 1-C8 alkyl, -O- (C 1-C8 alkyl), -aryl 、-C(O)R'、-OC(O)R'、-C(O)OR'、-C(O)NH2、-C(O)NHR'、-C(O)N(R')2-NHC(O)R'、-SO3R'、-S(O)2R'、-S(O)R'、-OH、- halogen, -N 3、-NH2、-NH(R')、-N(R')2 and-CN; wherein each R' is independently selected from H, -C 1-C8 alkyl, and aryl.
The term "C 1-C12 alkyl" as used herein refers to straight or branched, saturated or unsaturated hydrocarbons having 1 to 12 carbon atoms. The C 1-C12 alkyl group may be unsubstituted or substituted with one or more groups including, but not limited to: -C 1-C8 alkyl, -O- (C 1-C8 alkyl), -aryl 、-C(O)R'、-OC(O)R'、-C(O)OR'、-C(O)NH2、-C(O)NHR'、-C(O)N(R')2-NHC(O)R'、-SO3R'、-S(O)2R'、-S(O)R'、-OH、- halogen, -N 3、-NH2、-NH(R')、-N(R')2 and-CN; wherein each R' is independently selected from H, -C 1-C8 alkyl, and aryl.
The term "C 1-C6 alkyl" as used herein refers to straight or branched, saturated or unsaturated hydrocarbons having from 1 to 6 carbon atoms. Representative "C 1-C6 alkyl" groups include, but are not limited to, methyl, -ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl; and branched C 1-C6 alkyl groups include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, and 2-methylbutyl; unsaturated C 1-C6 alkyl includes, but is not limited to, vinyl, -allyl, -1-butenyl, -2-butenyl, -isobutenyl, -1-pentenyl, -2-pentenyl, 3-methyl-1-butenyl, -2-methyl-2-butenyl, -2, 3-dimethyl-2-butenyl, 1-hexyl, 2-hexyl and 3-hexyl. The C 1-C6 alkyl group may be unsubstituted or substituted with one or more groups as described above for the C 1-C8 alkyl group.
The term "C 1-C4 alkyl" as used herein refers to straight or branched, saturated or unsaturated hydrocarbons having 1 to 4 carbon atoms. Representative "C 1-C4 alkyl" groups include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl; and branched C 1-C4 alkyl includes, but is not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl; unsaturated C 1-C4 alkyl groups include, but are not limited to, vinyl, -allyl, -1-butenyl, -2-butenyl, and-isobutenyl. The C 1-C4 alkyl group may be unsubstituted or substituted with one or more groups as described above for the C 1-C8 alkyl group.
"Alkoxy" is an alkyl group bonded to an oxygen single bond. Exemplary alkoxy groups include, but are not limited to, methoxy (-OCH 3) and ethoxy (-OCH 2CH3)."C1-C5 alkoxy "groups are alkoxy groups having 1 to 5 carbon atoms.
"Alkenyl" is a C 2-C18 hydrocarbon containing a normal, secondary, tertiary, or cyclic carbon atom and having at least one site of unsaturation (i.e., a carbon-carbon sp 2 double bond). Examples include, but are not limited to: ethylene or vinyl (-ch=ch 2), allyl (-CH 2CH＝CH2), cyclopentenyl (-C 5H7), and 5-hexenyl (-CH 2CH2CH2CH2CH＝CH2)."C2-C8 alkenyl ") are hydrocarbons containing 2 to 8 normal, secondary, tertiary, or cyclic carbon atoms and having at least one site of unsaturation (i.e., a carbon-carbon sp 2 double bond).
"Alkynyl" is a C2-C18 hydrocarbon containing a normal, secondary, tertiary or cyclic carbon atom and having at least one site of unsaturation (i.e., a carbon-carbon sp triple bond). Examples include, but are not limited to: acetylenes (-c≡ch) and propargyls (-CH 2C≡CH)."C2-C8 alkynyl ") are hydrocarbons containing 2 to 8 normal, secondary, tertiary or cyclic carbon atoms and having at least one site of unsaturation (i.e., a carbon-carbon sp triple bond).
"Alkylene" refers to a saturated, branched, or straight-chain or cyclic hydrocarbon group having 1 to 18 carbon atoms with two monovalent radical centers obtained by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkane. Typical alkylene groups include, but are not limited to: methylene (-CH 2 -), 1, 2-ethyl (-CH 2CH2 -), 1, 3-propyl (-CH 2CH2CH2 -), 1, 4-butyl (-CH 2CH2CH2CH2 -), etc.
Examples of "C 1-C10 alkylene" are straight chain saturated hydrocarbon radicals of the formula- (CH 2)1-10) -C 1-C10 alkylene include methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene and decylene.
"Alkenylene" refers to an unsaturated, branched or straight or cyclic hydrocarbon group having 2 to 18 carbon atoms with two monovalent radical centers obtained by removing two hydrogen atoms from the same or two different carbon atoms of the parent olefin. Typical alkenylenes include, but are not limited to: 1, 2-ethylene (-ch=ch-).
"Alkynylene" refers to an unsaturated, branched or straight or cyclic hydrocarbon group having 2 to 18 carbon atoms with two monovalent radical centers obtained by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkyne. Typical alkynylene groups include, but are not limited to: acetylene (-C.ident.C-), propargyl (-CH 2 C.ident.C-), and 4-pentynyl (-CH 2CH2CH2 C.ident.C-).
"Aryl" refers to a carbocyclic aryl group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. Carbocyclic or heterocyclic aryl groups may be unsubstituted or substituted with one or more groups including, but not limited to: -C 1-C8 alkyl, -O- (C 1-C8 alkyl), -aryl 、-C(O)R'、-OC(O)R'、-C(O)OR'、-C(O)NH2、-C(O)NHR'、-C(O)N(R')2-NHC(O)R'、-S(O)2R'、-S(O)R'、-OH、- halogen, -N 3、-NH2、-NH(R')、-N(R')2 and-CN; wherein each R' is independently selected from H, -C 1-C8 alkyl, and aryl.
"C 5-C20 aryl" is an aryl group having 5 to 20 carbon atoms in a carbocyclic aromatic ring. Examples of C 5-C20 aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. The C 5-C20 aryl group may be substituted or unsubstituted, as described above for the aryl group. "C 5-C14 aryl" is an aryl group having 5 to 14 carbon atoms in a carbocyclic aromatic ring. Examples of C 5-C14 aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. The C 5-C14 aryl group may be substituted or unsubstituted, as described above for the aryl group.
An "arylene" group is an aryl group having two covalent bonds and which may be in the ortho, meta, or para configuration, as shown in the structure:
Wherein the phenyl group may be unsubstituted or substituted with up to four groups including, but not limited to: -C 1-C8 alkyl, -O- (C 1-C8 alkyl), -aryl 、-C(O)R'、-OC(O)R'、-C(O)OR'、-C(O)NH2、-C(O)NHR'、-C(O)N(R')2-NHC(O)R'、-S(O)2R'、-S(O)R'、-OH、- halogen, -N 3、-NH2、-NH(R')、-N(R')2 and-CN; wherein each R' is independently selected from H, -C 1-C8 alkyl, and aryl.
"Arylalkyl" refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom (typically a terminal or sp 3 carbon atom) is replaced with an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like. The arylalkyl group contains from 6 to 20 carbon atoms, for example, the alkyl portion (including alkyl, alkenyl, or alkynyl) of the arylalkyl group has from 1 to 6 carbon atoms, and the aryl portion has from 5 to 14 carbon atoms.
"Heteroarylalkyl" refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom (typically the terminal or sp 3 carbon atom) is replaced with a heteroaryl group. Typical heteroarylalkyl groups include, but are not limited to, 2-benzimidazolylmethyl, 2-furanylethyl, and the like. The heteroarylalkyl group contains 6 to 20 carbon atoms, for example, the alkyl portion of the heteroarylalkyl group (including alkyl, alkenyl or alkynyl groups) has 1 to 6 carbon atoms, and the heteroaryl portion has 5 to 14 carbon atoms and 1 to 3 heteroatoms selected from N, O, P and S. The heteroaryl portion of the heteroarylalkyl group may be a single ring having 3 to 7 ring members (2 to 6 carbon atoms) or a double ring having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P and S), for example: a bicyclo [4,5], [5,6] or [6,6] system.
"Substituted alkyl", "substituted aryl" and "substituted arylalkyl" mean alkyl, aryl and arylalkyl, respectively, wherein one or more hydrogen atoms are each independently substituted with substituents. Typical substituents include, but are not limited to ：-X、-R、-O-、-OR、-SR、-S-、-NR2、-NR3、＝NR、-CX3、-CN、-OCN、-SCN、-N＝C＝O、-NCS、-NO、-NO2、＝N2、-N3、NC(＝O)R、-C(＝O)R、-C(＝O)NR2、-SO3 -、-SO3H、-S(＝O)2R、-OS(＝O)2OR、-S(＝O)2NR、-S(＝O)R、-OP(＝O)(OR)2、-P(＝O)(OR)2、-PO- 3、-PO3H2、-C(＝O)R、-C(＝O)X、-C(＝S)R、-CO2R、-CO2-、-C(＝S)OR、-C(＝O)SR、-C(＝S)SR、-C(＝O)NR2、-C(＝S)NR2、-C(＝NR)NR2, wherein each X is independently halogen: F. cl, br or I; and each R is independently-H, C 2-C18 alkyl, C 6-C20 aryl, C 3-C14 heterocycle, a protecting group or a prodrug moiety. Alkylene, alkenylene, and alkynylene groups as described above may also be similarly substituted.
"Heteroaryl" and "heterocycle" refer to ring systems in which one or more ring atoms are heteroatoms (e.g., nitrogen, oxygen, and sulfur). The heterocyclyl contains 3 to 20 carbon atoms and 1 to 3 heteroatoms selected from N, O, P and S. The heterocycle may be a single ring having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P and S) or having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P and S), for example: a bicyclo [4,5], [5,6] or [6,6] system.
Exemplary heterocycles are described, for example, in the following documents: paquette, leo A, "PRINCIPLES OF MODERN HETEROCYCLIC CHEMISTRY" (W.A. Benjamin, new York, 1968), especially chapters 1, 3,4,6, 7 and 9; "THE CHEMISTRY of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, new York,1950 to date), in particular volumes 13, 14, 16, 19 and 28; and J.am.chem.Soc. (1960) 82:5566.
Examples of heterocycles include, by way of illustration and not limitation, pyridinyl, dihydropyridinyl, tetrahydropyridinyl (piperidinyl), thiazolyl, tetrahydrothienyl, thioxotetrahydrothienyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthyl (THIANAPHTHALENYL), indolyl, indolenyl (indolenyl), quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl (4-piperidonyl), pyrrolidinyl, 2-pyrrolidinonyl, pyrrolinyl, tetrahydrofuranyl, bis-tetrahydrofuranyl, tetrahydropyranyl, bis-tetrahydropyranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azacinyl (azocinyl), triazinyl, 6H-1,2, 5-thiadiazinyl 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromene, xanthenyl, phenothiazinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4 aH-carbazolyl, beta-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolizinyl, isoindolinyl, quinazolinyl, morpholinyl, oxazolidinyl, benzotriazole, benzisoxazole, oxindole, and process for preparing the same benzoxazolinyl isatin acyl (isatinoyl).
By way of example and not limitation, carbon-bonded heteroatoms are bonded at the following positions: the 2, 3, 4,5 or 6 position of pyridine, the 3, 4,5 or 6 position of pyridazine, the 2,4, 5 or 6 position of pyrimidine, the 2, 3, 5 or 6 position of pyrazine, the 2, 3, 4 or 5 position of furan, tetrahydrofuran, thiafuran, thiophene, pyrrole or tetrahydropyrrole ring, the 2,4 or 5 position of oxazole, imidazole or thiazole, the 3, 4 or 5 position of isoxazole, pyrazole or isothiazole, the 2 or 3 position of aziridine, the 2, 3 or 4 position of azetidine, the 2, 3, 4,5, 6, 7 or 8 position of quinoline, or the 1, 3, 4,5, 6, 7 or 8 position of isoquinoline. More typically, the carbon-bonded heterocycle includes 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl.
By way of example and not limitation, nitrogen-bonded heteroatoms are bonded at the following positions: aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole; the 2-position of isoindole or isoindolinone; morpholine at position 4; and carbazole at the 9-position or β -carboline. More typically, nitrogen-bonded heterocycles include 1-aziridinyl (1-aziridyl), 1-azetidinyl (1-azetedyl), 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl and 1-piperidinyl.
"C 3-C8 heterocycle" refers to an aromatic or non-aromatic C 3-C8 carbocycle in which 1 to 4 of the ring carbon atoms are independently substituted with heteroatoms selected from O, S and N. Representative examples of C 3-C8 heterocycles include, but are not limited to, benzofuranyl, benzothiophene, indolyl, benzopyrazolyl, coumarin, isoquinolyl, pyrrolyl, thienyl, furanyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, quinolinyl, pyrimidinyl, pyridyl, pyridonyl, pyrazinyl, pyridazinyl, isothiazolyl, isoxazolyl, and tetrazolyl. The C 3-C8 heterocycle may be unsubstituted or substituted with up to seven groups including, but not limited to: -C 1-C8 alkyl, -O- (C 1-C8 alkyl), -aryl 、-C(O)R'、-OC(O)R'、-C(O)OR'、-C(O)NH2、-C(O)NHR'、-C(O)N(R')2-NHC(O)R'、-S(O)2R'、-S(O)R'、-OH、- halogen, -N 3、-NH2、-NH(R')、-N(R')2 and-CN; wherein each R' is independently selected from H, -C 1-C8 alkyl, and aryl.
"C 3-C8 heterocycle" refers to a C 3-C8 heterocycle group as defined above wherein one of the hydrogen atoms of the heterocycle group is replaced by a bond. The C 3-C8 heterocycle may be unsubstituted or substituted with up to six groups including, but not limited to: -C 1-C8 alkyl, -O- (C 1-C8 alkyl), -aryl 、-C(O)R'、-OC(O)R'、-C(O)OR'、-C(O)NH2、-C(O)NHR'、-C(O)N(R')2-NHC(O)R'、-S(O)2R'、-S(O)R'、-OH、- halogen, -N 3、-NH2、-NH(R')、-N(R')2 and-CN; wherein each R' is independently selected from H, -C 1-C8 alkyl, and aryl.
"C 3-C20 heterocycle" refers to an aromatic or non-aromatic C 3-C8 carbocycle in which 1 to 4 of the ring carbon atoms are independently substituted with heteroatoms selected from O, S and N. The C 3-C20 heterocycle may be unsubstituted or substituted with up to seven groups including, but not limited to: -C 1-C8 alkyl, -O- (C 1-C8 alkyl), -aryl 、-C(O)R'、-OC(O)R'、-C(O)OR'、-C(O)NH2、-C(O)NHR'、-C(O)N(R')2-NHC(O)R'、-S(O)2R'、-S(O)R'、-OH、- halogen, -N 3、-NH2、-NH(R')、-N(R')2 and-CN; wherein each R' is independently selected from H, -C 1-C8 alkyl, and aryl.
"C 3-C20 heterocycle" refers to a C 3-C20 heterocycle group as defined above wherein one of the hydrogen atoms of the heterocycle group is replaced by a bond.
"Carbocycle" means a saturated or unsaturated ring, which is a single ring having 3 to 7 carbon atoms or a double ring having 7 to 12 carbon atoms. Monocyclic carbocycles have 3 to 6 ring atoms, more typically 5 or 6 ring atoms. The bicyclic carbocycle has 7 to 12 ring atoms, for example, 9 or 10 ring atoms arranged as a bicyclo [4,5], [5,6] or [6,6] system, or as a bicyclo [5,6] or [6,6] system. Examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohexyl-3-enyl, cycloheptyl and cyclooctyl.
"C 3-C8 carbocycle" is a 3-, 4-, 5-, 6-, 7-, or 8-membered saturated or unsaturated non-aromatic carbocycle. Representative C 3-C8 carbocycles include, but are not limited to, -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclopentadienyl, -cyclohexyl, -cyclohexenyl, -1, 3-cyclohexadienyl, -1, 4-cyclohexadienyl, -cycloheptyl, -1, 3-cycloheptadienyl, -1,3, 5-cycloheptatrienyl, -cyclooctyl, and-cyclooctadienyl. The C 3-C8 carbocyclic group may be unsubstituted or substituted with one or more groups including, but not limited to: -C 1-C8 alkyl, -O- (C 1-C8 alkyl), -aryl 、-C(O)R'、-OC(O)R'、-C(O)OR'、-C(O)NH2、-C(O)NHR'、-C(O)N(R')2-NHC(O)R'、-S(O)2R'、-S(O)R'、-OH、- halogen, -N 3、-NH2、-NH(R')、-N(R')2 and-CN; wherein each R' is independently selected from H, -C 1-C8 alkyl, and aryl.
"C 3-C8 carbocycle" refers to a C 3-C8 carbocycle group as defined above wherein one of the hydrogen atoms of the carbocycle group is replaced by a bond.
"Linker" refers to a chemical moiety comprising a covalent bond or chain of atoms that covalently links an antibody to a drug moiety. In various embodiments, the linking group includes a divalent group, such as an alkyl diradical, an aryl diradical, a heteroaryl diradical, such as: - (CR 2)nO(CR2)n -, repeating units of alkoxy (e.g. polyethylene oxy, PEG, polyethylene oxy) and alkylamino (e.g. polyethylene amino, jeffamine TM); and diacids and amides, including succinates, succinamides, diglycolates, malonates, and caproamides, hi various embodiments, the linker may comprise one or more amino acid residues such as valine, phenylalanine, lysine and homolysine.
The term "chiral" refers to a property of non-overlapping with a mirror partner, while the term "achiral" refers to a molecule that overlaps with its mirror partner.
The term "stereoisomers" refers to compounds having the same chemical composition but different arrangements of atoms or groups in space.
"Diastereoisomers" means stereoisomers which have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral characteristics, and reactivity. Mixtures of diastereomers can be separated under high resolution analytical procedures such as electrophoresis and chromatography.
"Enantiomer" refers to two stereoisomers of a compound that are mirror images of each other that are non-superimposable.
Stereochemical definitions and conventions used herein generally follow: S.P. Parker, mcGraw-Hill Dictionary of CHEMICAL TERMS (1984) McGraw-Hill Book Company, new York; and Eliel, e. And Wilen, s., stereochemistry of Organic Compounds (1994) John Wiley & Sons, inc., new York. Many organic compounds exist in optically active form, i.e. they have the ability to rotate plane-polarized light planes. In describing optically active compounds, the prefixes D and L or R and S are used to represent the absolute configuration of the molecule about its chiral center. The prefixes d and 1 or (+) and (-) are used to denote the sign of the rotation of the compound to plane polarized light, where (-) or 1 indicates that the compound is left-handed. Compounds with (+) or d prefix are dextrorotatory. These stereoisomers are identical for a given chemical structure, except that they are mirror images of each other. A particular stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often referred to as an enantiomeric mixture. The 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur without stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two optically inactive enantiomeric species.
"Leaving group" refers to a functional group that may be substituted with another functional group. Certain leaving groups are well known in the art, and examples include, but are not limited to, halides (e.g., chloride, bromide, or iodide), methanesulfonyl (methanesulfonyl), p-toluenesulfonyl (toluenesulfonyl), trifluoromethanesulfonyl (trifluoromethanesulfonate), and trifluoromethanesulfonate.
The term "protecting group" refers to a substituent typically used to block or protect a particular functional group while reacting with other functional groups on a compound. For example, an "amino protecting group" is a substituent attached to an amino group that blocks or protects an amino functional group in a compound. Suitable amino protecting groups include, but are not limited to, acetyl, trifluoroacetyl, t-Butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). For general description of protecting groups and their use, see T.W.Greene, protective Groups in Organic Synthesis, john Wiley & Sons, new York,1991 or newer versions.
III method
Provided herein are methods of treating a B cell proliferative disorder, such as Diffuse Large B Cell Lymphoma (DLBCL), e.g., relapsed/refractory DLBCL, in a subject in need thereof (e.g., a human subject), comprising administering to the subject an effective amount of (a) an immunoconjugate comprising an antibody that binds CD79B linked to a cytotoxic agent, (B) an anti-CD 20 antibody, and (c) one or more chemotherapeutic agents.
In some embodiments, the anti-CD 79b immunoconjugate is a poloxamer vedotin-piiq. In some embodiments, the anti-CD 20 antibody is rituximab. In some embodiments, the one or more chemotherapeutic agents comprises gemcitabine. In some embodiments, the one or more chemotherapeutic agents comprise oxaliplatin. In some embodiments, the one or more chemotherapeutic agents are gemcitabine and oxaliplatin.
The term "co-administration or co-ADMINISTERING" refers to administration of an anti-CD 79b immunoconjugate, an anti-CD 20 antibody and the one or more chemotherapeutic agents as two (or more) separate formulations (or as a single formulation comprising an anti-CD 79b immunoconjugate, an anti-CD 20 antibody and the one or more chemotherapeutic agents). Where separate formulations are used, co-administration may be performed simultaneously or sequentially in any order, wherein preferably there is a period of time for all active agents to exert their biological activity simultaneously. In some embodiments, the anti-CD 79b immunoconjugate, the anti-CD 20 antibody, and the one or more chemotherapeutic agents are administered simultaneously or sequentially in combination. In some embodiments, when all of the therapeutic agents are co-administered sequentially, the doses are administered separately at two or more times on the same day, or one or more of the agents are administered on day 1 (e.g., on day 1 of the 21 day cycle) and the other agents are co-administered on about day 2 (e.g., on day 2 of the 21 day cycle). In some embodiments, the term "sequentially" means within 7 days after administration of the first component, e.g., 4 days, 3 days, 2 days, or 1 day after administration of the first component; and the term "simultaneously" means simultaneously. In some embodiments, the term "sequentially" means within less than 1 day after administration of the first component, for example within less than 24 hours, less than 20 hours, less than 15 hours, less than 10 hours, less than 12 hours, less than 8 hours, less than 6 hours, less than 3 hours, less than 2 hours, or less than 1 hour after administration of the first component. In some embodiments, the anti-CD 79b immunoconjugate and the anti-CD 20 antibody are co-administered sequentially on about day 1 of each 21-day cycle, and the one or more chemotherapeutic agents are co-administered sequentially on about day 2 of each 21-day cycle.
The anti-CD 79b immunoconjugates, anti-CD 20 antibodies, and the one or more chemotherapeutic agents provided herein for use in any of the methods of treatment described herein will be formulated, administered, and administered in a manner consistent with good medical practice. Factors to be considered in this case include the particular condition being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the condition, the site of delivery of the agent, the method of administration, the timing of administration, and other factors known to the practitioner. The immunoconjugate is not necessarily required, but is optionally co-formulated with one or more of the formulations currently used for the prevention or treatment of the condition in question.
The amounts of co-administered anti-CD 79b immunoconjugate, anti-CD 20 antibody and the one or more chemotherapeutic agents and the time of co-administration will depend on the type (species, sex, age, weight, etc.) and condition of the patient being treated and the severity of the disease or disorder being treated. The anti-CD 79b immunoconjugate, anti-CD 20 antibody and the one or more chemotherapeutic agents are suitably co-administered in one treatment or in a series of treatments, for example, on the same day or the next day thereafter.
In some embodiments, the dose of an anti-CD 79b immunoconjugate (such as poloxamer-velocin-piiq) is between 1.4-5mg/kg, 1.4-4mg/kg, 1.4-3.2mg/kg, 1.4-2.4mg/kg, or any of 1.4-1.8 mg/kg. In some embodiments of any of the methods, the anti-CD 79b immunoconjugate is any one of about 1.4mg/kg、1.5mg/kg、1.6mg/kg、1.7mg/kg、1.8mg/kg、1.9mg/kg、2.0mg/kg、2.2mg/kg、2.4mg/kg、2.6mg/kg、2.8mg/kg、3.0mg/kg、3.2mg/kg、3.4mg/kg、3.6mg/kg、3.8mg/kg、4.0mg/kg、4.2mg/kg、4.4mg/kg、4.6mg/kg and/or 4.8 mg/kg. In some embodiments, the dose of anti-CD 79b immunoconjugate is about 1.4mg/kg. In some embodiments, the dose of anti-CD 79b immunoconjugate is about 1.8mg/kg. In some embodiments, the dose of anti-CD 79b immunoconjugate is about 2.4mg/kg. In some embodiments, the dose of anti-CD 79b immunoconjugate is about 3.2mg/kg. In some embodiments, the dose of anti-CD 79b immunoconjugate is about 3.6mg/kg. In some embodiments of any of the methods, the anti-CD 79b immunoconjugate is administered in a q3wk manner. In some embodiments of any of the methods, the anti-CD 79b immunoconjugate is administered once in each 21-day cycle. In some embodiments of any of these methods, the anti-CD 79b immunoconjugate is administered on about day 1 of each 21-day cycle. In some embodiments, the anti-CD 79b immunoconjugate is administered by intravenous infusion. In some embodiments, the dose administered by infusion is in the range of about 1mg to about 2,000mg per dose, typically 1,2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or more doses total administered every three weeks (e.g., on day 1 of each 21 day cycle). In some embodiments, the dose administered by infusion is in the range of about 1mg to about 2,000mg per dose, typically on about day 1 of each 21-day cycle, for up to eight 21-day cycles. Alternatively, the dosage ranges from about 1mg to about 2,000mg, from about 1mg to about 1,800mg, from about 400mg to about 1200mg, from about 600mg to about 1000mg, from about 10mg to about 500mg, from about 10mg to about 300mg, from about 10mg to about 200mg, and from about 1mg to about 200mg. In some embodiments, the dose administered by infusion is in the range of about 1 μg/m 2 to about 10,000 μg/m 2 per dose, typically about day 1 of each 21 day cycle, for a total of 1,2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or more doses. In some embodiments, the dose administered by infusion is in the range of about 1 μg/m 2 to about 10,000 μg/m 2 per dose, typically one dose every three weeks (e.g., on day 1 of each 21 day cycle) for up to eight 21 day cycles. Alternatively, the dosage ranges from about 1 μg/m 2 to about 1000 μg/m 2, from about 1 μg/m 2 to about 800 μg/m 2, About 1 μg/m 2 to about 600 μg/m 2, about 1 μg/m 2 to about 400 μg/m 2, About 10 μg/m 2 to about 500 μg/m 2, about 10 μg/m 2 to about 300 μg/m 2, about 10 μg/m 2 to about 200 μg/m 2 and about 1 μg/m 2 to about 200 μg/m 2. The frequency of administration may be weekly, more times than daily, monthly, more times than weekly, monthly, every three weeks, every 21 days, every 21 day cycle, on day 1 of every 21 day cycle, or intermittently to alleviate or mitigate symptoms of the disease. Administration may be continued using any of the intervals disclosed herein for up to eight 21-day periods, or until symptoms of the tumor or B-cell proliferative disorder being treated (e.g., DLBCL) are alleviated. After achieving symptomatic relief or alleviation, administration may continue where such relief or alleviation may be prolonged by continued administration.
In some embodiments, the dose of anti-CD 20 antibody (e.g., rituximab) is between about 300-1600mg/m 2 and/or 300-2000 mg. In some embodiments, the dose of anti-CD 20 antibody is about 300mg/m 2、375mg/m2、600mg/m2、1000mg/m2 or 1250mg/m 2 and/or any one of 300mg, 1000mg or 2000 mg. In some embodiments, the anti-CD 20 antibody is rituximab and the dose administered is 375mg/m 2. In some embodiments, the anti-CD 20 antibody is administered in q3w (i.e., every 3 weeks). In some embodiments, the anti-CD 20 antibody is administered once every 21-day cycle (e.g., on day 1 of every 21-day cycle). In some embodiments, the anti-CD 20 antibody is rituximab. In some embodiments, the dose of rituximab may be 375mg/m 2 on day 1 of each 21-day cycle. In some embodiments, the dose of rituximab may be 375mg/m 2 on day 1 of each 21-day cycle of up to eight 21-day cycles. In some embodiments, the dose of rituximab may be 375mg/m 2 on day 1 of each 21-day cycle of eight 21-day cycles.
In some embodiments, the frequency of administration of an anti-CD 20 antibody (e.g., rituximab) may be weekly, multiple times per month but less than weekly, monthly, every three weeks, every 21 days, every 21 day cycle, on day 1 of every 21 day cycle, or intermittently, to alleviate or mitigate symptoms of the disease. Administration may be continued using any of the intervals disclosed herein for up to eight 21-day periods, or until symptoms of the tumor or B-cell proliferative disorder being treated (e.g., DLBCL) are alleviated. After achieving symptomatic relief or alleviation, administration may continue where such relief or alleviation may be prolonged by continued administration.
In some embodiments, the dose of the one or more chemotherapeutic agents is between about 50mg/m 2 to about 2000mg/m 2. In some embodiments, the one or more chemotherapeutic agents are administered at a dose of about 50mg/m 2 to about 100mg/m 2, about 100mg/m 2 to about 200mg/m 2, About 200mg/m 2 to about 300mg/m 2, about 300mg/m 2 to about 400mg/m 2, About 400mg/m 2 to about 500mg/m 2, about 500mg/m 2 to about 600mg/m 2, About 600mg/m 2 to about 700mg/m 2, about 700mg/m 2 to about 800mg/m 2, about 800mg/m 2 to about 900mg/m 2, about 900mg/m 2 to about 1000mg/m 2, About 1000mg/m 2 to about 1100mg/m 2, about 1100mg/m 2 to about 1200mg/m 2, About 1200mg/m 2 to about 1300mg/m 2, about 1300mg/m 2 to about 1400mg/m 2, between about 1400mg/m 2 to about 1500mg/m 2 or about 1500mg/m 2 to about 2000mg/m 2.
In some embodiments, the dose of the one or more chemotherapeutic agents includes a dose of about 500mg/m 2 to about 1500mg/m 2 (e.g., about 500mg/m 2 to about 600mg/m 2, About 600mg/m 2 to about 700mg/m 2, about 700mg/m 2 to about 800mg/m 2, about 800mg/m 2 to about 900mg/m 2, about 900mg/m 2 to about 1000mg/m 2, About 1000mg/m 2 to about 1100mg/m 2, about 1100mg/m 2 to about 1200mg/m 2, About 1200mg/m 2 to about 1300mg/m 2, about 1300mg/m 2 to about 1400mg/m 2, About 1400mg/m 2 to about 1500mg/m 2). In some embodiments, the dose of the one or more chemotherapeutic agents comprises gemcitabine at a dose of about 1000mg/m 2. In some embodiments, the dose of gemcitabine is administered in q3w or about once every 21 day period (e.g., on day 2 of every 21 day period). In some embodiments, the dose of gemcitabine is administered once every 21-day period (e.g., on day 2 of each 21-day period) for up to eight 21-day periods. In some embodiments, the dose of gemcitabine is administered once every 21-day period (e.g., on day 2 of each 21-day period) for eight 21-day periods. In some embodiments, the dosage of the one or more chemotherapeutic agents comprises a dosage of between about 50mg/m 2 and about 200mg/m 2 (e.g., Between 50mg/m 2 and about 100mg/m 2 or about 100mg/m 2 and about 200mg/m 2). In some embodiments, the dose of the one or more chemotherapeutic agents comprises oxaliplatin at a dose of about 100mg/m 2. In some embodiments, the dose of oxaliplatin is administered in the form of q3w or about once every 21 day period (e.g., on day 2 of every 21 day period). In some embodiments, the dose of oxaliplatin is administered once every 21-day period (e.g., on day 2 of each 21-day period) for up to eight 21-day periods. In some embodiments, the dose of gemcitabine is administered once every 21-day period (e.g., on day 2 of each 21-day period) for eight 21-day periods. In some embodiments, the one or more chemotherapeutic agents comprise gemcitabine and oxaliplatin, and the gemcitabine and oxaliplatin are administered intravenously once on about day 2 of each 21-day cycle. In some embodiments, the one or more chemotherapeutic agents comprise gemcitabine and oxaliplatin, and the gemcitabine and oxaliplatin are administered intravenously once every day 2 of the 21 day cycle for up to about eight cycles.
In some embodiments, the chemotherapeutic agent (e.g., gemcitabine and oxaliplatin) is administered weekly, multiple times per week but less than once per day, multiple times per month but less than once per week, once per month, once per three weeks, once per 21-day cycle, on about day 2 of each 21-day cycle, or intermittently to alleviate or mitigate symptoms of the disease. Administration may be continued using any of the intervals disclosed herein for up to about eight 21-day periods, or until symptoms of the tumor or B-cell proliferative disorder being treated are alleviated. After achieving symptomatic relief or alleviation, administration may continue where such relief or alleviation may be prolonged by continued administration.
Exemplary dosing regimens for combination therapies of anti-CD 79b immunoconjugates (such as polo-bezozumab vedotin-piiq) with other agents include, but are not limited to: an anti-CD 79b immunoconjugate such as huMA79bv28-MC-vc-PAB-MMAE is administered at a dose of about 1.4-5mg/kg on about day 1 of each 21-day cycle, and an anti-CD 20 antibody (e.g., rituximab) is administered at a dose of about 300-1600mg/m 2 on about day 1 of each 21-day cycle, And one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) are administered at a dose of about 50mg/m 2 to about 2000mg/m 2 on about day 2 of each 21-day cycle (e.g., gemcitabine is administered at a dose of about 500mg/m 2 to about 2000mg/m 2, and oxaliplatin is administered at a dose of about 50mg/m 2 to about 200mg/m 2). In some embodiments, an anti-CD 79b immunoconjugate (such as a poloxamer-velocin-piiq) is administered at a dose of about 1.8mg/kg on about day 1 of each 21-day cycle, an anti-CD 20 antibody (e.g., rituximab) is administered at a dose of about 375mg/m 2 on about day 1 of each 21-day cycle, and the one or more chemotherapeutic agents are administered on about day 2 of each 21-day cycle (e.g., gemcitabine is administered at a dose of about 1000mg/m 2, And oxaliplatin is administered at a dose of about 100mg/m 2). In some embodiments, the anti-CD 79b immunoconjugate is administered at a dose of about 1.8 mg/kg. In some embodiments, the anti-CD 79b immunoconjugate is a poloxamer vedotin-piiq and is administered at a dose of about 1.8 mg/kg. In some embodiments, the anti-CD 20 antibody is administered at a dose of about 375mg/m 2. In some embodiments, the anti-CD 20 antibody is rituximab and is administered at a dose of about 375mg/m 2. In some embodiments, the one or more chemotherapeutic agents include gemcitabine administered at a dose of about 1000mg/m 2 and oxaliplatin administered at a dose of about 100mg/m 2. In some embodiments, the anti-CD 79b immunoconjugate is a poloxamer-vedotin-piiq and is administered at a dose of about 1.8mg/kg, the anti-CD 20 antibody is rituximab and is administered at a dose of about 375mg/m 2, and the one or more chemotherapeutic agents are gemcitabine administered at a dose of about 1000mg/m 2 and oxaliplatin administered at a dose of about 100mg/m 2.
The immunoconjugates provided herein, the anti-CD 20 antibodies provided herein, and the one or more chemotherapeutic agents provided herein for use in any of the methods of treatment described herein may be administered by any suitable means, including parenteral, intrapulmonary, and intranasal, and if desired for topical treatment, intralesional administration. Parenteral infusion includes intramuscular, intravenous (e.g., intravenous), intraarterial, intraperitoneal, or subcutaneous administration. Administration may be by any suitable route, for example by injection, such as intravenous or subcutaneous injection, depending in part on whether administration is brief or chronic. Various dosing schedules are contemplated herein, including but not limited to single or multiple administrations at various points in time, bolus administrations, and pulse infusion.
Provided herein are methods of treating diffuse large B-cell lymphoma (DLBCL, e.g., recurrent/refractory DLBCL) in a subject in need thereof (human subject), comprising administering to the subject an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26, and wherein p is between 1 and 8; (b) an anti-CD 20 antibody; and (c) one or more chemotherapeutic agents. In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising: a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID No. 19; and a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO. 20.
Also provided herein are methods for treating diffuse large B-cell lymphoma (DLBCL, e.g., recurrent/refractory DLBCL) in an individual in need thereof (a human individual), comprising administering to the individual an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26, and wherein p is between 1 and 8; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; wherein following administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin, the human does not develop a grade 3 or higher (e.g., grade 3 or higher, grade 4 or higher, or any of grade 5 or higher) peripheral neuropathy that does not regress to grade 1 or less within 14 days (e.g., within any of 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day). In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day periods.
Also provided herein are methods for treating diffuse large B-cell lymphoma (DLBCL, e.g., recurrent/refractory DLBCL) in an individual in need thereof (a human individual), comprising administering to the individual an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26, and wherein p is between 1 and 8; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; wherein administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not cause the human to develop a grade 3 or higher (e.g., grade 3 or higher, grade 4 or higher, or any of grade 5 or higher) peripheral neuropathy that does not regress to grade 1 or lower within 14 days (e.g., within any of 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day). In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day periods.
Also provided herein are methods for treating diffuse large B-cell lymphoma (DLBCL, e.g., recurrent/refractory DLBCL) in an individual in need thereof (a human individual), comprising administering to the individual an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26, and wherein p is between 1 and 8; (b) Rituximab; (c) gemcitabine; and (d) oxaliplatin; Wherein 33% or less (e.g., about 33% or less, about 32% or less, about 31% or less, about 30% or less, about 29% or less, about 28% or less, about 27% or less, about 26% or less, about 25% or less, about 24% or less, about 23% or less, about 22% or less, about 21% or less, about 20% or less, about 19% or less, about 18% or less, about 17% or less, about 16% or less, about 15% or less) of the plurality of persons receiving the treatment after administration of the immunoconjugate, rituximab, gemcitabine and oxaliplatin, About 14% or less, about 13% or less, about 12% or less, about 11% or less, about 10% or less, about 9% or less, about 8% or less, about 7% or less, about 6% or less, about 5% or less, about 4% or less, about 3% or less, about 2% or less, about 1% or less, or about 0.5% or less) of the human being suffering from peripheral neuropathy of 3 or more (e.g., any of 3 or more, 4 or more, or 5 or more) within 14 days (e.g., 14 days, 13 days, 12 days, 11 days), Within any of 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day) does not fade to grade 1 or less. In some embodiments, in a plurality of people receiving treatment, less than about 40% (e.g., less than about 40%, about 39% or less, about 38% or less, about 37% or less, about 36% or less, about 35% or less, about 34% or less, about 33% or less, about 32% or less, about 31% or less, about 30% or less, about 29% or less, about 28% or less, about 27% or less, about 26% or less, about 25% or less, about 24% or less, about 23% or less, about, About 22% or less, about 21% or less, about 20% or less, about 19% or less, about 18% or less, about 17% or less, about 16% or less, about 15% or less, about 14% or less, about 13% or less, about 12% or less, about 11% or less, about 10% or less, about 9% or less, about 8% or less, about 7% or less, about 6% or less, about 5% or less, about 4% or less, about 3% or less, about 2% or less, about 1% or less, or about 0.5% or less) of the human being is at a level 3 or higher (e.g., level 3 or higher), Grade 4 or higher or any of grade 5 or higher) that does not resolve to grade 1 or lower within 14 days (e.g., within any of 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day). In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day periods.
Also provided herein are methods for treating diffuse large B-cell lymphoma (DLBCL, e.g., recurrent/refractory DLBCL) in an individual in need thereof (a human individual), comprising administering to the individual an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26, and wherein p is between 1 and 8; (b) Rituximab; (c) gemcitabine; and (d) oxaliplatin; Wherein administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in 33% or less (e.g., about 33% or less, about 32% or less, about 31% or less, about 30% or less, about 29% or less, about 28% or less, about 27% or less, about 26% or less, about 25% or less, about 24% or less, about 23% or less, about 22% or less, about 21% or less, about 20% or less, about 19% or less, about 18% or less, about 17% or less, about 16% or less, about 15% or less, about 14% or less, about 15% or less, about, About 13% or less, about 12% or less, about 11% or less, about 10% or less, about 9% or less, about 8% or less, about 7% or less, about 6% or less, about 5% or less, about 4% or less, about 3% or less, about 2% or less, about 1% or less, or any of about 0.5% or less) of the human being suffering from peripheral neuropathy of 3 or more (e.g., any of 3 or more, 4 or more, or 5 or more) within 14 days (e.g., 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days), within any of 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day) does not fade to grade 1 or lower. In some embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of humans results in less than about 40% (e.g., less than about 40%, about 39% or less, about 38% or less, about 37% or less, about 36% or less, about 35% or less, about 34% or less, about 33% or less, about 32% or less, about 31% or less, about 30% or less, about 29% or less, about 28% or less, about 27% or less, about 26% or less, about 25% or less, about 24% or less, about 23% or less, about 22% or less, about, About 21% or less, about 20% or less, about 19% or less, about 18% or less, about 17% or less, about 16% or less, about 15% or less, about 14% or less, about 13% or less, about 12% or less, about 11% or less, about 10% or less, about 9% or less, about 8% or less, about 7% or less, about 6% or less, about 5% or less, about 4% or less, about 3% or less, about 2% or less, about 1% or less, or about 0.5% or less) of human subjects having peripheral neuropathy at 3 levels or more (e.g., any of 3 levels or more, 4 levels or more, or 5 levels or more), The grade 3 or higher peripheral neuropathy does not regress to grade 1 or less within 14 days (e.g., within any of 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day). In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day periods.
In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising: a heavy chain comprising the amino acid sequence of SEQ ID NO. 37; and a light chain comprising the amino acid sequence of SEQ ID NO. 35. In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising: a heavy chain comprising the amino acid sequence of SEQ ID NO. 36; and a light chain comprising the amino acid sequence of SEQ ID NO. 38. In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising: a heavy chain comprising the amino acid sequence of SEQ ID NO. 36; and a light chain comprising the amino acid sequence of SEQ ID NO. 35. In some embodiments, p is between 2 and 7, between 2 and 6, between 2 and 5, between 3 and 5, or between 3 and 4. In some embodiments, p is between 2 and 5. In some embodiments, p is between 3 and 4. In some embodiments, p is 3.5. In some embodiments, the anti-CD 79b immunoconjugate is a poloxamer vedotin-piiq. In some embodiments, the anti-CD 20 antibody is rituximab. In some embodiments, the one or more chemotherapeutic agents include any of the chemotherapeutic agents provided herein. In some embodiments, the one or more chemotherapeutic agents comprises gemcitabine. In some embodiments, the one or more chemotherapeutic agents comprise oxaliplatin. In some embodiments, the one or more chemotherapeutic agents are gemcitabine and oxaliplatin.
In some embodiments, the anti-CD 79b antibody comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO. 37; and a light chain comprising the amino acid sequence of SEQ ID NO. 35. In some embodiments, the anti-CD 79b antibody comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO. 36; and a light chain comprising the amino acid sequence of SEQ ID NO. 38. In some embodiments, the immunoconjugate is Iladatuzumab vedotin. In certain embodiments, p is between 2 and 5. In certain embodiments, p is 2. In some embodiments, the immunoconjugate is administered at a dose of about 1mg/kg to about 5 mg/kg. In some embodiments, the immunoconjugate is administered at a dose of about 1.2mg/kg, about 1.8mg/kg, about 2.4mg/kg, about 3.6mg/kg, or about 4.8 mg/kg. In some embodiments, the immunoconjugate is administered at a dose of about 1.8 mg/kg.
As used herein, the term "Iladatuzumab vedotin" refers to an anti-CD 79b immunoconjugate having international non-patent drug name (INN) number 10647 or CAS accession number 1906205-77-3. Iladatuzumab vedotin are also interchangeably referred to as "DCDS0780A" or "RO7032005".
The anti-CD 79b immunoconjugate (e.g., poluzumab vedotin-piiq), the anti-CD 20 antibody (such as rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) may be administered by the same route of administration or by different routes of administration. In some embodiments, the anti-CD 79b immunoconjugate is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally. In some embodiments, an anti-CD 20 antibody (such as rituximab) is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally. In some embodiments, the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) are administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, implantable, inhaled, intrathecally, intraventricularly, or intranasally. In some embodiments, the anti-CD 79b immunoconjugate, the anti-CD 20 antibody (such as rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) are each administered by intravenous infusion. An effective amount of an anti-CD 79b immunoconjugate (e.g., polotouzumab vedotin-piiq), an anti-CD 20 antibody (such as rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) can be administered to prevent or treat a disease.
In some embodiments, an anti-CD 79b immunoconjugate (e.g., polotouzumab vedotin-piiq) is administered at a dose of between about 1.4mg/kg to about 2mg/kg (e.g., about 1.4mg/kg to about 1.6mg/kg, about 1.6mg/kg to about 1.8mg/kg, or about 1.8mg/kg to about 2 mg/kg). In some embodiments, the anti-CD 79b immunoconjugate is administered at a dose of 1.8 mg/kg. In some embodiments, the anti-CD 79b immunoconjugate is a poloxamer vedotin-piiq. In some embodiments, the poloxamer-vedotin-piiq is administered at a dose of 1.8 mg/kg. Alternatively or additionally, in some embodiments, the anti-CD 20 antibody (e.g., rituximab) is administered at about 300-1800mg/m 2 (e.g., about 300mg/m 2 to about 600mg/m 2), About 600mg/m 2 to about 900mg/m 2, about 900mg/m 2 to about 1200mg/m 2, About 1200mg/m 2 to about 1500mg/m 2 or about 1500mg/m 2 to about 1800mg/m 2) and/or about 300-2000mg (e.g., About 300mg to about 600mg, about 600mg to about 900mg, about 900mg to about 1200mg, about 1200mg to about 1500mg, about 1500mg to about 1750mg, or about 1750mg to about 2000 mg). In some embodiments, the anti-CD 20 antibody is rituximab. In some embodiments, rituximab is administered at a dose of about 375mg/m 2. Alternatively or additionally, in some embodiments, the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) are administered in an amount of between about 50mg/m 2 and about 2000mg/m 2 (e.g., between about 50mg/m 2 and about 100mg/m 2), About 100mg/m 2 to about 200mg/m 2, about 200mg/m 2 to about 400mg/m 2, About 400mg/m 2 to about 600mg/m 2, about 600mg/m 2 to about 800mg/m 2, About 800mg/m 2 to about 1000mg/m 2, about 1000mg/m 2 to about 1200mg/m 2, About 1200mg/m 2 to about 1400mg/m 2, about 1400mg/m 2 to about 1600mg/m 2, About 1600mg/m 2 to about 1800mg/m 2 or about 1800mg/m 2 to about 2000mg/m 2). In some embodiments, the one or more chemotherapeutic agents comprises gemcitabine. In some embodiments, gemcitabine is administered at a dose of about 1000mg/m 2. In some embodiments, the one or more chemotherapeutic agents comprise oxaliplatin. In some embodiments, oxaliplatin is administered at a dose of about 100mg/m 2. In some embodiments, the one or more chemotherapeutic agents are gemcitabine and oxaliplatin, and the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2.
In some embodiments, the anti-CD 20 antibody is rituximab. In some embodiments, an immunoconjugate (e.g., polozotocide velutinin-piiq) is administered at a dose of about 1.8mg/kg, rituximab is administered at a dose of about 375mg/m 2, gemcitabine is administered at a dose of about 1000mg/m 2, and oxaliplatin is administered at a dose of about 100mg/m 2. In some embodiments, the pertuzumab vedotin-piiq is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2.
In some embodiments, an anti-CD 79b immunoconjugate (e.g., polotoxin-piiq), an anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) are administered for at least one 21-day period (e.g., any one of about one, about two, about three, about four, about five, about six, about seven, or about eight or more 21-day periods).
In some embodiments, an anti-CD 79b immunoconjugate (e.g., poluzumab vedotin-piiq), an anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) are administered for up to eight 21-day cycles (e.g., any one of about one, about two, about three, about four, about five, about six, about seven, or about eight or more 21-day cycles). In some embodiments, the immunoconjugate (e.g., polotophyllizumab vedotin-piiq) is administered intravenously about day 1 of each 21-day cycle. In some embodiments, the immunoconjugate is a poloxamer-vedotin-piiq, and the poloxamer-vedotin-piiq is administered intravenously about day 1 of each 21 day cycle. Alternatively or additionally, in some embodiments, an anti-CD 20 antibody (e.g., rituximab) is administered intravenously on about day 1 of each 21-day cycle. In some embodiments, the anti-CD 20 antibody is rituximab, and the rituximab is administered on about day 1 of each 21-day cycle. Alternatively or additionally, in some embodiments, the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) are administered intravenously on about day 2 of each 21-day cycle. In some embodiments, the chemotherapeutic agent is gemcitabine and oxaliplatin, and the gemcitabine and oxaliplatin are administered intravenously on about day 2 of each 21 day cycle.
In some embodiments, the immunoconjugate (e.g., polotostuzumab vedotin-piiq), the anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) are administered for at least one 21-day period, wherein the immunoconjugate and the anti-CD 20 antibody are administered intravenously on about day 1 of each 21-day period, and wherein the one or more chemotherapeutic agents are administered intravenously on about day 2 of each 21-day period. In some embodiments, the immunoconjugate (e.g., polotouzumab vedotin-piiq), the anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) are administered for up to eight 21-day cycles, wherein the immunoconjugate and the anti-CD 20 antibody are administered intravenously on about day 1 of each 21-day cycle, and wherein the one or more chemotherapeutic agents are administered intravenously on about day 2 of each 21-day cycle. In some embodiments, the one or more chemotherapeutic agents are gemcitabine and oxaliplatin. In some embodiments, the anti-CD 20 antibody is rituximab. In some embodiments, the immunoconjugate (e.g., polotouzumab vedotin-piiq), rituximab, gemcitabine, and oxaliplatin are administered for up to eight 21-day cycles, wherein the immunoconjugate and rituximab are administered intravenously on about day 1 of each 21-day cycle, and wherein the gemcitabine and oxaliplatin are administered intravenously on about day 2 of each 21-day cycle. In some embodiments, the immunoconjugate (e.g., polozotocide velutinin-piiq) is administered at a dose of about 1.8mg/kg, rituximab is administered at a dose of about 375mg/m 2, gemcitabine is administered at a dose of about 1000mg/m 2, and oxaliplatin is administered at a dose of about 100mg/m 2, Wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for up to eight 21-day cycles, and wherein the immunoconjugate and rituximab are administered on day 1 of each 21-day cycle, and the gemcitabine and oxaliplatin are administered on day 2 of each 21-day cycle. In some embodiments, an immunoconjugate (e.g., polotoxin bead vedotin-piiq), rituximab, gemcitabine, and oxaliplatin is administered for at least one 21-day period, wherein the immunoconjugate and rituximab are administered intravenously on about day 1 of each 21-day period, and wherein the gemcitabine and oxaliplatin are administered intravenously on about day 2 of each 21-day period. In some embodiments, the immunoconjugate (e.g., polozotocide velutinin-piiq) is administered at a dose of about 1.8mg/kg, rituximab is administered at a dose of about 375mg/m 2, gemcitabine is administered at a dose of about 1000mg/m 2, and oxaliplatin is administered at a dose of about 100mg/m 2, Wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day cycle, and wherein the immunoconjugate and rituximab are administered on day 1 of each 21-day cycle, and the gemcitabine and oxaliplatin are administered on day 2 of each 21-day cycle.
Provided herein are methods of treating diffuse large B-cell lymphoma (DLBCL, e.g., recurrent/refractory DLBCL) in a subject in need thereof (human subject), comprising administering to the subject an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) a heavy chain comprising the amino acid sequence of SEQ ID NO. 36; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO. 35, and wherein p is between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate is administered at a dose of about 1.8mg/kg, rituximab is administered at a dose of about 375mg/m 2, gemcitabine is administered at a dose of about 1000mg/m 2, and oxaliplatin is administered at a dose of about 100mg/m 2; and wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for up to eight 21-day cycles, wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein the gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle. In some embodiments, the immunoconjugate is a poloxamer vedotin-piiq.
Provided herein are methods of treating diffuse large B-cell lymphoma (DLBCL, e.g., recurrent/refractory DLBCL) in a subject in need thereof (human subject), comprising administering to the subject an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) a heavy chain comprising the amino acid sequence of SEQ ID NO. 36; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO. 35, and wherein p is between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate is administered at a dose of about 1.8mg/kg, rituximab is administered at a dose of about 375mg/m 2, gemcitabine is administered at a dose of about 1000mg/m 2, and oxaliplatin is administered at a dose of about 100mg/m 2; and wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day period, wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day period, and wherein the gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day period. In some embodiments, the immunoconjugate is a poloxamer vedotin-piiq.
Also provided herein are methods of treating diffuse large B-cell lymphoma (DLBCL, e.g., recurrent/refractory DLBCL) in an individual in need thereof (a human individual), comprising administering to the individual an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) a heavy chain comprising the amino acid sequence of SEQ ID NO. 36; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO. 35, and wherein p is between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for up to eight 21-day cycles, wherein in each cycle the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle; and wherein following administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin, the human does not develop a grade 3 or higher (e.g., grade 3 or higher, grade 4 or higher, or any of grade 5 or higher) peripheral neuropathy that does not regress to grade 1 or less within 14 days (e.g., within any of 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day). In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day periods.
Also provided herein are methods of treating diffuse large B-cell lymphoma (DLBCL, e.g., recurrent/refractory DLBCL) in an individual in need thereof (a human individual), comprising administering to the individual an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) a heavy chain comprising the amino acid sequence of SEQ ID NO. 36; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO. 35, and wherein p is between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle; and wherein following administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin, the human does not develop a grade 3 or higher (e.g., grade 3 or higher, grade 4 or higher, or any of grade 5 or higher) peripheral neuropathy that does not regress to grade 1 or less within 14 days (e.g., within any of 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day). In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day periods.
Also provided herein are methods of treating diffuse large B-cell lymphoma (DLBCL, e.g., recurrent/refractory DLBCL) in an individual in need thereof (a human individual), comprising administering to the individual an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) a heavy chain comprising the amino acid sequence of SEQ ID NO. 36; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO. 35, and wherein p is between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for up to eight 21-day cycles, wherein in each cycle the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle; and wherein administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not cause the human to develop a grade 3 or higher (e.g., grade 3 or higher, grade 4 or higher, or any of grade 5 or higher) peripheral neuropathy that does not regress to grade 1 or less within 14 days (e.g., within any of 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day). In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day periods.
Also provided herein are methods of treating diffuse large B-cell lymphoma (DLBCL, e.g., recurrent/refractory DLBCL) in an individual in need thereof (a human individual), comprising administering to the individual an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) a heavy chain comprising the amino acid sequence of SEQ ID NO. 36; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO. 35, and wherein p is between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle; and wherein administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not cause the human to develop a grade 3 or higher (e.g., grade 3 or higher, grade 4 or higher, or any of grade 5 or higher) peripheral neuropathy that does not regress to grade 1 or less within 14 days (e.g., within any of 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day). In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day periods.
Also provided herein are methods of treating diffuse large B-cell lymphoma (DLBCL, e.g., recurrent/refractory DLBCL) in an individual in need thereof (a human individual), comprising administering to the individual an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) a heavy chain comprising the amino acid sequence of SEQ ID NO. 36; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO. 35, and wherein p is between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; Wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for up to eight 21-day cycles, wherein in each cycle the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle; And wherein 33% or less (e.g., about 33% or less, about 32% or less, about 31% or less, about 30% or less, about 29% or less, about 28% or less, about 27% or less, about 26% or less, about 25% or less, about 24% or less, about 23% or less, about 22% or less, about 21% or less, about 20% or less, about 19% or less, about 18% or less, about 17% or less, about 16% or less, about 30% or less, about 29% or less, about 28% or less, about 27% or less, about 26% or less, about 20% or less, about 19% or less, about 17% or less, about 16% or less, about, About 15% or less, about 14% or less, about 13% or less, about 12% or less, about 11% or less, about 10% or less, about 9% or less, about 8% or less, about 7% or less, about 6% or less, about 5% or less, about 4% or less, about 3% or less, about 2% or less, about 1% or less, or about 0.5% or less) of human beings with a peripheral neuropathy of 3 or more (e.g., any of 3 or more, 4 or more, or 5 or more) stage within 14 days (e.g., 14 days, 13 days), Within any of 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day) does not fade to grade 1 or less. In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day periods. In some embodiments, in a plurality of people receiving treatment, less than about 40% (e.g., less than about 40%, about 39% or less, about 38% or less, about 37% or less, about 36% or less, about 35% or less, about 34% or less, about 33% or less, about 32% or less, about 31% or less, about 30% or less, about 29% or less, about 28% or less, about 27% or less, about 26% or less, about 25% or less, about 24% or less, about 23% or less, about, About 22% or less, about 21% or less, about 20% or less, about 19% or less, about 18% or less, about 17% or less, about 16% or less, about 15% or less, about 14% or less, about 13% or less, about 12% or less, about 11% or less, about 10% or less, about 9% or less, about 8% or less, about 7% or less, about 6% or less, about 5% or less, about 4% or less, about 3% or less, about 2% or less, about 1% or less, or about 0.5% or less) of the human being is at a level 3 or higher (e.g., level 3 or higher), Grade 4 or higher or any of grade 5 or higher) that does not resolve to grade 1 or lower within 14 days (e.g., within any of 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day). In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day periods.
Also provided herein are methods of treating diffuse large B-cell lymphoma (DLBCL, e.g., recurrent/refractory DLBCL) in an individual in need thereof (a human individual), comprising administering to the individual an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) a heavy chain comprising the amino acid sequence of SEQ ID NO. 36; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO. 35, and wherein p is between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; Wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for up to eight 21-day cycles, wherein in each cycle the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle; And wherein administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in 33% or less (e.g., about 33% or less, about 32% or less, about 31% or less, about 30% or less, about 29% or less, about 28% or less, about 27% or less, about 26% or less, about 25% or less, about 24% or less, about 23% or less, about 22% or less, about 21% or less, about 20% or less, about 19% or less, about 18% or less, about 17% or less, about 16% or less, about 15% or less, about, About 14% or less, about 13% or less, about 12% or less, about 11% or less, about 10% or less, about 9% or less, about 8% or less, about 7% or less, about 6% or less, about 5% or less, about 4% or less, about 3% or less, about 2% or less, about 1% or less, or about 0.5% or less) of the human being is suffering from peripheral neuropathy of 3 or more (e.g., any of 3 or more, 4 or more, or 5 or more) within 14 days (e.g., 14 days, 13 days, 12 days, 11 days, 10 days, 3 or more) of the peripheral neuropathy, Within any of 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day) does not fade to grade 1 or less. In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day periods. In some embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of humans results in less than about 40% (e.g., less than about 40%, about 39% or less, about 38% or less, about 37% or less, about 36% or less, about 35% or less, about 34% or less, about 33% or less, about 32% or less, about 31% or less, about 30% or less, about 29% or less, about 28% or less, about 27% or less, about 26% or less, about 25% or less, about 24% or less, about 23% or less, about 22% or less, about, About 21% or less, about 20% or less, about 19% or less, about 18% or less, about 17% or less, about 16% or less, about 15% or less, about 14% or less, about 13% or less, about 12% or less, about 11% or less, about 10% or less, about 9% or less, about 8% or less, about 7% or less, about 6% or less, about 5% or less, about 4% or less, about 3% or less, about 2% or less, about 1% or less, or about 0.5% or less) of human subjects having peripheral neuropathy at 3 levels or more (e.g., any of 3 levels or more, 4 levels or more, or 5 levels or more), The grade 3 or higher peripheral neuropathy does not regress to grade 1 or less within 14 days (e.g., within any of 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day). In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day periods.
Also provided herein are methods of treating diffuse large B-cell lymphoma (DLBCL, e.g., recurrent/refractory DLBCL) in an individual in need thereof (a human individual), comprising administering to the individual an effective amount of: (a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) a heavy chain comprising the amino acid sequence of SEQ ID NO. 36; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO. 35, and wherein p is between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; Wherein the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; wherein the immunoconjugate and rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein gemcitabine and oxaliplatin are administered intravenously on day 2 of each 21-day cycle; And wherein administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in 33% or less (e.g., about 33% or less, about 32% or less, about 31% or less, about 30% or less, about 29% or less, about 28% or less, about 27% or less, about 26% or less, about 25% or less, about 24% or less, about 23% or less, about 22% or less, about 21% or less, about 20% or less, about 19% or less, about 18% or less, about 17% or less, about 16% or less, about 15% or less, about, About 14% or less, about 13% or less, about 12% or less, about 11% or less, about 10% or less, about 9% or less, about 8% or less, about 7% or less, about 6% or less, about 5% or less, about 4% or less, about 3% or less, about 2% or less, about 1% or less, or about 0.5% or less) of a human suffering from peripheral neuropathy of 3 or more (e.g., any of 3 or more, 4 or more, or 5 or more) within 14 days (e.g., 14 days, 13 days, 12 days, 11 days), Within any of 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day) does not fade to grade 1 or less. In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day periods. In some embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of humans results in less than about 40% (e.g., less than about 40%, about 39% or less, about 38% or less, about 37% or less, about 36% or less, about 35% or less, about 34% or less, about 33% or less, about 32% or less, about 31% or less, about 30% or less, about 29% or less, about 28% or less, about 27% or less, about 26% or less, about 25% or less, about 24% or less, about 23% or less, about 22% or less, about, About 21% or less, about 20% or less, about 19% or less, about 18% or less, about 17% or less, about 16% or less, about 15% or less, about 14% or less, about 13% or less, about 12% or less, about 11% or less, about 10% or less, about 9% or less, about 8% or less, about 7% or less, about 6% or less, about 5% or less, about 4% or less, about 3% or less, about 2% or less, about 1% or less, or about 0.5% or less) of human subjects having peripheral neuropathy at 3 levels or more (e.g., any of 3 levels or more, 4 levels or more, or 5 levels or more), The grade 3 or higher peripheral neuropathy does not regress to grade 1 or less within 14 days (e.g., within any of 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day). In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day periods.
In some embodiments, an anti-CD 20 antibody (e.g., rituximab) is administered prior to an immunoconjugate (e.g., prior to one of a maximum of about 1 hour, a maximum of about 2 hours, a maximum of about 4 hours, a maximum of about 6 hours, a maximum of about 12 hours, a maximum of about 16 hours, a maximum of about 18 hours, a maximum of about 22 hours, a maximum of about 24 hours, a maximum of about 1 day, a maximum of about 2 days, a maximum of about 3 days, or more) such as, for example, the poisotobulab vedotin-piiq. In some embodiments, the anti-CD 20 antibody is rituximab, and the rituximab is administered prior to the immunoconjugate. In some embodiments, the immunoconjugate is administered prior to the anti-CD 20 antibody (e.g., up to about 1 hour, up to about 2 hours, up to about 4 hours, up to about 6 hours, up to about 12 hours, up to about 16 hours, up to about 18 hours, up to about 22 hours, up to about 24 hours, or up to about 1 day, up to about 2 days, up to about 3 days, or more). In some embodiments, the anti-CD 20 antibody is rituximab and the immunoconjugate is administered prior to rituximab.
In some embodiments, the one or more chemotherapeutic agents are administered sequentially. In some embodiments, the chemotherapeutic agent is gemcitabine and oxaliplatin. In some embodiments, gemcitabine is administered prior to oxaliplatin (e.g., prior to one of up to about 1 hour, up to about 2 hours, up to about 4 hours, up to about 6 hours, up to about 12 hours, up to about 16 hours, up to about 18 hours, up to about 22 hours, up to about 24 hours, or up to about 1 day, up to about 2 days, up to about 3 days, or more). In some embodiments, oxaliplatin is administered prior to gemcitabine (e.g., prior to one of up to about 1 hour, up to about 2 hours, up to about 4 hours, up to about 6 hours, up to about 12 hours, up to about 16 hours, up to about 18 hours, up to about 22 hours, up to about 24 hours, or up to about 1 day, up to about 2 days, up to about 3 days, or more).
In some embodiments, the immunoconjugate, anti-CD 20 antibody, and the one or more chemotherapeutic agents are administered for any one of one, two, three, four, five, six, seven, or eight 21-day cycles. In some embodiments, the chemotherapeutic agent is gemcitabine and oxaliplatin. In some embodiments, the anti-CD 20 antibody is rituximab. In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for any one of one, two, three, four, five, six, seven, or eight 21-day cycles. In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for eight 21-day periods.
In some embodiments, which may be combined with any of the preceding embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for at least two, at least three, at least four, at least five, at least six, or at least seven 21-day periods. In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered for eight 21-day periods. In some embodiments, rituximab is administered prior to the immunoconjugate. In some embodiments, gemcitabine is administered prior to oxaliplatin. In some embodiments, the immunoconjugate is a poloxamer vedotin-piiq.
In some embodiments, the human receives at least one prior therapy for DLBCL. In some embodiments, the human adult is. In some embodiments, the human is histologically diagnosed with diffuse large B-cell lymphoma of non-specific finger type (NOS), or has a history of the conversion of indolent disease to DLBCL. In some embodiments, the human has received at least one prior systemic therapy for DLBCL. In some embodiments, the human receives at least two prior therapies for DLBCL. For example, in some cases, the human has received a prior autologous Hematopoietic Stem Cell Transplant (HSCT) (consolidated autologous HSCT after chemotherapy is considered a prior therapy normal). In another example, the human has received a prior allogeneic HSCT, and the human is no longer receiving immunosuppressive therapy and is free of active Graft Versus Host Disease (GVHD) (allogeneic HSCT after chemotherapy is considered a prior therapy normal). In some embodiments, the person has received prior topical therapy, such as radiation therapy. In some embodiments, DLBCL is recurrent or refractory. In some embodiments, DLBCL is recurrent if the DLBCL recurs after the duration of remission is greater than or equal to 6 months after completion of the last treatment line. In some embodiments, DLBCL is refractory if it progresses during prior therapy or within 6 months (< 6 months) after prior therapy. In some embodiments, the person has at least one lesion that is measurable in two dimensions, e.g., a lesion having a longest dimension greater than 1.5cm as measured by Computed Tomography (CT) or Magnetic Resonance Imaging (MRI). In some embodiments, the human eastern tumor co-operating group (ECOG) physical stamina score is 0,1 or 2. In some embodiments, the human is an unintended autologous or allogeneic Stem Cell Transplant (SCT). In some embodiments, the human has not received prior therapy using a combination of gemcitabine and a platinum-based agent. In some embodiments, the human does not have a peripheral neuropathy of grade 1 according to the U.S. national cancer institute's adverse event common terminology standard version 5.0. In some embodiments, the human does not have primary or secondary Central Nervous System (CNS) lymphomas. In some embodiments, the human does not develop Richter conversion or prior capillary leak syndrome (CLL). In some embodiments, the human is not a candidate for Hematopoietic Stem Cell Transplantation (HSCT) prior to administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, the human is not a candidate for autologous Hematopoietic Stem Cell Transplantation (HSCT) prior to administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, the human receives at least two prior therapies for DLBCL. In some embodiments, the human has not received prior therapy with polotophyllizumab vedotin-piiq for DLBCL. In some embodiments, the human adult is. In some embodiments, the adult is otherwise afflicted with recurrent or refractory non-specific diffuse large B-cell lymphoma.
In some embodiments, non-specific (NOS) diffuse large B-cell lymphoma (DLBCL) (e.g., recurrent or refractory diffuse non-specific large B-cell lymphoma) refers to DLBCL that does not meet the unique clinical manifestations, tissue morphology, tumor cell phenotype, and/or pathogen-related criteria of other DLBCL subtypes. DLBC NOS is generally an invasive disease, accounting for about 80-85% of all DLBCL cases. The overall long-term survival of DLBCL NOS patients receiving standard chemotherapy regimen treatment was about 65%. See, for example: grimm et al (2019) Annals of Diagnostic Pathology,38:6-10.
In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not result in the human experiencing a grade 3 or higher peripheral neuropathy (e.g., any of grade 3 or higher, grade 4 or higher, or grade 5 or higher) that does not resolve to grade 1 or lower within 14 days. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not result in the human experiencing peripheral neuropathy of grade 4 or higher (e.g., any of grade 4 or higher or grade 5 or higher). In some embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of humans results in 33% or less (e.g., about 33% or less, about 32% or less, about 31% or less, about 30% or less, about 29% or less, about 28% or less, about 27% or less, about 26% or less, about 25% or less, about 24% or less, about 23% or less, about 22% or less, about 21% or less, about 20% or less, about 19% or less, about 18% or less, about 17% or less, about 16% or less, about 15% or less, about 16% or less, about, About 14% or less, about 13% or less, about 12% or less, about 11% or less, about 10% or less, about 9% or less, about 8% or less, about 7% or less, about 6% or less, about 5% or less, about 4% or less, about 3% or less, about 2% or less, about 1% or less, or about 0.5% or less) of a human suffering from peripheral neuropathy of 3 or more (e.g., any of 3 or more, 4 or more, or 5 or more) within 14 days (e.g., 14 days, 13 days, 12 days, 11 days), Within any of 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day) does not fade to grade 1 or less. In some embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of humans results in less than about 40% (e.g., less than about 40%, about 39% or less, about 38% or less, about 37% or less, about 36% or less, about 35% or less, about 34% or less, about 33% or less, about 32% or less, about 31% or less, about 30% or less, about 29% or less, about 28% or less, about 27% or less, about 26% or less, about 25% or less, about 24% or less, about 23% or less, about 22% or less, about, About 21% or less, about 20% or less, about 19% or less, about 18% or less, about 17% or less, about 16% or less, about 15% or less, about 14% or less, about 13% or less, about 12% or less, about 11% or less, about 10% or less, about 9% or less, about 8% or less, about 7% or less, about 6% or less, about 5% or less, about 4% or less, about 3% or less, about 2% or less, about 1% or less, or about 0.5% or less) of human subjects having peripheral neuropathy at 3 levels or more (e.g., any of 3 levels or more, 4 levels or more, or 5 levels or more), The grade 3 or higher peripheral neuropathy does not regress to grade 1 or less within 14 days (e.g., within any of 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day). In certain embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day periods.
In some embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in peripheral neuropathy in less than about 8% (e.g., less than any of about 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%) of the people in the plurality of people, e.g., any of grade 3 or higher, grade 4 or higher, or grade 5 or higher. In some embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in less than about 6% (e.g., less than about any one of 6%, 5%, 4%, 3%, 2%, or 1%) of the plurality of people resulting in discontinuing the peripheral neuropathy of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin treatment. In some embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day periods.
In some embodiments, the human does not develop peripheral neuropathy of grade 4 or higher (e.g., any of grade 4 or higher or grade 5 or higher) after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not result in the human experiencing peripheral neuropathy of grade 4 or higher (e.g., any of grade 4 or higher or grade 5 or higher). In some embodiments, the human does not develop a degree 4 or higher (e.g., any of a degree 4 or higher or a degree 5 or higher) neurotoxicity after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not result in the human experiencing neurotoxicity of grade 4 or higher (e.g., any of grade 4 or higher or grade 5 or higher). In some embodiments, neurotoxicity refers to sensory and/or motor peripheral neuropathy. In certain embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day periods.
In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in a human survival of at least about 10 months or more, at least about 11 months or more, at least about 12 months or more, at least about 13 months or more, at least about 14 months or more, or at least about 15 months or more after initiation of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin treatment. In some embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in a median total survival of the plurality of people after initiation of the treatment with the immunoconjugate, rituximab, gemcitabine, and oxaliplatin of at least about 10 months or more, at least about 11 months or more, at least about 12 months or more, at least about 13 months or more, at least about 14 months or more, or at least about 15 months or more. In some embodiments, administration of an immunoconjugate (e.g., poluzumab vedotin-piiq), an anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) according to the methods described herein results in an increase in total survival (OS) compared to administration of the anti-CD 20 antibody (e.g., rituximab) and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin). OS was measured from the time of first administration of immunoconjugate, anti-CD 20 antibody and the one or more chemotherapeutic agents to death from any cause. In some embodiments, the OS (e.g., median OS) is measured in days, weeks, months, or years. In some embodiments, administration of an immunoconjugate (e.g., polotoxin-piiq), an anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) according to the methods described herein results in an OS (e.g., median OS) that is extended by at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about, At least about 4.5 times, at least about 5 times, at least about 5.5 times, or at least about 6 times or more. The OS (e.g., median OS) may be estimated according to any method known in the art. In some cases, the OS (e.g., median OS) is estimated using Kaplan-Meier method. In some embodiments, the estimated value of the treatment effect is expressed as a mortality risk ratio using a hierarchical Cox proportional hazards analysis (e.g., including a 95% confidence limit). In some embodiments, brookmeyer-Crowley is used to construct the 95% confidence interval for the median OS. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in a lifetime of the human that is extended, e.g., by at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 4.5-fold, at least about 5-fold, at least about 5.5-fold, or at least about 6-fold or more, as compared to administration of any of rituximab, gemcitabine, and oxaliplatin to the corresponding human. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in an overall survival of these people (e.g., median OS) that is extended by at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 4.5-fold, at least about 5-fold, at least about 5.5-fold, or at least about 6-fold or more as compared to any of the corresponding plurality of people receiving rituximab, gemcitabine, and oxaliplatin administration. In some embodiments, which may be combined with any of the preceding embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in a1 year overall survival rate of the plurality of people of at least about 42% or greater, at least about 45% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100%. In some embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in a total 2-year survival rate of the plurality of people of at least about 67% or more, at least about 70% or more, at least about 80% or more, at least about 90% or more, at least about 95% or more, or about 100%. In some embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in a 3.5 year overall survival rate of the plurality of people of at least about 38% or greater, at least about 40% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100%. In some embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in a 5-year overall survival rate of the plurality of people of at least about 15% or more, at least about 20% or more, at least about 30% or more, at least about 40% or more, at least about 50% or more, at least about 60% or more, at least about 70% or more, at least about 80% or more, at least about 90% or more, at least about 95% or more, or about 100%. In some embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in a total survival rate of 1 year, 2 years, 3.5 years, or 5 years that is extended, for example, by at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 4.5-fold, at least about 5-fold, at least about 5.5-fold, or at least about 6-fold or more, as compared to one of a corresponding plurality of people receiving rituximab, gemcitabine, and oxaliplatin administration. In some embodiments, the 1 year overall survival refers to the proportion of the number of people who did not die for any reason 1 year after initiation of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin treatment in the number of people receiving the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, the total survival rate of 2 years refers to the proportion of the number of people who did not die for any reason 2 years after initiation of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin treatment in the number of people receiving the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, the 3.5 year overall survival refers to the proportion of individuals who did not die for any reason 3.5 years after initiation of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin treatment in the plurality of individuals receiving the immunoconjugate, rituximab, gemcitabine, and oxaliplatin administration. in some embodiments, the 5-year overall survival refers to the proportion of the number of people who did not die for any reason 5 years after initiation of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin treatment in the number of people receiving the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin.
In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in a progression free survival of the human. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in a progression free survival of the human of at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about, at least about 22 months, at least about 23 months, at least about 24 months, or at least about 25 months. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in a progression free survival of the human of at least about 4 months after initiation of the treatment with the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in a progression free survival of the human of at least about 5 months after initiation of the treatment with the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in a progression free survival of the human of at least about 6 months after initiation of the treatment with the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in a progression free survival of the human of at least about 9.5 months after initiation of the treatment with the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in a progression free survival of the human of at least about 11 months after initiation of the treatment with the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in a progression free survival of the human of at least about 14 months after initiation of the treatment with the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, administration of an immunoconjugate (e.g., poluzumab vedotin-piiq), an anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) according to the methods described herein results in an extended Progression Free Survival (PFS) compared to administration of the anti-CD 20 antibody (e.g., rituximab) and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin). In some embodiments, PFS is measured from the time that an immunoconjugate (e.g., polotophyllizumab vedotin-piiq), an anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) were first administered to first develop disease progression or death for any reason according to the Lugano 2014 remission criteria (Cheson et al, (2014) J Clin Oncol 32:3059-3068). in some embodiments, PFS is measured in days, weeks, months, or years. In some embodiments, administration of an immunoconjugate (e.g., poluzumab vedotin-piiq), an anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) according to the methods described herein results in a PFS that is extended by at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 4.5-fold, for example, as compared to administration of an anti-CD 20 antibody (e.g., rituximab) and one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) Any of at least about 5 times, at least about 5.5 times, or at least about 6 times or more. In some embodiments, PFS is calculated using the Kaplan-Meier method. In some embodiments, the estimated value of the treatment effect is expressed as a risk ratio using a hierarchical Cox proportional hazards analysis (e.g., including a 95% confidence limit). In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in a progression free survival that is prolonged, e.g., by at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 4.5-fold, at least about 5-fold, at least about 5.5-fold, or at least about 6-fold or more, as compared to administration of any of rituximab, gemcitabine, and oxaliplatin to the corresponding human. In some embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in an extension of the progression-free survival (e.g., median progression-free survival) of the plurality of people by, for example, any one of at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 4.5-fold, at least about 5-fold, at least about 5.5-fold, or at least about 6-fold or more as compared to the progression-free survival (e.g., median progression-free survival) of a corresponding plurality of people receiving rituximab, gemcitabine, and oxaliplatin administration. In some embodiments, progression free survival is measured from the time of first administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to the time of first occurrence of disease progression (based on remission including PET CT data or not including any PET data) or death for any reason according to Lugano 2014 remission criteria. In some embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in a1 year progression free survival of the plurality of people of at least about 30% or more, at least about 40% or more, at least about 50% or more, at least about 60% or more, at least about 70% or more, at least about 80% or more, at least about 90% or more, at least about 95% or more, or about 100%. In some embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in a 2-year progression-free survival rate of at least about 63% or greater, at least about 65% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% for the plurality of people. In some embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in a 5-year progression-free survival rate of at least about 14% or greater, at least about 15% or greater, at least about 20% or greater, at least about 30% or greater, at least about 40% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of the plurality of people. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in a progression free survival of 1 year, 2 years, 3.5 years, or 5 years that is prolonged, e.g., at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 4.5-fold, at least about 5-fold, at least about 5.5-fold, or at least about 6-fold or more, as compared to any of the corresponding plurality of people receiving rituximab, gemcitabine, and oxaliplatin administration. In some embodiments, a1 year progression free survival refers to the proportion of people who, among the plurality of people receiving administration of immunoconjugate, rituximab, gemcitabine, and oxaliplatin, did not develop disease progression (based on remission including PET CT data or not including any PET data) or die for any reason according to the Lugano 2014 remission criteria 1 year after initiation of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin treatment. in some embodiments, 2-year progression-free survival refers to the proportion of people who, among the plurality of people receiving administration of immunoconjugate, rituximab, gemcitabine, and oxaliplatin, did not develop disease progression (based on remission including PET CT data or not including any PET data) or die for any reason according to the Lugano 2014 remission criteria 2 years after initiation of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin treatment. In some embodiments, 3.5 year progression free survival refers to the proportion of people who, among the plurality of people receiving administration of immunoconjugate, rituximab, gemcitabine and oxaliplatin, did not develop disease progression (based on remission including PET CT data or excluding any PET data) or caused death for any reason according to the Lugano 2014 remission criteria 3.5 years after initiation of the immunoconjugate, rituximab, gemcitabine and oxaliplatin treatment. In some embodiments, 5 year progression free survival refers to the proportion of people who, among the plurality of people receiving administration of immunoconjugate, rituximab, gemcitabine and oxaliplatin, did not develop disease progression (based on remission including PET CT data or not including any PET data) or die for any reason according to the Lugano 2014 remission criteria 5 years after initiation of the immunoconjugate, rituximab, gemcitabine and oxaliplatin treatment.
In some embodiments, OS and PFS are evaluated in patients receiving HSCT.
In some embodiments, relief from administration of an immunoconjugate (e.g., polotoxin velutinin-piiq), an anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) according to the methods provided herein is measured by any method known in the art. In some embodiments, the alleviation of administration of an immunoconjugate (e.g., polotoxin-piiq), an anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) according to the methods provided herein is measured by Positron Emission Tomography (PET) and/or Computed Tomography (CT). In some embodiments, relief from treatment according to the methods provided herein is assessed using the 2014Lugano standard (Cheson et al, (2014) J Clin Oncol 32:3059-3068). In some embodiments, relief from treatment according to the methods provided herein is assessed during treatment or at the end of treatment. In some embodiments, patient relief from treatment according to the methods provided herein is assessed by comparison to an assessment result prior to administration of treatment according to the methods provided herein. In some embodiments, a CT scan is performed every 6 months. In some embodiments, PET scanning is performed before and at the end of administration of a treatment according to the methods provided herein. In some embodiments, a PET and/or CT (e.g., PET-CT) scan includes a skull base to mid-thigh. In some embodiments, a whole-body PET-CT scan is performed. In some embodiments, the CT scan includes an intravenous contrast agent, which may include, but is not limited to, chest, neck, abdomen, and pelvis scans. In some embodiments, for example, if disease progression or recurrence is suspected, radiological assessment of the tumor is performed. In some embodiments, bone marrow biopsies are used to assess the response of bone to treatment according to the methods provided herein, which can be performed according to any method known in the art. In some cases, a bone marrow biopsy is performed on a patient negative for PET-CT skeletal signal. In some embodiments, PET-CT and/or CT scans are obtained prior to administration of a treatment according to the methods provided herein, and are obtained during and after administration of a treatment according to the methods provided herein according to clinical indications. In some embodiments, PET-CT and/or CT scans are performed up to two years after administration of a treatment according to the methods provided herein.
In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in complete remission in humans. In some embodiments, the complete remission comprises a complete metabolic reaction based on PET-CT according to Lugano2014 remission criteria (Cheson et al, (2014) J Clin Oncol 32:3059-3068). In some embodiments, administration of an immunoconjugate (e.g., poluzumab vedotin-piiq), an anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) according to the methods described herein results in an increase in the rate of complete remission (CRR), e.g., as compared to administration of the anti-CD 20 antibody (e.g., rituximab) and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin). In some embodiments, CRR refers to the proportion of patients who achieve a complete metabolic response at the end of treatment with an immunoconjugate (e.g., polotouzumab vedotin-piiq), an anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin), e.g., according to Lugano 2014 remission criteria based on positron emission tomography and computed tomography (PET-CT) analysis. in some embodiments, administration of an immunoconjugate (e.g., polotoxin-piiq), an anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) according to the methods described herein results in an increase in CRR of at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 4.5-fold, for example, as compared to administration of an anti-CD 20 antibody (e.g., rituximab) and one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) Any of at least about 5 times, at least about 5.5 times, or at least about 6 times or more. In some embodiments, CRR is measured without including PET data. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in an increase in the rate of complete remission (CRR) of these people compared to any one of the corresponding plurality of people receiving rituximab, gemcitabine, and oxaliplatin administration, for example, by at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 4.5-fold, at least about 5-fold, at least about 5.5-fold, or at least about 6-fold or more. In some embodiments, which may be combined with any of the preceding embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in a complete remission rate of the plurality of people of at least about 35% or greater, at least about 40% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100%.
In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in partial remission in a human. In some embodiments, the partial remission comprises a partial metabolic response comprising PET CT data according to Lugano 2014 remission criteria. In some embodiments, administration of an immunoconjugate (e.g., poluzumab vedotin-piiq), an anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) according to the methods described herein results in an increase in Objective Remission Rate (ORR) compared to administration of the anti-CD 20 antibody (e.g., rituximab) and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin). In some embodiments, ORR refers to the proportion of patients who achieve a complete or partial metabolic response at the end of treatment with an immunoconjugate (e.g., polotouzumab vedotin-piiq), an anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin), e.g., according to Lugano 2014 remission criteria based on positron emission tomography and computed tomography (PET-CT) analysis. In some embodiments, ORR refers to the proportion of patients who achieve a complete or partial metabolic response at the end of treatment with an immunoconjugate (e.g., polotouzumab vedotin-piiq), an anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin), e.g., according to Lugano 2014 remission criteria. In some embodiments, administration of an immunoconjugate (e.g., polotoxin-piiq), an anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) according to the methods described herein results in an increase in ORR of at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 4.5-fold, for example, as compared to administration of an anti-CD 20 antibody (e.g., rituximab) and one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) Any of at least about 5 times, at least about 5.5 times, or at least about 6 times or more. In some embodiments, the ORR is measured without including PET data. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in an increase in the Objective Remission Rate (ORR) of these people over any of the corresponding plurality of people receiving rituximab, gemcitabine, and oxaliplatin, for example, by at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 4.5-fold, at least about 5-fold, at least about 5.5-fold, or at least about 6-fold or more. In some embodiments, which may be combined with any of the preceding embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in an objective remission rate of the plurality of people of at least about 44% or more, at least about 45% or more, at least about 50% or more, at least about 60% or more, at least about 70% or more, at least about 80% or more, at least about 90% or more, at least about 95% or more, or about 100%. In some embodiments, which may be combined with any of the preceding embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in a partial remission rate of the plurality of people of at least about 10% or greater, at least about 20% or greater, at least about 30% or greater, at least about 40% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100%. In some embodiments, which may be combined with any of the preceding embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in an increase in the rate of partial remission of these people compared to any of the corresponding plurality of people receiving rituximab, gemcitabine, and oxaliplatin administration, for example, by at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 4.5-fold, at least about 5-fold, at least about 5.5-fold, or at least about 6-fold or more. In some embodiments, the partial remission rate refers to the proportion of patients who achieve a partial metabolic response at the end of treatment with an immunoconjugate (e.g., polotouzumab vedotin-piiq), an anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin), e.g., according to the Lugano 2014 remission criteria based on positron emission tomography and computed tomography (PET-CT) analysis. In some embodiments, the partial remission rate refers to the proportion of patients who achieve a partial metabolic response at the end of the treatment with an immunoconjugate (e.g., polotouzumab vedotin-piiq), an anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin), e.g., according to the Lugano 2014 remission standard.
In some embodiments, administration of an immunoconjugate (e.g., poluzumab vedotin-piiq), an anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) according to the methods described herein results in an improved overall remission (BOR) rate compared to administration of the anti-CD 20 antibody (e.g., rituximab) and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin). In some embodiments, administration of an immunoconjugate (e.g., polotoxin-piiq), an anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) according to the methods described herein results in an increase in the BOR ratio of at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 4.5-fold, at least about 5-fold, at least about 3.5-fold, at least about, at least about 5.5 times or at least about 6 times or more. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in an improvement in the optimal overall remission (BOR) rate of these people over any of the corresponding plurality of people receiving rituximab, gemcitabine, and oxaliplatin, e.g., by at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 4.5-fold, at least about 5-fold, at least about 5.5-fold, or at least about 6-fold or more.
In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in a human event-free survival. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in a human event-free survival of at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about, at least about 22 months, at least about 23 months, at least about 24 months, or at least about 25 months. in some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in a human event-free survival of at least about 4 months after initiation of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin treatment. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in a human event-free survival of at least about 5 months after initiation of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin treatment. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in a human event-free survival of at least about 6 months after initiation of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin treatment. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in a human event-free survival of at least about 9.5 months after initiation of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin treatment. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in a human event-free survival of at least about 11 months after initiation of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin treatment. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in a human event-free survival of at least about 14 months after initiation of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin treatment. In some embodiments, administration of an immunoconjugate (e.g., poluzumab vedotin-piiq), an anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) according to the methods described herein results in an extended event-free survival (EFS eff) compared to administration of the anti-CD 20 antibody (e.g., rituximab) and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin). In some embodiments, EFS eff refers to the time from the first administration of an immunoconjugate (e.g., polotobulab vedotin-piiq), an anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) to any of the occurrence of disease progression or recurrence, death for any reason, or initiation of another anti-lymphoma therapy. In some embodiments, EFS eff is measured in days, weeks, months, or years. In some embodiments, administration of an immunoconjugate (e.g., poluzumab vedotin-piiq), an anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) according to the methods described herein results in an increase in EFS eff of at least about 1.1 fold, at least about 1.5 fold, and/or, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 4.5-fold, at least about 5-fold, at least about 5.5-fold, or at least about 6-fold or more. In some embodiments, EFS eff is analyzed using a method of analyzing PFS (e.g., as described above). In some embodiments, the event-free survival period ranges from the first administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to the first occurrence of (i) disease progression or recurrence (based on inclusion of PET CT data or not inclusion of any PET data); (ii) death from any cause; or (iii) starting a new anti-lymphoma therapy (NALT). In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin results in a prolongation of the event-free survival of the human compared to administration of any one of rituximab, gemcitabine, and oxaliplatin to a corresponding human, e.g., by at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 4.5-fold, at least about 5-fold, at least about 5.5-fold, or at least about 6-fold or more. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in an extension of the event-free survival of these people compared to any of the corresponding plurality of people receiving rituximab, gemcitabine, and oxaliplatin administration, for example, by at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 4.5-fold, at least about 5-fold, at least about 5.5-fold, or at least about 6-fold or more. In some embodiments, which may be combined with any of the preceding embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in a 2-year event-free survival rate of the plurality of people of at least about 44% or greater, at least about 45% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100%. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in an increase in event-free survival rate of these people of, for example, at least about 1.1 fold, at least about 1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 3.5 fold, at least about 4 fold, at least about 4.5 fold, at least about 5 fold, at least about 5.5 fold, or at least about 6 fold or more over any of the corresponding plurality of people receiving rituximab, gemcitabine, and oxaliplatin administration for 1 year, 2 year, 3.5 year, or 5 year. In some embodiments, event-free survival of 1 year refers to the absence of (i) disease progression or recurrence (based on inclusion of PET CT data or not including any PET data) 1 year after initiation of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin treatment in a plurality of humans receiving the administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin; (ii) Death for any reason; or (iii) the proportion of people who begin any of the new anti-lymphoma treatments (NALT). In some embodiments, a 2-year event-free survival rate refers to a number of persons receiving administration of immunoconjugate, rituximab, gemcitabine, and oxaliplatin that did not develop (i) disease progression or recurrence (based on inclusion of PET CT data or not inclusion of any PET data) 2 years after initiation of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin treatment; (ii) death from any cause; or (iii) the proportion of people who begin any of the new anti-lymphoma treatments (NALT). In some embodiments, a 3.5 year event-free survival rate refers to a number of persons receiving administration of immunoconjugate, rituximab, gemcitabine, and oxaliplatin that did not develop (i) disease progression or relapse (based on inclusion of PET CT data or not inclusion of any PET data) 3.5 years after initiation of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin treatment; (ii) death from any cause; or (iii) the proportion of people who begin any of the new anti-lymphoma treatments (NALT). In some embodiments, 5-year event-free survival refers to the absence of (i) disease progression or recurrence (based on inclusion of PET CT data or not including any PET data) in a plurality of persons receiving administration of immunoconjugate, rituximab, gemcitabine, and oxaliplatin 5 years after initiation of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin treatment; (ii) Death for any reason; or (iii) the proportion of people who begin any of the new anti-lymphoma treatments (NALT).
In some embodiments, the event-free survival period begins from the first administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin or from the first administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin treatment to the first occurrence of (i) disease progression or recurrence (based on inclusion of PET CT data or not inclusion of any PET data); (ii) death from any cause; or (iii) the time to begin any of the new anti-lymphoma treatments (NALT).
In some embodiments, administration of an immunoconjugate (e.g., poluzumab vedotin-piiq), an anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) according to the methods described herein results in an extension of the duration of remission (DOR) as compared to administration of the anti-CD 20 antibody (e.g., rituximab) and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin). In some embodiments, DOR is measured in patients who receive treatment according to the methods provided herein, who are objectively alleviated from the date of first onset of complete or partial response to the date of first onset of progressive disease or death (using Lugano 2014 criteria). In some embodiments, DOR is measured in days, weeks, months, or years. In some embodiments, administration of an immunoconjugate (e.g., poluzumab vedotin-piiq), an anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) according to the methods described herein results in a prolongation of the DOR of any of at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 4.5-fold, at least about 5.5-fold, or at least about 6-fold or more, e.g., as compared to administration of the anti-CD 20 antibody (e.g., rituximab) and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin). In some embodiments, the DOR is analyzed using a method of analyzing PFS (e.g., as described above), except that the DOR analysis is not stratified. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in an extended duration of remission (DOR) of these people compared to any of the corresponding plurality of people receiving rituximab, gemcitabine, and oxaliplatin administration, for example, by at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 4.5-fold, at least about 5-fold, at least about 5.5-fold, or at least about 6-fold or more.
In some embodiments, the relief of treatment with an immunoconjugate (e.g., polotobulab vedotin-piiq), an anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) according to the methods provided herein is assessed using a Patient Report Outcome (PRO) approach. Examples of PRO means include, but are not limited to, FACT/GOG-Ntx12 neuropathy (Kopec et al, (2006) J Supportive Oncol,4:W1-W8; calhoun et al ,(2003)Int J Gynecol Cancer,13:741-748)、EQ-5D-5L(EuroQol(1990)Health Policy,16:199-208;Brooks(1996)Health Policy,37:53-72;Herdman et al, (2011) 20:1727-1736; janssen et al ,(2013)Qual Life Res,22:1717-1727;http://www(dot)euroqol(dot)org/about-eq-5d/valuation-of-eq-5d;Devlin et al, (2017) Health Economics, 1-16), EORTC QLQ-C30 (Aaronson et al, (1993) J NATL CANCER INST,85:365-376; fitzsimamons et al, (1999) 35:939-941) and FACT/Lym (Cella et al, (1993) J Clin ONcol,11:570-579; cellua et al, (2005) Blood,106:750; carter et al, (2008) Blood,112:2376; hlubocky et al, (2013) Lymphoma, ID147176; webster et al, (2003) Health Qual Life Outcomes, 1:79).
In some embodiments, adverse events following administration of an immunoconjugate (e.g., polo-toxazumab vedotin-piiq), an anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) according to the methods provided herein are evaluated according to the U.S. national institute of cancer adverse event common terminology standard 5 th edition (NCI CTCAE V5.0.0), cancer treatment function evaluation system/gynaecological oncology group-neurotoxicity 12 item scale (FACT/gos-Ntx 12), clinical laboratory examination results, electrocardiogram (ECG), and/or vital signs. In some embodiments, adverse events leading to treatment withdrawal, adverse events leading to dose reduction or interruption, grade 3 adverse events, adverse events leading to death, serious adverse events, and/or adverse events of particular concern are analyzed. In some embodiments, adverse events provided herein are analyzed relative to exposure to an immunoconjugate (e.g., polotoxin-piiq), an anti-CD 20 antibody (e.g., rituximab), and/or the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin).
In some embodiments, the incidence of peripheral neuropathy in patients receiving an immunoconjugate (e.g., polotouzumab vedotin-piiq), an anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) administered according to the methods provided herein is assessed using a FACT/gos-Ntx 12 score and/or using NCI CTCAE V5.0.0. Symptoms of peripheral neuropathy (sensory and/or motor) include, but are not limited to, dysesthesia, hyperesthesia, paresthesia, malaise, burning, weakness, gait disturbances or neuropathic pain. In some embodiments, the incidence of peripheral neuropathy is calculated, for example, based on adverse event analysis. In some embodiments, all patients suffering from peripheral neuropathy are followed after termination of treatment according to the methods provided herein until the peripheral neuropathy subsides or stabilizes. In some embodiments, fewer than 50% (e.g., fewer than about 50％、45％、40％、35％、34％、33％、32％、31％、30％、29％、28％、27％、26％、25％、24％、23％、22％、21％、20％、19％、18％、17％、16％、15％、14％、13％、12％、11％、10％、9％、8％、7％、6％、5％、4％、3％、2％、1％ or 0.5% of any of) of the patients receiving administration of an immunoconjugate (e.g., poluzumab vedotin-piiq), an anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) according to the methods provided herein develop peripheral neuropathy of no less than grade 3 (e.g., any of grade 3 or higher, grade 4 or higher, or grade 5 or higher), The grade-3 peripheral neuropathy does not regress to grade-1 within 14 days (e.g., within any of 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day). in some embodiments, less than 40% of patients receiving an immunoconjugate (e.g., polotophyllizumab vedotin-piiq), an anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) administered according to the methods provided herein develop a grade No. 3 (e.g., any of grade 3 or higher, grade 4 or higher, or grade 5 or higher) peripheral neuropathy that does not resolve to grade No. 1 within 14 days. In some embodiments, less than 33% of patients receiving an immunoconjugate (e.g., polotophyllizumab vedotin-piiq), an anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) administered according to the methods provided herein develop a grade No. 3 (e.g., any of grade 3 or higher, grade 4 or higher, or grade 5 or higher) peripheral neuropathy that does not resolve to grade No. 1 within 14 days. In some embodiments, less than 30% of patients receiving an immunoconjugate (e.g., polotophyllizumab vedotin-piiq), an anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) administered according to the methods provided herein develop a grade No. 3 (e.g., any of grade 3 or higher, grade 4 or higher, or grade 5 or higher) peripheral neuropathy that does not resolve to grade No. 1 within 14 days. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not result in the human experiencing peripheral neuropathy of grade 4 or higher (e.g., any of grade 4 or higher or grade 5 or higher). In some embodiments, the human does not develop peripheral neuropathy of grade 4 or higher (e.g., any of grade 4 or higher or grade 5 or higher) after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, the human does not develop a degree 4 or higher (e.g., any of a degree 4 or higher or a degree 5 or higher) neurotoxicity after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, neurotoxicity refers to sensory and/or motor peripheral neuropathy. In some embodiments, administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of humans results in 33% or less (e.g., about 33% or less, about 32% or less, about 31% or less, about 30% or less, about 29% or less, about 28% or less, about 27% or less, about 26% or less, about 25% or less, about 24% or less, about 23% or less, about 22% or less, about 21% or less, about 20% or less, about 19% or less, about 18% or less, about 17% or less, about 16% or less, about 15% or less, about 16% or less, about, About 14% or less, about 13% or less, about 12% or less, about 11% or less, about 10% or less, about 9% or less, about 8% or less, about 7% or less, about 6% or less, about 5% or less, about 4% or less, about 3% or less, about 2% or less, about 1% or less, or about 0.5% or less) of a human suffering from peripheral neuropathy of 3 or more (e.g., any of 3 or more, 4 or more, or 5 or more) within 14 days (e.g., 14 days, 13 days, 12 days, 11 days), Within any of 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day) does not fade to grade 1 or less. In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to a plurality of people results in peripheral neuropathy in less than about 40% (e.g., less than about 40％、35％、34％、33％、32％、31％、30％、29％、28％、27％、26％、25％、24％、23％、22％、21％、20％、19％、18％、17％、16％、15％、14％、13％、12％、11％、10％、9％、8％、7％、6％、5％、4％、3％、2％、1％ or any of 0.5%) in a person of the plurality of people on a level 3 or higher (e.g., any of a level 3 or higher, a level 4 or higher, or a level 5 or higher) within 14 days (e.g., 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 11 days), Within any of 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or1 day) does not fade to grade 1 or less. In certain embodiments, the immunoconjugate, rituximab, gemcitabine, and oxaliplatin have been administered for at least four 21-day periods.
In some embodiments, the incidence of drug-induced liver injury is assessed.
In some embodiments, the immunogenicity of an immunoconjugate (e.g., polotophyllizumab vedotin-piiq) when administered according to the methods provided herein is assessed. In some embodiments, the immunogenicity of an immunoconjugate (e.g., polotoxin bead mab vetetin-piiq) when administered according to the methods provided herein is assessed by measuring the anti-drug antibody (ADA) against the immunoconjugate. In some embodiments, ADA in patient serum samples is measured using a validated antibody-bridged enzyme-linked immunosorbent assay (ELISA).
In some embodiments, after completing the treatment for at least one 21-day period, the incidence of adverse events is assessed for patients receiving an immunoconjugate (e.g., poluzumab vedotin-piiq), an anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) according to the methods provided herein. In some embodiments, after completion of at least two 21-day cycles of treatment, the incidence of adverse events is assessed for patients receiving an immunoconjugate (e.g., poluzumab vedotin-piiq), an anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) according to the methods provided herein.
In some embodiments, the dose of an immunoconjugate (e.g., polotophyllizumab vedotin-piiq), an anti-CD 20 antibody (e.g., rituximab), and/or the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) is adjusted according to the incidence of adverse events. In some embodiments, the adverse event is based on laboratory test results obtained within 72 hours prior to infusion on day 1 of a cycle. In certain embodiments, symptoms are graded according to the U.S. national cancer institute adverse event common terminology standard, 5 th edition (NCI CTCAE V5.0.0).
In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not result in neutropenia in humans. In some embodiments, the methods provided herein further comprise administering to the human a prophylactic treatment for neutropenia before, during, and/or after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to the human. In some embodiments, prophylactic treatment for neutropenia includes, for example, administering G-CSF in each treatment cycle. In some embodiments, if grade 3 or grade 4 neutropenia occurs, the immunoconjugate (e.g., polotobulab vedotin-piiq), the anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) treatment is suspended until Absolute Neutrophil Count (ANC) returns to >1000/μl. In some embodiments, if management of neutropenia is desired, a growth factor (e.g., G-CSF) is administered. See, for example: smith et al (2016) J Clin Oncol,24:3187-205. In some embodiments, if the ANC of the human is restored to >1000/μl at or before day 7, the immunoconjugate (e.g., poluzumab vedotin-piiq), the anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) are restored for treatment without any additional dose reduction. In some embodiments, if the ANC of the human is restored to > 1000/. Mu.L after day 7, the dose of the Polollipopolysaccharide vedotin-piiq is reduced to 1.4mg/kg. In some embodiments, if a dose reduction of the polotouzumab vedotin-piiq occurred previously, the immunoconjugate (e.g., polotouzumab vedotin-piiq), the anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) treatment is discontinued.
In some embodiments, if grade 3 or grade 4 thrombocytopenia occurs, the immunoconjugate (e.g., polotobulab vedotin-piiq), anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) treatment is suspended until the platelets return to >75,000/μl. In some embodiments, if the human platelets return to >75,000/μl at or before day 7, the immunoconjugate (e.g., poluzumab vedotin-piiq), the anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) are restored for treatment without any additional dose reduction. In some embodiments, if platelets return to >75,000/μl after day 7, the dose of the poloxamer vedotin-piiq is reduced to 1.4mg/kg. In some embodiments, if a dose reduction of the polotouzumab vedotin-piiq occurred previously, the immunoconjugate (e.g., polotouzumab vedotin-piiq), the anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) treatment is discontinued.
In some embodiments, if a grade 2 or grade 3 peripheral neuropathy occurs, the immunoconjugate (e.g., poluzumab vedotin-piiq), the anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) treatment is delayed until improvement to grade 1 or less. In some embodiments, if grade 2 or grade 3 peripheral neuropathy returns to grade 1 within 14 days or less, then immunoconjugate (e.g., poluzumab vedotin-piiq), anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) treatment is resumed, wherein the dose of poluzumab vedotin-piiq is permanently reduced to 1.4mg/kg and the dose of oxaliplatin is 75mg/m 2. In some embodiments, if the patient had previously developed grade 2 peripheral neuropathy and/or if the dose of the poloxamer vedotin-piiq was reduced to 1.4mg/kg before and the dose of oxaliplatin was 75mg/m 2, then the poloxamer vedotin-piiq monotherapy is discontinued in the event that grade 2 or grade 3 peripheral neuropathy did not return to grade 1 on or before day 14. In some embodiments, if the subject had previously developed a grade 3 peripheral neuropathy, the treatment is discontinued. In some embodiments, oxaliplatin and polotophyllizumab velutin-piiq are permanently discontinued if grade 2 or grade 3 peripheral neuropathy returns to grade 1 after ≡14 days or after the planned date of the next cycle. In some embodiments, if a grade 4 peripheral neuropathy occurs, the immunoconjugate (e.g., poluzumab vedotin-piiq), the anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) treatment are discontinued.
In some embodiments, oxaliplatin infusion is prolonged to 6 hours if throat dysesthesia occurs.
In some embodiments, if a level 1-2 infusion-related reaction (IRR) occurs, the infusion is slowed or paused. In some embodiments, the subject is given supportive care. In some embodiments, supportive treatment comprises acetaminophen/paracetamol and an antihistamine such as diphenhydramine and/or an intravenous physiological saline. In some embodiments, supportive treatment for bronchospasm, urticaria, or dyspnea includes antihistamines, oxygen, corticosteroids (e.g., 100mg IV prednisolone or equivalent), and/or bronchodilators. In some embodiments, the recovery infusion rate is incremented after the symptoms subside. In some embodiments, for an incremental infusion rate after restarting after complete resolution of symptoms, 50% of the rate achieved before interruption is used to resume infusion. In some embodiments, the infusion rate is incremented at 50 mg/hr every 30 minutes in the absence of infusion-related symptoms. In some embodiments, if level 1-2 IRR occurs, the poloxamer vedotin is infused in the next cycle over 90 minutes. In some embodiments, if an infusion-related reaction does not occur, then the poloxamer vedotin is infused over 30 minutes. In some embodiments, the pre-operative drug is administered during all cycles. In some embodiments, if wheezing or urticaria symptoms recur, the immunoconjugate (e.g., poluzumab vedotin-piiq), the anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) treatment is discontinued.
In some embodiments, if a level 3 IRR occurs, infusion is aborted. In some embodiments, the subject is given supportive care. In some embodiments, supportive treatment comprises acetaminophen/paracetamol and an antihistamine such as diphenhydramine and/or an intravenous physiological saline. In some embodiments, supportive treatment for bronchospasm, urticaria, or dyspnea includes antihistamines, oxygen, corticosteroids (e.g., 100mg IV prednisolone or equivalent), and/or bronchodilators. In some embodiments, the recovery infusion rate is incremented after the symptoms subside. In some embodiments, for an incremental infusion rate after restarting after complete resolution of symptoms, 50% of the rate achieved before interruption is used to resume infusion. In some embodiments, the infusion rate is incremented at 50 mg/hr every 30 minutes in the absence of infusion-related symptoms. In some embodiments, if some adverse events recur with the same severity, the immunoconjugate (e.g., poluzumab vedotin-piiq), anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) treatment is discontinued.
In some embodiments, if grade 4 IRR occurs, the immunoconjugate (e.g., polotophyllizumab vedotin-piiq), anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) treatment is discontinued.
In some embodiments, if total bilirubin >3.0mg/dL is observed, the immunoconjugate (e.g., polotobulab vedotin-piiq), anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) treatment is delayed until total bilirubin returns to 1.5mg/dL or less within 14 days or less. In some embodiments, if an increase in liver transaminase >3 x baseline value and an increase in direct bilirubin >2 x ULN is observed, without any signs of cholestasis or jaundice or liver dysfunction, and without other contributors (e.g., worsening of metastatic disease or concomitant exposure to known hepatotoxic agents or recorded infectious etiology), immunoconjugate (e.g., polo-toxazumab vetin-piiq), anti-CD 20 antibody (e.g., rituximab) and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) treatment is discontinued.
In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not result in tumor lysis syndrome in humans. In some embodiments, the methods provided herein further comprise administering to the human a prophylactic treatment against tumor lysis syndrome before, during, and/or after administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to the human. In some embodiments, the prophylactic treatment comprises hydration, e.g., 3 liters of fluid per day, which begins, e.g., about 1 day or 2 days prior to administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, the prophylactic treatment comprises allopurinol (e.g., 300 mg/day orally) or a suitable alternative treatment (e.g., labyrinase) that begins about 48 hours to about 72 hours prior to administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, the prophylactic treatment comprises: hydration, e.g., 3 liters of fluid per day, which begins, e.g., about 1 or 2 days prior to administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin; and allopurinol (e.g., 300 mg/day orally) or a suitable alternative therapy (e.g., labyrine), which begins about 48 hours to about 72 hours prior to administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, if a human is at risk of developing oncolytic syndrome, e.g., if the human has a high tumor burden (e.g., lymphocyte count ≡25×10 9/L or large lymphadenopathy), a prophylactic treatment for oncolytic syndrome is administered to the human. In some embodiments, the prophylactic treatment against tumor lysis syndrome is administered at each administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin. In some embodiments, if grade 3 or grade 4 Tumor Lysis Syndrome (TLS) occurs, the immunoconjugate (e.g., polotouzumab vedotin-piiq), the anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) treatment are suspended. In some embodiments, the next dose is delayed by up to 14 days. In some embodiments, after complete elimination of TLS, full amounts of immunoconjugate (e.g., polotobulab vedotin-piiq), anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) treatment are restored during the next planned infusion in combination with prophylactic treatment.
In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not result in infection of human subjects. In some embodiments, the infection is a pneumosporoal infection or a herpes virus infection. In some embodiments, the methods provided herein further comprise administering to the human a prophylactic treatment against the infection before, during, and/or after the immunoconjugate, rituximab, gemcitabine, and oxaliplatin are administered to the human. In some embodiments, the prophylactic treatment for infection includes one or more suitable antiviral drugs. In some embodiments, the human receives prophylactic treatment for reactivation of hepatitis b, for example as described in the following documents: powers et al, 2013; united states national integrated cancer network (NCCN) 2017.
In some embodiments, if grade 3 or grade 4 non-hematological toxicity (excluding hair loss, nausea, and vomiting) occurs, the immunoconjugate (e.g., poluzumab vedotin-piiq), the anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) are delayed for up to 14 days. In some embodiments, if an improvement to grade 1 or baseline level is observed, a reduced or full amount of immunoconjugate (e.g., poluzumab vedotin-piiq), anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) treatment is restored.
In some embodiments, if grade 2 non-hematological toxicity occurs, immunoconjugates (e.g., poluzumab vedotin-piiq), anti-CD 20 antibodies (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) are delayed for up to 14 days. In some embodiments, if an improvement to +.1 or baseline level is observed, then the immunoconjugate (e.g., polotouzumab vedotin-piiq), the anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) are treated at a dose prior to administration.
In some embodiments, the immunoconjugate (e.g., polotophyllizumab vedotin-piiq), the anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) are not modulated if grade 1 non-hematological toxicity occurs.
In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not result in reactivation of human hepatitis b. In some embodiments, the methods provided herein further comprise administering to the human a prophylactic treatment for hepatitis b reactivation prior to, during, and/or after administering the immunoconjugate, rituximab, gemcitabine, and oxaliplatin to the human. In some embodiments, the prophylactic treatment for reactivation of hepatitis b includes an antiviral drug, for example as described in the following documents: powers et al, 2013; united states national integrated cancer network (NCCN) 2017. In some embodiments, the methods provided herein further comprise administering an antiviral drug to the human upon detection of hepatitis b reactivation (e.g., a suitable nucleoside analog) in the human. In some embodiments, hepatitis b reactivation is determined by new detectable HBV-DNA levels. In some embodiments, if the HBV-DNA level is in the range of 29IU/mL to 100IU/mL recommended by the World Health Organization (WHO), the HBV-DNA level is re-detected within 2 weeks. In some embodiments, if HBV-DNA levels are positive, then immunoconjugate (e.g., polotophyllizumab vedotin-piiq), anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) are paused for treatment and the subject is subjected to nucleoside analog treatment. In some embodiments, if HBV-DNA levels are observed to be >100IU/mL at the WHO recommended threshold, then immunoconjugate (e.g., polo-bezozumab vedotin-piiq), anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) treatment is suspended and a nucleoside analog is administered. In some embodiments, if an increase in HBV-DNA viral load (greater than 100 IU/mL) is observed during the appropriate antiviral treatment, the immunoconjugate (e.g., poluzumab vedotin-piiq), anti-CD 20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) treatment is discontinued.
In some embodiments, administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not result in one or more adverse events selected from the group consisting of: drug-induced liver injury, progressive multifocal leukoencephalopathy, systemic hypersensitivity, anaphylaxis, anaphylactoid reactions, and secondary malignancy. In some embodiments, the drug-induced liver injury comprises a combination of elevated ALT or AST and elevated bilirubin or clinical jaundice in a human, as defined by the Law of haemangionella (Hy's Law). In some embodiments, drug-induced liver injury includes the combination of ALT or AST > 3X baseline values with total bilirubin > 2X ULN (where > 35% is direct bilirubin) occurring in an in vivo treatment. In some embodiments, the drug-induced liver injury comprises the combination of an ALT or AST >3 x baseline value with clinical jaundice that occurs in an in vivo treatment. In some embodiments, systemic hypersensitivity, anaphylaxis and anaphylactoid reactions are assessed using Sampson criteria.
An immunoconjugate is provided comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, for use in a method of treating diffuse large B-cell lymphoma (DLBCL, e.g., recurrent/refractory DLBCL) in a subject in need thereof (human subject). In some embodiments, the immunoconjugate is used according to any one of the methods provided herein. In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising: (i) a VH comprising the amino acid sequence of SEQ ID NO. 19; and (ii) VL comprising the amino acid sequence of SEQ ID NO. 20. In some embodiments, the immunoconjugate is a poloxamer vedotin-piiq.
Also provided is the use of an immunoconjugate comprising formula (I)
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, for use in the manufacture of a medicament for treating diffuse large B cell lymphoma (DLBCL, e.g., recurrent/refractory DLBCL) in an individual in need thereof (human individual), wherein the medicament is for (e.g., formulated for) administration in combination with an anti-CD 20 antibody (e.g., rituximab) and one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin). In some embodiments, a drug (i.e., a drug comprising an immunoconjugate) is used in the methods described herein. In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising: (i) a VH comprising the amino acid sequence of SEQ ID NO. 19; and (ii) VL comprising the amino acid sequence of SEQ ID NO. 20. In some embodiments, the immunoconjugate is a poloxamer vedotin-piiq.
An immunoconjugate is provided comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) a VH comprising the amino acid sequence of SEQ ID NO. 19; and (ii) VL comprising the amino acid sequence of SEQ ID NO. 20, and wherein p is between 2 and 5, for use in a method of treating diffuse large B-cell lymphoma (DLBCL, e.g., recurrent/refractory DLBCL) in an individual in need thereof, the method comprising administering to the individual an effective amount of (a) an immunoconjugate, (B) rituximab, and (c) one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin), wherein the immunoconjugate is administered at a dose between about 1.4mg/kg and about 1.8mg/kg, rituximab is administered at a dose between 375mg/m 2, and the one or more chemotherapeutic agents are administered at a dose between 50-2000mg/m 2 (e.g., gemcitabine is administered at a dose of 1000mg/m 2, and oxaliplatin is administered at a dose of 100mg/m 2), in some embodiments, the immunoconjugate comprises an anti-CD antibody comprising the heavy chain of the light chain of SEQ ID NO. 3 and CD79, in some embodiments, an anti-CD antibody comprising the heavy chain of SEQ ID NO. 79, an anti-antibody of SEQ ID NO. 35, and an antibody of which comprises the heavy chain of SEQ ID NO. 79, in some embodiments, an antibody of the heavy chain of SEQ ID NO. 3 and an antibody of SEQ ID NO. 79, and an antibody of which comprises the heavy chain of antibodies of SEQ ID NO. 35, and an antibody of SEQ ID NO. 79, comprising the amino acid sequence of SEQ ID NO. 36; and a light chain comprising the amino acid sequence of SEQ ID NO. 38. In some embodiments, the immunoconjugate is a poloxamer vedotin-piiq.
Also provided is an immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) a VH comprising the amino acid sequence of SEQ ID NO. 19; and (ii) VL comprising the amino acid sequence of SEQ ID NO:20, and wherein p is between 2 and 5, for use in the manufacture of a medicament for treating diffuse large B-cell lymphoma (DLBCL, e.g., recurrent/refractory DLBCL) in an individual in need thereof (human individual), wherein the medicament is for (e.g., formulated for) administration in combination with rituximab and one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin), wherein the medicament is formulated for administration of an immunoconjugate of between about 1.4mg/kg and about 1.8mg/kg, rituximab is for administration at a dose of 375mg/m 2, and the one or more chemotherapeutic agents are for administration at a dose of 50-2000mg/m 2 (e.g., gemcitabine is administered at a dose of 1000mg/m 2, and oxaliplatin is administered at a dose of 100mg/m 2). In some embodiments, the medicament (i.e., the medicament comprising the immunoconjugate) is used according to the methods described herein. In some embodiments, p is between 3 and 4. In some embodiments, p is 3.5. In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising: a heavy chain comprising the amino acid sequence of SEQ ID NO. 36; and a light chain comprising the amino acid sequence of SEQ ID NO. 35. In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising: a heavy chain comprising the amino acid sequence of SEQ ID NO. 37; and a light chain comprising the amino acid sequence of SEQ ID NO. 35. In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising: a heavy chain comprising the amino acid sequence of SEQ ID NO. 36; and a light chain comprising the amino acid sequence of SEQ ID NO. 38. In some embodiments, the immunoconjugate is a poloxamer vedotin-piiq. Immunoconjugates comprising anti-CD 79b antibodies and a drug/cytotoxic agent ("anti-CD 79b immunoconjugates")
In some embodiments, an anti-CD 79b immunoconjugate comprises: anti-CD 79B antibodies (abs) that target cancer cells, such as Diffuse Large B Cell Lymphoma (DLBCL) cells; a drug moiety (D); and a linker moiety (L) linking Ab to D. In some embodiments, the anti-CD 79b antibody is linked to the linker moiety (L) by one or more amino acid residues such as lysine and/or cysteine. In some embodiments, the immunoconjugate comprises the formula Ab- (L-D) p, wherein: (a) Ab is an anti-CD 79b antibody; (b) L is a linker; (c) D is a cytotoxic agent; and (d) p is in the range of 1-8.
An exemplary anti-CD 79b immunoconjugate comprises formula I:
(I)Ab-(L-D)p
Wherein p is 1 to about 20 (e.g., 1 to 15, 1 to 10,1 to 8, 2 to 5, or 3 to 4). In some embodiments, the number of drug moieties that can be conjugated to an anti-CD 79b antibody is limited by the number of free cysteine residues. In some embodiments, the free cysteine is introduced into the antibody amino acid by methods described elsewhere herein. Exemplary anti-CD 79b immunoconjugates of formula I include, but are not limited to, anti-CD 79b antibodies comprising 1,2, 3 or 4 engineered cysteines (Lyon, r. Et al (2012) Methods in enzyme.502:123-138). In some embodiments, one or more free cysteine residues are already present in the anti-CD 79b antibody without the use of engineering, in which case the existing free cysteine residues may be used to conjugate the anti-CD 79b antibody to a drug/cytotoxic agent. In some embodiments, the anti-CD 79b antibody is exposed to reducing conditions prior to conjugation to the drug/cytotoxic agent in order to generate one or more free cysteine residues.
A. exemplary linker groups
A "linker" (L) is a bifunctional or multifunctional moiety useful for linking one or more drug moieties (D) to an anti-CD 79b antibody (Ab) to form an anti-CD 79b immunoconjugate of formula I. In some embodiments, anti-CD 79b immunoconjugates may be prepared using a linker having a reactive functional group to covalently attach to the drug and the anti-CD 79b antibody. For example, in some embodiments, the cysteine thiol of an anti-CD 79b antibody (Ab) may form a bond with a reactive functional group of a linker or drug-linker intermediate to prepare an anti-CD 79b immunoconjugate.
In one aspect, the linker has a functional group capable of reacting with the free cysteine present on the anti-CD 79b antibody to form a covalent bond. Exemplary reactive functional groups include, but are not limited to, for example, maleimides, haloacetamides, alpha-haloacetyl, activated esters such as succinimidyl esters, 4-nitrophenyl esters, pentafluorophenyl esters, tetrafluorophenyl esters, anhydrides, acid chlorides, sulfonyl chlorides, isocyanates, and isothiocyanates. See, e.g., klussman et al (2004), bioconjugate Chemistry (4): conjugation methods at page 766 of 765-773, and examples herein.
In some embodiments, the linker has a functional group capable of reacting with an electrophilic group present on the anti-CD 79b antibody. Exemplary electrophilic groups include, but are not limited to, for example, aldehyde and ketone carbonyl groups. In some embodiments, the heteroatom of the reactive functional group of the linking group can react with an electrophilic group on the antibody and form a covalent bond with the antibody unit. Exemplary reactive functional groups include, but are not limited to, for example, hydrazides, oximes, amino groups, hydrazines, thiocarbamides, hydrazinecarboxylic acid esters, and aryl hydrazides.
In some embodiments, the linker comprises one or more linker components. Exemplary linker components include, for example, 6-maleimidocaproyl ("MC"), maleimidopropionyl ("MP"), valine-citrulline ("val-cit" or "vc"), alanine-phenylalanine ("ala-phe"), p-aminobenzyloxycarbonyl ("PAB"), N-succinimidyl 4- (2-pyridylthio) pentanoate ("SPP"), and 4- (N-maleimidomethyl) cyclohexane-1 carboxylate ("MCC"). Various linker components are known in the art, some of which are described below.
In some embodiments, the linker is a "cleavable linker" that facilitates drug release. Non-limiting exemplary cleavable linkers include acid labile linkers (e.g., comprising hydrazones), protease-sensitive (e.g., peptidase-sensitive) linkers, photolabile linkers, or disulfide-containing linkers (Chari et al, CANCER RESEARCH:127-131 (1992); U.S. Pat. No. 5,162).
In certain embodiments, the linker (L) has the following formula II:
(II)-Aa-Ww-Yy
Wherein A is a "drawing unit" and a is an integer from 0 to 1; w is an "amino acid unit" and W is an integer from 0 to 12; y is a "spacer unit" and Y is 0, 1 or 2; and Ab, D and p are as defined above for formula I. Exemplary embodiments of such linkers are described in U.S. patent No. 7,498,298, which is expressly incorporated herein by reference.
In some embodiments, the linker component comprises a "stretch unit" that links the antibody to another linker component or drug moiety. Non-limiting exemplary stretcher units are shown below (where wavy lines represent sites of covalent attachment to an antibody, drug or other linker component):
In some embodiments, the linker component comprises "amino acid units". In some such embodiments, the amino acid units enable the protease to cleave the linker, thereby facilitating release of the drug/cytotoxic agent from the anti-CD 79b immunoconjugate upon exposure to an intracellular protease, such as a lysosomal enzyme (Doronina et al (2003) Nat. Biotechnol. 21:778-784). Exemplary amino acid units include, but are not limited to, amino acids, tripeptides, tetrapeptides, and pentapeptides. Exemplary dipeptides include, but are not limited to, valine-citrulline (vc or val-cit), alanine-phenylalanine (af or ala-phe); phenylalanine-lysine (fk or phe-lys); phenylalanine-homolysine (phe-homolys); n-methyl-valine-citrulline (Me-val-cit). Exemplary tripeptides include, but are not limited to, glycine-valine-citrulline (gly-val-cit) and glycine-glycine (gly-gly-gly). The amino acid units may include naturally occurring amino acid residues and/or minor amino acids and/or non-naturally occurring amino acid analogs, such as citrulline. The amino acid units may be designed and optimized for enzymatic cleavage by specific enzymes (e.g., tumor-associated proteases, cathepsins B, C, and D or plasmin proteases).
In some embodiments, the linker component comprises a "spacer" unit that directly or indirectly connects the antibody to the drug moiety through the stretch unit and/or the amino acid unit. The spacer units may be "self-eliminating" or "non-self-eliminating". A "non-self-eliminating" spacer unit is one in which a portion or all of the spacer unit remains bound to the drug moiety after cutting the ADC. Examples of non-self-eliminating spacer units include, but are not limited to, glycine spacer units and glycine-glycine spacer units. In some embodiments, an ADC comprising a glycine-glycine spacer unit is cleaved by a tumor cell associated protease, resulting in release of the glycine-drug moiety from the remainder of the ADC. In some such embodiments, the glycine-drug moiety is subjected to a hydrolysis step in the tumor cell, thereby cleaving the glycine-glycine spacer unit from the drug moiety.
The "self-eliminating" spacer unit may release the drug moiety. In certain embodiments, the spacer unit of the linker comprises a p-aminobenzyl unit. In some such embodiments, the para-aminobenzyl alcohol is attached to the amino acid unit by an amide bond, and a carbamate, methyl carbamate, or carbonate is formed between the benzyl alcohol and the drug (Hamann et al (2005) Expert Opin. Ther. Patents (2005) 15:1087-1103). In some embodiments, the spacer unit is para-amino and para-aminobenzyloxycarbonyl (PAB). In some embodiments, an anti-CD 79b immunoconjugate comprises a self-eliminating linker comprising the structure:
Wherein Q is-C 1-C8 alkyl, -O- (C 1-C8 alkyl) -halogen, -nitro or-cyano; m is an integer ranging from 0 to 4; and p is in the range of 1 to about 20. In some embodiments, p is in the range of 1 to 10, 1 to 7, 1 to 5, or 1 to 4.
Other examples of self-eliminating spacers include, but are not limited to, aromatic compounds that are electronically similar to PAB groups, such as 2-aminoimidazole-5-methanol derivatives (U.S. Pat. No. 7,375,078; hay et al (1999) Bioorg. Med. Chem. Lett. 9:2237) and o-or p-aminobenzyl acetals. In some embodiments, spacers that cyclize upon hydrolysis of the amide bond may be used, such as substituted and unsubstituted 4-aminobutyric acid amides (Rodrigues et al (1995) CHEMISTRY BIOLOGY 2:223), appropriately substituted bicyclo [2.2.1] and bicyclo [2.2.2] ring systems (Storm et al (1972) J.Amer.chem.Soc.94:5815) and 2-aminophenylpropionic acid amides (Amsberry et al (1990) J.org.chem.55:5867). The linkage of the drug to the alpha-carbon of the glycine residue is another example of a self-eliminating spacer that can be used in ADCs (Kingsbury et al (1984) J.Med. Chem. 27:1447).
In some embodiments, the linker L may be a dendron linker for covalently attaching more than one drug moiety to an antibody by branching the multifunctional linker moiety (Sun et al (2002) Bioorganic & MEDICINAL CHEMISTRY LETTERS 12:2213-2215; sun et al (2003) Bioorganic & MEDICINAL CHEMISTRY 11:1761-1768). Dendritic linkers can increase the molar ratio of drug to antibody, i.e., loading, which is related to the efficacy of the ADC. Thus, where an antibody carries only one reactive cysteine thiol group, a large number of drug moieties can be attached through a dendritic linker.
Non-limiting exemplary linkers are shown below in the context of anti-CD 79 immunoconjugates of formulae III, IV, V:
(III)
fIV)
(v) Wherein (Ab) is an anti-CD 79b antibody, (D) is a drug/cytotoxic agent, "Val-Cit" is valine-citrulline dipeptide, MC is 6-maleimidocaproyl, PAB is p-aminobenzyloxycarbonyl, and p is 1 to about 20 (e.g., 1 to 15, 1 to 10, 1 to 8, 2 to 5, or 3 to 4).
In some embodiments, the anti-CD 79b immunoconjugate comprises a structure represented by any one of formulas VI-V below:
(VI)(VII)
(VIII)(IX)
(X)
Wherein X is:
Y is:
each R is independently H or C1-C6 alkyl; and n is 1 to 12.
In general, peptide-type linkers can be prepared by forming peptide bonds between two or more amino acids and/or peptide fragments. Such peptide bonds can be prepared, for example, according to liquid phase synthesis methods (e.g., E.And K.L u bke (1965), "THE PEPTIDES", volume 1, pages 76 to 136, ACADEMIC PRESS).
In some embodiments, the linking group is substituted with a group that modulates solubility and/or reactivity. As non-limiting examples, charged substituents such as sulfonate (-SO 3) or ammonium may increase the water solubility of the linker reagent and promote the coupling reaction of the linker reagent with the antibody and/or drug moiety, or the coupling reaction of Ab-L (anti-CD 79b antibody-linker intermediate) with D or D-L (drug/cytotoxic-linker intermediate) with Ab, depending on the synthetic route used to prepare the anti-CD 79b immunoconjugate. In some embodiments, a portion of the linker is coupled to the antibody and a portion of the linker is coupled to the drug, then the anti-CD 79 Ab- (linker moiety) a is coupled to the drug/cytotoxic agent- (linker moiety) b to form the anti-CD 79b immunoconjugate of formula I. In some such embodiments, the anti-CD 79b antibody comprises more than one (linker moiety) a substituent such that more than one drug/cytotoxic agent is coupled to the anti-CD 79b antibody in the anti-CD 79b immunoconjugate of formula I.
The anti-CD 79b immunoconjugates provided herein explicitly contemplate, but are not limited to, anti-CD 79b immunoconjugates prepared with the following linker reagents: bis-maleimido-trioxyethylene glycol (BMPEO), N- (. Beta. -maleimidopropoxy) -N-hydroxysuccinimide ester (BMPS), N- (. Epsilon. -maleimidocaproyloxy) succinimidyl Ester (EMCS), N- [ gamma. -maleimidobutyroyloxy ] succinimidyl ester (GMBS), 1, 6-hexane-bis-vinylsulfone (HBVS), succinimidyl 4- (N-maleimidomethyl) cyclohexane-1-carboxy- (6-amidohexanoate) (LC-SMCC), m-maleimidobenzoyl-N-hydroxysuccinimide ester (MBS), 4- (4-N-maleimidophenyl) butanoic acid hydrazide (MPBH), succinimidyl 3- (bromoacetamido) propionate (SBAP), succinimidyl Iodoacetate (SIA), succinimidyl (4-iodoacetyl) aminobenzoate (SIAB), N-succinimidyl-3- (2-pyridyldithio) propionate (SPDP), N-succinimidyl 4- (2-pyridylsulfonyl) methyl) cyclohexane-1-carboxylate (SMCC), and (1-pyridylsulfonyl) cyclohexane-carboxylate (SMCC, succinimidyl 4- (p-maleimidophenyl) butyrate (SMPB), succinimidyl 6- [ (beta-maleimidopropionamide) hexanoate ] (SMPH), iminothiolane (IT), sulfo-EMCS, sulfo-GMBS, sulfo-KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC and sulfo-SMPB, and succinimidyl- (4-vinyl sulfone) benzoate (SVSB), and includes bismaleimide reagents: dithiobismaleimide ethane (DTME), 1, 4-bismaleimide butane (BMB), 1, 4-bismaleimide-2, 3-dihydroxybutane (BMDB), bismaleimide hexane (BMH), bismaleimide ethane (BMOE), BM (PEG) 2 (shown below) and BM (PEG) 3 (shown below); difunctional derivatives of imidoesters (such as dimethyl imidoester hydrochloride, reactive esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis- (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis- (p-diazoniumbenzoyl) -ethylenediamine), diisocyanates (such as toluene 2, 6-diisocyanate) and bis-reactive fluorine compounds (such as 1, 5-difluoro-2, 4-dinitrobenzene) in some embodiments, the bismaleimide reagent attaches the thiol group of cysteine in the antibody to a thiol-containing drug moiety, linker or linker-drug intermediate other functional groups reactive with the thiol group include, but are not limited to, iodoacetamide bromoacetamide, vinylpyridine, disulfide, pyridyl disulfide, isocyanate and isothiocyanate.
Certain useful linker reagents are available from various commercial sources such as Pierce Biotechnology, inc (Rockford, IL), molecular Biosciences inc (Boulder, CO), or synthesized according to procedures described in the art; for example, as described in the following documents: toki et al (2002) J.org.chem.67:1866-1872; dubowchik et al (1997) Tetrahedron Letters,38:5257-60; walker, M.A. (1995) J.org.chem.60:5352-5355; frisch et al (1996)Bioconjugate Chem.7:180-186;US 6214345;WO 02/088172;US 2003130189;US2003096743;WO 03/026577;WO 03/043583; and WO 04/032828.
Carbon-14 labeled 1-isothiocyanatobenzyl-3-methyldiethylenetriamine pentaacetic acid (MX-DTPA) is an exemplary chelator for conjugating radionucleotides to antibodies. See, for example, WO94/11026.
B. anti-CD 79b antibodies
In some embodiments, an immunoconjugate (e.g., an anti-CD 79b immunoconjugate) comprises an anti-CD 79b antibody comprising at least one, two, three, four, five, or six HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID No. 21; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26. In some such embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising at least one of: (i) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; and/or (ii) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24. In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising at least one of: (i) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; And/or (ii) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24. In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising at least one, at least two, or all three VH HVR sequences selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID No. 21; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23. In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising: HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23. In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising: HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; and HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26. In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising: HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22. In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID No. 21; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23.
In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising at least one, at least two, or all three VL HVR sequences selected from: (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26. In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising at least one, at least two, or all three VL HVR sequences selected from: (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26. In some embodiments, the immunoconjugate comprises: (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26. In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising: HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24. In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising: (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26.
In some embodiments, an immunoconjugate comprises an anti-CD 79b antibody comprising (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; and (iii) HVR-H3 comprising an amino acid sequence selected from SEQ ID NO. 23; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from: (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26. In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising at least one of: (i) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; and/or (ii) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24.
In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID No. 21; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26 (see Table A). In some embodiments, the immunoconjugate comprises at least one of: HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; and/or HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24 (see Table A). In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID No. 21; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26 (see Table A).
Table a: HVR amino acid sequence.
Name of the name Sequence(s) SEQ ID NO
huMA79bv28 HVR H1 GYTFSSYWIE 21
huMA79bv28 HVR H2 GEILPGGGDTNYNEIFKG 22
huMA79bv28 HVR H3 TRRVPIRLDY 23
huMA79bv28 HVR L1 KASQSVDYEGDSFLN 24
huMA79bv28 HVR L2 AASNLES 25
huMA79bv28 HVR L3 QQSNEDPLT 26
In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3 of an anti-CD 79b antibody of Polotuzumab vedotin-piiq (numbered according to the method described by Kabat et al).
In some embodiments, the anti-CD 79b immunoconjugate comprises a humanized anti-CD 79b antibody. In some embodiments, the anti-CD 79b antibody comprises an HVR in any one of the embodiments provided herein, and further comprises a human acceptor framework, e.g., a human immunoglobulin framework or a human consensus framework. In some embodiments, the human acceptor framework is a human VL kappa 1 (VLKI) framework and/or a VH framework VH III. In some embodiments, the humanized anti-CD 79b antibody comprises: (a) HVR-H1 comprising the amino acid sequence of SEQ ID No. 21; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26.
In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising at least one, two, three, four, five, six, seven, or eight Framework Regions (FR) selected from: (a) Heavy chain FR (HC FR) 1 comprising the amino acid sequence of SEQ ID NO. 27; (b) HC FR2 comprising the amino acid sequence of SEQ ID NO. 28; (c) HC FR3 that comprises the amino acid sequence of SEQ ID NO. 29; (d) HC FR4 comprising the amino acid sequence of SEQ ID NO. 30; (e) A light chain FR (LC FR) 1 comprising the amino acid sequence of SEQ ID NO. 31; (f) LC FR2 that comprises the amino acid sequence of SEQ ID NO. 32; (g) LC FR3 that comprises the amino acid sequence of SEQ ID NO. 33; and (h) LC FR4 that comprises the amino acid sequence of SEQ ID NO:34 (see Table B).
In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising at least one, at least two, at least three, or all four HC FR sequences selected from: (a) HC FR1 comprising the amino acid sequence of SEQ ID NO. 27; (b) HC FR2 comprising the amino acid sequence of SEQ ID NO. 28; (c) HC FR3 that comprises the amino acid sequence of SEQ ID NO. 29; and (d) HC FR4 comprising the amino acid sequence of SEQ ID NO. 30. In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising at least one, at least two, at least three, or all four LC FR sequences selected from: (a) LC FR1 comprising the amino acid sequence of SEQ ID No. 31; (b) LC FR2 comprising the amino acid sequence of SEQ ID No. 32; (c) LC FR3 that comprises the amino acid sequence of SEQ ID NO. 33; and (d) LC FR4 comprising the amino acid sequence of SEQ ID NO. 34.
In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising: (a) HC FR1 comprising the amino acid sequence of SEQ ID NO. 27; (b) HC FR2 comprising the amino acid sequence of SEQ ID NO. 28; (c) HC FR3 that comprises the amino acid sequence of SEQ ID NO. 29; and (d) HC FR4 comprising the amino acid sequence of SEQ ID NO. 30. In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising: (a) LC FR1 comprising the amino acid sequence of SEQ ID No. 31; (b) LC FR2 comprising the amino acid sequence of SEQ ID No. 32; (c) LC FR3 that comprises the amino acid sequence of SEQ ID NO. 33; and (d) LC FR4 comprising the amino acid sequence of SEQ ID NO. 34.
In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising: (a) A VH domain comprising at least one, at least two, at least three, or all four HC FR sequences selected from: (i) HC FR1 comprising the amino acid sequence of SEQ ID NO. 27; (ii) HC FR2 comprising the amino acid sequence of SEQ ID NO. 28; (iii) HC FR3 comprising the amino acid sequence of SEQ ID NO. 29; and (iv) HC FR4 comprising the amino acid sequence of SEQ ID NO. 30; and (b) a VL domain comprising at least one, at least two, at least three, or all four LC FR sequences selected from the group consisting of: (i) LC FR1 comprising the amino acid sequence of SEQ ID No. 31; (ii) LC FR2 comprising the amino acid sequence of SEQ ID No. 32; (iii) LC FR3 comprising the amino acid sequence of SEQ ID No. 33; and (iv) LC FR4 comprising the amino acid sequence of SEQ ID NO. 34.
In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising: (a) HC FR1 comprising the amino acid sequence of SEQ ID NO. 27; (b) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (c) HC FR2 comprising the amino acid sequence of SEQ ID NO. 28; (d) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (e) HC FR3 that comprises the amino acid sequence of SEQ ID NO. 29; (f) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (g) HC FR4, comprising the amino acid sequence of SEQ ID NO. 30; (h) LC FR1 comprising the amino acid sequence of SEQ ID NO. 31; (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (j) LC FR2 comprising the amino acid sequence of SEQ ID No. 32; (k) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; (l) LC FR3 that comprises the amino acid sequence of SEQ ID NO. 33; (m) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26; and (n) LC FR4 comprising the amino acid sequence of SEQ ID NO. 34.
Table B: heavy and light chain framework region amino acid sequences.
In some embodiments, an immunoconjugate (e.g., an anti-CD 79b immunoconjugate) comprises an anti-CD 79b antibody comprising a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 19. In some embodiments, the VH sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO. 19, comprises a substitution (e.g., a conservative substitution), insertion or deletion relative to a reference sequence, but an anti-CD 79b immunoconjugate comprising the sequence retains the ability to bind CD79 b. In some embodiments, in SEQ ID NO. 19, a total of 1 to 10 amino acids are substituted, inserted and/or deleted. In some embodiments, a total of 1 to 5 amino acids are substituted, inserted and/or deleted in SEQ ID NO. 19. In some embodiments, substitutions, insertions, or deletions occur in regions outside the HVR (i.e., in the FR). In some embodiments, an immunoconjugate (e.g., an anti-CD 79b immunoconjugate) comprises the VH sequence of SEQ ID NO:19, which includes post-translational modifications of the sequence. In some embodiments, VH comprises one, two, or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID No. 21; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; and (c) HVR-H3 comprising SEQ ID NO 17or SEQ ID NO:23.
EVQLVESGGG LVQPGGSLRL SCAASGYTFS SYWIEWVRQA
PGKGLEWIGE ILPGGGDTNY NEIFKGRATF SADTSKNTAY
LQMNSLRAED TAVYYCTRRV PIRLDYWGQG TLVTVSS(SEQ ID NO:19)
In some embodiments, an immunoconjugate (e.g., an anti-CD 79b immunoconjugate) comprises an anti-CD 79b antibody comprising a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 20. In certain embodiments, the VL sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO. 20, comprises a substitution (e.g., a conservative substitution), insertion or deletion relative to a reference sequence, but an anti-CD 79b immunoconjugate comprising the sequence retains the ability to bind CD79 b. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted and/or deleted in SEQ ID NO. 20. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted and/or deleted in SEQ ID NO. 20. In certain embodiments, substitutions, insertions, or deletions occur in regions outside the HVR (i.e., in the FR). In some embodiments, the anti-CD 79b immunoconjugate comprises an anti-CD 79b antibody comprising the VL sequence of SEQ ID NO. 20, which comprises a post-translational modification of the sequence. In some embodiments, the VL comprises one, two, or three HVRs selected from: (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26. In some embodiments, the VL comprises one, two, or three HVRs selected from: (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26.
DIQLTQSPSS LSASVGDRVT ITCKASQSVD YEGDSFLNWY
QQKPGKAPKL LIYAASNLES GVPSRFSGSG SGTDFTLTIS SLQPEDFATY
YCQQSNEDPL TFGQGTKVEI KR(SEQ ID NO:20)
In some embodiments, an immunoconjugate (e.g., an anti-CD 79b immunoconjugate) comprises an anti-CD 79b antibody comprising a VH as in any one of the embodiments provided herein and a VL as in any one of the embodiments provided herein. In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising the VH and VL sequences of SEQ ID NO:19 and SEQ ID NO:20, respectively, including post-translational modifications of those sequences.
In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising the VH and VL of the anti-CD 79b antibody of pototouzumab vedotin-piiq.
In some embodiments, an immunoconjugate (e.g., an anti-CD 79b immunoconjugate) comprises an anti-CD 79b antibody that binds to the same epitope as the anti-CD 79b antibody described herein. For example, in some embodiments, an immunoconjugate (e.g., an anti-CD 79b immunoconjugate) comprises an anti-CD 79b antibody that binds to the same epitope as an anti-CD 79b antibody comprising the VH sequence of SEQ ID No. 19 and the VL sequence of SEQ ID No. 20.
In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody that is a monoclonal, chimeric, humanized, or human antibody. In some embodiments, the immunoconjugate comprises an antigen-binding fragment of an anti-CD 79b antibody described herein, e.g., fv, fab, fab ', scFv, diabody, or F (ab') 2 fragment. In some embodiments, the immunoconjugate comprises a substantially full length anti-CD 79b antibody, e.g., an IgG1 antibody or other antibody class or isotype described elsewhere herein.
In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising: a heavy chain comprising the amino acid sequence of SEQ ID NO. 36; and/or a light chain comprising the amino acid sequence of SEQ ID NO. 35. In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising: a heavy chain comprising the amino acid sequence of SEQ ID NO. 37; and/or a light chain comprising the amino acid sequence of SEQ ID NO. 35. In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising: a heavy chain comprising the amino acid sequence of SEQ ID NO. 36; and/or a light chain comprising SEQ ID NO. 38. In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising: a heavy chain comprising the amino acid sequence of SEQ ID NO. 36; and a light chain comprising the amino acid sequence of SEQ ID NO. 35. In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising: a heavy chain comprising the amino acid sequence of SEQ ID NO. 37; and a light chain comprising the amino acid sequence of SEQ ID NO. 35. In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising: a heavy chain comprising the amino acid sequence of SEQ ID NO. 36; and a light chain comprising the amino acid sequence of SEQ ID NO. 38.
In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising the heavy and light chains of the anti-CD 79b antibody in the poloxamer-piiq.
In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising the heavy and light chains of the anti-CD 79b antibody in Iladatuzumab vedotin. In some embodiments, the anti-CD 79b antibody comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO. 37; and a light chain comprising the amino acid sequence of SEQ ID NO. 35.
C. drug/cytotoxic agent
The anti-CD 79 immunoconjugate comprises an anti-CD 79b antibody (e.g., an anti-CD 79b antibody described herein) conjugated to one or more drugs/cytotoxic agents, such as a chemotherapeutic agent or drug, a growth inhibitory agent, a toxin (e.g., a bacterial, fungal, plant, or animal-derived protein toxin, an enzymatically active toxin, or a fragment thereof), or a radioisotope (i.e., a radioactive conjugate). Such immunoconjugates target chemotherapeutic molecules by targeting potent cytotoxic drugs to antigen-expressing cancer cells, such as tumor cells, combine the properties of antibodies and cytotoxic drugs (Teicher, b.a. (2009) Current Cancer Drug Targets 9:982-1004), thereby increasing the therapeutic index by maximizing efficacy and minimizing off-target toxicity (Carter, p.j. And hunter p.d. (2008) THE CANCER journal.14 (3): 154-169; chari, r.v. (2008) acc.chem.res.41:98-107). That is, the anti-CD 79 immunoconjugate selectively delivers an effective dose of the drug to cancer cells/tissue, thereby achieving higher selectivity while increasing the therapeutic index ("therapeutic window"), i.e., decreasing the effective dose (Polakis p. (2005) Current Opinion in Pharmacology 5:382-387).
Anti-CD 79 immunoconjugates for use in the methods provided herein include those having anti-cancer activity. In some embodiments, the anti-CD 79 immunoconjugate comprises an anti-CD 79b antibody conjugated (i.e., covalently attached) to a drug moiety. In some embodiments, the anti-CD 79b antibody is covalently attached to the drug moiety through a linker. The drug moiety (D) of the anti-CD 79 immunoconjugate may comprise any compound, moiety or group having a cytotoxic or cytostatic effect. The drug moiety may confer cytotoxicity and cytostatic effects thereto by mechanisms including, but not limited to, tubulin binding, DNA binding or intercalation, and inhibition of RNA polymerase, protein synthesis, and/or topoisomerase. Exemplary drug moieties include, but are not limited to, maytansinoids, dolastatin, auristatin, calicheamicin, anthracyclines, du Kamei, vinca alkaloids, taxanes, trichothecenes, CC1065, camptothecins, escitalophate Li Naifa and its cytotoxic stereoisomers, isosteres, analogues and derivatives.
(I) Maytansine and maytansinoids
In some embodiments, the anti-CD 79b immunoconjugate comprises an anti-CD 79b antibody conjugated to one or more maytansinoid molecules. Maytansinoids are derivatives of maytansine and are mitotic inhibitors that act by inhibiting tubulin polymerization. Maytansine was first isolated from east african shrubs (Maytenus serrata) (U.S. patent No. 3896111). Subsequently, it was found that certain microorganisms also produce maytansinoids, such as maytansinol and C-3 maytansinol esters (U.S. Pat. No. 4,151,042). Synthetic maytansine is disclosed, for example, in U.S. patent nos. 4,137,230;4,248,870;4,256,746;4,260,608;4,265,814;4,294,757;4,307,016;4,308,268;4,308,269;4,309,428;4,313,946;4,315,929;4,317,821;4,322,348;4,331,598;4,361,650;4,364,866;4,424,219;4,450,254;4,362,663; and 4,371,533.
Maytansinoid drug moieties are attractive drug moieties in antibody-drug conjugates because they: (i) relatively easy to prepare by fermentation or chemical modification or derivatization of the fermentation product, (ii) easy to derivatize with functional groups suitable for conjugation to antibodies via non-disulfide bonds, (iii) stable in plasma, and (iv) effective against a variety of tumor cell lines.
Certain maytansinoids suitable for use as part of maytansinoids are known in the art and may be isolated from natural sources according to known methods or produced using genetic engineering techniques (see, e.g., yu et al (2002) PNAS 99:7968-7973). Maytansinoids can also be prepared synthetically according to known methods.
Exemplary maytansinoid moieties include, but are not limited to, those having a modified aromatic ring, such as: c-19-dechlorination (US 4256746) (e.g., prepared by reduction of Anatomycin P2 with lithium aluminum hydride); c-20-hydroxy (or C-20-demethyl) +/-C-19-dechlorination (U.S. Pat. Nos. 4361650 and 4307016) (e.g., prepared by demethylation using Streptomyces or Actinomyces or dechlorination using LAH); c-20-desmethoxy, C-20-acyloxy (-OCOR), +/-dechlorination (U.S. Pat. No. 4,294,757) (e.g., prepared by acylation with an acid chloride), and those having modifications at other positions of the aromatic ring.
Exemplary maytansinoid moieties also include those having modifications such as: C-9-SH (U.S. Pat. No. 4424219) (e.g., prepared by reacting maytansinol with H2S or P2S 5); c-14-alkoxymethyl (desmethoxy/CH 2 OR) (US 4331598); c-14-hydroxymethyl or acyloxymethyl (CH 2OH or CH2 OAc) (U.S. Pat. No. 4450254) (e.g., prepared by Nocardia); c-15-hydroxy/acyloxy (US 4364866) (e.g., prepared by conversion of maytansinol with Streptomyces); c-15-methoxy (U.S. Pat. Nos. 4313946 and 4315929) (e.g., isolated from the peach (Trewia nudiflora)); C-18-N-demethyl (U.S. Pat. Nos. 4362663 and 4322348) (e.g., prepared by demethylating maytansinol with Streptomyces); and 4, 5-deoxy (US 4371533) (e.g., prepared by titanium trichloride/LAH reduction of maytansinol).
Many positions on maytansinoids can be used as attachment positions. For example, ester linkages can be formed by reaction with hydroxyl groups using conventional coupling techniques. In some embodiments, the reaction may be carried out at the C-3 position with a hydroxyl group, the C-14 position modified with a hydroxymethyl group, the C-15 position modified with a hydroxyl group, and the C-20 position with a hydroxyl group. In some embodiments, the linkage is formed at the C-3 position of the maytansinol or maytansinol analog.
Maytansinoid moieties include those having the following structure:
Wherein the wavy line indicates the covalent attachment of the sulfur atom of the maytansinoid moiety to the linker of the anti-CD 79b immunoconjugate. Each R may independently be H or C1-C6 alkyl. The alkylene chain attaching the amide group to the sulfur atom may be a methane, an ethylene or a propyl group, i.e., m is 1, 2 or 3 (US 633410;US 5208020;Chari et al (1992) Cancer Res.52:127-131; liu et al (1996) Proc. Natl. Acad. Sci USA 93:8618-8623).
All stereoisomers of maytansinoid drug moieties are contemplated for use in the anti-CD 79b immunoconjugates used in the methods provided herein, i.e., any combination of R and S configurations on chiral carbons (U.S. Pat. No. 3,218 (RE 39151); U.S. Pat. No. 5,0820; widdison et al (2006) J.Med. Chem.49:4392-4408, which is incorporated herein by reference in its entirety). In some embodiments, the maytansinoid moiety has the following stereochemical structure:
exemplary embodiments of maytansinoid moieties include, but are not limited to DM1; DM3; and DM4 having the following structure:
wherein the wavy line indicates the covalent attachment of the sulfur atom of the drug to the linker (L) of the anti-CD 79b immunoconjugate.
Other exemplary maytansinoid anti-CD 79b immunoconjugates have the following structures and abbreviations (wherein Ab is an anti-CD 79b antibody and p is 1to about 20. In some embodiments, p is 1to 10, p is 1to 7,p, or p is 1to 4):
Exemplary antibody-drug conjugates in which DM1 is linked to the thiol group of an antibody via a BMPEO linker have the following structure and abbreviation:
wherein Ab is an anti-CD 79b antibody; n is 0, 1 or 2; and p is from 1 to about 20. In some embodiments, p is 1 to 10, p is 1 to 7,p is 1 to 5, or p is 1 to 4.
Immunoconjugates comprising maytansinoids, methods of making and therapeutic uses thereof are disclosed, for example, in U.S. Pat. nos. 5,208,020 and 5,416,064; US2005/0276812 A1; and european patent EP 0 425 235b1, the disclosures of which are expressly incorporated herein by reference. See also: liu et al Proc.Natl. Acad. Sci. USA 93:8618-8623 (1996); and Chari et al CANCER RESEARCH 52:127-131 (1992).
In some embodiments, the anti-CD 79b antibody-maytansinoid conjugate may be prepared by chemically linking the anti-CD 79b antibody to a maytansinoid molecule without significantly reducing the biological activity of the antibody or maytansinoid molecule. See, for example, U.S. Pat. No. 5,208,020 (the disclosure of which is expressly incorporated herein by reference). In some embodiments, anti-CD 79b immunoconjugates conjugated to an average of 3-4 maytansinoid molecules per antibody molecule have been shown to enhance cytotoxicity of target cells without negatively affecting the function or solubility of the antibody. In some cases, even one toxin/antibody molecule is expected to be more cytotoxic than the use of naked anti-CD 79b antibodies.
Exemplary linking groups for preparing antibody-maytansinoid conjugates include, for example, those described herein and those disclosed in the following documents: U.S. patent No. 5208020; EP patent 0 425 235b1; chari et al CANCER RESEARCH 52:127-131 (1992); US 2005/0276812A1; and US2005/016993 A1, the disclosures of which are expressly incorporated herein by reference.
(2) Oritastatin dolastatin
The drug moiety includes dolastatin, auristatin, and analogs and derivatives thereof (US 5635483;US 5780588;US 5767237;US 6124431). Auristatin is a derivative of the marine mollusc compound dolastatin-10. While not wishing to be bound by any particular theory, dolastatin and auristatin have been shown to interfere with microtubule dynamics, GTP hydrolysis, and nuclear and cell division (Woyke et al (2001) Antimicrob. Agents and chemotherS.45 (12): 3580-3584) and have anticancer (US 5663149) and antifungal activity (Pettit et al (1998) Antimicrob. Agents chemotherS.42: 2961-2965). The dolastatin/auristatin drug moiety can be attached to the antibody via the N (amino) or C (carboxy) terminus of the peptide drug moiety (WO 02/088172; doronina et al (2003) Nature Biotechnology (7): 778-784; francisco et al (2003) Blood 102 (4): 1458-1465).
Exemplary auristatin embodiments include N-terminally linked monomethyl auristatin drug moieties DE and DF disclosed in US 7498298 and US 7659241, the disclosures of which are expressly incorporated herein by reference in their entirety:
wherein the wavy lines of DE and DF represent covalent attachment sites to an antibody or antibody linker component, and independently at each position:
r 2 is selected from H and C 1-C8 alkyl;
R 3 is selected from H, C 1-C8 alkyl, C 3-C8 carbocycle, aryl, C 1-C8 alkyl-aryl, C 1-C8 alkyl- (C 3-C8 carbocycle), C 3-C8 heterocycle, and C 1-C8 alkyl- (C 3-C8 heterocycle);
r 4 is selected from H, C 1-C8 alkyl, C 3-C8 carbocycle, aryl, C 1-C8 alkyl-aryl, C 1-C8 alkyl- (C 3-C8 carbocycle), C 3-C8 heterocycle, and C 1-C8 alkyl- (C 3-C8 heterocycle);
R 5 is selected from H and methyl;
Or R 4 and R 5 combine to form a carbocycle, and have the formula- (CR aRb)n -wherein R a and R b are independently selected from H, C 1-C8 alkyl, and C 3-C8 carbocycle and n are selected from 2, 3, 4, 5 and 6;
R 6 is selected from H and C 1-C8 alkyl;
R 7 is selected from H, C 1-C8 alkyl, C 3-C8 carbocycle, aryl, C 1-C8 alkyl-aryl, C 1-C8 alkyl- (C 3-C8 carbocycle), C 3-C8 heterocycle, and C 1-C8 alkyl- (C 3-C8 heterocycle);
Each R 8 is independently selected from H, OH, C 1-C8 alkyl, C 3-C8 carbocycle, and O- (C 1-C8 alkyl);
R 9 is selected from H and C 1-C8 alkyl;
r 10 is selected from aryl or C 3-C8 heterocycle;
Z is O, S, NH or NR 12, wherein R 12 is C 1-C8 alkyl;
R 11 is selected from H, C 1-C20 alkyl, aryl, C 3-C8 heterocycle, - (R 13O)m-R14 or- (R 13O)m-CH(R15)2);
m is an integer in the range of 1-1000;
R 13 is C 2-C8 alkyl;
R 14 is H or C1-C8 alkyl;
R 15 is independently at each occurrence H, COOH, - (CH 2) n-N(R16)2、-(CH2)n-SO3 H or- (CH 2)n-SO3-C1-C8 alkyl;
R 16 is independently at each occurrence H, C 1-C8 alkyl or- (CH 2)n -COOH);
R 18 is selected from the group consisting of-C (R 8)2-C(R8)2 -aryl, -C (R 8)2-C(R8)2-(C3-C8 heterocycle) and-C (R 8)2-C(R8)2-(C3-C8 carbocycle), and
N is an integer ranging from 0 to 6.
In one embodiment, R 3、R4 and R 7 are independently isopropyl or sec-butyl, and R 5 is-H or methyl. In one exemplary embodiment, R 3 and R 4 are each isopropyl, R 5 is-H, and R 7 is sec-butyl.
In yet another embodiment, R 2 and R 6 are each methyl, and R 9 is-H.
In yet another embodiment, R 8 at each occurrence is-OCH 3.
In one exemplary embodiment, R 3 and R 4 are each isopropyl, R 2 and R 6 are each methyl, R 5 is-H, R 7 is sec-butyl, R 8 is-OCH 3at each occurrence, and R 9 is-H.
In one embodiment, Z is-O-or-NH-.
In one embodiment, R 10 is aryl.
In one exemplary embodiment, R 10 is phenyl.
In one exemplary embodiment, when Z is-O-, R 11 is-H, methyl, or t-butyl.
In one embodiment, when Z is-NH, R 11 is-CH (R 15)2, wherein R 15 is- (CH 2) n-N(R16)2 and R 16 is-C 1-C8 alkyl or- (CH 2)n -COOH).
In another embodiment, when Z is-NH, R 11 is-CH (R 15) 2, where R 15 is- (CH 2)n-SO3 H).
An exemplary auristatin embodiment of formula DE is MMAE, where the wavy line indicates covalent attachment to the linker (L) of the anti-CD 79b immunoconjugate:
one exemplary auristatin embodiment of formula D F is MMAF, where the wavy line indicates covalent attachment to the linker (L) of the anti-CD 79b immunoconjugate:
Other exemplary embodiments include monomethyl valine compounds having phenylalanine carboxyl modification at the C-terminus of the pentapeptide auristatin drug moiety (WO 2007/008848) and monomethyl valine compounds having phenylalanine side chain modification at the C-terminus of the pentapeptide auristatin drug moiety (WO 2007/008603).
Non-limiting exemplary embodiments of anti-CD 79b immunoconjugates of formula I comprising MMAE or MMAF and various linker components have the following structure and abbreviation (wherein "Ab" is an anti-CD 79b antibody; p is 1 to about 8; "Val-Cit" is valine-citrulline dipeptide; and "S" is a sulfur atom:
In certain embodiments, the anti-CD 79b immunoconjugate comprises the structure Ab-MC-vc-PAB-MMAE, wherein p is, for example, about 1 to about 8; about 2 to about 7; about 3 to about 5; about 3 to about 4; or about 3.5. In some embodiments, the anti-CD 79b immunoconjugate is huMA79bv28-MC-vc-PAB-MMAE, e.g., the anti-CD 79b immunoconjugate comprises the structure Ab-MC-vc-PAB-MMAE, wherein p is, e.g., about 1 to about 8; about 2 to about 7; about 3 to about 5; about 3 to about 4; or about 3.5, wherein the anti-CD 79b antibody (Ab) comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO. 36; and a light chain comprising the amino acid sequence of SEQ ID NO. 35. In some embodiments, the anti-CD 79b immunoconjugate is a poloxamer vedotin-piiq. Polotuzumab vedotin-piiq has IUPHAR/BPS number 8404, KEGG number D10761, and may also be referred to as "DCDS4501A" or "RG7596".
Non-limiting exemplary embodiments of anti-CD 79b immunoconjugates of formula I comprising MMAF and various linker components further comprise Ab-MC-PAB-MMAF and Ab-PAB-MMAF. Immunoconjugates comprising MMAF attached to an antibody through a non-proteolytically cleavable linker have been demonstrated to have comparable activity to immunoconjugates comprising MMAF attached to an antibody through a proteolytically cleavable linker (Doronina et al (2006) Bioconjugate chem.17:114-124). In some such embodiments, it is believed that drug release is affected by antibody degradation in the cell.
Non-limiting exemplary embodiments of anti-CD 79b immunoconjugates of formula I comprising MMAE and various linker components further comprise Ab-MC-PAB-MMAE and Ab-PAB-MMAE.
In general, peptide-based drug moieties can be prepared by forming peptide bonds between two or more amino acids and/or peptide fragments. Such peptide bonds can be prepared, for example, according to liquid phase synthesis methods (see E, for example.And K.L u bke, "THE PEPTIDES", volume 1, pages 76-136, 1965,Academic Press). In some embodiments, the auristatin/dolastatin drug moiety can be prepared according to the following method: US 7498298; US 5635483; US 5780588; pettit et al (1989) J.am.chem.Soc.111:5463-5465; pettit et al (1998) Anti-Cancer Drug Design 13:243-277; pettit, g.r. et al Synthesis,1996, 719-725; pettit et al (1996) J.chem. Soc. Perkin Trans.1:859-863; and Doronina (2003) Nat. Biotechnol.21 (7): 778-784.
In some embodiments, the auristatin/dolastatin drug moiety of formula DE (such as MMAE) and the auristatin/dolastatin drug moiety of formula D F (such as MMAF) and their drug-linker intermediates and derivatives (such as MC-MMAF, MC-MMAE, MC-vc-PAB-MMAF, and MC-vc-PAB-MMAE) can be prepared using methods described in the following documents: US 7498298; doronina et al (2006) Bioconjugate chem.17:114-124; and Doronina et al (2003) Nat.Biotech.21:778-784, and then conjugated to an antibody of interest.
(3) Calicheamicin
In some embodiments, the anti-CD 79b immunoconjugate comprises an anti-CD 79b antibody conjugated to one or more calicheamicin molecules. Antibiotics of the calicheamicin family and analogs thereof are capable of producing sub-picomolar double-stranded DNA breaks (Hinman et al, (1993) CANCER RESEARCH 53:3336-3342; lode et al, (1998) CANCER RESEARCH 58:2925-2928). Calicheamicin has an intracellular site of action, but in some cases does not readily cross the cytoplasmic membrane. Thus, in some embodiments, cellular uptake of these agents by antibody-mediated internalization can greatly enhance their cytotoxic effects. Non-limiting exemplary methods of preparing anti-CD 79b antibody immunoconjugates comprising a calicheamicin drug moiety are described, for example, in US 5712374; US 5714586; US 5739116; and US 5767285.
(4) Other drug fractions
In some embodiments, the anti-CD 79b immunoconjugate comprises geldanamycin (Mandler et al (2000) J.Nat.cancer Inst.92 (19): 1573-1581; mandler et al (2000) Bioorganic & Med. Chem. Letters 10:1025-1028; mandler et al (2002) Bioconjugate chem.13:786-791); and/or enzymatically active toxins or fragments thereof, including, but not limited to, diphtheria a chain, non-binding active fragments of diphtheria toxin, exotoxin a chain (from pseudomonas aeruginosa), ricin a chain, abrin a chain, capsule radixin a chain, alpha-furin, aleurone, caryophyllin, pokeweed antiviral proteins (PAPI, PAPII and PAP-S), balsam pear inhibitors, curcumin, crotonin, soapbark inhibitors, gelatin, mi Tuojun, restrictocin, phenomycin, enomycin and trichothecene. See, for example, WO 93/21232.
The drug moiety also includes compounds having nucleolytic activity (e.g., ribonucleases or DNA endonucleases).
In certain embodiments, the anti-CD 79b immunoconjugate comprises a highly radioactive atom. A variety of radioisotopes may be used to produce the radioconjugated antibodies. Examples include At211、I131、I125、Y90、Re186、Re188、Sm153、Bi212、P32、Pb212 and radioactive isotopes of Lu. In some embodiments, when an anti-CD 79b immunoconjugate is used for detection, it may contain a radioactive atom for scintigraphy studies, e.g., tc 99 or I 123, or a spin label for Nuclear Magnetic Resonance (NMR) imaging (also known as magnetic resonance imaging, MRI), such as zirconium-89, iodine-123, iodine 131, indium-111, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese, or iron. Zirconium-89 can be complexed with various metal chelators and conjugated with antibodies, for example for PET imaging (WO 2011/056983).
Radiolabels or other labels may be incorporated into anti-CD 79b immunoconjugates by known means. For example, peptides may be biosynthesized or chemically synthesized using suitable amino acid precursors (comprising, for example, one or more fluorine-19 atoms in place of one or more hydrogen atoms). In some embodiments, labels such as Tc 99、I123、Re186、Re188 and In 111 may be attached via cysteine residues In the anti-CD 79b antibody. In some embodiments, yttrium-90 may be attached via a lysine residue of an anti-CD 79b antibody. In some embodiments, iodine-123 may be incorporated using the IODOGEN method (Fraker et al (1978) biochem. Biophys. Res. Commun. 80:49-57). "Monoclonal Antibodies in Immunoscintigraphy" (Chatal, CRC Press 1989) describes certain other methods.
In some embodiments, the anti-CD 79b immunoconjugate may comprise an anti-CD 79b antibody conjugated to a prodrug activating enzyme. In some such embodiments, the prodrug activating enzyme converts a prodrug (e.g., a peptide-based chemotherapeutic agent, see WO 81/01145) to an active drug such as an anticancer drug. In some embodiments, such immunoconjugates may be used in antibody-dependent enzyme-mediated prodrug therapy ("ADEPT"). Enzymes that can be conjugated to anti-CD 79b antibodies include, but are not limited to, alkaline phosphatase, which can be used to convert phosphate-containing prodrugs to free drugs; arylsulfatase, useful for converting sulfate-containing prodrugs into free drugs; cytosine deaminase, which can be used to convert non-toxic 5-fluorocytosine into the anticancer drug 5-fluorouracil; proteases, such as Serratia proteases, thermophilic proteases, subtilisins, carboxypeptidases and cathepsins (such as cathepsins B and L), which can be used to convert peptide-containing prodrugs into free drugs; d-alanyl-carboxypeptidase useful in converting prodrugs containing D-amino acid substituents; carbohydrate-cleaving enzymes, such as beta-galactosidase and neuraminidase, can be used to convert glycosylated prodrugs into free drugs; beta-lactamase useful for converting a drug derived from beta-lactam into a free drug; and penicillin amidases, such as penicillin V amidase and penicillin G amidase, which can be used to convert drugs derivatized at their amine nitrogen to have phenoxyacetyl or phenylacetyl groups, respectively, into free drugs. In some embodiments, the enzyme may be covalently bound to the antibody by recombinant DNA techniques well known in the art. See, e.g., neuberger et al, nature 312:604-608 (1984).
D. Drug loading rate
Drug loading is expressed as p, the average number of drug moieties per anti-CD 79b antibody in the molecule of formula I. The drug loading per antibody ranged from 1 to 20 drug moieties (D). The anti-CD 79b immunoconjugate of formula I comprises a collection of anti-CD 79b antibodies conjugated to a drug moiety in the range of 1 to 20. The average number of drug moieties per anti-CD 79b antibody in the anti-CD 79b immunoconjugate obtained by the coupling reaction can be characterized by conventional methods such as mass spectrometry, ELISA assays, and HPLC. Quantitative distribution of anti-CD 79b immunoconjugates expressed in p can also be determined. In some cases, isolation, purification, and characterization of a homogeneous anti-CD 79b immunoconjugate in which p is a particular value obtained from an anti-CD 79b immunoconjugate having other drug loading amounts can be achieved by reverse phase HPLC or electrophoresis, etc.
For certain anti-CD 79b immunoconjugates, p may be limited by the number of binding sites on the anti-CD 79b antibody. For example, where the attachment is a cysteine thiol, as described in certain of the exemplary embodiments above, the anti-CD 79b antibody may have only one or a few cysteine thiol groups, or may have only one or a few thiol groups with sufficiently high reactivity through which the attachment groups may be attached. In certain embodiments, higher drug loading, e.g., p >5, may result in aggregation, insolubility, toxicity, or decreased cell permeability of certain anti-CD 79b immunoconjugates. In certain embodiments, the average drug loading of the anti-CD 79b immunoconjugate ranges from 1 to about 8; about 2 to about 6; about 3 to about 5; or about 3 to about 4. Indeed, studies have shown that for certain antibody-drug conjugates, the optimal ratio of drug moieties per antibody may be less than 8, and may be from about 2 to about 5 (US 7498298). In certain embodiments, the optimal ratio of drug moieties per antibody is about 3 to about 4. In certain embodiments, the optimal ratio of drug moieties per antibody is about 3.5.
In certain embodiments, during the conjugation reaction, less than the theoretical maximum number of drug moieties are conjugated to the anti-CD 79b antibody. Antibodies may comprise lysine residues that are unreactive with, for example, a drug-linker intermediate or linker reagent, as described below. Typically, antibodies do not contain many free and reactive cysteine thiol groups that may be attached to the drug moiety; indeed, most of the cysteine thiol residues in antibodies exist as disulfide bonds. In certain embodiments, the anti-CD 79b antibody may be reduced with a reducing agent such as Dithiothreitol (DTT) or tricarbonyl ethyl phosphine (TCEP) under conditions of partial or complete reduction to form a reactive cysteine thiol group. In certain embodiments, the anti-CD 79b antibody is denatured to exhibit reactive nucleophilic groups such as lysine or cysteine.
The drug loading (drug/antibody ratio) of the anti-CD 79b immunoconjugate can be controlled in different ways, for example: (i) limit the molar excess of drug-linker intermediate or linker reagent relative to antibody, (ii) limit the coupling reaction time or temperature, and (iii) reduce conditions for partial or limiting cysteine thiol modification.
It will be appreciated that when more than one nucleophilic group is reacted with a drug-linker intermediate and a linker reagent, then the resulting product is a mixture of anti-CD 79b immunoconjugate compounds having a distribution of one or more drug moieties attached to the anti-CD 79b antibody. The average amount of drug in each antibody can be calculated from the mixture by a double ELISA antibody assay which is specific for the antibody and specific for the drug. Individual anti-CD 79b immunoconjugate molecules in the mixture can be identified by mass spectrometry and isolated by HPLC, e.g., hydrophobic interaction chromatography (see, e.g., mcDonagh et al (2006) prot. Engr. Design & Selection19 (7): 299-307; hamble et al (2004) clin. Cancer res.10:7063-7070; hamble et al, k.j, et al "Effect of drug loading on the pharmacology,pharmacokinetics,and toxicity of an anti-CD30 antibody-drug conjugate", abstract number 624, american cancer society, 2004, 3 months 27 to 31 days of 2004, AACR treaty, 45 volumes, 3 months 2004; alley, s.c. et al "Controlling the location of drug ATTACHMENT IN anti-drug conjugates", abstract number 627, american cancer society, 2004, 27 to 31 days of 2004, AACR treaty, 45 volumes, 2004 3 months). In certain embodiments, homogeneous anti-CD 79b immunoconjugates having a single drug loading can be separated from the conjugation mixture by electrophoresis or chromatography.
E. Method for preparing anti-CD 79b immunoconjugates
Anti-CD 79b immunoconjugates of formula I can be prepared by a variety of routes employing organic chemical reactions, conditions and reagents known to those skilled in the art, including, but not limited to, for example: (1) The nucleophilic group of the anti-CD 79b antibody reacts with the divalent linker reagent to form Ab-L via a covalent bond, and then with drug moiety D; and (2) the nucleophilic group of the drug moiety reacts with a divalent linking group reagent to form D-L via a covalent bond, and then reacts with the nucleophilic group of the anti-CD 79b antibody. An exemplary method for preparing an anti-CD 79b immunoconjugate of formula I by the latter route is described in US 7498298, which is expressly incorporated herein by reference.
Nucleophilic groups on antibodies include, but are not limited to: (i) an N-terminal amine group; (ii) side chain amine groups such as lysine; (iii) side chain thiol groups such as cysteine; and (iv) sugar hydroxyl or amino groups in which the antibody is glycosylated. Amine groups, thiol groups, and hydroxyl groups are nucleophilic groups capable of reacting with electrophilic groups on the linker moiety and linker reagent to form covalent bonds, the electrophilic groups comprising: (i) Active esters such as NHS esters, HOBt esters, haloformates, and acyl halides; (ii) alkyl and benzyl halides, such as haloacetamides; and (iii) aldehyde, ketone, carboxyl, and maleimide groups. Some antibodies have reducible interchain disulfide bonds, i.e., cysteine bridges. The anti-CD 79b antibody may be reacted with a linker reagent by treatment with a reducing agent such as DTT (dithiothreitol) or tricarbonyl ethyl phosphine (TCEP) such that the anti-CD 79b antibody is fully or partially reduced. Thus, each cysteine bridge would theoretically form two reactive thiol nucleophiles. Additional nucleophilic groups can be introduced into an anti-CD 79b antibody by modification of lysine residues, for example, by reacting the lysine residues with 2-iminothiolane (Traut reagent) to convert amines to thiols. Reactive sulfhydryl groups may also be introduced into anti-CD 79b antibodies by introducing one, two, three, four or more cysteine residues (e.g., by preparing variant antibodies comprising one or more unnatural cysteine amino acid residues).
The anti-CD 79b immunoconjugates described herein can also be made by reaction of an electrophilic group on an anti-CD 79b antibody, such as, for example, an aldehyde or ketone carbonyl group, with a linker reagent or a nucleophilic group on a drug. Nucleophilic groups useful on linker reagents include, but are not limited to, hydrazides, oximes, amino groups, hydrazines, thiocarbamides, hydrazinecarboxylic acid esters, and aryl hydrazides. In one embodiment, the anti-CD 79b antibody is modified to introduce an electrophilic moiety capable of reacting with a linker reagent or a nucleophilic substituent on a drug. In another embodiment, the sugar of the glycosylated anti-CD 79b antibody may be oxidized, for example with a periodate oxidizing reagent, to form an aldehyde or ketone group, which may react with the amine group of the linker reagent or drug moiety. The resulting imine schiff base groups may form a stable linkage or may be reduced, for example by borohydride reagents, to form stable amine linkages. In one embodiment, the reaction of the carbohydrate moiety of glycosylated anti-CD 79b antibodies with galactose oxidase or sodium metaperiodate may generate carbonyl (aldehyde and ketone) groups in the anti-CD 79b antibodies that may react with the appropriate groups of the drug (Hermanson, bioconjugate Techniques). In another example, an anti-CD 79b antibody comprising an N-terminal serine or threonine residue can be reacted with sodium metaperiodate to produce an aldehyde in place of the first amino acid (Geoghegan and Stroh (1992) Bioconjugate chem.3:138-146; U.S. Pat. No. 5,62852). Such aldehydes may react with drug moieties or linker nucleophiles.
Exemplary nucleophilic groups on the drug moiety include, but are not limited to: amine, sulfhydryl, hydroxyl, hydrazide, oxime, hydrazine, thiocarbazide, hydrazine carboxylate, and aryl hydrazide groups that are capable of reacting with a linker moiety and an electrophilic group on a linker reagent to form a covalent bond, the linker reagent comprising: (i) Active esters such as NHS esters, HOBt esters, haloformates, and acyl halides; (ii) alkyl and benzyl halides, such as haloacetamides; (iii) aldehydes, ketones, carboxyl groups and maleimide groups.
Non-limiting exemplary cross-linking agents useful in preparing anti-CD 79b immunoconjugates are described herein in the section entitled "exemplary linkers". Methods of using such cross-linking agents to join two moieties (including a protein moiety and a chemical moiety) are known in the art. In some embodiments, fusion proteins comprising an anti-CD 79b antibody and a cytotoxic agent may be prepared, for example, by recombinant techniques or peptide synthesis. The recombinant DNA molecule may comprise regions encoding the cytotoxic portion of the antibody and conjugate adjacent to each other or separated by regions encoding linker peptides that do not disrupt the desired properties of the conjugate. In yet another embodiment, an anti-CD 79b antibody may be conjugated to a "receptor" (such as streptavidin) for tumor pretargeting, wherein the antibody-receptor conjugate is administered to a patient, followed by removal of unbound conjugate from the circulation using a scavenger, and then administration of a "ligand" (e.g., avidin) conjugated to a cytotoxic agent (e.g., a drug or radionucleotide). Further details regarding anti-CD 79b immunoconjugates are provided in U.S. Pat. No. 8545850 and WO/2016/049214, which are expressly incorporated herein by reference in their entirety.
Anti-CD 20 agents
Depending on the binding properties and biological activity of the anti-CD 20 antibody to the CD20 antigen, blood 103 (2004) 2738-2743 can be found in accordance with Cragg, M.S. et al; and Cragg, M.S. et al, the method described by Blood101 (2003) 1045-1052 distinguishes between two types of anti-CD 20 antibodies (type I and type II anti-CD 20 antibodies), see table C.
Table C: type I and type II anti-CD 20 antibodies
Examples of type I anti-CD 20 antibodies include, for example, rituximab, H147 IgG3 (ECACC, hybridoma), 2c6 IgG1 (as disclosed in WO 2005/103081), 2f2 IgG1 (as disclosed in WO 2004/035607 and WO 2005/103081), and 2H7 IgG1 (as disclosed in WO 2004/056312).
In some embodiments, the anti-CD 20 antibody used in the methods of treatment provided herein is rituximab. In some embodiments, rituximab (reference antibody; examples of type I anti-CD 20 antibodies) is a genetically engineered chimeric human γ1 murine constant domain that comprises a monoclonal antibody to the human CD20 antigen. However, the antibody is not glycoengineered and is not deflucosylated, so the fucose content is at least 85%. The chimeric antibody comprises a human γ1 constant domain and is identified by the name "C2B8" in U.S. Pat. No. 5,736,137 to IDEC Pharmaceuticals Corporation, 4/17/1998 (Andersen et al). Rituximab is approved for the treatment of diffuse large B-cell lymphoma (DLBCL), recurrent or refractory low grade or follicular, CD20 positive B-cell non-hodgkin's lymphoma. In vitro mechanism of action studies have shown that rituximab exhibits human Complement Dependent Cytotoxicity (CDC) (Reff, m.e. et al, blood 83 (2) (1994) -445). Furthermore, it shows activity in assays measuring Antibody Dependent Cellular Cytotoxicity (ADCC).
In some embodiments, an anti-CD 20 antibody for use in the methods of treatment provided herein comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3 of rituximab (numbered according to the method of Kabat et al). In some embodiments, the anti-CD 20 antibodies used in the methods of treatment provided herein comprise VH and VL of rituximab. In some embodiments, the anti-CD 20 antibodies used in the methods of treatment provided herein comprise heavy and light chains of rituximab. As used herein, the term "rituximab" refers to an anti-CD 20 antibody having CAS accession number 174722-31-7.
In some embodiments, the anti-CD 20 antibody used in the methods of treatment provided herein is a defucosylated anti-CD 20 antibody.
Examples of type II anti-CD 20 antibodies include, for example, humanized B-Ly1 antibodies IgG1 (chimeric humanized IgG1 antibodies as disclosed in WO 2005/044859), 11B8 IgG1 (as disclosed in WO 2004/035607), and AT80 IgG1. Typically, type II anti-CD 20 antibodies of IgG1 isotype are characterized by characteristic CDC properties. Type II anti-CD 20 antibodies have reduced CDC (for IgG1 isotypes) compared to type I antibodies of IgG1 isotype. In some embodiments, a type II anti-CD 20 antibody (e.g., GA101 antibody) has increased antibody-dependent cellular cytotoxicity (ADCC). In some embodiments, the type II anti-CD 20 antibody, more preferably a defucosylated humanized B-Ly1 antibody, is as described in WO 2005/044859 and WO 2007/031875.
In some embodiments, the anti-CD 20 antibody used in the methods of treatment provided herein is a GA101 antibody. In some embodiments, GA101 antibodies as used herein refer to any one of the following antibodies that bind human CD 20: (1) an antibody comprising: HVR-H1 comprising the amino acid sequence of SEQ ID NO. 5; HVR-H2 comprising the amino acid sequence of SEQ ID NO. 6; HVR-H3 comprising amino acid sequence of SEQ ID NO. 7; HVR-L1 comprising the amino acid sequence of SEQ ID NO. 8; HVR-L2 comprising the amino acid sequence of SEQ ID NO. 9; and HVR-L3 comprising the amino acid sequence of SEQ ID NO. 10; (2) an antibody comprising: a VH domain comprising the amino acid sequence of SEQ ID No. 11; and a VL domain comprising the amino acid sequence of SEQ ID NO. 12; (3) An antibody comprising the amino acid sequence of SEQ ID NO. 13 and the amino acid sequence of SEQ ID NO. 14; (4) an antibody called otophyllizumab; or (5) an antibody comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO. 13 and comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO. 14. In one embodiment, the GA101 antibody is an IgG1 isotype antibody.
In some embodiments, the anti-CD 20 antibody used in the methods of treatment provided herein is a humanized B-Ly1 antibody. In some embodiments, humanized B-Ly1 antibodies refer to humanized B-Ly1 antibodies as disclosed in WO 2005/044859 and WO 2007/031875, which are obtained from a murine monoclonal anti-CD 20 antibody B-Ly1 (murine heavy chain variable region (VH): SEQ ID NO:3; murine light chain variable region (VL): SEQ ID NO: 4-see Poppema, S. and Visser, L, biotest Bulletin (1987) 131-139) chimeric and subsequently humanized with a human constant domain from IgG1 (see WO 2005/044859 and WO 2007/031875). Humanized B-Ly1 antibodies are disclosed in detail in WO 2005/044859 and WO 2007/031875.
In some embodiments, the humanized B-Ly1 antibody has a heavy chain variable region (VH) selected from the group consisting of SEQ ID NO:15-16 and SEQ ID NO:40-55 ((B-HH 2 to B-HH9 and B-HL8 to B-HL17 corresponding to WO 2005/044859 and WO 2007/031875), in some embodiments the variable domain is selected from the group consisting of SEQ ID NO:15, 16, 42, 44, 46, 48 and 50 (B-HH 2, BHH-3, B-HH6, B-HH8, B-HL11 and B-HL13 corresponding to WO 2007/031875), in some embodiments the humanized B-Ly1 antibody has a light chain variable region (VL) of SEQ ID NO:55 (B-VL) corresponding to WO 2005/044859 and WO 2007/031875), in some embodiments the humanized B-Ly1 antibody has a light chain variable region (VL) corresponding to SEQ ID NO:55 (B-VL) corresponding to WO 2005/044859 and WO 2007/031875, and the humanized B-Ly1 antibody corresponding to human chain variable region (B-HH 6, B-HH8, B-HL11 and B-HL 13) corresponding to WO 2007/03159/0315, in some embodiments the humanized B-Ly1 antibody has a light chain variable region (VL) corresponding to human chain variable region corresponding to SEQ ID NO:55 (B-L1, B-plug-L1) and thus forming human antibody according to WO 2007/031 5 and so forth in WO 2007/031 1/7, the procedure described in Nature Biotechnol.17 (1999) 176-180 and WO 99/154342 is Glycoengineered (GE) in the Fc region. In some embodiments, the defucosylated glycoengineered humanized B-Ly1 is B-HH6-B-KV1 GE. In some embodiments, the anti-CD 20 antibody is otophyllizumab (suggestion INN, WHO Drug Information, volume 26, volume 4, 2012, page 453). As used herein, otophyllab is synonymous with GA101 or RO 5072759. It is under the trade nameCommercially available for therapeutic use and provided in 1000mg/40mL (25 mg/mL) single dose vials. It replaces all previous versions (e.g., volume 25, phase 1, 2011, pages 75-76) and is originally called Afutuzumab (proposal INN, WHO Drug Information, volume 23, phase 2, 2009, page 176; volume 22, phase 2, 2008, page 124). In some embodiments, the humanized B-Ly1 antibody is an antibody comprising: a heavy chain comprising the amino acid sequence of SEQ ID NO. 17; and a light chain comprising the amino acid sequence of SEQ ID NO. 18; or antigen binding fragments of such antibodies. In some embodiments, the humanized B-Ly1 antibody comprises: a heavy chain variable region comprising the three heavy chain CDRs of SEQ ID No. 17; and a light chain variable region comprising the three light chain CDRs of SEQ ID NO. 18.
In some embodiments, an anti-CD 20 antibody for use in the methods of treatment provided herein comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3 of Otuzumab-b (numbered according to the method of Kabat et al). In some embodiments, the anti-CD 20 antibodies used in the methods of treatment provided herein comprise VH and VL of otophyllizumab. In some embodiments, the anti-CD 20 antibodies used in the methods of treatment provided herein comprise heavy and light chains of octuzumab.
In some embodiments, the humanized B-Ly1 antibody is a desfucosylated glycoengineered humanized B-Ly1. Such glycoengineered humanized B-Ly1 antibodies have an altered glycosylation pattern in the Fc region, preferably with reduced levels of fucose residues. In some embodiments, the amount of fucose is about 60% or less of the total amount of oligosaccharides at Asn297 (in one embodiment, the amount of fucose is between about 40% and about 60%, in another embodiment, the amount of fucose is about 50% or less, and in yet another embodiment, the amount of fucose is about 30% or less). In some embodiments, the oligosaccharides of the Fc region are bisected. These glycoengineered humanized B-Ly1 antibodies have increased ADCC.
In FACS assays (Becton Dickinson) employing Raji cells (ATCC-No. ccl-86), the anti-CD 20 antibody conjugated to Cy5 and rituximab conjugated to Cy5 were used to determine the "binding capacity ratio of anti-CD 20 antibody compared to rituximab to CD20 on Raji cells (ATCC-No. ccl-86) by direct immunofluorescence measurement (measuring Mean Fluorescence Intensity (MFI)), as described in example 2, and the calculation formula is as follows:
Binding capacity to CD20 on Raji cells (ATCC-No. ccl-86) =ratio of
MFI is the average fluorescence intensity. As used herein, "Cy5 labeling ratio" means the number of Cy5 labeling molecules per molecule of antibody.
Typically, the type II anti-CD 20 antibody has a binding capacity of 0.3 to 0.6, in one embodiment 0.35 to 0.55, in yet another embodiment 0.4 to 0.5, for CD20 on Raji cells (ATCC-No. ccl-86) as compared to rituximab.
The term "antibody with increased antibody-dependent cellular cytotoxicity (ADCC)" as defined herein means an antibody with increased ADCC as measured by any suitable method known to one of ordinary skill in the art.
An exemplary accepted in vitro ADCC is as follows:
1) The assay uses target cells known to express a target antigen recognized by the antigen-binding region of the antibody;
2) The assay uses human Peripheral Blood Mononuclear Cells (PBMCs) isolated from blood of randomly selected healthy donors as effector cells;
3) The assay was performed according to the following protocol:
i) PBMCs were isolated using standard density centrifugation procedures and suspended in RPMI cell culture medium at a density of 5 x 10 6 cells/ml;
ii) target cells were grown by standard tissue culture methods, harvested from exponential growth phase, cell viability higher than 90%, washed in RPMI cell culture medium, labeled with 51 Cr of 100 micro curie, washed twice with cell culture medium, and resuspended in cell culture medium at a density of 10 5 cells/ml;
iii) Transferring 100 microliters of the final target cell suspension described above into each well of a 96-well microtiter plate;
iv) serial dilutions of antibodies from 4000ng/ml to 0.04ng/ml in cell culture medium, followed by addition of 50 microliters of the resulting antibody solution to target cells in a 96-well microtiter plate, and detection of various antibody concentrations covering the entire concentration range described above in triplicate;
v) for Maximum Release (MR) control, 50 microliters of 2% (VN) aqueous non-ionic detergent (Nonidet, sigma, st.louis) was received in the other 3 wells in the plate containing labeled target cells in place of the antibody solution (point iv above);
vi) for Spontaneous Release (SR) control, 50 microliters of RPMI cell culture medium was received in place of antibody solution in another 3 wells in the plate containing labeled target cells (point iv above);
vii) the 96-well microtiter plate was then centrifuged at 50×g for 1 min and incubated at 4 ℃ for 1 hour;
viii) 50 microliters of PBMC suspension (point i above) was added to each well to give a 25:1 effector to target cell ratio and the plate was incubated in an incubator at 37℃for 4 hours in a 5% CO 2 atmosphere;
ix) harvesting cell-free supernatant from each well and quantifying the radioactivity released by the Experiment (ER) using a gamma counter;
x) calculating the percent specific lysis at each antibody concentration according to the formula (ER-MR)/(MR-SR) ×100, wherein ER is the average radioactivity at the antibody concentration measured quantitatively (see point ix above), MR is the average radioactivity of the MR control measured quantitatively (see point V above) (see point ix above), SR is the average radioactivity of the SR control measured quantitatively (see point vi above) (see point ix above);
4) "increased ADCC" is defined as an increase in the maximum percent of specific lysis observed in the above-described detected antibody concentration ranges and/or a decrease in the concentration of antibody required to reach half of the maximum percent of specific lysis observed in the above-described detected antibody concentration ranges. In one embodiment, the increase in ADCC relative to ADCC, measured using the above-described assay, is mediated by the same antibody, produced by the same type of host cell, using the same standard production, purification, formulation and storage methods known to those of skill in the art, except that the comparison antibody (lacking increased ADCC) is not produced by a host cell engineered to overexpress GnTIII and/or engineered to have reduced expression of the fucosyltransferase 8 (FUT 8) gene (e.g., including a design specifically designed for FUT8 knockdown).
In some embodiments, "increased ADCC" may be obtained, for example, by mutation and/or glycoengineering of the antibody. In some embodiments, the anti-CD 20 antibody is glycoengineered to have a double antennary oligosaccharide attached to the Fc region of the antibody bisected by GlcNAc. In some embodiments, the anti-CD 20 antibody is glycoengineered to lack fucose on carbohydrates attached to the Fc region by expressing the antibody in host cells deficient in protein fucosylation (e.g., lec13 CHO cells, or cells in which the alpha-1, 6-fucosyltransferase gene (FUT 8) is deleted or FUT gene expression is knocked down). In some embodiments, the anti-CD 20 antibody sequence has been engineered in its Fc region to enhance ADCC. In some embodiments, such engineered anti-CD 20 antibody variants comprise an Fc region having one or more amino acid substitutions at positions 298, 333, and/or 334 (EU numbering of residues) of the Fc region.
In some embodiments, the term "Complement Dependent Cytotoxicity (CDC)" refers to the lysis of human cancer target cells by an antibody of the invention in the presence of complement. CDC can be measured by treating a CD20 expressing cell preparation with an anti-CD 20 antibody according to the invention in the presence of complement. CDC was found if antibodies at a concentration of 100nM induced lysis (cell death) of 20% or more of the tumor cells after 4 hours. In some embodiments, the assay uses 51 Cr or Eu labeled tumor cells and measures released 51 Cr or Eu. Controls included co-incubating tumor target cells with complement in the absence of antibody.
In some embodiments, the anti-CD 20 antibody is a monoclonal antibody, such as a human antibody. In some embodiments, the anti-CD 20 antibody is an antibody fragment, e.g., fv, fab, fab ', scFv, diabody, or F (ab') 2 fragment. In some embodiments, the anti-CD 20 antibody is a substantially full length antibody, such as an IgG1 antibody, an IgG2a antibody, or other antibody types or isotypes as defined herein.
In some embodiments, the anti-CD 20 antibody is ABP 798 (amagen, usa), zytux (AryoGen Pharmed, iran), acellBia/Usmal (Biocad, russia), BI 695500 (bollingentjohn, germany), truxima (Celltrion, korea), blitzima (Celltrion, korea), ritemvia (Celltrion, korea), rituzena/Tuxella (Celltrion, korea), CT-P10 (Celltrion, korea), reditux (Dr Reddy's Laboratories, india), maball (Hetero Group, india), mabTas (Intas Biopharmaceuticals, india), JHL1101 (camptotheca, taiwan), novex (RTXM) (mAbxience/Laboratorio Elea, spanish/argentine), mabionCD20 (Mabion, polan; mylan, india), PF-05280586 (Pfizer), kikuzubam (Kikuzubam, mexico), rituximab (Kikuzubam), kikuzubam (Kikuzubam, india), kikuzubam 101 (samsung biologicals (Kikuzubam), korea), kikuzubam/Kikuzubam (GP 2013) (san d, switzerland), HLX01 (Shanghai complex macro han biotechnology company, china), TL011 (Kikuzubam, israel; lonza, switzerland) or Kikuzubam (Kikuzubam, turkis).
VI antibodies
In some embodiments, antibodies (e.g., anti-CD 79b antibodies or anti-CD 20 antibodies) used in the methods of treatment provided herein can bind any feature, alone or in combination, as described below.
A. Affinity for antibodies
In certain embodiments, antibodies (e.g., anti-CD 79b antibodies or anti-CD 20 antibodies) for use in the methods of treatment provided herein have dissociation constants (Kd) of +.mu.M, +.100 nM, +.50 nM, +.10 nM, +.5 nM, +.1 nM, +.0.1 nM, +.0.01 nM or+.0.001 nM and optionally +.10 10 -13 M (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 one embodiment, kd is measured by radiolabeled antigen binding assay (RIA) with the antibody of interest and its antigen in Fab form, as described in the assay below. The solution binding affinity of Fab to antigen is measured by equilibrating Fab with a minimum concentration (125 I) of labeled antigen in the presence of a series of unlabeled antigen titrations, followed by capture of bound antigen with an anti-Fab antibody coated plate (see, e.g., chen et al, j. Mol. Biol.293:865-881 (1999)). To determine the assay conditions, the capture anti-Fab antibodies (Cappel Labs) were coated with 5. Mu.g/ml in 50mM sodium carbonate (pH 9.6)Microplates (Thermo Scientific) were left overnight and then blocked with 2% (w/v) bovine serum albumin in PBS for two to five hours at room temperature (about 23 ℃). In a non-adsorbed plate (Nunc# 269620), 100pM or 26pM [ 125 I ] -antigen was mixed with serial dilutions of the target Fab (e.g., consistent with the evaluation of anti-VEGF antibody Fab-12 in Presta et al, cancer Res.57:4593-4599 (1997)). The Fab of interest was then incubated overnight; however, incubation may last longer (e.g., about 65 hours) to ensure equilibrium is reached. Thereafter, the mixture was transferred to a capture plate for incubation at room temperature (e.g., one hour). The solution was then removed and 0.1% polysorbate 20 in PBSThe plate was washed eight times. When the plates have dried, 150 μl/well of scintillator (MICROSCINT-20 TM; packard) is added and the plates are counted for tens of minutes on a TOPCON TM gamma counter (Packard). The concentration of each Fab that gave less than or equal to 20% of maximum binding was selected for use in the competitive binding assay.
According to another embodiment, the immobilized antigen CM5 chip is used at about 10 Response Units (RU) at 25℃-2000 Or-3000 (BIAcore, inc., piscataway, NJ), kd is measured by surface plasmon resonance assay. Briefly, carboxymethylated dextran biosensor chips (CM 5, BIACORE, inc.) were activated with N-ethyl-N '- (3-dimethylaminopropyl) -carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) according to the manufacturer's instructions. The antigen was diluted to 5. Mu.g/ml (about 0.2. Mu.M) with 10mM sodium acetate pH 4.8, followed by injection at a flow rate of 5. Mu.L/min to obtain about 10 Response Units (RU) of conjugated protein. After antigen injection, 1M ethanolamine was injected to block unreacted groups. For kinetic measurements, two-fold serial dilutions (0.78 nM to 500 nM) of Fab in PBS containing 0.05% polysorbate 20 (TWEEN-20 TM) surfactant (PBST) were injected at 25℃at a flow rate of about 25. Mu.L/min. Using simple one-to-one Langmuir combined modelEvaluation Software 3.2 version 3.2), association rate (k on) and dissociation rate (k off) were calculated by fitting the association and dissociation sensor maps simultaneously. The equilibrium dissociation constant (Kd) is calculated as the ratio k off/kon. See, e.g., chen et al, J.mol. Biol.293:865-881 (1999). If the association rate exceeds 10 6M-1s-1 by the above surface plasmon resonance assay, the association rate can be determined by using a fluorescence quenching technique, i.e. an increase or decrease in fluorescence emission intensity (excitation = 295nM; emission = 340nM,16nM bandpass) of 20nM anti-antigen antibody (Fab form) in PBS pH 7.2 at 25 ℃ in the presence of increasing concentrations of antigen as measured with a stirred cuvette in a spectrometer such as a spectrometer equipped with a flow stop device (Aviv Instruments) or 8000 series SLM-amico TM spectrophotometer (ThermoSpectronic).
B. antibody fragments
In certain embodiments, the antibody (e.g., an anti-CD 79b antibody or an anti-CD 20 antibody) used in the methods of treatment provided herein is an antibody fragment. Antibody fragments include, but are not limited to, 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 reviews of scFv fragments, see, for example, pluckth gun in The harmacology of Monoclonal Antibodies, volume 113, rosenburg and Moore et al (Springer-Verlag, new York), pages 269-315 (1994); see also WO 93/16185; and U.S. patent nos. 5,571,894 and 5,587,458. For a discussion of Fab fragments and F (ab') 2 fragments comprising salvage receptor binding epitope residues and having an extended in vivo half-life, see U.S. Pat. No. 5,869,046.
Diabodies are antibody fragments having two antigen binding sites, which may 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). Trisomy and tetrasomy antibodies are also described in Hudson et al, nat.Med.9:129-134 (2003).
A single domain antibody is an antibody fragment comprising all or part of the heavy chain variable domain or all or part of the light chain variable domain of an antibody. In certain embodiments, the single domain antibody is a human single domain antibody (domntis, inc., waltham, MA; see, e.g., U.S. patent No. 6,248,516B1).
Antibody fragments may be prepared by a variety of techniques, including but not limited to proteolytic digestion of intact antibodies, produced by recombinant host cells, such as e.coli (e.coli) or phage, as described herein.
C. chimeric and humanized antibodies
In certain embodiments, the antibody (e.g., an anti-CD 79b antibody or an anti-CD 20 antibody) used in the methods of treatment provided herein is a chimeric antibody. Some chimeric antibodies are described, for example, in U.S. Pat. No.4,816,567 and Morrison et al, proc.Natl. Acad.Sci.USA,81:6851-6855 (1984). In one example, a 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 example, a chimeric antibody is a "class switch" antibody in which the class or subclass has been altered from that of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof.
In certain embodiments, the chimeric antibody is a humanized antibody. Typically, the non-human antibodies are humanized to reduce immunogenicity to humans, while retaining the specificity and affinity of the parent non-human antibody. Typically, a humanized antibody comprises one or more variable domains in which the HVRs, e.g., CDRs (or portions thereof), are derived from a non-human antibody and the FRs (or portions thereof) are derived from a human antibody sequence. The humanized antibody optionally will also comprise at least a portion of a human constant region. In some embodiments, some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., an antibody from which HVR residues are derived), e.g., to restore or improve antibody specificity or affinity.
Humanized antibodies and methods for their preparation are reviewed in, for example, almagro and Franson, front. Biosci.13:1619-1633 (2008), and further described, for example, in Riechmann et al, nature 332:323-329 (1988); queen et al, proc.Nat' l Acad.Sci.USA 86:10029-10033 (1989); U.S. Pat. nos. 5,821,337, 7,527,791, 6,982,321 and 7,087,409; kashmiri et al, methods 36:25-34 (2005) (describing SDR (a-CDR) porting); padlan, mol. Immunol.28:489-498 (1991) (describing "surface reshaping"); dall' Acqua et al, methods 36:43-60 (2005) (describing "FR shuffling"); and Osbourn et al, methods 36:61-68 (2005) and Klimka et al, br.J.cancer,83:252-260 (2000) (described "guide selection" Methods for FR shuffling).
Human framework regions useful for humanization include, but are not limited to: the framework regions selected using the "best match" method (see, e.g., sims et al, J. Immunol.151:2296 (1993)); framework regions derived from the consensus sequence of human antibodies of a particular subset of light or heavy chain variable regions (see, e.g., carter et al, proc. Natl. Acad. Sci. USA,89:4285 (1992); and Presta et al, J. Immunol.,151:2623 (1993)); human mature (somatic mutation) framework regions or human germline framework regions (see, e.g., almagro and Franson, 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)).
D. Human antibodies
In certain embodiments, the antibody (e.g., an anti-CD 79b antibody or an anti-CD 20 antibody) used in the methods of treatment provided herein is a human antibody. Various techniques known in the art may be used to produce human antibodies. Human antibodies are generally described 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: the immunogen is administered to a transgenic animal that has been modified to produce a fully human antibody or a fully antibody having a human variable region in response to antigen challenge. Such animals typically contain all or part of the human immunoglobulin loci that replace endogenous immunoglobulin loci, either present extrachromosomal to the animal or randomly integrated into the animal's chromosome. In such transgenic mice, the endogenous immunoglobulin loci have typically been inactivated. For a review of methods of obtaining human antibodies from transgenic animals, see Lonberg, nat. Biotech.23:1117-1125 (2005). See also, for example: U.S. Pat. nos. 6,075,181 and 6,150,584, which describe xenomoose TM technology; description of the inventionU.S. patent No. 5,770,429 to the art; description of K-MU.S. Pat. No. 7,041,870 and description of the technologyTechnical U.S. patent application publication No. US2007/0061900. Human variable regions from whole antibodies produced by such animals may be further modified, for example by combining with different human constant regions.
Human antibodies can also be prepared by hybridoma-based methods. Human myeloma and mouse-human hybrid myeloma cell lines for the production of human monoclonal antibodies have been described. (see, e.g., kozbor J. Immunol.,133:3001 (1984); brodeur et al, monoclonal Antibody Production Techniques and Applications, pages 51-63 (MARCEL DEKKER, inc., new York, 1987); and Boerner et al, J. Immunol.,147:86 (1991)) human antibodies produced via human B cell hybridoma technology are also described by Li et al, proc. Natl. Acad. Sci. USA,103:3557-3562 (2006). Additional methods include, for example, those described in U.S. Pat. No.7,189,826 (describing the production of monoclonal human IgM antibodies from hybridoma cell lines) and Ni, xiandai Mianyixue,26 (4): 265-268 (2006) (describing human-human hybridomas). 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 produced by isolating Fv clone variable domain sequences selected from a human phage display library. Such variable domain sequences can then be combined with the intended human constant domain. Techniques for selecting human antibodies from antibody libraries are described below.
E. Antibodies derived from libraries
In some embodiments, antibodies (e.g., anti-CD 79b antibodies or anti-CD 20 antibodies) for use in the methods of treatment provided herein can be isolated by screening a combinatorial library for antibodies having one or more desired activities. For example, a variety of methods are known in the art for generating phage display libraries and screening such libraries to obtain antibodies with desired binding characteristics. Such methods are reviewed in, for example, hoogenboom et al Methods in Molecular Biology 178:178:1-37 (O' Brien et al, human Press, totowa, NJ, 2001), and further described, for example, in 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, methods in Molecular Biology 248:248:161-175 (Lo, 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. Methods 284 (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 from which antigen-binding phage can then be screened as described in Winter et al, ann.rev.immunol.,12:433-455 (1994). Phage typically display antibody fragments as single chain Fv (scFv) fragments or Fab fragments. Libraries from immunized sources provide high affinity antibodies to immunogens without the need to construct hybridomas. Alternatively, the initial repertoire (e.g., from humans) can be cloned to provide a single source of antibodies to a wide range of non-self and self-antigens without any immunization, as described by Griffiths et al, EMBO J,12:725-734 (1993). Finally, an initial library can also be made by: cloning unrearranged V gene segments from stem cells; and using PCR primers containing random sequences to encode highly variable CDR3 regions and accomplish in vitro rearrangement as described by 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. publication nos. 2005/007974, 2005/019455, 2005/0266000, 2007/017126, 2007/0160598, 2007/0237764, 2007/0292936, and 2009/0002360.
Antibodies or antibody fragments isolated from a human antibody library are herein considered human antibodies or human antibody fragments.
F. Multispecific antibodies
In certain embodiments, the antibody (e.g., an anti-CD 79b antibody or an anti-CD 20 antibody) used in the methods of treatment provided herein is a multispecific antibody, e.g., a bispecific antibody. A multispecific antibody is a monoclonal antibody having binding specificities for at least two different sites. In certain embodiments, one of the binding specificities is for one antigen (e.g., CD79b or CD 20), and the other is for any other antigen. In certain embodiments, one of the binding specificities is for one antigen (e.g., CD79b or CD 20) and the other is for CD3. See, for example, U.S. Pat. No. 5,821,337. In certain embodiments, the bispecific antibody can bind to two different epitopes of a single antigen (e.g., CD79b or CD 20). Bispecific antibodies can also be used to localize cytotoxic agents to cells expressing an antigen (e.g., CD79b or CD 20). Bispecific antibodies can be made as full length antibodies or antibody fragments.
Techniques for preparing multispecific antibodies include, but are not limited to, recombinant co-expression of two immunoglobulin heavy chain-light chain pairs with different specificities (see, e.g., milstein and Cuello, nature 305:537 (1983), WO 93/08829 and Traunecker et al, EMBO J.10:3655 (1991)) and "pestle" engineering (see, e.g., U.S. Pat. No. 5,731,168). Multispecific antibodies can also be made by the following techniques: engineering electrostatic manipulation effects to produce antibody Fc-heterodimer molecules (WO 2009/089004 A1); crosslinking two or more antibodies or fragments (see, e.g., U.S. Pat. No. 4,676,980 and Brennan et al, science 229:81 (1985)); bispecific antibodies were generated using leucine zippers (see, e.g., kostelny et al, J.Immunol.148 (5): 1547-1553 (1992)); bispecific antibody fragments were made using "diabody" technology (see, e.g., hollinger et al, proc. Natl. Acad. Sci. USA 90:6444-6448 (1993)); single chain Fv (sFv) dimers (see, e.g., gruber et al, J.Immunol.152:5368 (1994)); and the preparation of trispecific antibodies as described, for example, in Tutt et al J.Immunol.147:60 (1991).
Engineered antibodies having three or more functional antigen binding sites, including "octopus antibodies", are also included herein (see, e.g., US2006/0025576 A1).
Antibodies or fragments herein also include "dual acting Fab" or "DAF" which comprise antigen binding sites that bind to CD79b as well as other different antigens (see, e.g., US 2008/0069820).
G. Antibody variants
In certain embodiments, amino acid sequence variants of antibodies (e.g., anti-CD 79b antibodies or anti-CD 20 antibodies) for use in the methods of treatment provided herein are contemplated. For example, it may be desirable to improve the binding affinity and/or other biological properties of an anti-CD 79b antibody or an anti-CD 20 antibody. Amino acid sequence variants of antibodies can be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody or by peptide synthesis. Such modifications include, for example, deletions from, and/or insertions into and/or substitutions of, residues within the amino acid sequence of an antibody. Any combination of deletions, insertions, and substitutions may be made to achieve the final construct, provided that the final construct has the desired characteristics, such as antigen binding.
(I) Substitution, insertion and deletion variants
In certain embodiments, antibody variants having one or more amino acid substitutions are provided. Sites of interest for substitution mutations include HVRs and FR. Conservative substitutions are shown under the heading "preferred substitutions" in table D. Further substantial changes are provided under the heading "exemplary substitutions" of table D, and are further described below with reference to the amino acid side chain class. Amino acid substitutions may be introduced into the antibody of interest and the product screened for a desired activity (e.g., retained/improved antigen binding, reduced immunogenicity, or improved ADCC or CDC).
Table D
Original residue Exemplary substitution Preferred substitution
Ala(A) Val；Leu；Ile Val
Arg(R) Lys；Gln；Asn Lys
Asn(N) Gln；His；Asp；Lys；Arg Gln
Asp(D) Glu；Asn Glu
Cys(C) Ser；Ala Ser
Gln(Q) Asn；Glu Asn
Glu(E) Asp；Gln Asp
Gly(G) Ala Ala
His(H) Asn；Gln；Lys；Arg Arg
Ile(I) Leu; val; met; ala; phe; norleucine (N-leucine) Leu
Leu(L) Norleucine; ile; val; met; ala; phe (Phe) Ile
Lys(K) Arg；Gln；Asn Arg
Met(M) Leu；Phe；Ile Leu
Phe(F) Trp；Leu；Val；Ile；Ala；Tyr Tyr
Pro(P) Ala Ala
Ser(S) Thr Thr
Thr(T) Val；Ser Ser
Trp(W) Tyr；Phe Tyr
Tyr(Y) Trp；Phe；Thr；Ser Phe
Val(V) Ile; leu; met; phe; ala; norleucine (N-leucine) Leu
Amino acids can be grouped according to common side chain characteristics:
(1) Hydrophobic: norleucine, met, ala, val, leu, ile;
(2) Neutral hydrophilicity: cys, ser, thr, asn, gin;
(3) Acid: asp, glu;
(4) Alkaline: his, lys, arg;
(5) Residues that affect chain orientation: gly, pro;
(6) Aromatic: trp, tyr, phe.
Non-conservative substitutions will require exchanging members of one of these classes for the other class.
One type of substitution variant involves substitution of one or more hypervariable region residues of a parent antibody (e.g., a humanized antibody or a human antibody). Typically, one or more of the resulting variants selected for further investigation will have alterations (e.g., improvements) in certain biological properties (e.g., increased affinity, reduced 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. Briefly, one or more HVR residues are mutated and variant antibodies are displayed on phage and screened for a particular biological activity (e.g., binding affinity).
Alterations (e.g., substitutions) may be made in the HVR, for example, to improve antibody affinity. Such changes may occur in HVR "hot spots", i.e. residues encoded by codons that undergo high frequency mutations during somatic maturation (see, e.g., chowdhury, methods mol. Biol.207:179-196 (2008)) and/or SDR (a-CDRs) (detection of binding affinity of the resulting variant VH or VL). Methods for achieving affinity maturation by construction and reselection from secondary libraries have been described, for example, in Hoogenboom et al Methods in Molecular Biology 178:178:1-37 (O' Brien et al, human Press, totowa, NJ, 2001). In some embodiments of affinity maturation, diversity is introduced into a variable gene selected for maturation purposes by any of a variety of methods (e.g., error-prone PCR, strand shuffling, 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 targeting methods in which several HVR residues (e.g., 4-6 residues at a time) are randomized. HVR residues involved in antigen binding can be specifically identified, for example, using alanine scanning mutagenesis or modeling. In particular, CDR-H3 and CDR-L3 are often targeted.
In certain embodiments, substitutions, insertions, or deletions may occur within one or more HVRs, provided that such alterations do not substantially reduce the antigen binding capacity of the antibody. For example, conservative changes (e.g., conservative substitutions as provided herein) may be made in the HVR that do not substantially reduce binding affinity. Such changes may be outside of HVR "hot spots" or SDR. In certain embodiments of the variant VH and VL sequences provided above, each HVR remains unchanged or comprises no more than one, two, or three amino acid substitutions.
A method that can be used to identify antibody residues or regions that can be targeted for mutagenesis is called "alanine scanning mutagenesis" as described by Cunningham and Wells (1989) Science, 244:1081-1085. In this method, residues or a set of target residues (e.g., charged residues such as Arg, asp, his, lys and Glu) are identified and replaced with neutral or negatively charged amino acids (e.g., alanine or polyalanine) to determine whether the interaction of the antibody with the antigen is affected. Additional substitutions may be introduced at amino acid positions that exhibit functional sensitivity to the initial substitution. Alternatively or additionally, the crystal structure of the antigen-antibody complex is used to identify the point of contact between the antibody and the antigen. Such contact residues and adjacent residues that are candidates for substitution may be targeted or eliminated. Variants may be screened to determine if they possess the desired properties.
Amino acid sequence insertions include amino and/or carboxy terminal fusions ranging in length from one residue to polypeptides containing one hundred or more residues, as well as intrasequence insertions of one or more amino acid residues. Examples of terminal insertions include antibodies with an N-terminal methionyl residue. Other insertional variants of antibody molecules include fusion with an enzyme that increases the serum half-life of the antibody (e.g., for ADEPT) or the N-or C-terminus of the antibody of the polypeptide.
(Ii) Glycosylation variants
In certain embodiments, an antibody (e.g., an anti-CD 79b antibody or an anti-CD 20 antibody) for use in a method of treatment provided herein is altered to increase or decrease the degree of glycosylation of the antibody. The addition or deletion of glycosylation sites to antibodies can be conveniently accomplished by altering the amino acid sequence to create or remove one or more glycosylation sites.
When an antibody comprises an Fc region, the carbohydrates attached thereto may be altered. Natural antibodies produced by mammalian cells typically comprise branched-chain double-antenna oligosaccharides, which are typically linked to Asn297 of the CH2 domain of the Fc region by N-bonding. See, for example, wright et al TIBTECH 15:26-32 (1997). Oligosaccharides may include various carbohydrates, such as mannose, N-acetylglucosamine (GlcNAc), galactose and sialic acid, and fucose attached to GlcNAc in the "backbone" of a double-antennary oligosaccharide structure. In some embodiments, oligosaccharides in the antibodies of the invention may be modified to produce antibody variants with certain improved properties.
In one embodiment, antibody variants are provided having a carbohydrate structure lacking fucose linked (directly or indirectly) to an Fc region. For example, the fucose content of such antibodies may be 1% to 80%, 1% to 65%, 5% to 65%, or 20% to 40%. The amount of fucose is determined by calculating the average amount of fucose at Asn297 within the sugar chain relative to the sum of all sugar structures (e.g. complex, hybrid and high mannose structures) attached to Asn297 as measured by MALDI-TOF mass spectrometry, for example as described in WO 2008/077546. Asn297 refers to an asparagine residue at about position 297 in the Fc region (Eu numbering of Fc region residues); however, asn297 may also be located about ±3 amino acids upstream or downstream of position 297, i.e. between positions 294 and 300, due to minor sequence variations in the antibody. Such fucosylated variants may have improved ADCC function. See, for example, U.S. patent publication No. US2003/0157108 (Presta, l.); US2004/0093621 (Kyowa Hakko Kogyo Co., ltd.). Examples of publications relating to "defucosylation" or "fucose deficient" antibody variants include ：US 2003/0157108;WO 2000/61739;WO 2001/29246;US2003/0115614;US 2002/0164328;US2004/0093621;US2004/0132140;US2004/0110704;US2004/0110282;US2004/0109865;WO 2003/085119;WO 2003/084570;WO 2005/035586;WO 2005/035778;WO2005/053742;WO2002/031140;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 deficient in protein fucosylation (Ripka et al Arch. Biochem. Biophys.249:533-545 (1986), U.S. patent application Ser. No. 2003/0157108A1, presta, L, and WO 2004/056312A1, adams et al, especially example 11), and knockout cell lines such as CHO cells in which the alpha-1, 6-fucosyltransferase gene (FUT 8) has been knocked out (see, e.g., yamane-Ohnuki et al Biotech. Bioeng.87:614 (2004); kanda, Y. Et al Biotechnol. Bioeng.,94 (4): 680-688 (2006), and WO 2003/085107).
Antibodies are also provided with bisected oligosaccharides, for example, wherein a double-antennary oligosaccharide attached to the Fc region of the antibody is bisected by GlcNAc. Such antibody variants may have reduced fucosylation and/or improved ADCC function. Examples of such antibody variants are described, for example, in WO 2003/011878 (Jean-Maiset et al); U.S. Pat. No. 6,602,684 (Umana et al); and US 2005/0123946 (Umana et al). Also provided are antibody variants having at least one galactose residue in the oligosaccharide attached to the Fc region. Such antibody variants may have improved CDC function. Such antibody variants are described, for example, in WO 1997/30087 (Patel et al); WO 1998/58964 (Raju, s.); and WO 1999/22764 (Raju, S.).
(Iii) Fc variants
In certain embodiments, one or more amino acid modifications may be introduced into the Fc region of an antibody (e.g., an anti-CD 79b antibody or an anti-CD 20 antibody) for use in the methods of treatment provided herein, thereby producing an Fc region variant. The Fc region variant may include a human Fc region sequence (e.g., a human IgG1, igG2, igG3, or IgG4 Fc region) that includes amino acid modifications (e.g., substitutions) at one or more amino acid positions.
In certain embodiments, the invention contemplates antibody variants having some, but not all, effector functions, which make them desirable candidates for use, where the half-life of the antibody in vivo is important and certain effector functions (such as complement and ADCC) are unnecessary or detrimental. In vitro and/or in vivo cytotoxicity assays may be performed to confirm a reduction/depletion of CDC and/or ADCC activity. For example, an Fc receptor (FcR) binding assay may be performed to ensure that the antibody lacks fcγr binding (and thus may lack ADCC activity), but retains FcRn binding capacity. The principal cells NK cells mediating ADCC express Fc only (RIII, whereas monocytes express Fc (RI, fc (RII and Fc (RIII. Hematopoietic cells) FcR expression is summarized in Table 3 on pages 464 of Ravetch and Kinet, annu. Rev. Immunol.9:457-492 (1991)), non-limiting examples of in vitro assays for assessing ADCC activity of molecules of interest are described in U.S. Pat. No. 5,500,362 (see e.g., hellstrom, I.et al Proc. Nat. L. Acad. Sci. USA 83:7059-7063 (1986)) and Hellstrom, I et al, proc. Nat. Acad. Sci. USA 82:1499-1502 (1985), 5,821,337 (see Bruggeman, M. Exp. Med.166:1351-1361 (1987)), alternatively, non-radioactive assays (see e.g., for measuring cytotoxicity of cells of the formula 33, and of the cell type: view cells: view, ind. 32)Nonradioactive cytotoxicity assay (Promega, madison, wis.). Useful effector cells for such assays include Peripheral Blood Mononuclear Cells (PBMC) and Natural Killer (NK) cells. Alternatively or additionally, ADCC activity of the molecule of interest may be assessed in vivo, for example, in an animal model such as that disclosed in Clynes et al Proc.Nat' l.Acad.Sci.USA 95:652-656 (1998). A C1q binding assay may also be performed to confirm that the antibody is unable to bind to C1q and thus lacks CDC activity. See, e.g., C1q and C3C binding ELISA in WO 2006/029879 and WO 2005/100402. To assess complement activation, CDC assays may be performed (see, e.g., gazzano-Santoro et al, J.Immunol. Methods 202:163 (1996); cragg, M.S. et al, blood 101:1045-1052 (2003); and Cragg, M.S. and M.J. Glennie, blood 103:2738-2743 (2004)). FcRn binding and in vivo clearance/half-life assays can also be performed using methods known in the art (see, e.g., petkova, s.b. et al, int' l.immunol.18 (12): 1759-1769 (2006)).
Antibodies with reduced effector function include those with substitutions of one or more of Fc region residues 238, 265, 269, 270, 297, 327 and 329 (U.S. Pat. No. 6,737,056). Such Fc mutants include Fc mutants having substitutions at two or more of amino acids 265, 269, 270, 297 and 327, including so-called "DANA" Fc mutants in which residues 265 and 297 are substituted with alanine (U.S. Pat. No. 7,332,581).
Certain antibody variants having improved or reduced binding to FcR are described. ( See, for example, U.S. Pat. nos. 6,737,056; WO 2004/056312; and Shields et al J.biol.chem.9 (2): 6591-6604 (2001). )
In certain embodiments, the antibody variant comprises an Fc region with one or more amino acid substitutions that improve ADCC, e.g., substitutions at positions 298, 333, and/or 334 (residues numbering according to EU) of the Fc region.
In some embodiments, alterations are made in the Fc region resulting in altered (i.e., improved or reduced) C1q binding and/or Complement Dependent Cytotoxicity (CDC), for example, as described in U.S. Pat. No. 6,194,551, WO 99/51642, and Idusogie et al J.Immunol.164:4178-4184 (2000).
Antibodies with extended half-life and improved neonatal Fc receptor (FcRn) binding responsible for transfer of maternal IgG to the fetus (Guyer et al, J.Immunol.117:587 (1976), and Kim et al, J.Immunol.24:249 (1994)) are described in US2005/0014934A1 (Hinton et al). Those antibodies comprise an Fc region having one or more substitutions therein that improve binding of the Fc region to FcRn. Such Fc variants include Fc variants having substitutions at one or more of the following Fc region residues: 238. 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424, or 434, for example, substitution of the Fc region residue 434 (U.S. patent No. 7,371,826).
For other examples of variants of the Fc region, see additionally: duncan and Winter, nature322:738-40 (1988); U.S. Pat. nos. 5,648,260; U.S. Pat. nos. 5,624,821; WO 94/29351.
(Iv) Through cysteine engineering engineered antibody variants
In certain embodiments, it may be desirable to produce a cysteine engineered antibody, e.g., "thioMAbs", in which one or more residues of the anti-CD 79b antibody or anti-CD 20 antibody used in the methods of treatment provided herein are substituted with cysteine residues. In certain embodiments, the substituted residue is present at an accessible site of the antibody. As further described herein, reactive thiol groups are located at accessible sites of antibodies by substitution of those residues with cysteines, and can be used to conjugate antibodies with other moieties (such as drug moieties or linker-drug moieties) to create immunoconjugates. In certain embodiments, any one or more of the following residues may be substituted with a cysteine: v205 of light chain (Kabat numbering); a118 (EU numbering) of heavy chain; and S400 (EU numbering) of the heavy chain Fc region. For exemplary cysteine engineered anti-CD 79b antibodies for use in the methods described herein, see, e.g., WO 2009/012668. Cysteine engineered antibodies may be generated as described, for example, in U.S. patent No. 7,521,541.
(V) Antibody derivatives
In certain embodiments, the antibodies (e.g., anti-CD 79b antibodies or anti-CD 20 antibodies) used in the methods of treatment provided herein can be further modified to include additional non-protein moieties known and readily available in the art. Moieties suitable for derivatization of 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), ethylene glycol/propylene glycol copolymers, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1, 3-dioxolane, poly-1, 3, 6-trioxane, ethylene/maleic anhydride copolymers, polyaminoacids (homo-or random copolymers) and dextran or poly (n-vinylpyrrolidone) polyethylene glycol, propylene glycol homopolymers, polypropylene oxide/ethylene oxide copolymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may be advantageous in manufacturing due to its stability in water. The polymer may have any molecular weight and may or may not have branching. The number of polymers attached to the antibody may vary, and if more than one polymer is attached, they may be the same or different molecules. In general, the number and/or type of polymers used for derivatization may be determined based on considerations including, but not limited to, the particular characteristics or functions of the antibody to be improved, whether the antibody derivative will be used in a defined-condition therapy, and the like.
In another embodiment, conjugates of antibodies and non-protein moieties that can be selectively heated by exposure to radiation are provided. In one embodiment, the non-protein moiety is a carbon nanotube (Kam et al, proc. Natl. Acad. Sci. USA 102:11600-11605 (2005)). The radiation may have any wavelength and includes, but is not limited to, wavelengths that do not harm ordinary cells, but heat the non-proteinaceous portion to a temperature at which cells proximal to the antibody-non-proteinaceous portion are killed.
H. recombinant methods and compositions
Recombinant methods and compositions can be used to produce antibodies, for example, as described in U.S. Pat. No. 4,816,567. In one embodiment, an isolated nucleic acid encoding an antibody described herein is provided. Such nucleic acids encode amino acid sequences that may constitute the VL of an antibody and/or amino acid sequences that constitute the VH of an antibody (e.g., the light chain and/or heavy chain of an antibody). In further embodiments, one or more vectors (e.g., expression vectors) comprising such nucleic acids are provided. In further embodiments, host cells comprising such nucleic acids are provided. In one such embodiment, the host cell comprises (e.g., has been transformed with) the following: (1) A vector comprising a nucleic acid encoding an amino acid sequence comprising a VL of an antibody and an amino acid sequence comprising a VH of an antibody; or (2) a first vector comprising a nucleic acid encoding an amino acid sequence of a VL of an antibody and a second vector comprising a nucleic acid encoding an amino acid sequence of a VH of an antibody. In one embodiment, the host cell is a eukaryotic cell, such as a Chinese Hamster Ovary (CHO) cell or lymphocyte (e.g., Y0, NS0, sp20 cell). In one embodiment, a method of producing an antibody is provided, wherein the method comprises culturing a host cell comprising a nucleic acid encoding the antibody as provided above under conditions suitable for expression of the antibody, and optionally recovering the antibody from the host cell (or host cell culture medium).
For recombinant production of antibodies, nucleic acids encoding the antibodies (e.g., as described above) are isolated and inserted into one or more vectors for further cloning and/or expression in a host cell. Such nucleic acids can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of an antibody).
Suitable host cells for cloning or expressing the antibody-encoding vectors include prokaryotic or eukaryotic cells as described herein. For example, antibodies can be produced in bacteria, particularly when glycosylation and Fc effector function are not required. For expression of antibody fragments and polypeptides in bacteria, see, e.g., U.S. Pat. No. 5,648,237, U.S. Pat. No. 5,789,199, and U.S. Pat. No. 5,840,523. (see also Charlton, methods in Molecular Biology, volume 248 (b.k.c.lo, et al, humana Press, totowa, NJ, 2003), pages 245-254, wherein expression of antibody fragments in E.coli (E.coli.) is described) antibodies can be isolated from bacterial cell pastes in soluble fractions after expression and can be further purified.
In addition to prokaryotes, eukaryotic microorganisms such as filamentous fungi or yeast, including fungal and yeast strains whose glycosylation pathways have been "humanized" resulting in the production of antibodies with a partially or fully human glycosylation pattern, are also suitable cloning or expression hosts for vectors encoding antibodies. 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 are also derived 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 transfection of Spodoptera frugiperda (Spodoptera frugiperda) cells.
Plant cell cultures may also be used as hosts. See, for example, U.S. Pat. No. 5,959,177, U.S. Pat. No. 6,040,498, U.S. Pat. No. 6,420,548, U.S. Pat. No. 7,125,978, and U.S. Pat. No. 6,417,429 (PLANTIBODIES TM techniques for producing antibodies in transgenic plants are described).
Vertebrate cells can also be used as hosts. For example, mammalian cell lines suitable for growth in suspension may be useful. Other examples of useful mammalian host cell lines are the monkey kidney CV1 line (COS-7) transformed by SV 40; human embryonic kidney cell lines (293 or 293 cells as described, for example, in Graham, F.L. et al, J.Gen. Virol.36:59 (1977); hamster kidney cells (BHK); mouse Sertoli cells (e.g., TM4 cells described in Mather, J.P., biol.Reprod.23:243-251 (1980)); monkey kidney cells (CV 1); african green monkey kidney cells (VERO-76); human cervical cancer cells (HELA); canine kidney cells (MDCK); brutro rat hepatocytes (BRL 3A); human lung cells (W138); human hepatocytes (Hep G2); mouse mammary tumor (MMT 060562); TRI cells (as in Mather, J.P. et al, annals N.Y. Acad. 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, NS0, and Sp2/0. For reviews of certain mammalian host cell lines suitable for antibody production see, e.g., yazaki and Wu, methods in Molecular Biology, vol.248 (B.K.C. Lo, humana Press, totowa, NJ), pages 255-268 (2003).
I. Measurement
The physical/chemical properties and/or biological activity of antibodies (e.g., anti-CD 79b antibodies or anti-CD 20 antibodies) used in the methods of treatment provided herein can be identified, screened, or characterized by various assays known in the art.
In one aspect, the enzyme is prepared by, for example, ELISA,The antibodies (e.g., anti-CD 79b antibodies or anti-CD 20 antibodies) used in the methods of treatment provided herein are detected by known methods such as FACS or western blotting.
In another aspect, antibodies that compete with any of the antibodies described herein for binding to a target antigen can be identified using a competition assay. In certain embodiments, such competing antibodies bind to the same epitope (e.g., linear or conformational epitope) bound by the antibodies described herein. Detailed exemplary methods for locating the epitope to which an antibody binds are provided in: morris (1996), "Epitope Mapping Protocols", incorporated by reference in volume 66 of Methods in Molecular Biology (Humana Press, totowa, NJ).
In an exemplary competition assay, the immobilized antigen is incubated in a solution comprising a first labeled antibody that binds to the antigen (e.g., any of the antibodies described herein) and a second unlabeled antibody that is being tested for its ability to compete with the first antigen-binding molecule for binding to the antigen. The second antibody may be present in the hybridoma supernatant. As a control, the immobilized antigen was incubated in a solution containing the first labeled antibody but not the second unlabeled antibody. After incubation under conditions that allow the first antibody to bind to the antigen, excess unbound antibody is removed and the amount of label associated with the immobilized antigen is measured. If the amount of label associated with the immobilized antigen in the test sample is substantially reduced relative to the control sample, it is indicated that the second antibody is competing with the first antibody for binding to the antigen. See Harlow and Lane (1988) Antibodies, A Laboratory Manual, chapter 14 (Cold Spring Harbor Laboratory, cold Spring Harbor, N.Y.).
VII chemotherapeutic agents
In some embodiments, the one or more chemotherapeutic agents include a compound for use in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib @Gene tek (Genentech)/OSI pharmaceutical company, osipharm @), bortezomib @Qiannium pharmaceutical Co (Millennium pharm), disulfiram, epigallocatechin gallate, halosporide A, carfilzomib, 17-AAG (geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant @Aspirin (AstraZeneca)), sunitinib @, andThe Pfizer/Sugen and letrozoleNovartis (Novartis)), imatinib mesylateNorhua, phenacetinNorhua, oxaliplatin @Cynophenanthrene (Sanofi)), 5-FU (5-fluorouracil), folinic acid, rapamycin (sirolimus,Hui's (Wyeth)), lapatinib @, andGSK572016, glaxo SMITH KLINE, luo Nafa m Lonafamib (SCH 66336), sorafenib @Bayer Labs (Bayer Labs)), gefitinib @Aliskir), AG1478; alkylating agents such as thiotepa andCyclophosphamide; alkyl sulfonates such as busulfan, imperoshu and piposhu; aziridines such as benzotepa (benzodopa), carboquinone, metutinib (meturedopa), and uredept (uredopa); ethylimines and methyl melamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphamide, and trimethylol melamine; annonaceous acetogenins (especially bullatacin) and bullatacin (bullatacinone)); camptothecins (including topotecan and irinotecan); Bryostatin; calistatin (callystatin); CC-1065 (including adorinone (adozelesin), carbozelesin (carzelesin) and bizelesin (bizelesin) synthetic analogues thereof); nostoc (cryptophycin) (in particular, nostoc 1 and nostoc 8); corticosteroids (including prednisone and prednisolone); cyproterone acetate; 5-reductase (including finasteride and dutasteride); vorinostat, romidepsin, ubibetastat, valproic acid, mo Xisi he (mocetinostat), dolastatin (dolastatin); Aldi interleukin, talc, du Kamei elements (including synthetic analogues KW-2189 and CB1-TM 1); eleutherobin (eleutherobin); a podophylline; the stoichiometriol (sarcodictyin); sponge chalone; nitrogen mustards such as chlorambucil, chlorpheniramine, cyclophosphamide, estramustine, ifosfamide, mechlorethamine hydrochloride, melphalan, mechlorethamine (novembichin), mechlorethamine cholesterol, prednisone mustard, qu Luolin amine (trofosfamide), uratemustine (uracil mustard); Nitrosoureas such as carmustine, chlorourea, fotemustine, lomustine, nimustine and ranimustine; antibiotics such as enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gamma 1I and calicheamicin omega 1I (Angew chem. Intl. Ed. Engl. 1994. 33: 183-186)), dactinomycin (dynemicin), including dactinomycin A, bisphosphonates such as chlorophosphonate, ai Simi stars, and new oncostatin (neocarzinostatin) chromophores and related chromophores of chromoprotein enediyne antibiotics; Aclacinomycin (aclacinomysin), actinomycin (actinomycin), anthramycin (authramycin), azoserine (azaserine), bleomycin, actinomycin (calinanomycin), cartrubicin (carabicin), carminomycin (caminomycin), carcinophilin (carzinophilin), chromomycin (chromomycinis), dactinomycin, daunomycin, dithiin (detorubicin), 6-azido-5-oxo-L-norleucine,(Doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrroline-doxorubicin and deoxydoxorubicin, epirubicin, isorubicin, everolimus (everolimus), sotrataurin, idarubicin, maramycin (marcellomycin); mitomycin, such as mitomycin C, mycophenolic acid, norgamycin, olivomycin, percomycin, methylmitomycin, puromycin, doxorubicin (quelamycin), rodobicin (rodorubicin), streptozotocin, tuberculin, ubenimex, clean statin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-Fu); folic acid analogs such as, for example, dimethylfolic acid (denopterin), methotrexate, pterin (pteropterin), and methotrexate; purine analogs such as fludarabine, 6-mercaptopurine, thioadenine (thiamiprine), thioguanine; pyrimidine analogs such as ambcitabine, azacytidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enotabine, fluorouridine; androgens such as carbosterone, drotasone propionate, cyclothiolane, emasculan, and testosterone; anti-adrenergic agents such as aminoglutethimide, mitotane, qu Luosi; folic acid supplements such as folinic acid; acetoglucurolactone; aldehyde phosphoramide glycosides; aminolevulinic acid; enuracil; amsacrine; double Qu Buxi (bestrabucil); a specific group; edatroxas (edatraxate); ground phosphoramide (defofamine); colchicine; imine quinone; -irinotecan (elfomithine); ammonium elegance; epothilones; an ethyleneoxy pyridine; gallium nitrate; hydroxyurea; lentinan; lonidamine (lonidainine); a maytansinoid, which is selected from the group consisting of, such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mo Pai darol (mopidamnol); diamine nitroacridine (nitraerine); prastatin; egg ammonia nitrogen mustard (phenamet); pirarubicin; losoxantrone (losoxantrone); podophylloic acid; 2-ethyl hydrazine; methyl benzyl hydrazine; Polysaccharide complex (JHS natural products company (JHS Natural Products, eugene, oreg.)) in Eugene, oregon, usa; carrying out a process of preparing the raw materials; rhizomycin (rhizoxin); schizophyllan (sizofuran); germanium spiroamine; tenuazonic acid; triiminoquinone; 2,2',2 "-trichlorotriethylamine; trichothecene toxins (especially T-2 toxin, verakulin A (verracurin A), plaque a, and serpentine hormone (anguidine)); a urethane; vindesine; dacarbazine; mannitol nitrogen mustard; dibromomannitol; dibromodulcitol; pipobromine; ganciclovir (gacytosine); arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxanes, such as TAXOL (Bristol-Myers Squibb Oncology, princeton, n.j.), beta.mexican cancer specialty (Bristol, n.j.) (Without hydrogenated castor oil), albumin engineered nanoparticle formulations of paclitaxel (american pharmaceutical partner company (American Pharmaceutical Partners, schaumberg, ill.)) and (Shao Bake, illinois)(Docetaxel, celecoxib-avantis (Sanofi-Aventis)); chlorambucil; (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; (vinorelbine); nortrilon (novantrone); teniposide; edatrase; daunomycin; aminopterin; capecitabine Ibandronate; CPT-11; topoisomerase inhibitor RFS2000; difluoromethyl ornithine (DMFO); retinoids such as retinoic acid; pharmaceutically acceptable salts, acids and derivatives of any of the above; and combinations of two or more of the foregoing, such as CHOP (abbreviation for cyclophosphamide, doxorubicin, vincristine, and prednisolone combination therapy) and FOLFOX (abbreviation for oxaliplatin (ELOXATIN TM) in combination with treatment regimen of 5-FU and folinic acid). Other examples of chemotherapeutic agents include bendamustine (or bendamustine hydrochloride)Ibrutinib (ibrutinib), lenalidomide and/or alilapril (idelalisib) (GS-1101).
In some embodiments, the one or more chemotherapeutic agents include an anti-hormonal agent that is used to modulate, reduce, block, or inhibit the action of growth hormone that can promote cancer, and is typically in the form of systemic or systemic therapy. They may be hormones themselves. Examples include: antiestrogens and Selective Estrogen Receptor Modulators (SERMs) including, for example, tamoxifen (includingTamoxifen, raloxifeneDroloxifene, 4-hydroxy tamoxifen, trawoxifene, raloxifene, LY117018, onapristone and toremifeneAntiprogestin; estrogen receptor down-regulation (ERD); estrogen receptor antagonists, such as fulvestrantDrugs acting on ovarian suppression or closure, e.g. Luteinizing Hormone Releasing Hormone (LHRH) antagonists, such as leuprolide acetate @, e.gAnd) Goserelin acetate (goserelin acetate), buserelin acetate (buserelin acetate) and triptorelin (tripterelin); antiandrogens such as flutamide, nilutamide, and bicalutamide; and aromatase inhibitors which inhibit aromatase and thereby regulate estrogen production in the adrenal gland, e.g. 4 (5) -imidazoles, aminoglutethimide, megestrol acetateExemestaneFumesteine (formestanie), fatrozole (fadrozole), and FucloxazoleLetrozoleAnd anastrozoleFurthermore, the definition of such chemotherapeutic agents includes: bisphosphonates, such as chlorophosphonate (e.g.Or (b)) Etidronate saltsNE-58095, zoledronic acid/zoledronateAlendronatePamidronate saltTilofosinate saltOr risedronateTroxacitabine (1, 3-dioxolane cytosine nucleoside analog); antisense oligonucleotides, particularly those that inhibit the expression of genes in signaling pathways involved in abnormal cell proliferation, such as PKC- α, ralf, H-Ras, and epidermal growth factor receptor (EGF-R); vaccines, such asVaccines and gene therapy vaccines (e.gVaccine(s),Vaccine and method for producing the sameA vaccine.
In some embodiments, the one or more chemotherapeutic agents include a topoisomerase 1 inhibitor (e.g.,) ; Antiestrogens such as fulvestrant; kit inhibitors, such as imatinib or EXEL-0862 (a tyrosine kinase inhibitor); EGFR inhibitors such as erlotinib or cetuximab; anti-VEGF inhibitors, such as bevacizumab; arinotecan; rmRH (e.g.,) ; Lapatinib and lapatinib ditosylate (an ErbB-2 and EGFR dual tyrosine kinase small molecule inhibitor, also known as GW 572016); 17AAG (geldanamycin derivatives as heat shock protein (Hsp) 90 poisons), and pharmaceutically acceptable salts, acids and derivatives of any of the above.
In some embodiments, the one or more chemotherapeutic agents include antibodies, such as alemtuzumab (Campath), bevacizumabGene tek (Genentech)); cetuximab @Imclone); panitumumab @Amantadine (Amgen)), rituximab @Gene Talcr/Baijian Aidi (Biogen Idec)), pertuzumab @2C4, gene tek), trastuzumab @Gene tek), tositumomab (Bexxar, corixia) and antibody drug conjugate gemtuzumab ozagrel @Wheatstone (Wyeth)). Other humanized monoclonal antibodies of therapeutic potential in combination with the compounds include: abelmoschus antibody (apolizumab), abelmoschus antibody, abilmosome, barbituzumab, mo Bi valuzumab (bivatuzumab mertansine), mo Kantuo valuzumab (cantuzumab mertansine), cetrimab (cedelizumab), cetuzumab (certolizumab pegol), cetuximab (cidfusituzumab), cetuximab (cidtuzumab), Daclizumab, eculizumab (ecalizumab), efalizumab (efalizumab), epratuzumab (epratuzumab), erlivizumab erlizumab, pantoprizumab (felvizumab), rituximab (fontolizumab), gemtuzumab octopamicin, oxuzumab (inotuzumab ozogamicin), ipilimumab, pull Bei Zhushan (labetuzumab), rituximab, matuzumab, mepaniamab, mevaluzumab, Mo Tuowei Belizumab (motovizumab), natalizumab, nituzumab, nor Luo Weizhu Belizumab (nolovizumab), nu Ma Weizhu Belizumab (numavizumab), orelizumab (ocrelizumab), omalizumab, panizumab, pacololizumab (pascolizumab), pefuxib (pecfusituzumab), hillside Bemamab (pectuzumab), pekezumab (pexelizumab), ralizumab (ralivizumab), Raney monoclonal antibody, ralividizumab (reslivizumab), ralizumab (reslizumab), ralizumab (resyvizumab), luo Weizhu monoclonal antibody (rovelizumab), lu Lizhu monoclonal antibody (ruplizumab), cetrimizumab, pinocembrizumab (Sontuzumab), tiuzumab (tacatuzumab tetraxetan), talizumab (tadocizumab), talizumab, tifeizumab (tefibazumab), Tozucchini, tolizumab (toralizumab), cetrimizumab (tucotuzumab celmoleukin), tukuxizucchini (tucusituzumab), wu Mawei zucchini (umavizumab), wu Zhushan, uteukinumab (ustekinumab), utezucchini and interleukin-12 (ABT-874/J695, wheatstone research and Atbang laboratories) are anti-interleukin-12, a recombinant human specific sequence full length IgG1 lambda antibody genetically modified to recognize interleukin-12 p40 protein.
In some embodiments, the one or more chemotherapeutic agents comprise an alkylating agent. Alkylating agents are a class of antineoplastic or anticancer agents that act by inhibiting transcription of DNA into RNA, thereby preventing protein synthesis. Alkylating agents replace hydrogen atoms on DNA with alkyl groups (C nH2n+1) leading to cross-linking within the DNA strand, leading to DNA strand breaks, which lead to base pairing abnormalities, inhibit cell division, and ultimately lead to cell death. This effect occurs in all cells, but rapidly dividing cells such as cancer cells are generally most sensitive to the effect of alkylating agents.
Alkylating agents generally fall into six categories: (1) Nitrogen mustards including, but not limited to, for example, mechlorethamine, cyclophosphamide, ifosfamide, bendamustine, melphalan, and chlorambucil; (2) Ethylamine and methyleneamine derivatives including, but not limited to, for example, altretamine and thiotepa; (3) Alkyl sulfonates including, but not limited to, for example busulfan; (4) Nitrosoureas including, but not limited to, for example carmustine and lomustine; (5) Triazenes including, but not limited to, for example, dacarbazine and procarbazine, temozolomide; and (6) platinum-containing antineoplastic agents including, but not limited to, cisplatin, carboplatin, and oxaliplatin, for example. Any known alkylating agent (including but not limited to those listed above) may be used in the methods of treatment provided herein. Bendamustine is an exemplary alkylating agent for use in the methods described herein. Bendamustine has the chemical name 4- (5- (bis (2-chloroethyl) amino) -1-methyl-1H-benzo [ d ] imidazol-2-yl) butanoic acid, the molecular formula is C16H21Cl2N3O2, and the molecular weight is 358.263g/mol. Bendamustine (CAS accession No. 16506-27-7) is a difunctional methyl chloroethylamine derivative that contains a purine-like benzimidazole ring. Bendamustine is available as a solution in powder and solution dosage forms. In some embodiments, the alkylating agent used in the methods described herein is a salt or solvate of bendamustine. In some embodiments, the bendamustine salt is bendamustine hydrochloride (CAS contains 3543-75-7), having the formula C 16H21Cl2N3O2. HCl, and the molecular weight is 394.72g/mol. Bendamustine hydrochloride is commercially available as BENDEKA, TREANDA, TREAKISYM, RIBOMUSTIN, LEVACT, MUSTIN, et al.
In some embodiments, the one or more chemotherapeutic agents include gemcitabine (e.g.,). Gemcitabine is an antimetabolite nucleoside analog (2 ',2' -difluorodeoxycytidine). Since only the biphosphate and triphosphate forms are cytotoxic, they are activated after intracellular phosphorylation by deoxycytidine kinase. Specifically, the triphosphate form competes with deoxycytidine triphosphate for incorporation into DNA as an inactive base, and the diphosphate form inhibits ribonucleotide reductase (an enzyme critical for normal DNA synthesis). According to IUPAC nomenclature, gemcitabine may also be referred to as "2' -deoxy-2 ',2' -difluorocytidine monohydrochloride" (β -isomer) and has the following structure:
the term "2' -deoxy-2 ',2' -difluorocytidine monohydrochloride (β -isomer)" or "gemcitabine" is used to encompass (unless otherwise indicated) pharmaceutically acceptable solvates (including hydrates) and polymorphs or pharmaceutically acceptable salts thereof. Pharmaceutical compositions of 2' -deoxy-2 ',2' -difluorocytidine monohydrochloride (β -isomer) can include one or more diluents, vehicles, and/or excipients. An example of a pharmaceutical composition comprising 2' -deoxy-2 ',2' -difluorocytidine monohydrochloride (β -isomer) is (Gemcitabine hydrochloride).Comprising 2' -deoxy-2 ',2' -difluorocytidine monohydrochloride (beta-isomer) as active ingredient, and other inactive ingredients, in sterile form, for intravenous use only.The vials contained 200mg or 1g gemcitabine hydrochloride (expressed as the free base) formulated with mannitol (200 mg or 1g, respectively) and sodium acetate (12.5 mg or 62.5mg, respectively) as sterile lyophilized powders. Hydrochloric acid and/or sodium hydroxide may have been added to adjust the pH.
In some embodiments, the one or more chemotherapeutic agents include oxaliplatin (e.g.,). Oxaliplatin is a chemotherapeutic agent with the molecular formula C 8H14N2O4 Pt and the chemical name cis- [ (1R, 2R) -1, 2-cyclohexanediamine-N, N ] [ oxalato (2-) -O, O ] platinum. The chemical structure is as follows:
the term "cis- [ (1R, 2R) -1, 2-cyclohexanediamine-N, N ] [ oxalato (2-) -O, O ] platin" or "oxaliplatin" is used to encompass (unless otherwise indicated) pharmaceutically acceptable solvates (including hydrates) and polymorphs or pharmaceutically acceptable salts thereof. The platinum atom of oxaliplatin forms a 1, 2-intrachain crosslink between two adjacent guanosine residues, bending the duplex approximately 30 degrees toward the major groove. Oxaliplatin has a non-hydrolyzable Diaminocyclohexane (DACH) carrier ligand that remains in the final cytotoxic metabolite of the drug. Its reaction with DNA and other macromolecules proceeds by hydrolysis of one or both carboxylate groups of the oxalate salt, leaving a DACH platinum mono-adduct or a bifunctional DACH-platinum cross-link. The inherent chemical and steric nature of the DACH-platinum adducts appears to contribute to the lack of cross-resistance to cisplatin (reviewed in Di Francesco et al, (2002) Cell Mol Life Sci,59 (11): 1914-27). Alkaline hydrolysis of oxaliplatin results in two successive steps in an oxalic acid monodentate complex (pKa 7.23) and an oxaliplatin dihydrate complex. The monodentate intermediate is believed to react rapidly with endogenous compounds (Jerremalm et al, (2003) J Pharm Sci,92 (2): 436-438). The crystal structure of oxaliplatin bound to a DNA dodecamer duplex having the sequence 5' -d (CCTCTGGTCTCC) has been reported; the platinum atom forms a 1, 2-intrachain crosslink between two adjacent guanosine residues, bending the duplex approximately 30 degrees toward the major groove. Crystallography provides structural evidence for the importance of chirality in mediating interactions between oxaliplatin and double-stranded DNA (Spingler et al, (2001) Inorg Chem,40 (22): 5596-602). Thus, oxaliplatin was successful in that it was able to induce DNA damage caused by massive adducts as well as intra-and inter-strand cross-links (Takahara et al, (1995) Nature,377 (6550): 649-52) and was able to induce apoptosis (Boulikas and Vougiouka, (2003) Oncol Rep,10 (6): 1663-82).
In some embodiments, the one or more chemotherapeutic agents include gemcitabine and oxaliplatin (e.g.,And). In some embodiments, the one or more chemotherapeutic agents are gemcitabine and oxaliplatin (e.g.,And)。
VIII pharmaceutical preparation
Pharmaceutical formulations of any of the agents described herein (e.g., an anti-CD 79b immunoconjugate, a CD20 agent, and one or more chemotherapeutic agents) for use in any of the methods described herein are made by mixing such agents with the desired purity with one or more optional pharmaceutically acceptable carriers (Remington's Pharmaceutical Sciences, 16 th edition, osol, a. Code (1980)) in the form of a lyophilized formulation or aqueous solution. Pharmaceutically acceptable carriers are generally non-toxic to the recipient at the dosages and concentrations employed, including but not limited to: buffers such as phosphates, citrates and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzyl ammonium chloride, hexamethyl ammonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butanol or benzyl alcohol, alkyl p-hydroxybenzoates, such as methyl or propyl p-hydroxybenzoate, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol); a low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., zinc protein complexes); and/or nonionic surfactants such as polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers herein also include interstitial drug dispersants such as soluble neutral active hyaluronidase glycoprotein (sHASEGP), such as human soluble PH-20 hyaluronidase glycoprotein, e.g., rHuPH20 @Baxter International, inc.). Certain exemplary shasegps and methods of use (including rHuPH 20) are described in U.S. patent publication nos. 2005/026086 and 2006/0104968. In one aspect, sHASEGP is combined with one or more additional glycosaminoglycanases (such as chondroitinase).
Exemplary lyophilized antibody or immunoconjugate formulations are described in U.S. Pat. No. 6,267,958. Aqueous antibodies or immunoconjugates include those described in U.S. Pat. No. 6,171,586 and WO2006/044908, the latter formulations comprising histidine-acetate buffer.
The formulations herein may also contain more than one active ingredient necessary for the particular indication being treated, preferably active ingredients having complementary activities that do not adversely affect each other.
The active ingredient may be embedded in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin-microcapsules and poly (methylmethacylate) microcapsules, respectively); embedded in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules); or embedded in a macroemulsion. Such techniques are disclosed in Remington's Pharmaceutical Sciences, 16 th edition, osol, a. Ed (1980).
A slow release preparation may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody or immunoconjugate, which matrices are in the form of shaped articles, e.g., films, or microcapsules.
Formulations for in vivo administration are typically sterile. Sterility can be readily achieved, for example, by filtration through sterile filtration membranes.
Further details regarding pharmaceutical formulations comprising anti-CD 79 immunoconjugates are provided in WO 2009/099728, which is expressly incorporated herein by reference in its entirety.
IX kit and article of manufacture
In another embodiment, an article of manufacture or kit comprising an anti-CD 79b immunoconjugate (such as described herein) and at least one additional agent is provided. In some embodiments, the at least one additional agent is an anti-CD 20 antibody (such as rituximab) and one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin). In some embodiments, the article of manufacture or kit further comprises a package insert comprising instructions for using the anti-CD 79B immunoconjugate with at least one additional agent such as an anti-CD 20 antibody (e.g., rituximab) and one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) to treat or delay progression of a B cell proliferative disorder (e.g., DLBCL, such as recurrent/refractory DLBCL) in an individual. Any of the anti-CD 79b immunoconjugates and anti-cancer agents known in the art may be included in the article of manufacture or kit. In some embodiments, the kit comprises an immunoconjugate comprising formula (la)
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26, and wherein p is between 1 and 8; which is used in combination with an anti-CD 20 antibody, such as rituximab, and one or more chemotherapeutic agents, e.g., gemcitabine and oxaliplatin, to treat a human in need thereof having diffuse large B-cell lymphoma (DLBCL). In some embodiments, the kit is used according to any of the methods provided herein.
In some embodiments, the kit comprises an immunoconjugate comprising formula (la)
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26, and wherein p is between 1 and 8; it is used in combination with rituximab, gemcitabine and oxaliplatin for the treatment of a human suffering from Diffuse Large B Cell Lymphoma (DLBCL) in need thereof. In some embodiments, the kit is used according to any of the methods provided herein.
In some embodiments, the kit comprises an immunoconjugate comprising formula (la)
Wherein Ab is an anti-CD 79b antibody comprising: (i) A heavy chain comprising a VH comprising the amino acid sequence of SEQ ID No. 19; (ii) A light chain comprising a VL comprising the amino acid sequence of SEQ ID No. 20, and wherein p is between 2 and 5. In some embodiments, p is between 3 and 4, e.g., 3.5. In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising: a heavy chain comprising the amino acid sequence of SEQ ID NO. 36; and a light chain comprising the amino acid sequence of SEQ ID NO. 35. In certain embodiments, the anti-CD 79b immunoconjugate comprises the structure Ab-MC-vc-PAB-MMAE. In some embodiments, the anti-CD 79b immunoconjugate is a poloxamer vedotin-piiq. In some embodiments, the at least one additional agent is an anti-CD 20 antibody (such as rituximab) and one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin). In some embodiments, the kits are for treating DLBCL in an individual (e.g., an individual having one or more features described herein) according to the methods provided herein.
In some embodiments, the kit comprises an immunoconjugate comprising formula (la)
Wherein Ab is an anti-CD 79b antibody comprising: (i) A heavy chain comprising a VH comprising the amino acid sequence of SEQ ID No. 19; (ii) A light chain comprising a VL comprising the amino acid sequence of SEQ ID No. 20, and wherein p is between 2 and 5. In some embodiments, p is between 3 and 4, e.g., 3.5. In some embodiments, the immunoconjugate comprises an anti-CD 79b antibody comprising: a heavy chain comprising the amino acid sequence of SEQ ID NO. 36; and a light chain comprising the amino acid sequence of SEQ ID NO. 35. In certain embodiments, the anti-CD 79b immunoconjugate comprises the structure Ab-MC-vc-PAB-MMAE. In some embodiments, the anti-CD 79b immunoconjugate is a poloxamer vedotin-piiq. In some embodiments, the at least one additional agent is rituximab, gemcitabine, and oxaliplatin. In some embodiments, the kits are for treating DLBCL in an individual (e.g., an individual having one or more features described herein) according to the methods provided herein.
In some embodiments, the anti-CD 79b immunoconjugate, the anti-CD 20 antibody (such as rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) are in the same container or in separate containers. Suitable containers include, for example, bottles, vials, bags, and syringes. The container may be formed from a variety of materials, for example glass, plastic (such as polyvinyl chloride or polyolefin) or metal alloys (such as stainless steel or hastelloy). In some embodiments, the container contains the formulation and the label on or associated with the container may indicate instructions for use. The article of manufacture or kit may also include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use. In some embodiments, the article of manufacture further comprises one or more additional agents (e.g., chemotherapeutic agents and antineoplastic agents). Suitable containers for one or more reagents include, for example, bottles, vials, bags, and syringes.
Table E: amino acid sequence.
The description is to be construed as sufficient to enable those skilled in the art to practice the invention. Various modifications of the invention, in addition to those shown and described herein, will become apparent to those skilled in the art from the foregoing description, and fall within the scope of the appended claims. All publications, patents, and patent applications cited herein are incorporated by reference in their entirety for all purposes.
Examples
The following are examples of the methods and compositions of the present disclosure. It should be understood that various other embodiments may be practiced given the general description provided above.
Example 1: phase III, open label, multicenter, randomized study to evaluate the safety and efficacy of the combination of Polotuzumab vedotin with rituximab plus gemcitabine plus oxaliplatin (Pola-R-GemOx) with R-GemOx alone to treat patients with relapsed/refractory diffuse large B-cell lymphoma.
This example describes a phase III, open-label, multicenter, randomized study evaluating the safety and efficacy of the combination of Polotuzumab vedotin with rituximab, gemcitabine, and oxaliplatin (Pola-R-GemOx) versus rituximab, gemcitabine, and oxaliplatin alone (R-GemOx) in treating relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) patients. In this study, treatment was performed in two phases: 1) An initial security import stage (stage 1) of evaluating the combined security of the Pola-R-GemOx; 2) A Random Control Test (RCT) stage (stage 2) comparing the safety and efficacy of Pola-R-GemOx with R-GemOx.
I. Research objective
A. stage 1: security importation period
Security targets and endpoints
Primary security objective
The main safety objective of phase 1 of the study was to evaluate the safety and tolerability of Pola-R-GemOx as a combination therapy.
Main safety endpoint
According to the national cancer institute adverse events common terminology standard, version 5 (NCI CTCAE V5.0.0), the primary safety endpoint of stage 1 of this study is physical examination results and the incidence, nature and severity of Adverse Events (AEs), of particular concern for peripheral neuropathy.
Secondary security target
The secondary safety objective of phase 1 of the study was to evaluate the safety and tolerability of Pola-R-GemOx as a combination therapy and to evaluate the immunogenicity of the polo-bead mab vedotin.
Secondary security endpoint
The secondary safety endpoint of phase 1 of the study was the incidence and assessment of peripheral neuropathy, as measured by the cancer treatment function evaluation system/gynaecological tumor group-neurotoxicity 12 term scale (FACT/gos-Ntx 12); the tolerability of Pola-R-GemOx, measured by dose interruption, dose reduction, and dose intensity; as well as the prevalence of anti-drug antibodies (ADA) at baseline and the incidence of ADA during the study.
Efficacy targets and endpoints
Secondary efficacy objective
The secondary efficacy objective of phase 1 of this study was to evaluate the efficacy of Pola-R-GemOx.
Secondary efficacy endpoint
The secondary efficacy endpoints for phase 1 of the study were as follows:
Complete Remission (CR), defined as the proportion of patients achieving complete metabolic response based on PET-CT according to Lugano 2014 remission criteria (Cheson et al (2014) J Clin Oncol 32:3059-3068).
Objective Remission Rate (ORR), defined as the proportion of patients who achieved complete or partial metabolic response (based on responses including PET CT data) at the end of treatment according to Lugano 2014 remission criteria.
Best Overall Relief (BOR), defined as the best relief recorded from the beginning of treatment until the end of treatment according to Lugano 2014 relief criteria.
Progression Free Survival (PFS), defined as the time from the first dose of study treatment to the first occurrence of disease progression (based on reactions including PET CT data or not including any PET data) or death for any reason, according to Lugano 2014 remission criteria.
Total survival (OS), defined as the time from first dose study treatment to death for any reason.
Event free survival (EFS eff), defined as the time from the first dose of study treatment to the earliest occurrence of any of the following:
o disease progression or recurrence (based on response including PET CT data or not including any PET data).
O die for any reason.
O starts any non-regimen prescribed anti-lymphoma treatment (NALT).
Pharmacokinetic targets and endpoints
Pharmacokinetic targets
The pharmacokinetic objective of phase 1 of this study was to evaluate the Pharmacokinetic (PK) profile of the polotophyllizumab vedotin.
Pharmacokinetic endpoint
The pharmacokinetic endpoint of phase 1 of this study was the PK profile of the combination of the poloxamer and vedotin with R-GemOx in recurrent or refractory DLBCL patients, and the potential PK interaction between the poloxamer and R-GemOx.
B. stage 2: random Control Test (RCT)
Efficacy targets and endpoints
Primary and secondary efficacy goals
The primary and secondary efficacy objective of phase 2 of this study was to evaluate the efficacy of Pola-R-GemOx compared to R-GemOx alone.
Main efficacy endpoint
The primary efficacy endpoint of phase 2 of the study was total survival (OS), which is defined as the time from randomization to death for any reason.
Secondary efficacy endpoint
The secondary efficacy endpoints for phase 2 of the study were as follows:
Key secondary endpoints included in the layered test procedure (see section V below):
o PFS, defined as the time from randomization to first occurrence of disease progression or death for any reason, according to Lugano 2014 remission criteria.
O CRR, defined as the proportion of patients who achieved complete metabolic response based on PET-CT at the end of treatment, according to Lugano 2014 remission criteria.
Oorr, defined as the proportion of patients who achieved a complete or partial metabolic response at the end of treatment according to Lugano 2014 remission criteria.
Secondary endpoint not adjusted for test multiplex procedure:
o BOR, defined as the best relief recorded from randomization until treatment end, according to Lugano 2014 relief criteria.
O CRR, defined as the proportion of patients who achieved complete metabolic response based on PET-CT at the end of treatment, according to Lugano 2014 remission criteria.
O ORR, defined as the proportion of patients who achieve a complete or partial metabolic response (based on responses including PET CT data) at the end of a treatment fraction, according to Lugano 2014 remission criteria.
Objective duration of remission (DoR) is defined as the time from the first occurrence of recorded objective remission (based on response including PET CT data) to disease progression (based on response including PET CT data or not including any PET data) or death for any reason (based on the prior occurrence) according to Lugano 2014 remission criteria.
O EFSeff, defined as the time from randomization to any of the earliest occurrences of:
disease progression or recurrence (based on response including PET CT data or not including any PET data).
Death for any reason.
Start any NALT.
Patient Reporting Outcome (PRO) targets and endpoints
Secondary and exploratory PRO targets
The secondary PRO objective of phase 2 of the study was to evaluate the impact of treatment and disease on health-related quality of life.
Secondary PRO endpoint
The secondary PRO endpoints for phase 2 of the study are as follows:
Body function and fatigue deterioration time measured by European cancer research and treatment tissue quality of life core 30 (EORTC QLQ-C30).
Time to progression of lymphoma symptoms as measured by the cancer treatment function evaluation system-lymphoma (FACT-Lym) sub-scale.
Changes in peripheral neuropathy from baseline as measured by the FACT/GOG-NTX-12 sub-scale score.
Exploratory PRO endpoint
Exploratory PRO endpoints at stage 2 of the study are descriptive summary statistics and changes from baseline for all of the EORTC QLQ-C30, FACT-Lym sub-scales, FACT/GOG-NTX-12 and EQ-5D-5L scales.
Security targets and endpoints
Security target
The safety objective of phase 2 of the study was to evaluate the safety and tolerability of Pola-R-GemOx compared to R-GemOx and to evaluate the immunogenicity of the polo-trastuzumab vedotin.
Study endpoint
The safety endpoint for phase 2 of the study was as follows:
incidence, nature and severity of AE (including peripheral neuropathy) according to NCI CTCAE V5.0.0 and physical examination results.
Tolerance assessed by dose interruption, dose reduction and dose intensity.
Incidence of peripheral neuropathy measured by FACT-GOG/Ntx12 and evaluation results.
Prevalence of anti-drug antibodies (ADA) at baseline and incidence of ADA during the study.
Biomarker targets and endpoints
Exploratory biomarker targets
The exploratory biomarker endpoint of phase 2 of this study was a biomarker that was determined to meet the following criteria:
Predictive of response to the poloxamer vedotin (i.e., predictive biomarker).
Associated with progression to more severe disease (i.e., prognostic biomarkers).
Provide evidence of the activity of the poisotophyllizumab vedotin, or increase knowledge and understanding of disease biology.
Exploratory biomarker endpoint
Exploratory biomarker targets for phase 2 of the study were associations between efficacy endpoints, including total survival (OS), progression Free Survival (PFS), and Complete Remission (CR) rates, as well as exploratory biomarkers such as molecular DLBCL pre-later cell-derived subtypes, BCL2 and MYC double expressitors, and key lymphoma mutations.
Pharmacokinetic targets and endpoints
Pharmacokinetic targets
The pharmacokinetic objective of phase 2 of the study was to evaluate the Pharmacokinetic (PK) profile of the polotophyllizumab vedotin.
Pharmacokinetic endpoint
The pharmacokinetic endpoints at phase 2 of the study were as follows:
PK profile of poluzumab vedotin combination with R-GemOx in recurrent or refractory DLBCL patients.
Potential PK interactions between potentizumab vedotin and R-GemOx.
II patients
About 10 patients entered the group safety lead-in phase (phase 1), about 206 patients entered the group randomization (phase 2), and a total of about 216 patients.
A. Inclusion criteria
Patients were included in the study if they met the following criteria:
Age > 18 years.
Histologically confirmed diagnosis of diffuse large B-cell lymphomas with non-specific fingers (NOS) or a history of the conversion of indolent disease to DLBCL.
Prior systemic therapy via at least one (1) line.
O allows for prior autologous Hematopoietic Stem Cell Transplantation (HSCT); chemotherapy and subsequent consolidation of autologous HSCT is considered a treatment line.
O as long as the patient stops all immunosuppressive treatments and does not have active Graft Versus Host Disease (GVHD), prior allogeneic HSCT is allowed; chemotherapy and subsequent allogeneic HSCT are considered a treatment line.
Local therapy (e.g., radiation therapy) is not considered a treatment line.
Recurrent or refractory disease, defined as follows:
Recurrent: the disease recurs after the last treatment line is completed and the duration of remission is more than or equal to 6 months.
O refractory: the disease progresses during the treatment or within 6 months (< 6 months) of prior therapy.
At least one two-dimensional measurable lesion, defined as a longest dimension measured by CT or MRI >1.5cm.
Eastern tumor cooperative group (ECOG) physical stamina score 0, 1 or 2.
Patients with an oeclog physical status of 3 were considered to be in RCT stage (stage 2), provided however that the status was associated with DLBCL and after a pre-period of 7 days of steroid treatment (e.g. 1mg/kg prednisone) in the screening stage. It must be observed that ECOG physical performance status subsequently improves to 2 or less to qualify for the study.
Having proper blood function, defined as:
o-hemoglobin is not less than 8g/dL.
Absolute Neutrophil Count (ANC) 1.5X10 9/L or 0.5X10 9 (if neutropenia is attributable to underlying disease and prior to steroid use).
O platelet count is ≡75×10 9/L or ≡50×10 9 (if thrombocytopenia is attributable to underlying disease).
For women with fertility: consent was maintained on either abstinence or contraceptive measures were used, and consent was not given to ova.
For men: agreeing to abstinence or using contraceptive methods and avoiding donation of sperm.
B. exclusion criteria
Patients were excluded from the study if they met the following criteria:
There is a history of severe allergy or anaphylaxis to humanized or murine monoclonal antibodies (or fusion proteins related to recombinant antibodies), or is known to be sensitive or allergic to murine products.
Rituximab, a gemcitabine or oscilant contraindications for thalidomide.
Peripheral neuropathy > grade 1 assessed according to NCI CTCAE V5.0.0 upon inclusion in the group.
Combinations of previously used pototouzumab vedotin or gemcitabine plus platinum-based agents.
Any previous or ongoing polotouzumab vedotin assay is entered into the panel.
Treatment with radiation therapy, chemotherapy, immunotherapy, immunosuppression therapy or any agent for the destination test for the treatment of cancer within 2 weeks prior to day 1 of cycle 1.
O all acute, clinically significant treatment-related toxicities (except hair loss) resulting from prior therapy must subside to < 2 levels before cycle 1 day 1.
Autologous or allogeneic stem cell transplantation is scheduled for recruitment.
O patients who received only one prior therapy suitable for stem cell transplantation were excluded from the trial. Reasons for unsuitable transplantation include age, physical status, complications, failure to transplant or surgery, inadequate response to rescue treatments, patient rejection, or choreography reasons.
Primary or secondary Central Nervous System (CNS) lymphomas at the time of recruitment.
Richter transformation or prior capillary leak syndrome (CLL) occurs.
Any of the following abnormal laboratory values (unless the abnormal laboratory values are caused by potential lymphomas):
o creatinine >1.5 x upper normal limit (ULN) or observed creatinine clearance <30mL/min.
O aspartate Aminotransferase (AST) or alanine Aminotransferase (ALT) >2.5 XULN.
O total bilirubin is more than or equal to 1.5 XULN; patients with the noted gilbert disease may be included in the group if total bilirubin is less than or equal to 3×uln.
O International Normalized Ratio (INR) or Prothrombin Time (PT) >1.5 x ULN in the absence of therapeutic anticoagulant.
O Partial Thromboplastin Time (PTT) or activated partial thromboplastin time (aPTT) in the absence of lupus anticoagulant >1.5 x ULN.
Other history of malignancy that might affect protocol compliance or interpretation of results. The exceptions include:
patients with curative treatment of basal cell carcinoma of the skin or squamous cell carcinoma or a history of carcinoma in situ of the cervix at any time prior to the study were eligible.
O patients who received radical appropriate treatment (and prior to group entry, the malignancy had been relieved for > 2 years without treatment) were eligible for any other malignancy.
Patients with low-grade early stage prostate cancer (Gleason score 6 points or less, stage 1 or stage 2) who did not require treatment at any time prior to the o study were eligible.
There is evidence that there are serious, uncontrolled concomitant diseases that may affect protocol compliance or interpretation of the results, including serious cardiovascular diseases (such as new york heart association NYHA class III or IV heart disease, myocardial infarction, unstable arrhythmias, or unstable angina over the last 6 months) or serious pulmonary diseases (including obstructive pulmonary disease and bronchospasm history).
Study recruitment was with known active bacterial, viral, fungal, mycobacterial, parasitic or other infections (excluding fungal infection of the nail bed), or any significant infection occurred within 4 weeks prior to day 1 of cycle 1.
Suspected or latent tuberculosis patients; the development of latent tuberculosis was confirmed by a positive interferon-gamma release assay.
The result of the chronic Hepatitis B Virus (HBV) infection detection was positive (defined as positive for serological detection of hepatitis B surface antigen [ HBsAg ]).
Patients with occult or prior HBV infection (defined as HBsAg negative and hepatitis b core antibody [ HBcAb ] positive) were enrolled if HBV DNA could not be detected, provided they received DNA detection on day 1 of each cycle and were DNA detected once a month for at least 12 months after the last cycle of study treatment.
Positive results for Hepatitis C Virus (HCV) antibody detection.
Patients positive for o HCV antibodies only meet the inclusion criteria when the PCR result of HCV RNA is negative.
There is a known history of Human Immunodeficiency Virus (HIV) serological response. For patients whose HIV status is unknown, HIV detection is performed at the time of screening if local regulatory requirements require it.
Overvaccine inoculation within 4 weeks prior to treatment.
Recently, too much surgery was accepted (within 6 weeks before the 1 st day of cycle 1 began), except for diagnosis.
Any other diseases, metabolic dysfunctions, physical examination findings or clinical laboratory findings, from which the presence of a disease or condition for which the use of study drugs or possibly affecting the interpretation of the results or possibly putting the patient at high risk of treatment complications is reasonably suspected.
Pregnancy or lactation, or is intended to be pregnant during the study period or within 12 days after the last administration of study medication.
III, study design
The study was a phase III, multicenter, open-label, randomized study directed to recurrent or refractory DLBCL patients. The study included screening phase, treatment phase (phase 1 and phase 2) and post-treatment phase. The post-treatment period included an end-of-treatment visit and a follow-up period that occurred 28 days after the last dose of study treatment. Adverse events, serious adverse events, and adverse events of particular concern were reported up to 90 days after the last drug administration of study drug or until non-regimen prescribed anti-lymphoma treatment was initiated (NALT).
The overall design of the study is shown in figure 1.
A. screening period
To meet the conditions for participation in this study, patients must have a histologically confirmed diagnosis of recurrent or refractory DLBCL.
Patients may undergo autologous Hematopoietic Stem Cell Transplantation (HSCT) prior to recruitment; chemotherapy and subsequent consolidation of autologous HSCT is considered a treatment line. Patients who received prior allogeneic HSCT meet the inclusion criteria, so long as they stopped all immunosuppressive treatments and were not suffering from active Graft Versus Host Disease (GVHD); chemotherapy and subsequent allogeneic HSCT are considered a treatment line. Local therapy (e.g., radiation therapy) is not considered a treatment line. Patients with greater than grade 1 peripheral neuropathy assessed according to NCI CTCAE V5.0.0 were excluded from the inclusion group. Other inclusion and exclusion criteria are described in section II above.
B. Treatment period
The treatment period was divided into two phases, the safety introduction phase (phase 1) and the randomized controlled trial (phase 2).
In stage 1, the safety lead-in period, 10 patients received trial study treatment with Pola-R-GemOx.
In phase 2, the Randomized Controlled Trial (RCT), patients received either the pilot study treatment of Pola-R-GemOx or the control study treatment of R-GemOx at a 1:1 ratio.
The main purpose of the randomized part of the study (phase 2) was to evaluate the efficacy of Pola-R-GemOx compared to R-GemOx in recurrent or refractory DLBCL patients (measured by OS). Assuming a median OS of 9.5 months (Mounier et al, (2013) haemato logica, 98:1726-1731) and a randomization ratio of 1:1, 121 events were required to detect an inter-group difference of 6.3 months for median OS (risk ratio [ HR ] =0.60), efficacy was 80%, and bilateral α was 0.05. Based on the statistical assumptions above, a recruitment period of about 11 months (18 patients per month) was expected, and a follow-up period of 14 months after the last patient was randomized, with a total of about 206 patients being included in phase 2 of the study (considering an estimated shedding rate of 10%). Patients were randomly assigned to the Pola-R-GemOx and R-GemOx treatment groups at a 1:1 ratio.
In both phases of the treatment period, the patient received either a maximum of 8 cycles of Pola-R-GemOx or 8 cycles of R-GemOx, each administered for a 21-day period.
Stage 1: security importation period
A total of 10 patients received Pola-R-GemOx treatment. These 10 patients were staggered in three queues:
queue 1: the first 3 patients.
Queue 2: middle 3 patients.
Queue 3: last 4 patients.
Within each cohort, safety was assessed at the end of the fourth cycle for all subjects, focusing on acute peripheral nerve viruses. Once all safety evaluations have been performed within one cohort and further subject accumulation cleared, the next cohort is started to be recruited. This procedure was continued until all three queues were recruited to completion.
All security evaluations were done in queue 1 and queue 2, respectively, and recruitment of the next queue was approved, with no group being entered in queues 2 and 3. Patients in the cohort were replaced if they stopped taking medication before treatment at cycle 4 due to disease progression, death, or any other reason that could not be directly attributed to peripheral neuropathy.
Once the entire cohort population has completed at least four cycles, the overall safety profile of Pola-R-GemOx (of particular concern for peripheral neuropathy) will be evaluated and advice is provided as to whether to open the next cohort (continue/not continue decision). The potential reason for stopping further inclusion in the next cohort is that if >33.33% of patients in the cohort develop ≡1 ≡3 peripheral neuropathy within 14 days. The potential beneficial effects of dose adjustments, the time course of resolution of peripheral neuropathy events, etc. will be considered when making a continue/no continue decision. In addition, in the safety assessment of cohorts 2 and 3, all patients completing the fourth treatment cycle were re-assessed to assess the potential for cumulative neurotoxicity of Pola-R-GemOx and the course of peripheral neuropathy regression.
Stage 1 also assessed the ADA and sparse PK characteristics of the combination of Pololizumab vedotin with R-GemOx.
A summary of the safety introduction period (stage 1) of this study is shown in FIG. 2.
After the tenth subject completed the entire treatment period (fig. 2), the safety and tolerability of the Pola-R-GemOx regimen was assessed and a decision was made (continue/not continue decision) as to whether to continue to stage 2 (RCT stage) of the study at the end of the tenth patient treatment (fig. 2). The formal continue/not continue decision at the end of stage 1 is determined by:
when the last patient in stage 1 treatment received the last administration of Pola-R-GemOx, the entire safety profile of the stage 1 study population will be examined, with particular attention paid to the frequency, course and reversibility of ≡3 peripheral neuropathy events:
if 3 or fewer patients fail to resolve to < 1 > grade < 3 > peripheral neuropathy within 14 days during treatment in stage 1 (n=10), the study will continue to stage 2, the Randomized Controlled Trial (RCT) stage.
O if 4 or more patients in stage 1 (n=10) develop ≡3 peripheral neuropathy failing to regress to ≡1 within 14 days during treatment, the study is suspended.
O evaluate whether the risk of peripheral neuropathy at the original study treatment dose was satisfactorily alleviated after dose adjustment.
Based on the above information, a suggestion is provided whether to proceed to stage 2 (i.e., RCT stage).
Stage 2: random control test
If the Pola-R-GemOx combination therapy is considered to be tolerable during the safety lead-in period (stage 1), then the RCT stage is started. A total of 206 eligible patients received either Pola-R-GemOx (trial treatment) or R-GemOx (control) at a 1:1 ratio at random.
Randomization is performed using hierarchically arranged blocks through IxRS. Layering factors include: 1) The number of previous systemic treatments or normals to treatment (1 vs. Gtoreq.2); 2) The last systemic treatment or outcome of therapy (recurrent vs. refractory); 3) Age (.ltoreq.70 years vs. >70 years). Stratification is based on previous systemic treatments or therapy line numbers: chemotherapy and subsequent consolidated autologous HSCT are considered as one treatment line; chemotherapy and its subsequent allogeneic HSCT are considered a treatment line; local therapy (e.g., radiation therapy) is not considered a treatment line. Stratification is performed for outcome based on last systemic therapy or treatment: recurrent disease is defined as disease that recurs more than or equal to 6 months after completion of the last treatment line; refractory disease is defined as a disease that progresses during treatment or within 6 months (< 6 months) of prior therapy.
The stratified treatment groups were approximately comparable in terms of disease progression and disease status, ensuring comparability between the test group (Pola-R-GemOx) and the control group (R-GemOx).
Mid-term security analysis was performed during the RCT stage. After the first 10 and 20 patients were randomized into groups and at least 2 treatment cycles were completed, respectively, a first and second safety metaphase analysis was performed. Thereafter, the frequency of mid-term safety assessments depends on the number of. Gtoreq.3 grade peripheral neuropathy events observed during the second mid-term safety assessment. The stopping rule does not take into account grade 3 peripheral neuropathy which reverts to grade 1 or less within 14 days.
Safety was assessed using NCI CTCAE V5.0.0 compliant adverse events, FACT/gos-Ntx 12 scores, clinical laboratory exam results, electrocardiography (ECG) and vital signs. Relief assessment is based on positron emission tomography-computed tomography (PET-CT) scans at the end of treatment, according to Lugano 2014 criteria.
Stage 2 the ADA and sparse PK characteristics of the combination of the Pololizumab vedotin and R-GemOx were evaluated. In addition, stage 2 assesses biomarkers and patient report outcomes.
C. End of study and duration of study
After the initial security lead-in period, recruitment for the randomization phase was performed within about 11 months.
This is an event driven trial. When the target death event (121 deaths) occurred, the clinical expiration date of the final OS analysis was confirmed, which was expected to be about 25 months after the first patient was randomized in the study RCT stage ([ FPI ].
The duration of the study and the final analysis time depend on the rate of recruitment and the number of events that occur. Death events were monitored throughout the study and study schedules were updated.
Dosage and time of administration of test drug
The test drug (IMP) used in this study was Pola-R-GemOx. The control therapy was R-GemOx.
The Pola-R-GemOx test treatment protocol is summarized in FIG. 3A.
The summary of the R-GemOx control treatment regimen is shown in FIG. 3B.
A. Polotuzumab Vedotin
Pololizumab velutin 1.8mg/kg was administered intravenously on day 1 of each 21-day cycle for 8 cycles only in the experimental treatment group (Pola-R-GemOx).
The poloxamer vedotin is administered after rituximab within the same day, or the next day if the rituximab dose is delayed.
Patient body weight obtained during the screening period (day-28 to day-1) was used for dose determination for all treatment cycles; if the body weight of the patient is greater than or less than 10% of the body weight obtained during the screening period within 96 hours prior to day 1 of a given treatment cycle, the dose is calculated using the new body weight. The body weight triggering the dose adjustment will serve as a new reference body weight for future dose adjustments. All subsequent doses were adjusted accordingly. Dose adjustments of <10% change in body weight are also acceptable if local care standards are met.
The initial dose is administered to a patient who is sufficiently filled with water (according to local guidelines) within 90±10 minutes. The pre-operative drug (e.g., 500-1000mg acetaminophen or paracetamol and 50-100mg diphenhydramine orally, per institutional standard practice) may be administered to the individual patient ≡30 minutes before the start of the administration of the polo-tuzumab vedotin. Whether or not administration of the corticosteroid is permitted is determined by the attending physician as appropriate. If an infusion-related response (IRR) is observed upon first infusion in the absence of a pre-operative drug, the pre-operative drug is administered prior to a subsequent dose.
For patients presenting with infusion-related symptoms, the infusion of the poloxamer vedotin is slowed or discontinued. After the initial dose, the patient was observed for fever, chills, hypotension, nausea or other infusion-related symptoms over 90 minutes. If the prior infusion was well tolerated, a subsequent dose of the poloxamer vedotin was administered within 30.+ -.10 minutes, followed by a 30 minute observation period following infusion.
Vital signs were assessed before the start of infusion, every 15±5 minutes during infusion, at the end of infusion, every 30±10 minutes (for 90 minutes after the completion of cycle 1 administration) and 30±10 minutes after completion of administration in the subsequent cycle during the administration of the pertuzumab vedotin.
Polotuzumab vedotin is a lyophilized formulation (140 mg/vial). Before administration, the lyophilized powder was reconstituted to a volume of 7.2mL with sterile water for injection.
B. rituximab
Intravenous rituximab administration on day 1 of each 21-day cycle375Mg/m 2 for up to 8 cycles. Rituximab is administered within the same day prior to the polozzlizumab vedotin; if the dose of rituximab is delayed, the next day the poloxamer vedotin is administered.
During rituximab administration during cycle 1, vital signs were obtained prior to infusion, and then recorded after the start of infusion, approximately once every 15±5 minutes (for 90 minutes) and once every 30±10 minutes (until 1 hour after the end of infusion). Vital signs were recorded before infusion, after infusion start and about once every 30±10 minutes (up to 1 hour after infusion end) during rituximab administration during the subsequent cycles.
Unless patient body weight was increased or decreased by 10% over screening (in which case BSA was recalculated and used for subsequent dosing), rituximab dose was calculated throughout the study using patient Body Surface Area (BSA) calculated at screening. In obese patients, there is no BSA upper limit, and actual body weight rather than adjusted body weight is recommended. Empirical dosage adjustments for obese patients (obesity is defined as body mass index > 30 measured in kilograms divided by square meters) were performed according to institutional guidelines.
Rituximab administration was completed at least 30 minutes prior to administration of other study treatments. If the patient has a high risk of IRR (high tumor burden, high peripheral lymphocyte count), rituximab is infused in several doses over 2 days. For patients with adverse events during rituximab infusion, rituximab administration may be continued the next day, if desired. If the rituximab dose is administered in 2 days, both infusions are performed at a rate that includes the appropriate pre-operative drug and first infusion.
All rituximab infusions were administered to the patient (unless contraindicated) after preoperative administration of acetaminophen (e.g., 650-1000 mg) and an antihistamine such as diphenhydramine hydrochloride (50-100 mg) for more than 30 minutes before each infusion was started. Additional glucocorticoids (e.g., 100mg IV prednisone or prednisolone, or equivalent) are allowed for use. For patients who have not developed symptoms associated with infusion from a previous infusion, the pre-operative medication for a subsequent infusion may be omitted.
Rituximab is administered by slow intravenous infusion through a dedicated line. The infusion rate of rituximab is controlled using an intravenous infusion pump (such as Braun Infusomat Space). An applicator having polyvinyl chloride (PVC), polyurethane (PUR) or Polyethylene (PE) as a product contacting surface and an iv bag having polyolefin, polypropylene (PP), PVC or PE as a product contacting surface are compatible. No additional in-line filter is used due to potential adsorption. In-line filters used to administer the poluzumab vedotin were not used to administer rituximab.
If the patient withstands the first cycle of study treatment without a significant infusion reaction, rituximab is administered as a bolus infusion according to local institutional guidelines.
The administration of first and subsequent infusions of rituximab is summarized in table 1.
Table 1: administration of rituximab for first and subsequent infusions.
C. Gemcitabine
Gemcitabine 1000mg/m 2 is administered intravenously on day 2 of each 21-day cycle for up to 8 cycles. Gemcitabine is administered within the same day prior to oxaliplatin. If rituximab is administered in two separate days, gemcitabine is administered on day 2 (i.e., the same day on which rituximab administration is completed) or the next day.
If hematological toxicity occurs, the cycle is postponed.
Methods of administering gemcitabine are described in El Gnaoui et al (2007) Ann Oncol, 18:1363-1368. Briefly, gemcitabine 1000mg/m 2 (in 500mL saline) is administered at a fixed dose rate of 10mg/m 2/min. This prolonged administration regimen has been shown to achieve higher intracellular drug concentrations than standard 30 minute intravenous infusion regimens.
D. Oxaliplatin
Oxaliplatin 100mg/m 2 was administered intravenously on day 2 of each 21-day cycle for up to 8 cycles. Oxaliplatin is administered within the same day prior to gemcitabine. If rituximab is administered in two separate days, oxaliplatin is administered on day 2 (i.e., the same day on which rituximab administration is completed) or the next day.
Methods of administering oxaliplatin are described in the local formulation information.
E. Dose adjustment
Dose adjustments or reductions were made as described in table 2. All adverse events were based on laboratory examination results obtained within 72 hours prior to infusion on day 1 of the cycle. Symptom classification was performed according to NCI-CTCAE v 5.0. For supportive treatment, acetaminophen/paracetamol and antihistamines such as diphenhydramine are received if the patient has not been treated with these drugs within the first 4 hours. Can be used for intravenous infusion of physiological saline. When bronchospasm, urticaria, or dyspnea occurs, the patient may need antihistamines, oxygen, corticosteroids (e.g., 100mg IV prednisolone or equivalent); and/or bronchodilators. Hypotensive patients in need of vasopressor support will permanently deactivate the study medication. For an incremental infusion rate after restarting after complete resolution of symptoms, infusion was resumed with 50% of the rate achieved before interruption. In the absence of infusion-related symptoms, the infusion rate was increased in 50 mg/hr increments every 30 minutes.
Table 2: guidelines for managing patients suffering from adverse events.
F. Concomitant therapy
Concomitant therapy consists of any drug (e.g., prescription, over-the-counter, vaccine, herbal or homeopathic, nutritional supplement) used by the patient from 7 days prior to initiation of study treatment to completion/discontinuation of treatment except for the treatment prescribed by the regimen. All such drugs were recorded.
Patients were allowed to use the following therapies during the study: oral contraceptives, hormone replacement therapy and/or other maintenance therapies.
Generally, researchers use supportive therapy to manage patient care according to clinical indications, according to local standard practices. Necessary supportive measures to provide optimal medical care according to institutional standards throughout the study include the use of growth factors (e.g., erythropoietin) in the presence of clinical indications. If clinically indicated, any patient is treated for antiemetic. During the study, it was at the discretion of the investigator whether herbal therapies were used that were not intended to treat cancer.
G. Preoperative medication
Preoperative drug before velostatin of polotophyllizumab
The infusion of the pertuzumab vedotin is followed by the infusion of rituximab. Thus, since preoperative administration is required prior to all rituximab infusions (see below), no additional preoperative administration of the poloxamer vedotin is required.
However, if the administration of the Polollipop is delayed, the Polollipop is administered after the pre-operative administration. The preoperative drug consists of 500-1000mg of acetaminophen or paracetamol and 50-100mg of diphenhydramine (according to institutional standard practice) taken orally more than or equal to 30 minutes before the start of the administration of the Polotuzumab vedotin. Whether or not administration of the corticosteroid is permitted is determined by the attending physician as appropriate.
Prior to rituximab is used for preoperative medicine
All rituximab infusions were administered to the patient after pre-operative administration. The following pre-operative medications are required prior to rituximab treatment:
Oral acetaminophen/paracetamol (650-1000 mg) at > 30 min before all infusions begin.
Antihistamines such as diphenhydramine (25-50 mg) are administered ≡30 minutes before each infusion is started (unless contraindicated).
Preoperative medicine for patients with high-risk tumor lysis syndrome
Patients with high tumor burden and at risk of tumor lysis were also considered by the investigator to receive tumor lysis precautions prior to beginning treatment.
The patient is fully supplemented with water. Starting 1-2 days prior to the first dose of study treatment, it is desirable to maintain a liquid intake of about 3L/day.
Furthermore, oral administration of 300 mg/day allopurinol or administration of a suitable alternative treatment (e.g., labyrine) and water supplementation is started 48-72 hours prior to day 1 of cycle 1 to treat patients with high tumor burden and considered at risk of tumor lysis. If the investigator deems appropriate, the patient will continue to receive repeated prophylaxis and be adequately supplemented with water prior to each subsequent treatment cycle.
Preventing infection
Anti-infection precautions against pneumosporic and herpesvirus infections are formulated according to institutional practices or investigator preferences based on individual patient risk factors. Patients receive prophylactic antiviral drugs to treat hepatitis b reactivation (in countries where such drugs are standard of care) (powers et al, 2013; nccn 2017).
Prevention and treatment of neutropenia
According to local/institutional guidelines, G-CSF is administered as the primary precaution during each treatment cycle. The dosage and form of G-CSF is at the discretion of the investigator. At the discretion of the investigator, additional G-CSF was allowed to be used to treat neutropenia.
Monitoring and treating hepatitis b reactivation
Patients with occult or prior HBV infection (defined as negative for HBsAg and positive for hepatitis B core antibody [ HBcAb ]) were included in the study if HBV DNA could not be detected. HBV DNA levels for these patients were obtained by real-time PCR using an assay with a sensitivity of at least 10IU/mL for at least 12 months on day 1 of each cycle and after the last study treatment cycle.
If the HBV-DNA assay is positive and above the World Health Organization (WHO) threshold of 100IU/mL, study treatment is suspended and the patient is treated with the appropriate nucleoside analogue (at least 1 year after the last rituximab administration) and immediately transferred to gastroenterologists or hepatologists for management. Once HBV DNA levels drop to undetectable levels, the patient's study treatment is resumed.
If HBV DNA detection results are positive and less than or equal to 100IU/mL, the patient is retested within 2 weeks. If the assay remains positive, study treatment is suspended and the patient is treated with the appropriate nucleoside analogue (at least 1 year after the last rituximab administration) and immediately transferred to the gastroenterologist or hepatologist for management. Once HBV DNA levels drop to undetectable levels, the patient's study treatment is resumed.
If the patient has HBV DNA levels exceeding 100IU/mL during treatment with antiviral drugs, the study treatment is permanently discontinued.
In countries where prophylactic antiviral drug therapy is used to treat hepatitis b reactivation as standard of care, patients receive prophylactic treatment.
Warning therapy
Oxaliplatin should be carefully administered to patients with a history of QT prolongation or a predisposition to QT prolongation, to patients taking drugs known to prolong QT intervals, and to patients with electrolyte disorders such as hypokalemia, hypocalcemia or hypomagnesemia. QT interval was closely monitored periodically before and after oxaliplatin administration. ECG recordings are obtained at the indicated time points and with clinical indications. Oxaliplatin treatment is discontinued if QT interval is prolonged.
For patients who are receiving potent CYP3A inhibitors, their adverse effects are closely monitored upon administration of the poloxamer vedotin (Han et al, (2013) J Clin Pharmacol, 53:866-77).
Concomitant drug P-gp inhibitors are considered to be alert, as they may lead to adverse reactions that require close monitoring. If the patient is taking any drug of the P-gp inhibitor class, the researcher will evaluate and record the use of drugs known or suspected to belong to these classes. Adverse effects were closely monitored for patients receiving potent P-gp inhibitors and vc-MMAE ADC (e.g., poloxamer vedotin).
Forbidden therapy
The use of other concomitant anti-tumor medication not defined in this protocol as study treatment, radiation therapy, or any other type of other contemporaneous trial medication results in the patient exiting the study treatment.
The following concomitant therapies are prohibited from being used, as follows:
forbid any trial therapies (outside of the study treatment prescribed in the regimen) within 2 weeks prior to and during the study treatment initiation.
Cytotoxic chemotherapy other than gemcitabine, oxaliplatin and intrathecal chemotherapy for CNS prophylaxis.
Immunotherapy or immunosuppression therapy in addition to study treatment.
Radioimmunotherapy.
Hormone therapy other than contraceptive, stable hormone replacement therapy or megestrol acetate.
Biological agents for the treatment of lymphomas.
O as clinically indicated, allows the use of biological agents such as hematopoietic growth factors as supportive therapies.
Any therapy intended for the treatment of lymphomas (except intrathecal CNS prophylaxis).
Radiotherapy.
Immunization.
Patients enrolled in this study were not given primary or booster vaccinations with live virus vaccine at least 28 days prior to the onset of rituximab treatment, at any time during the study, or until B cells were restored.
Patients in need of any of these agents will discontinue study treatment.
V. study evaluation
A. Patient and disease characterization
Medical history, including clinically significant disease, surgery, history of cancer (including prior cancer therapy, reasons for unsuitable transplantation, 2016WHO classification, current Ann Arbor staging and surgery), ECOG physical status and reproductive status. In addition, all medications (e.g., prescription, over-the-counter, vaccine, herbal or homeopathic, nutritional supplements) used by the patient within 7 days prior to the initiation of study treatment were recorded.
A complete physical examination was performed and any abnormalities found during the baseline period were recorded.
As part of the tumor evaluation, physical examination included evaluating the presence and extent of lymphadenectasis, hepatomegaly, and splenomegaly.
During the study, limited, symptom-oriented physical examinations were performed and limited to the major relevant systems (i.e., cardiovascular system, respiratory system, those related to symptoms, and those related to tumor assessment [ lymph nodes, liver, and spleen ]). Limited physical examination also monitors the symptoms of neuropathy, including hypoesthesia, hyperesthesia, paresthesia, dysesthesia, discomfort, burning, weakness, gait disorder, loss of balance, orthostatic hypotension, syncope or neuropathic pain. Changes from baseline abnormalities were recorded.
Vital signs, weight, height and BSA were recorded. Unless the weight change was >10% since the last BSA assessment (BSA was recalculated in this case), only the height and BSA at the time of screening were required. An ECG recording is obtained.
The test treatment group and the control group were compared. Demographic variables such as age, gender, race/race, and baseline characteristics (particularly stratified variables) were pooled for all patients receiving randomization per treatment group. Continuous variables were summarized using mean, standard deviation, median, range, and quartile range spacing. The classification variables are summarized proportionally.
Descriptive statistics of cumulative study drug dose, dose adjustment/discontinuation, and duration of exposure are provided. The ECG is analyzed descriptive. Changes in vital signs are analyzed using descriptive statistics of continuous variables.
The following evaluations were performed:
International Prognostic Index (IPI): a tool for assessing OS prognosis in NHL patients by a clinician (international non-hodgkin's lymphoma prognostic factor, 1993). The tool is based on measurements of five clinical factors including age, serum and Lactate Dehydrogenase (LDH) levels, ECOG physical status, cancer stage and externally affected sites.
Eastern tumor collaboration group (ECOG) physical stamina: a tool for evaluation by a clinician for describing the level of functionality of a patient in terms of caring for his own abilities, daily activities and physical abilities (walking, working, etc.) (ECOG ACRIN cancer research group, 2018).
The following laboratory checks were performed:
Hematology: white Blood Cell (WBC) count, red Blood Cell (RBC) count, hemoglobin, hematocrit, platelet count, differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes).
Serum or plasma chemistry: sodium, potassium, chloride, bicarbonate (or CO 2), glucose, blood Urea Nitrogen (BUN) or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin and (if any) direct bilirubin, alkaline phosphatase, aspartate Aminotransferase (AST), alanine Aminotransferase (ALT), uric acid and Lactate Dehydrogenase (LDH).
Coagulation: international Normalized Ratio (INR) or Prothrombin Time (PT) and Partial Thromboplastin Time (PTT) or activated partial thromboplastin time (aPTT).
Virology: HIV; hepatitis b surface antibodies (HBsAb), HBsAg and total HBcAb; if patient HBcAb is positive, HBV-DNA is detected by PCR; an HCV antibody; if the patient is positive for HCV antibodies, HCV RNA is detected by PCR.
Laboratory data with values outside the normal range. In addition, the selected laboratory data and changes in vital signs are summarized.
B. Statistical evaluation
The analysis population is defined as follows:
Intent To Treat (ITT) population: all patients receiving randomization were grouped according to their assigned treatment group (whether or not they received the assigned study treatment).
Security lead-in crowd: patients who received any amount of any study drug during the safety infusion phase (phase 1).
Security crowd: patients who received any amount of any study drug during the randomized control trial (phase 2).
PRO ratable population: PRO evaluable population includes all randomized patients assessed after baseline and at least 1 baseline. All PRO analyses were performed based on the treatment group assigned at randomization.
Pharmacokinetic evaluable population: the PK population includes all patients who received at least one dose of study drug and had concentration results after at least one dose.
For all efficacy analyses, patients were grouped according to treatment assigned at randomization. For all safety analyses, patients were grouped according to the actual treatments received.
Unless otherwise indicated, the test is assumed to be a two-sided test. The class I error (α) of this study was 0.05 (double sided).
C. Safety of
Safety was assessed using NCI CTCAE V5.0.0 compliant adverse events, FACT/gos-Ntx 12 scores, clinical laboratory exam results, electrocardiography (ECG) and vital signs.
Safety assessment includes monitoring and recording adverse events, including serious adverse events and adverse events of particular concern, performing safety laboratory assessments, measuring vital signs, and conducting other checks deemed critical to safety assessment of the study. After the study drug was started, all adverse events were reported until 90 days after the last dose of study drug or NALT started.
Safety was assessed by pooling adverse events and studying treatment exposure and presented by treatment group.
The verbatim description of the adverse event is summarized in terms of mapped terms, appropriate synonym dictionary levels, and toxicity levels. For each patient, the reported maximum severity is used in the summary if the same adverse event occurs multiple times.
Adverse events occurring in the following treatments were summarized separately: adverse events leading to withdrawal of study drug, adverse events leading to dose reduction or interruption, grade 3 adverse events, adverse events leading to death, serious adverse events, and adverse events of particular concern. Furthermore, exposure-adjusted assays and recurrent AE assays are provided as appropriate.
All deaths and causes of death were pooled.
Relevant laboratory values are summarized in time and NCI CTCAE V5.0.0 grade 3 and grade 4 values are determined as appropriate. The changes in NCI CTCAE grade are listed by treatment group.
Peripheral neuropathy measured by the FACT/GOG-Ntx12 score and NCI CTCAE V5.0.0 were pooled throughout the study. Furthermore, AE-based peripheral neuropathy incidence was calculated, including all patients who completed cycle 2 or reported such events before.
Patient report outcomes are analyzed by examining and summarizing deterioration times and changes in selected questions of different PRO tools from baseline.
Descriptive statistics of cumulative study drug dose, dose adjustment/discontinuation, and duration of exposure are provided. The ECG is analyzed descriptive. Changes in vital signs are analyzed using descriptive statistics of continuous variables.
Adverse events of particular interest for this study were as follows:
Peripheral neuropathy grade 3 or more.
Potential drug-induced liver injury cases, including ALT or AST elevation combined with bilirubin elevation or clinical jaundice (as defined by the Law of haeis (Hy's Law)). The following are reported as adverse events:
ALT or AST > 3X baseline values present in o treatment combined with total bilirubin > 2X ULN (where > 35% is direct bilirubin).
ALT or AST > 3X baseline values present in o treatment were combined with clinical jaundice.
Tumor lysis syndrome of any grade (regardless of causal relationship).
Progressive multi-range leukoencephalopathy.
Systemic hypersensitivity/anaphylaxis and anaphylactoid reactions defined according to Sampson criteria.
Second malignancy.
Events that are clearly consistent with the expected pattern of underlying disease progression are not recorded as adverse events. Adverse event reports that are not derived from PRO data.
The investigator follows each adverse event until the event subsides to baseline levels or better, the event is assessed by the investigator as stable, patient out of visit, or patient back out of agreement.
After the end of the adverse event reporting period (defined as 90 days after the last administration of study drug or beginning NALT), all deaths (regardless of cause) and severe AEs considered to be associated with prior exposure to study drug are reported.
All patients with AE developing peripheral neuropathy were followed after discontinuation of study treatment, and the possible exacerbations were monitored (Coasting phenomenon) until regressions or stabilization.
Tolerability was determined using dose interruption, dose reduction and dose intensity.
D. Efficacy of
Main efficacy endpoint
The main efficacy objective of the randomized part of this study was to evaluate the efficacy of Pola-R-GemOx compared to R-GemOx in recurrent or refractory DLBCL patients based on the following endpoints:
Total lifetime (OS), defined as the time from random grouping to death for any reason during the study.
Major efficacy analysis was done for ITT population, with patients grouped according to treatment assigned at randomization. Data for non-deceased patients is deleted on the last known patient survival date. Otherwise, the data on the randomized date +1 day is deleted.
The median OS for each treatment group was estimated using the Kaplan-Meier method, and a Kaplan-Meier curve was generated. OS between treatment groups was compared by a hierarchical log rank test. The risk ratio (HR) of death was estimated using a stratified Cox proportional hazards model. The layering factor is the same as the randomized layering factor of IxRS, described above. A 95% Confidence Interval (CI) for HR is provided. 95% CI of the median OS in each treatment group was constructed using Brookmeyer-Crowley method.
The class I error (α) of this study was 0.05 (double sided).
If the patient meets the conditions for HSCT and receives a transplant (for its greatest benefit), a sensitivity analysis will be performed on OS and PFS to assess the effects that the transplant may have. For this purpose, patient data at the time of implantation is deleted.
Secondary efficacy endpoint
The following section analyzes the secondary endpoint of the randomized part of the study (stage 2) in detail. Similar analysis is performed for the security import phase (phase 1), but is limited to descriptive statistics only.
PET-CT and CT scan results were obtained at the following times: screening (e.g., clinical indications during and after treatment); study drug was last administered 28 days later; and once every two months (PET-CT) and once every six months (CT) for a follow-up period of up to two years thereafter.
To control the overall type I error rate to a bilateral 0.05 significance level, a layered test procedure was used to adjust multiple statistical tests for primary and key secondary efficacy endpoints. The key secondary endpoints were tested in the following order:
·PFS。
Complete Remission Rate (CRR) at the end of treatment (based on response including PET-CT data).
Objective Remission Rate (ORR) at the end of treatment (based on response including PET-CT data).
A given hypothesis is rejected only after all previous hypotheses have been rejected at a bilateral 0.05 significance level.
The testing of the other endpoints was not multiplex adjusted and interpreted carefully.
At the end of treatment, lugano 2014 response criteria were used to evaluate remission based on physical examination and PET-CT scan. Tumor assessment was performed during the screening period, mid-treatment period (from day 15 of cycle 4 to day 1 of cycle 5) and at the end of treatment. Initial and at the end of treatment, the evaluation included PET. CT scans were completed every 6 months for 2 years in long follow-up or until the end of the study. All primary imaging data for tumor assessment were acquired.
PET-CT scans include skull base to mid thigh. Whole body PET-CT scans were performed when clinically appropriate. No image enhancement system (e.g., GE HEALTHCARE q.clear or similar system) is used. IV contrast CT scans include thoracic, abdominal and pelvic scans; if clinically indicated, a cervical CT scan is included. CT scans for response assessment are limited to the previously involved areas only when required by local regulatory authorities. If progressive disease is suspected, the investigator decides to repeat CT scans at any time as appropriate. Comprehensive tumor assessments (including radiologic assessments) are performed at any time when disease progression or recurrence is suspected. PET-CT is mandatory during the screening period and end of treatment evaluation.
Bone marrow biopsies were performed on patients negative for PET-CT skeletal signals.
For patients who are contraindicated for use of contrast agents (e.g., patients who are allergic to contrast agents or kidney injury), CT or combined PET-CT scanning without contrast agents is allowed, so long as they are capable of consistent and accurate measurement of the target lesion during study treatment.
Patients who developed PR or CR remission and needed subsequent treatment (e.g., CAR-T therapy or autologous stem cell transplantation) continued to participate in the study and remained evaluable.
Complete remission rate
The Complete Remission Rate (CRR) is defined as the proportion of patients with complete metabolic response (based on responses including PET-CT data) at the end of treatment according to Lugano 2014 remission criteria. Patients that do not meet these criteria (including patients that have not been assessed for any post-baseline tumor) are considered non-responders.
CRR was analyzed using ITT population.
CRR estimates were calculated for each treatment group and their 95% Confidence Intervals (CI) were calculated using the Clopper-Pearson method. CRR differences between treatment groups were calculated and their 95% CI was calculated using a normal approximation of binomial distribution. CRR between treatment groups was compared using a stratified Cochran-Mantel-Haenszel test. The layering factors are the same as described in the analysis for the primary endpoint OS.
The same analysis was repeated for CRR using a response that did not include PET data, thus considering patients with complete remission rather than complete metabolic response.
Objective remission rate
Objective remission is defined as complete or partial metabolic response at the end of treatment according to Lugano 2014 remission criteria. Patients that do not meet these criteria (including patients that have not been assessed for any post-baseline tumor) are considered non-responders.
ORR is defined as the proportion of patients who experience objective relief.
ORR was analyzed using ITT population.
The ORR estimates for each treatment group were calculated and their 95% CI was calculated using the Clopper-Pearson method. ORR differences between treatment groups were calculated and their 95% CI was calculated using a normal approximation of binomial distribution. ORR between treatment groups was compared using a stratified Cochran-Mantel-Haenszel test. The layering factors are the same as described in the analysis for the primary endpoint OS.
The same analysis was repeated for ORR using reactions that did not include PET data, and objective relief (based on reactions that did not include PET data) was then defined as complete or partial relief at the end of treatment (based on reactions that did not include PET data).
Optimal overall mitigation
The Best Overall Relief (BOR) is defined as the best relief (based on responses including PET-CT or CT data) during the study according to Lugano 2014 relief criteria.
BOR was analyzed using ITT population.
The BOR rate estimate was calculated for each treatment group and its 95% CI was calculated using the Clopper-Pearson method.
Progression free survival
Progression Free Survival (PFS) is defined as the time from randomization to first occurrence of disease progression or death of any cause (based on the first occurrence). Patients dying without reported disease progression are considered events at the date of death. Patients who did not progress nor die at the time of analysis (clinical cut-off) and those who were not interviewed were deleted on the last evaluable tumor evaluation date. Patients not receiving post-baseline tumor assessment were deleted at day +1 of randomization. The Kaplan-Meier estimate and associated median, 95% CI of 25 th and 75 th percentiles are provided. The Kaplan-Meier curve intuitively describes the differences between the treatment groups. Using a hierarchical Cox proportional risk analysis (including 95% confidence limits), the estimate of the work effect is expressed as a risk ratio.
Duration of remission
Duration of remission (DOR) was assessed in patients who underwent objective remission using Lugano 2014 remission criteria. DOR is defined as the time interval from the date of the first occurrence of a complete or partial reaction (based on the state of the first record) to the date of the first record of progressive disease or death (based on the first occurrence). Patients that did not progress and died at the time of analysis were deleted at the date of the last tumor evaluation. If no tumor assessment is made after the date of the first complete or partial reaction, DOR is deleted by 1 day of the date of the first complete or partial reaction. DOR is based on a non-randomized subset of patients (specifically, patients achieving objective remission), so comparisons between treatment groups are for descriptive purposes only. DOR analysis was performed using the method detailed for PFS analysis, except that the analysis was not stratified.
Event-free survival time
Event free survival (EFS eff) is defined as the time from randomization to earliest occurrence of:
Disease progression or recurrence.
Death for any reason.
Start any NALT.
Patients not having EFS eff events were deleted at the time of the last evaluable tumor assessment. Patients not receiving post-baseline tumor assessment were deleted at randomization. EFSeff assays were performed using the methods detailed for PFS assays.
E. patient reporting outcome
Patient Reporting Outcome (PRO) tools are completed to assess therapeutic benefit and more fully characterize the safety profile of the polotophyllizumab vedotin. Furthermore, the PRO tool is able to capture the direct experience of each patient on the polotoxin vedotin.
Unless otherwise indicated, PRO evaluable populations were used for descriptive analysis of visit summaries and changes from baseline, responder analysis, and mixed effect model repeat measurement (MMRM) modeling. The ITT population was used for completion analysis and deterioration time analysis.
PRO data was collected by using the following tools: FACT/GOG-Ntx12, EQ-5D-5L, EORTC QLQ-C30, and FACT/Lym.
FACT/GOG-Ntx12
FACT/GOG-Ntx12 is a tool containing 12 patients reporting outcomes, which is aimed at measuring chemotherapy-induced peripheral neuropathy (Kopec et al, (2006) J Supportive Oncol, 4:W1-W8). The FACT/gos-Ntx scores were reported throughout the trial period, including during phase 1 (safe lead-in period) and phase 2 (RCT). Descriptive statistics at each visit, as well as changes from baseline, will be reported per treatment group for each FACT/gos-Ntx-12 questionnaire scale. For missing items in the questionnaire, a proportionally assigned score is calculated according to the developer's guidelines (Calhoun et al, (2003) Int J Gynecol Cancer, 13:741-748). PRO completion rates at each time point were summarized per treatment group. For the neurotoxicity sub-scale, descriptive statistics at each visit and changes from baseline are reported for the safety lead-in population.
EQ-5D-5L
EuroQol 5-dimensional questionnaires [ level 5 version (EQ-5D-5L ]) ] are validated self-reporting Health questionnaires that calculate Health utility scores using 5 dimensions (EuroQol (1990) Health Policy,16:199-208; brooks (1996) Health Policy,37:53-72; herdman et al, (2011) 20:1727-1736; janssen et al, (2013) real Life Res, 22:1717-1727). All five dimensions can be combined into one five digit number that describes the patient's health. The descriptive figures are converted to a single summary exponential utility score using published weights. In this study, a set of British Crosswalk values (published by EuroQol research foundation at http:// www (dot) euroqol (dot) org/about-eq-5d/valuation-of-eq-5d; devlin et al, (2017) Health Economics, 1-16) was used. In addition, in the second part of the questionnaire, the current health status is measured by a Visual Analog Scale (VAS), ranging in value from 0 to 100.
For each EQ-5D-5L evaluation over time, the number and percentage of patients in each of the five categories for each question was evaluated. Summary of EQ-5D-5L exponential utility scores at each visit and related changes from baseline are provided per treatment group. A similar analysis was performed on the EuroQoL visual analog scale (EQ-VAS).
The exponential utility score and VAS are analyzed using a hybrid linear model. In addition, the ratio of patients with variations in EQ-5D-5L index and EQ-VAS score exceeding clinically significant thresholds is reported. Clinically significant improvement thresholds are defined as the change in exponential utility score +0.07 points and VAS score +7 points.
EORTC QLQ-C30
EORTC QLQ-C30 is a validated, reliable self-reporting measurement tool (Aaronson et al, (1993) J NATL CANCER INST,85:365-376; fitzsimons et al, (1999) 35:939-941). It consists of 30 questions that evaluate five aspects of patient functioning (physical, emotional, role, cognitive and social), three symptoms scales (fatigue, nausea and vomiting, pain), overall health/quality of life and six individual items (dyspnea, insomnia, loss of appetite, constipation, diarrhea and economic difficulties), with a recall period of the previous week.
For the EORTC QLQ-C30 questionnaire, the summary statistics and changes in linear conversion score from baseline at each visit for all projects and sub-scales are reported.
The exacerbation time is defined as the time from randomization to first recording to 10 minutes of a decrease in the EORTC QLQ-C30 body function scale from baseline. For fatigue, the deterioration time is defined as the time from randomization to a 10 minute increase in the first record from baseline. Patients who did not observe deterioration at the expiration of clinical data were deleted on the last missed evaluation date (if post-baseline evaluation) or on the randomization date +1 day (if post-baseline evaluation). The risk ratio of the deterioration time is estimated using a hierarchical Cox proportional hazards model. Providing a 95% CI of risk ratio. The median exacerbation time was estimated for each treatment group using the Kaplan-Meier method, and a Kaplan-Meier curve was generated.
EORTC QLQ-C30 data were scored according to the EORTC scoring manual (Fayers et al, (2001) European Organisation for RESEARCH AND TREATMENT of Cancer, brush, et al). Missing data was evaluated and reported at time points. If the data is incomplete, scores are calculated proportionally for all questionnaire sub-scales, according to the scoring manual and published validation report, with more than 50% of the constituent items completed. For a sub-table of less than 50% of completed items, the sub-table is considered missing. The completion rates are summarized in terms of the number and proportion of patients expected to complete EORTC QLQ-C30 at each time point.
FACT-Lym
FACT-Lym is a validated health-related quality of life (HRQoL) tool, specifically for lymphoma patients. It consists of the FACT general questionnaire (FACT-G) and the lymphoma specific score scale (FACT-Lym LYMS; range 0-60) (Cella et al, (1993) J Clin Oncol,11:570-579; cell a et al, (2005) Blood, 106:750). Three summary scales were calculated, namely the FACT-Lym test result index, FACT-G and FACT-Lym total score. The higher the score, the more excellent the HRQoL is reflected.
Descriptive statistics at each visit, as well as changes from baseline, will be reported per treatment group for each FACT-Lym questionnaire scale.
Clinically significant minimum differences in individual sub-scales and FACT-Lym TOT levels (i.e., minimum amounts of change deemed significant to the patient) are pre-specified and are used to define patient proportions reporting significant changes in the FACT-Lym LYMS (. Gtoreq.3 points), FACT-Lym TOI (. Gtoreq.6 points) and FACT-Lym TOT (. Gtoreq.7 points) scales as treatment outcomes (Carter et al, (2008) Blood, 112:2376).
The exacerbation time is defined as the time from randomization to first recording to >3 minutes from baseline decline (Carter et al, (2008) Blood,112:2376; hlubacky et al, (2013) Lymphoma, ID 147176). Patients who did not observe deterioration at the expiration of clinical data were deleted on the last missed evaluation date (if post-baseline evaluation) or on the randomization date +1 day (if post-baseline evaluation). The risk ratio of the deterioration time is estimated using a hierarchical Cox proportional hazards model. Providing a 95% CI of risk ratio. The median exacerbation time was estimated for each treatment group using the Kaplan-Meier method, and a Kaplan-Meier curve was generated. Supplemental term level analysis was performed on each B symptom term of FACT-Lym LYMS using the original 1 point exacerbation. For missing items in the questionnaire, a proportionally assigned score was calculated according to the developer's guidelines (Webster et al, (2003) Health Qual Life Outcomes, 1:79). PRO completion rates at each time point were summarized per treatment group.
F. Pharmacokinetic analysis
PK analysis of the blood samples was performed on the poloxamer vedotin at stage 1 and stage 2. Using validated methods, serum total antibody to velostat bead antibody (including all drug to antibody ratio [ DAR ] material, including DAR 0 and DAR. Gtoreq.1), plasma polostat bead-velostat conjugate (evaluated as acMMAE), and plasma unconjugated MMAE concentrations were quantified. Other potential catabolites in the sample were also analyzed.
Individual and average serum and plasma concentrations of polotophyllizumab, vedotin, gemcitabine and oxaliplatin are tabulated and plotted against time data. A summary statistic of the concentration data is calculated for each sample of each analyte. PK parameters, maximum concentration (C max) and trough concentration (C trough) were estimated (when the collected data is applicable). The estimates of these parameters are tabulated and summarized (mean and SD). PK parameters are determined based on the available data using appropriate techniques. The crowd PK analysis method was applied to PK parameter estimation. Potential drug interactions were assessed by comparing PK in the current study with historical data. Potential correlations between PK variability and demographic and pathophysiological covariates were explored using crowd PK analysis. Potential correlations between PK variability and pharmacodynamics, efficacy and safety outcomes were explored using exploratory graphical analysis and PK-pharmacodynamics models.
G. Immunogenicity analysis
In stages 1 and 2, validated antibody bridging ELISA was used to screen and confirm the presence or absence of anti-polotophyllizumab vedotin antibodies in patient serum samples, and to characterize and determine the titer of confirmed ADA positive samples.
The immunogenicity analysis population consisted of all patients who received at least one dose of polotouzumab vedotin and had at least one assessed post-baseline ADA sample. Patients were grouped according to treatment received, or if treatment was not received before the study was completed, according to treatment assigned.
The number and proportion of ADA positive and ADA negative patients at baseline (baseline incidence) and post-baseline (post-baseline incidence) were pooled by treatment group. In determining post-baseline incidence, if the patient is ADA negative or baseline data is absent, but ADA detection results are positive after study drug exposure (treatment-induced ADA response); or if they are ADA positive at baseline and the titer of one or more post-baseline samples is at least 0.60 titer units higher than the titer of the baseline sample (treatment-enhanced ADA response), then the patient is considered ADA positive. Patients are considered ADA negative if they are ADA negative or baseline data is missing and all post-baseline samples are negative, or if they are ADA positive at baseline without any post-baseline samples having a titer at least 0.60 titer units higher than the titer of the baseline sample (treatment is not affected).
The relationship between ADA status and safety, efficacy, PK and biomarker endpoints was analyzed and reported using standard language and/or terminology.
H. Biomarker analysis
At stage 2, biomarker detection assays were performed on tumor tissue and plasma samples.
Simple non-invasive plasma collection enables assessment of circulating tumor DNA (ctDNA), which is thought to be an apoptotic residue from tumor cells. ctDNA was quantified and its genomic mutation was assessed. In addition to correlating this information at baseline with clinical efficacy for prognosis and therapeutic efficacy outcome assessment, this information also allows monitoring residual disease at the molecular level and tracking clonal evolution.
Biomarkers associated with tumor biology and the mechanism of action of the poisotozumab vedotin and rituximab were analyzed.
The analysis evaluates the prognosis and/or predictive value of the candidate biomarker. The association between candidate biomarkers and OS, PFS and PET-CT CR rates, as well as other efficacy and safety metrics, and treatment independent, was explored to assess potential predictive and prognostic value, respectively. The effect of baseline prognostic signatures, including DLBCL subtype (i.e., COO) and the effect of mutation signatures on efficacy, was evaluated using univariate and/or multivariate statistical methods.
To date, the most mature subset of DLBCL biomarkers is a molecularly defined signature consistent with the stage of formation or cell origin (COO) of B cell-derived tumors, namely activated B cell-like (ABC) signature, germinal center B cell-like (GCB) or unclassified signature, BCL2/MYC dual expression signature (characterized by elevated MYC and BCL2 expression), and BCL2/MYC dual hit signature (translocation occurs in both BCL2 and MYC). In the recently revised WHO classification, a new subset of molecules was defined, namely, high-grade B-cell lymphomas (HGBL DH/TH) containing MYC and BCL2 and/or BCL6 rearrangements (Swerdlow et al, (2016) Blood, 127:2375-2390). More recently, molecular subtypes have been identified that surpass the above-mentioned classes, with different genotypes, epigenetic and clinical characteristics. Examples include the four genetic subtypes described by Schmitz et al, (2018) N Engl J Med,378:1396-1407, and the five DLBCL subtypes described by Chapuy et al, (2018) Nat Med, 24:679-690.
Biomarkers used in this study include, but are not limited to, any of the biomarkers discussed above, targets of polotobulizumab velocin (CD 79 b), tumor mutation analysis by New Generation Sequencing (NGS), and established DLBCL prognostic biomarkers (cell source, BCL2/MYC double expression, and BCL2/MYC double translocation). An exemplary exploratory biomarker summary is shown in table 3.
Table 3: biomarkers of retrospective exploratory study (stage 2).
CtDNA = circulating tumor DNA; IHC = immunohistochemistry; NGS = new generation sequencing.
I. Subgroup analysis
To assess the consistency of treatment-benefit study results in subgroups defined by demographics and related baseline characteristics, the OS and PFS in these subgroups were evaluated.
The uniformity of therapeutic benefit was assessed using a stratified Cox proportional hazards model, and a risk ratio of 95% ci was estimated. And summarizing the result by using the forest map.
J. mid-term safety analysis
Several interim analyses are performed on the security data, including checking the FACT/gos-Ntx 12. During the security import period (stage 1), the security data is analyzed at least 3 times. Safety data were analyzed after the first 10 and 20 patients in each treatment group received randomization during the RCT phase; the frequency of subsequent metaphase analysis of the RCT stage depends on the number of grade 3 peripheral neuropathy or more at the time of the 2 nd metaphase analysis. These metaphase safety analyses evaluate all enrolled patients until they completed the study treatment (as deemed necessary).
In summary, the present invention includes, but is not limited to, the following:
1. A method of treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of:
(e) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26, and
Wherein p is between 1 and 8,
(F) Rituximab is administered in the form of a solid,
(G) Gemcitabine, and
(H) Oxaliplatin.
2. The method of item 1, wherein the anti-CD 79b antibody comprises: (i) A heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID No. 19; and (ii) a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO. 20.
3. The method of item 1 or item 2, wherein the anti-CD 79b antibody comprises: (i) a heavy chain comprising the amino acid sequence of SEQ ID NO. 36; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO. 35.
4. The method of any one of items 1 to 3, wherein p is between 2 and 5.
5. The method of any one of items 1 to 4, wherein p is between 3 and 4.
6. The method of any one of claims 1 to 5, wherein the immunoconjugate is a polotouzumab vedotin-piiq.
7. The method of any one of items 1-2 or items 4-5, wherein the anti-CD 79b antibody comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO. 37; and a light chain comprising the amino acid sequence of SEQ ID NO. 35.
8. The method of any one of items 1-2 or items 4-5, wherein the anti-CD 79b antibody comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO. 36; and a light chain comprising the amino acid sequence of SEQ ID NO. 38.
9. The method of any one of clauses 1-2, clauses 4 or 7, wherein the immunoconjugate is Iladatuzumab vedotin.
10. The method of any one of claims 1-9, wherein the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2.
11. The method of any one of claims 1-10, wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for one or more 21-day periods.
12. The method of item 11, wherein the immunoconjugate is administered at a dose of about 1.8mg/kg per cycle, the rituximab is administered at a dose of about 375mg/m 2 per cycle, the gemcitabine is administered at a dose of about 1000mg/m 2 per cycle, and the oxaliplatin is administered at a dose of about 100mg/m 2 per cycle.
13. The method of item 11 or item 12, wherein the immunoconjugate and the rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein the gemcitabine and the oxaliplatin are administered intravenously on day 2 of each 21-day cycle.
14. The method of any one of claims 1 to 13, wherein the rituximab is administered prior to the immunoconjugate.
15. The method of any one of claims 1-14, wherein the gemcitabine is administered prior to the oxaliplatin.
16. The method of any one of claims 11-15, wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for up to eight 21-day cycles.
17. The method of any one of claims 11-16, wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for eight 21-day periods.
18. A method of treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of: (e) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) a heavy chain comprising the amino acid sequence of SEQ ID NO. 36; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO. 35,
And wherein p is between 2 and 5,
(F) Rituximab is administered in the form of a solid,
(G) Gemcitabine, and
(H) Oxaliplatin;
Wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2; and
Wherein the immunoconjugate and the rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein the gemcitabine and the oxaliplatin are administered intravenously on day 2 of each 21-day cycle.
19. The method of claim 18, wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for at least two, at least three, at least four, at least five, at least six, or at least seven 21-day cycles.
20. The method of item 18, wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for eight 21-day periods.
21. The method of any one of claims 18 to 20, wherein the rituximab is administered prior to the immunoconjugate.
22. The method of any one of claims 18-21, wherein the gemcitabine is administered prior to the oxaliplatin. K: KR PI PI09536A \01 New application submission
23. The method of any one of claims 18 to 22, wherein the immunoconjugate is a polotouzumab vedotin-piiq.
24. The method of any one of claims 1 to 23, wherein the human has received at least one prior therapy for DLBCL.
25. The method of any one of claims 1 to 24, wherein the human has received at least one prior systemic therapy for DLBCL.
26. The method of any one of claims 1 to 25, wherein the DLBCL is a histologically confirmed DLBCL, or the human has a history of inert disease conversion to DLBCL, unless otherwise indicated (NOS).
27. The method of any one of claims 1 to 26, wherein the DLBCL is recurrent or refractory DLBCL.
28. The method of any one of claims 1 to 27, wherein the human eastern tumor co-operative group (ECOG) physical status score is 0, 1 or 2.
29. The method of any one of claims 1 to 28, wherein the human is an unintended autologous or allogeneic Stem Cell Transplant (SCT).
30. The method of any one of claims 1-29, wherein the human is not a candidate for Hematopoietic Stem Cell Transplantation (HSCT) prior to administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
31. The method of any one of claims 1-30, wherein the human is not a candidate for autologous Hematopoietic Stem Cell Transplantation (HSCT) prior to administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
32. The method of any one of claims 1 to 31, wherein the human has received at least two prior therapies for DLBCL.
33. The method of any one of claims 1-32, wherein the human has not received prior therapy with a combination of gemcitabine and a platinum-based agent.
34. The method of any one of claims 1 to 33, wherein the human has not received prior therapy with poloxamer-velocin-piiq for DLBCL.
35. The method of any one of clauses 1 to 34, wherein the human does not have a peripheral neuropathy higher than grade 1 according to the U.S. national cancer institute adverse event common terminology standard version 5.0.
36. The method of any one of claims 1-35, wherein the human does not have primary or secondary central nervous system lymphoma.
37. The method of any one of claims 1 to 36, wherein the human adult is.
38. The method of claim 37, wherein the adult suffers from recurrent or refractory diffuse large B-cell lymphoma unless otherwise indicated.
39. The method of any one of claims 1-38, wherein administration of the immunoconjugate, rituximab, gemcitabine, and oxaliplatin does not result in grade 3 or higher peripheral neuropathy that does not regress to grade 1 or lower within 14 days.
40. The method of any one of claims 1-38, wherein administering the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of people results in 33% or less of the plurality of people experiencing grade 3 or higher peripheral neuropathy that does not regress to grade 1 or lower for 14 days.
41. A method of treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of:
(e) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26,
And wherein p is between 1 and 8,
(F) Rituximab is administered in the form of a solid,
(G) Gemcitabine, and
(H) Oxaliplatin;
wherein administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin does not result in no regression to grade 3 or higher peripheral neuropathy of grade 1 or lower within 14 days.
42. A method of treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of:
(e) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26, and
Wherein p is between 1 and 8,
(F) Rituximab is administered in the form of a solid,
(G) Gemcitabine, and
(H) Oxaliplatin;
wherein administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of people results in 33% or less of the plurality of people experiencing no regression to grade 3 or higher peripheral neuropathy of grade 1 or lower within 14 days.
43. A method of treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of:
(e) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) a heavy chain comprising the amino acid sequence of SEQ ID NO. 36; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO. 35,
And wherein p is between 2 and 5,
(F) Rituximab is administered in the form of a solid,
(G) Gemcitabine, and
(H) Oxaliplatin;
Wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2;
Wherein the immunoconjugate and the rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein the gemcitabine and the oxaliplatin are administered intravenously on day 2 of each 21-day cycle; and
Wherein administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin does not result in no regression to grade 3 or higher peripheral neuropathy of grade 1 or lower within 14 days.
44. A method of treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of:
(e) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) a heavy chain comprising the amino acid sequence of SEQ ID NO. 36; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO. 35,
And wherein p is between 2 and 5,
(F) Rituximab is administered in the form of a solid,
(G) Gemcitabine, and
(H) Oxaliplatin;
Wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for at least one 21-day period, wherein in each period the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2;
Wherein the immunoconjugate and the rituximab are administered intravenously on day 1 of each 21-day cycle, and wherein the gemcitabine and the oxaliplatin are administered intravenously on day 2 of each 21-day cycle; and
Wherein administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of people results in 33% or less of the plurality of people experiencing no regression to grade 3 or higher peripheral neuropathy of grade 1 or lower within 14 days.
45. The method of any one of claims 41-44, wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for at least two, at least three, at least four, at least five, at least six, or at least seven 21-day cycles.
46. The method of any one of claims 41-44, wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for eight 21-day periods.
47. The method of any one of claims 41-46, wherein the rituximab is administered prior to the immunoconjugate.
48. The method of any one of claims 41-47, wherein the gemcitabine is administered prior to the oxaliplatin.
49. The method of any one of claims 41-48, wherein the immunoconjugate is a poloxamer vedotin-piiq.
50. The method of any one of items 41-42 or items 45-48, wherein the anti-CD 79b antibody comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO. 37; and a light chain comprising the amino acid sequence of SEQ ID NO. 35.
51. The method of any one of items 41-42 or items 45-48, wherein the anti-CD 79b antibody comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO. 36; and a light chain comprising the amino acid sequence of SEQ ID NO. 38.
52. The method of any one of items 41-42, items 45-48, or item 50, wherein the immunoconjugate is Iladatuzumab vedotin.
53. The method of any one of claims 39-52, wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin have been administered for at least four 21-day cycles.
54. A kit comprising an immunoconjugate, the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26, and
Wherein p is between 1 and 8,
For use in combination with rituximab, gemcitabine, and oxaliplatin in the method according to any one of claims 1 to 53 to treat a human suffering from Diffuse Large B Cell Lymphoma (DLBCL) in need thereof.
55. A kit comprising potentizumab vedotin-piiq for use in combination with rituximab, gemcitabine and oxaliplatin according to the method of any one of items 1 to 53 to treat a human having Diffuse Large B Cell Lymphoma (DLBCL) in need thereof.
56. An immunoconjugate comprising an amino acid sequence, the immunoconjugate comprises the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO. 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26, and
Wherein p is between 1 and 8,
For use in a method of treating Diffuse Large B Cell Lymphoma (DLBCL) according to any one of items 1 to 53 in combination with rituximab, gemcitabine and oxaliplatin.
57. A method for treating recurrent or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human in need thereof, the method comprising administering to the human a dose of 1.8mg/kg of pertuzumab vedotin-piiq, a dose of 375mg/m 2 rituximab, a dose of 1000mg/m 2 of gemcitabine, and a dose of 100mg/m 2 of oxaliplatin.
58. A method for treating recurrent or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human in need thereof, the method comprising administering to the human a dose of 1.8mg/kg of pertuzumab vedotin-piiq, a dose of 375mg/m 2 of rituximab, a dose of 1000mg/m 2 of gemcitabine, and a dose of 100mg/m 2 of oxaliplatin, wherein the pertuzumab vedotin-piiq, the rituximab, the gemcitabine, and the oxaliplatin are administered for at least one 21 day cycle, wherein the pertuzumab vedotin-piiq and the rituximab are administered intravenously on day 1 of each 21 day cycle, and wherein the gemcitabine and the oxaliplatin are administered intravenously on day 2 of each 21 day cycle.
59. A method for treating recurrent or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human in need thereof, the method comprising administering to the human a dose of Iladatuzumab vedotin mg/kg, rituximab at a dose of 375mg/m 2, gemcitabine at a dose of 1000mg/m 2, and oxaliplatin at a dose of 100mg/m 2.
60. A method for treating recurrent or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human in need thereof, the method comprising administering to the human a dose of Iladatuzumab vedotin mg/kg, rituximab at a dose of 375mg/m 2, gemcitabine at a dose of 1000mg/m 2, and oxaliplatin at a dose of 100mg/m 2.
61. A method for treating recurrent or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human in need thereof, the method comprising administering to the human a dose of Iladatuzumab vedotin mg/kg, a dose of 375mg/m 2 rituximab, a dose of 1000mg/m 2 of gemcitabine, and a dose of 100mg/m 2 of oxaliplatin, wherein the Iladatuzumab vedotin, the rituximab, the gemcitabine, and the oxaliplatin are administered for at least one 21-day period, wherein the Iladatuzumab vedotin and the rituximab are administered intravenously on day 1 of each 21-day period, and wherein the gemcitabine and the oxaliplatin are administered intravenously on day 2 of each 21-day period.
62. A method for treating recurrent or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human in need thereof, the method comprising administering to the human Iladatuzumab vedotin at a dose of 3.6mg/kg, rituximab at a dose of 375mg/m 2, gemcitabine at a dose of 1000mg/m 2, and oxaliplatin at a dose of 100mg/m 2, wherein the Iladatuzumab vedotin, the rituximab, the gemcitabine, and the oxaliplatin are administered for at least one 21-day period, wherein the Iladatuzumab vedotin and the rituximab are administered intravenously on day 1 of each 21-day period, and wherein the gemcitabine and the oxaliplatin are administered intravenously on day 2 of each 21-day period.

Claims (10)

1. A method of treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of:
(a) An immunoconjugate comprising the formula
Wherein Ab is an anti-CD 79b antibody comprising: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO. 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO. 22; (iii) HVR-H3 comprising SEQ ID NO:
23, an amino acid sequence of seq id no; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO. 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO. 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO. 26, and
Wherein p is between 1 and 8,
(B) Rituximab is administered in the form of a solid,
(C) Gemcitabine, and
(D) Oxaliplatin.
2. The method of claim 1, wherein the anti-CD 79b antibody comprises: (i) A heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID No. 19; and (ii) a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO. 20.
3. The method of claim 1 or claim 2, wherein the anti-CD 79b antibody comprises: (i) a heavy chain comprising the amino acid sequence of SEQ ID NO. 36; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO. 35.
4. A method according to any one of claims 1 to 3, wherein p is between 2 and 5.
5. The method of any one of claims 1 to 4, wherein p is between 3 and 4.
6. The method of any one of claims 1 to 5, wherein the immunoconjugate is a polotouzumab vedotin-piiq.
7. The method of any one of claims 1-2 or claims 4-5, wherein the anti-CD 79b antibody comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO. 37; and a light chain comprising the amino acid sequence of SEQ ID NO. 35.
8. The method of any one of claims 1-2 or claims 4-5, wherein the anti-CD 79b antibody comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO. 36; and a light chain comprising the amino acid sequence of SEQ ID NO. 38.
9. The method of any one of claims 1-2, 4 or 7, wherein the immunoconjugate is Iladatuzumab vedotin.
10. The method of any one of claims 1-9, wherein the immunoconjugate is administered at a dose of about 1.8mg/kg, the rituximab is administered at a dose of about 375mg/m 2, the gemcitabine is administered at a dose of about 1000mg/m 2, and the oxaliplatin is administered at a dose of about 100mg/m 2.
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