CN120303298A

CN120303298A - Treatment approaches using B cell maturation antigen antagonists

Info

Publication number: CN120303298A
Application number: CN202380083316.9A
Authority: CN
Inventors: H·斯特鲁珀; B·克雷默; C·谢尔顿; A·托索利尼; I·V·古普塔
Original assignee: GlaxoSmithKline Intellectual Property Development Ltd
Current assignee: GlaxoSmithKline Intellectual Property Development Ltd
Priority date: 2022-12-05
Filing date: 2023-12-04
Publication date: 2025-07-11
Also published as: JP2025540200A; EP4630454A1; WO2024121711A1

Abstract

The present disclosure provides methods of treating diseases or disorders responsive to inhibition or blockade of B cell maturation antigen (BCMA) by administering one or more BCMA antagonists.

Description

Methods of treatment using B cell maturation antigen antagonists

Cross Reference to Related Applications

The present application claims priority from U.S. provisional application No. 63/430,249 filed on month 5 of 2022, 12, which is incorporated herein by reference in its entirety.

Technical Field

The present disclosure relates generally to methods of treating diseases or disorders responsive to inhibiting or blocking B Cell Maturation Antigen (BCMA) by administering one or more BCMA antagonists.

Background

B Cell Maturation Antigen (BCMA) is a cell surface receptor that is expressed in the plasmablast lineage and is upregulated on a variety of disease cell types including Multiple Myeloma (MM) cells. MM is an incurable malignant clonal plasma cell disorder and accounts for 1% of all cancers and 10% of all hematological malignancies worldwide. Patients with Newly Diagnosed Multiple Myeloma (NDMM) have a variety of treatment options available. Although nearly 100% of patients respond to first line treatment, the disease eventually recurs and the patient will need further treatment. For this malignancy, the duration and response rate of the response decreases dramatically with each subsequent line of treatment. Most patients with MM eventually become resistant to existing therapies and die from relapse.

Mar Bei Tuoshan anti (Belantamab mafodotin) is an antibody-drug conjugate (ADC) directed to BCMA conjugated to the microtubule disrupting agent monomethyl auristatin-F (MMAF) and has been demonstrated to have antitumor activity in MM cells. The mar Bei Tuoshan antibody is produced in afucosylated (afucosylated) form, which enhances interaction with fcyriiia receptor. This enhanced interaction increases the cytotoxicity (ADCC) and phagocytosis (ADCP) activity of antibody-dependent cells, including activity against MM cells. Thus, MA Bei Tuo mab has dual anti-tumor activity by delivery of MMAF cytotoxins as well as by ADCC/ADCP. Mar Bei Tuoshan antibodies and other MMAF-containing ADCs have been reported to have ocular toxicity, resulting in delay of dosing and dose reduction. Thus, there is a need for additional therapies with manageable toxicity for the treatment of MM and other diseases associated with aberrant BCMA expression.

Disclosure of Invention

In one aspect, the present disclosure provides a method of treating a disease or disorder responsive to inhibiting or blocking B Cell Maturation Antigen (BCMA) in a patient comprising administering Bei Lantuo mab (belantamab) to the patient at a dose of about 300 mg to about 2000 mg.

In one aspect, the present disclosure provides use of Bei Lantuo mab in the treatment of a disease or disorder responsive to inhibiting or blocking B Cell Maturation Antigen (BCMA) by administering Bei Lantuo mab at a dose of about 300 mg to about 2000 mg.

In one aspect, the present disclosure provides the use of Bei Lantuo mab in the manufacture of a medicament for treating a disease or disorder responsive to inhibiting or blocking B Cell Maturation Antigen (BCMA) by administering Bei Lantuo mab at a dose of about 300mg to about 2000 mg.

In embodiments, the dose is about 300 mg, about 900 mg, or about 2000 mg. In embodiments, the dose is administered at regular intervals for a period of time. In embodiments, the dose is administered once a week ± 3 days to once every four weeks ± 3 days. In embodiments, the dose is administered every two weeks ± 3 days. In embodiments, the dose is administered every three weeks ± 3 days. In embodiments, the dose is administered once every four weeks ± 3 days. In embodiments, the dose is administered on days 1 and 15 of a 28 day cycle. In embodiments, the dose is administered on day 1 of the 21 day cycle.

In embodiments, the patient has been treated with at least one previous line of cancer treatment. In embodiments, the patient has been treated with one, two, three, or four previous lines of cancer treatment. In embodiments, the previous line of cancer treatment includes anti-CD 38 monoclonal antibodies, proteasome inhibitors, and immunomodulators.

In embodiments, bei Lantuo mab is administered by intravenous infusion or subcutaneous injection.

In embodiments, the patient further receives at least one additional cancer treatment, such as an anti-CD 38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody. In embodiments, the additional cancer treatment is selected from lenalidomide, dexamethasone, darimumab, ai Shatuo ximab (isatuximab), pomalidomide, bortezomib, or a combination thereof, e.g., lenalidomide and dexamethasone. In embodiments, the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg, once daily, for a period of time. In embodiments, the patient receives lenalidomide on days 1-21 of a 28 day cycle. In embodiments, the additional cancer treatment is dexamethasone. In embodiments, the additional cancer treatment is dexamethasone at a dose of 20 mg to 40 mg, once a week. In embodiments, the patient receives dexamethasone on days 1, 8, 15, and 22 of the 28 day cycle. In embodiments, (i) the patient is less than 75 years old and is receiving dexamethasone at a dose of 40 mg a week, or (ii) the patient is at least 75 years old and is receiving dexamethasone at a dose of 20 a mg a week. In embodiments, (i) the patient has a BMI of at least 18.5 and is receiving dexamethasone at a dose of 40 mg a week, or (ii) the patient has a BMI of less than 18.5 and is receiving dexamethasone at a dose of 20 mg a week.

In embodiments, the method or use further comprises stopping administration of Bei Lantuo mab followed by administration of the mar Bei Tuoshan antibody. In embodiments, the method or use further comprises administering the mar Bei Tuo mab followed by discontinuing administration of the Bei Lantuo mab. In embodiments, the mar Bei Tuoshan antibody is administered at a dose of 2.5 mg/kg once every three weeks ± 3 days.

In embodiments, the method or use further comprises administering an introduced dose of MA Bei Tuo mab prior to beginning administration of Bei Lantuo mab, wherein the introduced dose of MA Bei Tuo mab is about 1.4 mg/kg to about 3.4 mg/kg once during the introduction period. In embodiments, the dose of MA Bei Tuo mab introduced is about 1.4 mg/kg to about 1.9 mg/kg, once during the introduction period. In embodiments, the introduced dose of MA Bei Tuo mab is about 1.4 mg/kg, about 1.9 mg/kg, about 2.5 mg/kg, or about 3.4 mg/kg, once during the introduction period. In embodiments, the introduced dose of MA Bei Tuo mab is about 1.4 mg/kg, once during the introduction period. In embodiments, the induction period is four weeks ± 3 days, and the mar Bei Tuoshan antibody is administered on day 1 of the induction period.

In embodiments, the method or use further comprises administering at least one additional cancer treatment, such as an anti-CD 38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody, to the patient during the lead-in period. In embodiments, the additional cancer treatment is selected from lenalidomide, dexamethasone, darimumab, ai Shatuo ximab, pomalidomide, bortezomib, or a combination thereof, e.g., lenalidomide and dexamethasone. In embodiments, the additional cancer treatment is lenalidomide, at a dose of 10 mg to 25mg, once daily for a period of time. In embodiments, lenalidomide is administered to the patient on days 1-21 of the lead-in period. In embodiments, lenalidomide is administered to the patient on days 1-21 of the lead-in period, and the lead-in period is 4 weeks ± 3 days. In embodiments, lenalidomide is administered to the patient on days 1-21 of the infusion period, and the infusion period is 28 days. In embodiments, the additional cancer treatment is dexamethasone. In embodiments, the additional cancer treatment is dexamethasone at a dose of 20 mg to 40 mg, once a week. In embodiments, dexamethasone is administered to the patient on days 1, 8, 15, and 22 of the lead-in period. In embodiments, dexamethasone is administered to the patient on days 1, 8, 15, and 22 of the infusion period, and the infusion period is 4 weeks ± 3 days. In embodiments, dexamethasone is administered to the patient on days 1, 8, 15, and 22 of the infusion period, and the infusion period is 28 days. In embodiments, (i) the patient is less than 75 years old and dexamethasone is administered to the patient at a dose of 40 mg a week, or (ii) the patient is at least 75 years old and dexamethasone is administered to the patient at a dose of 20 mg a week. In embodiments, (i) the patient has a BMI of at least 18.5 and dexamethasone is administered to the patient at a dose of 40 mg a week, or (ii) the patient has a BMI of less than 18.5 and dexamethasone is administered to the patient at a dose of 20: 20 mg a week.

In one aspect, the present disclosure provides a method of treating a disease or disorder responsive to inhibiting or blocking B Cell Maturation Antigen (BCMA) in a patient comprising administering to the patient a ma Bei Tuoshan antibody at a dose of about 1.4 mg/kg to about 3.4 mg/kg once every eight weeks ± 3 days, for example about 1.4 mg/kg to about 1.9 mg/kg once every eight weeks ± 3 days.

In one aspect, the present disclosure provides for the use of a mar Bei Tuoshan antibody in the treatment of a disease or disorder responsive to inhibiting or blocking B Cell Maturation Antigen (BCMA) by administering a mar Bei Tuoshan antibody at a dose of about 1.4 mg/kg to about 3.4 mg/kg once every eight weeks ± 3 days, for example about 1.4 mg/kg to about 1.9 mg/kg once every eight weeks ± 3 days.

In one aspect, the present disclosure provides the use of mar Bei Tuoshan for the manufacture of a medicament for the treatment of a disease or disorder responsive to inhibiting or blocking B Cell Maturation Antigen (BCMA) by administering a dose of mar Bei Tuoshan antibody of from about 1.4 mg/kg to about 3.4 mg/kg once every eight weeks ± 3 days, for example from about 1.4 mg/kg to about 1.9 mg/kg once every eight weeks ± 3 days.

In embodiments, the dose is about 1.4 mg/kg, about 1.9 mg/kg, about 2.5 mg/kg, or about 3.4 mg/kg, once every eight weeks ±3 days. In one aspect, the present disclosure provides a method of treating a disease or disorder responsive to inhibiting or blocking B Cell Maturation Antigen (BCMA) in a patient, the method comprising administering to the patient a therapeutically effective amount of a combination comprising a first BCMA antagonist and a second BCMA antagonist.

In one aspect, the present disclosure provides for the use of a combination comprising a first BCMA antagonist and a second BCMA antagonist to treat a disease or disorder responsive to inhibiting or blocking B Cell Maturation Antigen (BCMA) in a patient.

In one aspect, the present disclosure provides use of a combination comprising a first BCMA antagonist and a second BCMA antagonist in the manufacture of a medicament for treating a disease or disorder responsive to inhibiting or blocking B Cell Maturation Antigen (BCMA).

In embodiments, the first and second BCMA antagonists are independently selected from an anti-BCMA antibody or antigen binding fragment thereof, an anti-BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or antigen binding fragment thereof, and a chimeric antigen receptor T (CAR T) cell therapy targeting BCMA. In embodiments, the first and second BCMA antagonists are independently selected from Ai Jiwei am (idecabtagene vicleucel), cetosteara (ciltacabtagene autoleucel), tertuzumab (teclistamab), REGN5458, mar Bei Tuoshan antibody, bei Lantuo mab, SEA-BCMA, ABBV-383, elrantamab, pavurutumab, alnuctamab, MEDI2228, and CC99712. In embodiments, the first BCMA antagonist is a mar Bei Tuoshan antibody. In embodiments, the first BCMA antagonist is Bei Lantuo mab. In embodiments, the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is a corresponding unconjugated anti-BCMA antibody. In embodiments, the anti-BCMA antibody-drug conjugate is selected from the group consisting of mar Bei Tuoshan antibody, MEDI2228, and CC99712. In embodiments, the first BCMA antagonist is mar Bei Tuo mab and the second BCMA antagonist is Bei Lantuo mab.

In one aspect, the present disclosure provides a method of treating a disease or disorder responsive to inhibiting or blocking B Cell Maturation Antigen (BCMA) in a patient, the method comprising administering to the patient a therapeutically effective amount of a combination comprising a mar Bei Tuoshan antibody and Bei Lantuo mab.

In one aspect, the present disclosure provides the use of a combination comprising a mar Bei Tuoshan antibody and a Bei Lantuo mab in the treatment of a disease or disorder responsive to inhibiting or blocking B Cell Maturation Antigen (BCMA).

In one aspect, the present disclosure provides the use of a combination comprising a mar Bei Tuoshan antibody and a Bei Lantuo mab in the manufacture of a medicament for the treatment of a disease or disorder responsive to inhibition or blockade of B Cell Maturation Antigen (BCMA).

In embodiments, the method or use further comprises administering at least one additional cancer treatment, such as an anti-CD 38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody, to the patient. In embodiments, the additional cancer treatment is selected from lenalidomide, dexamethasone, darimumab, ai Shatuo ximab, pomalidomide, bortezomib, or a combination thereof, e.g., lenalidomide and dexamethasone.

In one aspect, the present disclosure provides a kit comprising (i) a first B Cell Maturation Antigen (BCMA) antagonist, and (ii) instructions for treating a disease or disorder responsive to inhibiting or blocking BCMA when combined with a second BCMA antagonist.

In one aspect, the disclosure provides a kit comprising (i) a mar Bei Tuoshan antibody, and (ii) instructions for treating a disease or disorder responsive to inhibiting or blocking B Cell Maturation Antigen (BCMA) when combined with Bei Lantuo mab.

In one aspect, the disclosure provides a kit comprising (i) Bei Lantuo mab, and (ii) instructions for treating a disease or disorder responsive to inhibiting or blocking B Cell Maturation Antigen (BCMA) when combined with mar Bei Tuo mab.

In one aspect, the present disclosure provides a method of treating a disease or disorder that inhibits or blocks B Cell Maturation Antigen (BCMA) response in a patient previously treated with a first BCMA antagonist, the method comprising administering to the patient a therapeutically effective amount of a second BCMA antagonist, wherein the patient stops administration of the first BCMA antagonist before beginning administration of the second BCMA antagonist, and the second BCMA antagonist is different from the first BCMA antagonist.

In one aspect, the present disclosure provides the use of a second BCMA antagonist in treating a disease or disorder responsive to inhibiting or blocking B Cell Maturation Antigen (BCMA) in a patient previously treated with a first BCMA antagonist, wherein administration of the first BCMA antagonist is stopped before administration of the second BCMA antagonist is started, and wherein the second BCMA antagonist is different from the first BCMA antagonist.

In one aspect, the present disclosure provides the use of a second BCMA antagonist in the manufacture of a medicament for treating a disease or disorder responsive to inhibiting or blocking B Cell Maturation Antigen (BCMA) in a patient previously treated with the first BCMA antagonist, wherein administration of the first BCMA antagonist is stopped before administration of the second BCMA antagonist is started, and wherein the second BCMA antagonist is different from the first BCMA antagonist.

In embodiments, the first and second BCMA antagonists are independently selected from an anti-BCMA antibody or antigen binding fragment thereof, an anti-BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or antigen binding fragment thereof, and a chimeric antigen receptor T (CAR T) cell therapy targeting BCMA. In embodiments, the first and second BCMA antagonists are independently selected from Ai Jiwei am, cildamascene, terituzumab, REGN5458, ma Bei Tuoshan antibody, bei Lantuo mab, SEA-BCMA, ABBV-383, elrantamab, pavurutumab, alnuctamab, MEDI2228, and CC99712. In embodiments, the first BCMA antagonist is a mar Bei Tuoshan antibody. In embodiments, the first BCMA antagonist is Bei Lantuo mab. In embodiments, the second BCMA antagonist is a mar Bei Tuoshan antibody. In embodiments, the second BCMA antagonist is Bei Lantuo mab. In embodiments, the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is a corresponding unconjugated anti-BCMA antibody. In embodiments, the anti-BCMA antibody-drug conjugate is selected from the group consisting of mar Bei Tuoshan antibody, MEDI2228, and CC99712. In embodiments, the first BCMA antagonist is mar Bei Tuo mab and the second BCMA antagonist is Bei Lantuo mab. In embodiments, the second BCMA antagonist is an anti-BCMA antibody-drug conjugate and the first BCMA antagonist is a corresponding unconjugated anti-BCMA antibody. In embodiments, the anti-BCMA antibody-drug conjugate is selected from the group consisting of mar Bei Tuoshan antibody, MEDI2228, and CC99712. In embodiments, the second BCMA antagonist is mar Bei Tuo mab and the first BCMA antagonist is Bei Lantuo mab.

In one aspect, the present disclosure provides a method of treating a disease or disorder responsive to inhibiting or blocking B Cell Maturation Antigen (BCMA) in a patient previously treated with a mab Bei Tuoshan, the method comprising administering to the patient a therapeutically effective amount of Bei Lantuo mab, wherein the patient ceases administration of the mab Bei Tuoshan prior to beginning administration of Bei Lantuo mab.

In one aspect, the present disclosure provides the use of Bei Lantuo mab in the treatment of a disease or disorder responsive to inhibition or blocking of B Cell Maturation Antigen (BCMA) in a patient previously treated with a mar Bei Tuoshan antibody, wherein administration of the mar Bei Tuoshan antibody is stopped before administration of the Bei Lantuo mab is started.

In one aspect, the present disclosure provides the use of Bei Lantuo mab for the manufacture of a medicament for treating a disease or disorder responsive to inhibiting or blocking B Cell Maturation Antigen (BCMA) in a patient previously treated with a mab Bei Tuoshan, wherein administration of the mab Bei Tuoshan antibody is stopped before administration of the Bei Lantuo mab is started.

In one aspect, the present disclosure provides a method of treating a disease or disorder responsive to inhibiting or blocking B Cell Maturation Antigen (BCMA) in a patient previously treated with Bei Lantuo mab, the method comprising administering to the patient a therapeutically effective amount of mar Bei Tuo mab, wherein the patient stops administration of Bei Lantuo mab before administration of mar Bei Tuo mab begins.

In one aspect, the present disclosure provides the use of a mar Bei Tuoshan antibody in the treatment of a disease or disorder responsive to inhibiting or blocking B Cell Maturation Antigen (BCMA) in a patient previously treated with Bei Lantuo mab, wherein administration of Bei Lantuo mab is stopped before administration of the mar Bei Tuo mab begins.

In one aspect, the present disclosure provides the use of marc Bei Tuoshan anti-tumor in the manufacture of a medicament for treating a disease or disorder responsive to inhibiting or blocking B Cell Maturation Antigen (BCMA) in a patient previously treated with Bei Lantuo mab, wherein administration of Bei Lantuo mab is stopped before administration of marc Bei Tuo mab is started.

In one aspect, the present disclosure provides a method of reducing corneal toxicity in a patient previously treated with a first B Cell Maturation Antigen (BCMA) antagonist, the method comprising administering to the patient a therapeutically effective amount of a second BCMA antagonist, wherein the patient stops administration of the first BCMA antagonist before beginning administration of the second BCMA antagonist, and the second BCMA antagonist is different from the first BCMA antagonist.

In one aspect, the present disclosure provides the use of a second BCMA antagonist for reducing corneal toxicity in a patient previously treated with a first B Cell Maturation Antigen (BCMA) antagonist, wherein administration of the first BCMA antagonist is stopped before administration of the second BCMA antagonist is started, and wherein the second BCMA antagonist is different from the first BCMA antagonist.

In one aspect, the present disclosure provides the use of a second BCMA antagonist in the manufacture of a medicament for reducing corneal toxicity in a patient previously treated with a first B Cell Maturation Antigen (BCMA) antagonist, wherein administration of the first BCMA antagonist is stopped before administration of the second BCMA antagonist is started, and wherein the second BCMA antagonist is different from the first BCMA antagonist.

In one aspect, the present disclosure provides a method of reducing corneal toxicity in a patient previously treated with a mab Bei Tuoshan, the method comprising administering to the patient a therapeutically effective amount of Bei Lantuo mab, wherein the patient ceases administration of the mab Bei Tuoshan before beginning administration of Bei Lantuo mab.

In one aspect, the present disclosure provides the use of Bei Lantuo mab to reduce corneal toxicity in a patient previously treated with a mab Bei Tuoshan antibody, wherein the patient ceases administration of the mab Bei Tuoshan antibody before beginning administration of the Bei Lantuo mab.

In one aspect, the present disclosure provides use of Bei Lantuo mab in the manufacture of a medicament for reducing corneal toxicity in a patient previously treated with a mab Bei Tuoshan antibody, wherein the patient ceases administration of the mab Bei Tuoshan antibody before beginning administration of the Bei Lantuo mab.

In one aspect, the present disclosure provides a method of reducing corneal toxicity in a patient previously treated with Bei Lantuo mab, the method comprising administering to the patient a therapeutically effective amount of mar Bei Tuo mab, wherein the patient ceases administration of Bei Lantuo mab before beginning administration of mar Bei Tuo mab.

In one aspect, the present disclosure provides the use of mar Bei Tuo mab to reduce corneal toxicity in a patient previously treated with Bei Lantuo mab, wherein the patient ceases administration of Bei Lantuo mab before beginning administration of mar Bei Tuo mab.

In one aspect, the present disclosure provides the use of marc Bei Tuoshan antibody in the manufacture of a medicament for reducing corneal toxicity in a patient previously treated with Bei Lantuo mab, wherein the patient ceases administration of Bei Lantuo mab before starting administration of marc Bei Tuo mab.

In embodiments, the methods and uses further comprise administering at least one additional cancer treatment, such as an anti-CD 38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody, to the patient. In embodiments, the additional cancer treatment is selected from lenalidomide, dexamethasone, darimumab, ai Shatuo ximab, pomalidomide, bortezomib, or a combination thereof, e.g., lenalidomide and dexamethasone.

In one aspect, the present disclosure provides a method of treating a disease or disorder in a patient, the method comprising administering a therapeutically effective amount of a combination comprising an antibody-drug conjugate and a corresponding unconjugated antibody.

In one aspect, the present disclosure provides the use of a combination comprising an antibody-drug conjugate and a corresponding unconjugated antibody in the treatment of a disease or disorder.

In one aspect, the present disclosure provides the use of a combination comprising an antibody-drug conjugate and a corresponding unconjugated antibody for the manufacture of a medicament for the treatment of a disease or disorder.

In one aspect, the present disclosure provides a method of treating a disease or disorder in a patient previously treated with an antibody-drug conjugate, the method comprising administering to the patient a therapeutically effective amount of a corresponding unconjugated antibody, wherein the patient ceases administration of the antibody-drug conjugate prior to commencing administration of the corresponding unconjugated antibody.

In one aspect, the present disclosure provides the use of an antibody in the treatment of a disease or disorder in a patient previously treated with an antibody-drug conjugate, wherein the antibody is the corresponding unconjugated antibody, and the patient ceases administration of the antibody-drug conjugate prior to commencing administration of the corresponding unconjugated antibody.

In one aspect, the present disclosure provides the use of an antibody in the manufacture of a medicament for treating a disease or disorder in a patient previously treated with an antibody-drug conjugate, wherein the antibody is a corresponding unconjugated antibody, and the patient ceases administration of the antibody-drug conjugate prior to commencing administration of the corresponding unconjugated antibody.

In embodiments, the antibody-drug conjugate is selected from the group consisting of gemtuzumab ozogamicin (gemtuzumab ozogamicin), vitamin b uximab (brentuximab vedotin), enmetrastuzumab (ado-trastuzumab emtansine), oxtrastuzumab (inotuzumab ozogamicin), polozokerite bead mab (polatuzumab vedotin), vitamin b You Shan antibody (enfortumab vedotin), detrastuzumab (fam-trastuzumab deruxtecan), goli Sha Tuozhu mab (sacituzumab govitecan), ma Bei Tuoshan antibody, rituximab (loncastuximab tesirine), tixomab (tisotumab vedotin), mostuzumab (moxetumomab pasudotox), MEDI2228, or CC99712.

In embodiments, the disease or disorder is a plasma cell disorder or a B cell disorder. In embodiments, the disease or disorder is BCMA-expressing cancer. In embodiments, the disease or disorder is Multiple Myeloma (MM). In embodiments, the MM is a relapsed and/or refractory MM, a newly diagnosed MM, a MM unsuitable for transplantation, or a newly diagnosed MM unsuitable for transplantation. In embodiments, the MM is a relapsed and/or refractory MM, a newly diagnosed MM, a MM unsuitable for transplantation, or a newly diagnosed MM unsuitable for transplantation.

In one aspect, the present disclosure provides a method of treating cancer in a patient having grade 1 corneal adverse effects due to administration of MA Bei Tuo mab, the method comprising temporarily stopping administration of MA Bei Tuoshan mab, administering a therapeutically effective amount of Bei Lantuo mab to the patient for an infusion period, and resuming administration of MA Bei Tuoshan mab after the infusion period.

In one aspect, the present disclosure provides the use of Bei Lantuo mab in treating cancer in a patient, wherein the patient has a grade 1 corneal adverse effect due to administration of mab Bei Tuo, wherein the administration of mab Bei Tuo is temporarily stopped during the administration of mab Bei Lantuo for an introduction period, and then the administration of mab Bei Tuoshan is resumed after the introduction period.

In one aspect, the present disclosure provides the use of Bei Lantuo mab in the manufacture of a medicament for treating cancer in a patient, wherein the patient has a grade 1 corneal adverse effect due to administration of mab Bei Tuo, wherein the administration of mab Bei Tuo is temporarily stopped during the administration of mab Bei Lantuo for an introduction period, and then the administration of mab Bei Tuoshan is resumed after the introduction period.

In one aspect, the present disclosure provides a method of treating cancer in a patient, wherein the patient has a grade 2 or more corneal adverse effect due to administration of MA Bei Tuo mab, the method comprising temporarily stopping administration of MA Bei Tuoshan mab, administering a therapeutically effective amount of Bei Lantuo mab to the patient for an infusion period, and resuming administration of MA Bei Tuoshan mab after the infusion period.

In one aspect, the present disclosure provides the use of Bei Lantuo mab in the treatment of cancer in a patient, wherein the patient has a grade 2 or more corneal adverse effect due to administration of mab Bei Tuo, wherein the administration of mab Bei Tuo is temporarily stopped for an introduction period during administration of mab Bei Lantuo, and then recovery of administration of mab Bei Tuoshan after the introduction period.

In one aspect, the present disclosure provides the use of Bei Lantuo mab in the manufacture of a medicament for treating cancer in a patient, wherein the patient has a grade 2 or more corneal adverse effect due to administration of the mab Bei Tuo, wherein the administration of the mab Bei Tuo is temporarily stopped during the administration of the mab Bei Lantuo for an introduction period, and then the administration of the mab Bei Tuoshan is resumed after the introduction period.

It should be understood that any and all embodiments of the present disclosure may be combined with any other embodiment or embodiments to describe additional more preferred embodiments. It should also be understood that each individual element of the preferred embodiment is its own independent preferred embodiment. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe additional embodiments.

Drawings

Fig. 1 is a graph depicting tumor volume growth curves as a function of study day for all treatment groups, as described in example 1.

Figure 2 is a graph depicting Kaplan-Meier survival curves for all treatment groups as a function of study day, as described in example 1.

Fig. 3 is a graph depicting tumor volume growth as a function of study day for different drug to antibody ratios (DAR), as described in example 3.

Fig. 4 is a graph depicting progression free survival of patients grouped according to the sBCMA level of the mar Bei Tuoshan anti-treatment arm (left) and the poc/dex treatment arm (right) as described in example 4.

Fig. 5 is a graph depicting reduced levels of sBCMA from cycle 1, end of day 1 infusion (EOI) with pre-administration of mar Bei Tuo mab to mar Bei Tuoshan anti-treatment, as described in example 4.

Fig. 6 is a graph depicting levels of sBCMA 24 hours after end of mar Bei Tuoshan anti-infusion (EOI), as described in example 4.

Fig. 7A and 7B are graphs depicting sBCMA levels of patients grouped according to response to treatment with a ma Bei Tuoshan antibody, as described in example 4. Figure 7A shows baseline sBCMA levels before administration of mar Bei Tuo mab and figure 7B shows sBCMA levels 24 hours after anti-EOI of mar Bei Tuoshan. Cr=complete response, VGPR =very good partial response, pr=partial response, MR/sd=minimal response/disease stability, PD/ne=progressive disease/non-evaluable.

Fig. 8 is a graph depicting the mean tumor volume curves of vehicle control and treatment groups between randomization and study termination of in vivo efficacy studies of Bei Lantuo mab and mar Bei Tuo mab in human multiple myeloma xenograft NOG mice, as described in example 5.

Fig. 9 is a graph showing Kaplan-Meier survival curves for all treatment groups in human multiple myeloma xenograft NOG mice as a function of study day for the in vivo efficacy studies of Bei Lantuo mab and mar Bei Tuo mab, as described in example 5.

Detailed Description

Definition of the definition

As used herein and in the claims, the term "comprising" encompasses "or" consists of, "e.g., a composition that" comprises "X may consist of X alone or may include some additional, e.g., x+y.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any compositions and methods similar or equivalent to those described herein can be used in the practice or testing of the methods of the present disclosure, the exemplary compositions and methods are described herein. Any of the aspects and embodiments of the disclosure described herein may be combined. For example, the subject matter of any of the dependent claims or independent claims disclosed herein may be combined in multiple ways (e.g., one or more recitations from each dependent claim may be combined into a single claim based on the independent claim on which it depends).

Ranges provided herein include all values within the specified ranges as well as values near the endpoints of the specified ranges. The figures and tables of the present disclosure also describe ranges and discrete values that can constitute elements of any of the methods and uses disclosed herein.

The concentrations described herein are determined at ambient temperature and pressure. This may be, for example, at room temperature or at temperatures and pressures within a particular portion of the process stream. The concentration is preferably determined at a standard state of 25 oC and 1 bar pressures.

As used herein, the term "antigen binding protein" refers to antibodies and other protein constructs, e.g., domains, that are capable of binding to an antigen.

As used herein, the term "antibody" refers to molecules having immunoglobulin-like domains (e.g., igG, igM, igA, igD or IgE), and includes monoclonal, recombinant, polyclonal, chimeric, human, humanized, multispecific antibodies (including bispecific antibodies) and heteroconjugate antibodies, single variable domains (e.g., domain Antibodies (DAB)), antigen-binding antibody fragments, fab, F (ab') ₂, fv, disulfide-linked Fv, single chain Fv, disulfide-linked scFv, diabodies (diabodies), TANDABS, and the like, as well as modified versions of any of the foregoing (see Holliger and Hudson, nature Biotechnology, 2005, vol 23, no. 9, 1126-1136 for abstracts in the alternative "antibody" forms).

The terms full antibody (full antibody), whole antibody (white antibody), or whole antibody (intact antibody) are used interchangeably herein to refer to a heterotetrameric glycoprotein having a molecular weight of about 150,000 daltons. An intact antibody consists of two identical Heavy Chains (HC) and two identical Light Chains (LC) linked by covalent disulfide bonds. This H ₂L₂ structure is folded to form three functional domains, which comprise two antigen binding fragments (referred to as "Fab" fragments) and one "Fc" crystallizable fragment. Fab fragments consist of an amino-terminal variable domain (heavy chain Variable (VH) or light chain Variable (VL)) and a carboxy-terminal constant domain (CH 1 (heavy chain) and CL (light chain)). The Fc fragment consists of two domains formed by dimerization of paired CH2 and CH3 regions. Fc may trigger effector function by binding to receptors on immune cells or by binding to Clq (the first component of the classical complement pathway). Five classes of antibodies IgM, igA, igG, igE and IgD are defined by different heavy chain amino acid sequences, called μ, α, γ, ε, and δ, respectively, each heavy chain being paired with a K or λ light chain. Most antibodies in serum belong to the IgG class, and human IgG exists in four subtypes (IgG 1, igG2, igG3, and IgG 4), whose sequences differ primarily in their hinge regions.

Fully human antibodies can be obtained using a variety of methods, for example using yeast-based libraries or transgenic animals (e.g., mice) capable of producing a repertoire of human antibodies. Yeasts presenting on their surface human antibodies that bind to the antigen of interest can be selected using FACS (fluorescence activated cell sorting) based methods or by capturing on beads using labeled antigens. Transgenic animals that have been modified to express human immunoglobulin genes can be immunized with an antigen of interest and antigen-specific human antibodies isolated using B cell sorting techniques. The human antibodies produced using these techniques can then be characterized for desired properties such as affinity, developability, and selectivity.

Alternative antibody formats include alternative scaffolds in which one or more CDRs of an antigen binding protein may be arranged on a suitable non-immunoglobulin scaffold or scaffold, e.g. an affibody, spA scaffold, LDL receptor class a domain, avimer (see e.g. us patent application publication nos. 2005/0053973, 2005/0089932, 2005/0164301) or EGF domain.

As used herein, the term "anti-BCMA antigen binding protein" refers to antibodies and other protein constructs, e.g., domains, capable of binding BCMA. The terms "BCMA binding protein" and "anti-BCMA antigen binding protein" are used interchangeably herein.

The anti-BCMA antigen binding proteins described herein can bind to human BCMA having, for example, a human BCMA comprising the amino acid sequence of GenBank accession No. Q02223.2, or a gene encoding a human BCMA having at least 90% homology or at least 90% identity thereto.

An exemplary anti-BCMA antigen binding protein and method of making the same is disclosed in international publication No. WO2012/163805, which is incorporated herein by reference in its entirety. Other exemplary anti-BCMA antigen binding proteins include those described in WO2016/014789、WO2016/090320、WO2016/090327、WO2016/020332、WO2016/079177、WO2014/122143、WO2014/122144、WO2017/021450、WO2016/014565、WO2014/068079、WO2015/166649、WO2015/158671、WO2015/052536、WO2014/140248、WO2013/072415、WO2013/072406、WO2014/089335、US2017/165373、WO2013/154760、WO2018/201051 and WO2017/051068, each of which is incorporated herein by reference in its entirety.

In some embodiments, a BCMA binding protein disclosed herein can be derived from rats, mice, primates (e.g., cynomolgus, old world monkeys or apes), or humans. BCMA binding proteins may be human, humanized or chimeric antibodies. BCMA binding proteins may comprise a constant region, which may be of any isotype or subclass. The constant region may be of the IgG isotype, e.g., igG1, igG2, igG3, igG4, or variants thereof. The BCMA binding protein constant region may be IgG1.

Thus, there is provided a BCMA binding protein which may comprise any one or a combination of CDRH1 of SEQ ID NO. 5, CDRH2 of SEQ ID NO. 6, CDRH3 of SEQ ID NO. 7, CDRL1 of SEQ ID NO. 8, CDRL2 of SEQ ID NO. 9, CDRL3 of SEQ ID NO. 10. CDRs may be modified by at least one amino acid substitution, deletion or addition, wherein the variant antigen-binding protein substantially retains the biological properties of the unmodified protein, e.g., binding to an antigen.

In some embodiments, the anti-BCMA antigen binding protein comprises CDRH1 according to SEQ ID No. 5, CDRH2 according to SEQ ID No. 6, CDRH3 according to SEQ ID No. 7, CDRL1 according to SEQ ID No. 8, CDRL2 according to SEQ ID No. 9, and CDRL3 according to SEQ ID No. 10.

In some embodiments, the anti-BCMA antigen binding protein comprises a heavy chain variable region (VH) according to SEQ ID No. 3 and a light chain variable region (VL) according to SEQ ID No. 4.

In some embodiments, the anti-BCMA antigen binding protein comprises a heavy chain (H) according to SEQ ID No. 1 and a light chain (L) according to SEQ ID No. 2.

In some embodiments, the anti-BCMA antigen binding protein is a T cell redirecting antibody (BiTE) with dual inhibition of BCMA and CD3 receptors, such as tertuzumab (PILLARISETTI et al, blood Advances 4, 4538-49, 2020) and Bei Lintuo outuzumab (blinatumomab), AMG 424, GBR 1342, BFR4350A, AMG 420, AMG 701, henatomab (elranatamab) (PF-06863135), REGN5458, TNB-383B (Alhallak et al, cancers, 2853, 2021). In some embodiments, the anti-BCMA antigen binding protein is a non-fucosylated BCMA-directed antibody, such as SEA-BCMA (Van Epps et al, CANCER RES, 2018;78 (13 Suppl): abstract 3833).

In some embodiments, the anti-BCMA antigen binding protein is a CAR-T cell therapeutic.

In some embodiments, an anti-BCMA antigen binding protein is used in the immunoconjugate. An "immunoconjugate" (interchangeably referred to as an "antibody-drug conjugate", "ADC" or "antigen binding protein-drug conjugate") comprises an anti-BCMA antigen binding protein conjugated to one or more drugs, e.g., a cytotoxic agent such as a chemotherapeutic agent, an immunotherapeutic agent, a growth inhibitor, a toxin (e.g., a protein toxin such as an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or a fragment thereof), an antiviral agent, a radioisotope (i.e., a radioactive conjugate), an antibiotic, or a small interfering RNA (siRNA).

In some cases, the anti-BCMA antigen binding protein may be an immunoconjugate having the general structure:

ABP- ((linker) n-Ctx) m

Wherein the method comprises the steps of

ABP is an antigen binding protein

The linker being absent or any cleavable or non-cleavable linker

Ctx is any cytotoxic agent described herein

N is 0, 1,2 or 3, and

M is 1, 2, 3, 4,5, 6, 7, 8, 9 or 10.

Exemplary linkers can include 6-Maleimidocaproyl (MC), maleimidopropionyl (MP), valine-citrulline (val-cit), alanine-phenylalanine (ala-phe), p-aminobenzyloxycarbonyl (PAB), N-succinimidyl 4- (2-pyridylthio) pentanoate (SPP), N-succinimidyl 4- (N-maleimidomethyl) cyclohexane-1 carboxylate (SMCC), and N-succinimidyl (4-iodo-acetyl) aminobenzoate (SIAB).

In some cases, the anti-BCMA antigen binding protein may be an immunoconjugate comprising a monoclonal antibody linked to MMAE or MMAF. In another embodiment, the anti-BCMA antigen binding protein may be an immunoconjugate comprising a monoclonal antibody linked to MMAE or MMAF through an MC linker, as shown in the following structure:

Where "p" is the drug-to-antibody ratio (DAR) and is an integer from 1 to 8, such as 2, 4, 6, or 8.

In some cases, the anti-BCMA antigen binding protein may be antibody Bei Lantuo mab. In another embodiment, the anti-BCMA antigen binding protein may be an immunoconjugate mar Bei Tuoshan antibody.

In some embodiments, the BCMA antagonist is a Chimeric Antigen Receptor (CAR) -T cell therapy that targets BCMA. As used herein, the term "chimeric antigen receptor" ("CAR") refers to an engineered receptor consisting of an extracellular antigen binding domain (typically derived from a monoclonal antibody or antigen binding fragment thereof, e.g., VH and VL domains in the form of scFv), optionally a spacer, a transmembrane region, and one or more intracellular effector domains. CARs are also known as chimeric T cell receptors or Chimeric Immune Receptors (CIRs). CARs are genetically introduced into hematopoietic cells, such as T cells, to redirect T cell specificity for a desired cell surface antigen, thereby producing a CAR-T therapeutic.

As used herein, the term "spacer" refers to an oligopeptide or polypeptide that has the function of linking a transmembrane domain to a target binding domain. This region may also be referred to as a "hinge region" or "stem region (stalk region)". The size of the spacer can be varied depending on the location of the target epitope to maintain a set distance (e.g., 14 nm) upon CAR: target binding.

As used herein, the term "transmembrane domain" refers to the portion of the CAR molecule that passes through the cell membrane.

As used herein, the term "intracellular effector domain" (also referred to as a "signaling domain") refers to a domain in a CAR that is responsible for intracellular signaling upon binding of an antigen binding domain to a target. The intracellular effector domain is responsible for activating at least one normal effector function of an immune cell in which the CAR is expressed. For example, the effector function of T cells may be cytolytic activity or helper activity including secretion of cytokines.

It will be appreciated by those skilled in the art that the VH and/or VL domains disclosed herein may be incorporated into a CAR-T therapeutic agent, for example, in the form of an scFv.

"CDR" is defined as the complementarity determining region amino acid sequence of an antigen binding protein. These are hypervariable regions of immunoglobulin heavy and light chains. There are three heavy chain CDRs and three light chain CDRs (or CDR regions) in the variable portion of the immunoglobulin. Thus, as used herein, "CDR" refers to all three heavy chain CDRs, all three light chain CDRs, all heavy and light chain CDRs, or at least two CDRs.

In this specification, amino acid residues in the variable domain sequence and variable domain region within the full-length antigen-binding sequence (e.g., within an antibody heavy chain sequence or an antibody light chain sequence) are numbered according to the Kabat numbering convention. Similarly, the terms "CDR", "CDRL1", "CDRL2", "CDRL3", "CDRH1", "CDRH2", "CDRH3" follow the Kabat numbering convention. For further information, see Kabat et al , Sequences of Proteins of Immunological Interest, 4^th Ed., U.S. Department of Health and Human Services, National Institutes of Health (1987).

It will be apparent to those skilled in the art that alternative numbering conventions exist for amino acid residues in the variable domain sequences and full length antibody sequences. CDR sequences are also of alternative numbering convention, such as those set forth in Chothia et al (1989) Nature 342:877-883. The structure and protein folding of an antigen binding protein may mean that other residues are considered to be part of the CDR sequence, and will be understood by those skilled in the art.

Other numbering conventions for CDR sequences available to those skilled in the art include the "AbM" (university of bas) and the "contact" method.

Table 1 below represents one definition using each numbering convention for each CDR or binding unit. It should be noted that some CDR definitions may vary depending on the respective publications used.

TABLE 1

Immunoconjugates (interchangeably termed "antibody-drug conjugates", "ADCs" or "antigen binding protein-drug conjugates") comprise an antigen binding protein (e.g., an antibody or antigen binding fragment thereof) conjugated to one or more drugs, e.g., a cytotoxic agent such as a chemotherapeutic agent, immunotherapeutic agent, growth inhibitory agent, toxin (e.g., a protein toxin, e.g., an enzymatically active toxin of bacterial, fungal, plant or animal origin, or fragment thereof), antiviral agent, radioisotope (i.e., a radio conjugate), antibiotic, or small interfering RNA (siRNA).

Immunoconjugates have been used to locally deliver cytotoxic agents, i.e. drugs that kill or inhibit Cell growth or proliferation (Lambert, j. (2005) curr. Opinion in Pharmacology 5:543-549; wu et al (2005) Nature Biotechnology 23(9):1137-1146; Payne, G. (2003) Cancer Cell 3:207-212; Syrigos and Epenetos (1999) Anticancer Research 19:605-614; Niculescu-Duvaz and Springer (1997) Adv. Drug Deliv. Rev. 26:151-172; U.S. Pat. No. 4,975,278). immunoconjugates allow, inter alia, targeted delivery of Drug moieties to tumors and accumulation within the cells, wherein systemic administration of unconjugated drugs may lead to unacceptable levels of toxicity to normal cells (Tsuchikama and An, protein and Cell, (2018) 9:33-46). Immunoconjugates are able to selectively deliver potent cytotoxic payloads to target cancer cells compared to traditional chemotherapy, thereby improving efficacy, reducing systemic toxicity, and achieving better Pharmacokinetics (PK)/Pharmacodynamics (PD) and biodistribution (Tsuchikama and An 2018); beck a. Et al (2017) Nature rev Drug disc 16:315-337).

Polyclonal and monoclonal antibodies have been reported to be useful in these strategies (Rowland et al, (1986) Cancer immunol. Immunother. 21:183-87). Drugs used in these methods include daunorubicin, doxorubicin, methotrexate, and vindesine (Rowland et al, (1986) supra). Toxins for antibody-toxin conjugates include bacterial toxins such as diphtheria toxin, plant toxins such as ricin, small molecule toxins such as 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), maytansinoids (maytansinoid) (EP 1391213; liu et al, (1996) Proc. Natl. Acad. Sci. USA 93:8618-8623), and calicheamicin (calicheamicin) (Lode et al (1998) Cancer Res. 58:2928; hin et al (1993) Cancer Res. 53:3336-3342).

In certain embodiments, the immunoconjugate comprises an antigen binding protein (such as an antibody) and a drug (such as a toxin, such as a chemotherapeutic agent). The drug may be modified (e.g., via standard synthetic chemistry) to allow its chemical attachment (e.g., containing a reactive handle to allow its chemical attachment) to the reactive end of the linker that connects the drug to the antigen binding protein.

Described herein are drugs, such as chemotherapeutic agents, for producing immunoconjugates. Enzymatically active toxins and fragments thereof that may be used include diphtheria toxin a chain, non-binding active fragments of diphtheria toxin, exotoxin a chain (from pseudomonas aeruginosa), ricin a chain, abrin a chain, modeccin a chain, α -sarcina, tung oil tree protein, caryophyllin protein, pokeweed (Phytolaca americana) proteins (PAPI, PAPII and PAP-S), balsam pear inhibitors, curcin, crotin, soapbox (sapaonaria officinalis) inhibitors, gelonin, mitogellin, restrictocin, phenomycin, ionomycin and trichothecene. See, for example, WO 93/21232 published on month 28 of 1993.

In addition to toxins, radioactive materials (e.g., radionucleotides) may also be used as drugs in ADCs. A variety of radionucleotides can be used to produce radioconjugated antibodies. Examples include 212Bi, 131I, 131In, 90Y, and 186Re.

Antigen binding proteins (e.g., antibodies) may also be conjugated to one or more toxins, including, but not limited to, calicheamicins, maytansinoids, dolastatins (dolastatin), auristatins (aurostatin), trichothecenes, and CC1065, as well as derivatives of these toxins that have toxin activity. Suitable cytotoxic agents include, but are not limited to, auristatin (auristatin), including poly valine-poly isoleucine-poly praline-phenylalanine (dovaline-valine-dolaisoleunine-dolaproine-phenalanine) (MMAF) and monomethyl auristatin E (MMAE) as well as MMAE in the form of esters, DNA minor groove binders, DNA minor groove alkylating agents, enediynes, lexitropsin, duocarmycin, taxanes such as paclitaxel and docetaxel, puromycin, urodoline, maytansinoids (maytansinoids), vinca alkaloids. Specific cytotoxic agents include topotecan, morpholino-doxorubicin, rhizomycin, cyanomorpholino-doxorubicin, dolastatin-10, echinomycin, combretatstatin, calicheamicin (CHALICHEAMICIN), maytansine (maytansine), DM-1, DM-4, and fusins. Other suitable cytotoxic agents include anti-tubulin agents such as australistatin, vinca alkaloids, podophyllotoxins, taxanes, baccatin derivatives, cryptophyllin, maytansinoids, combretastatin or dolastatin. Anti-tubulin agents include dimethylvaline-valine-doleileu-dolapril-phenylalanine-p-phenylenediamine (AFP), MMAF, MMAE, auristatin E, vincristine, vinblastine, vindesine, vinorelbine, VP-16, camptothecine, paclitaxel, docetaxel, epothilone a, epothilone B, nocodazole, colchicine (colcimid), estramustine, cimadodine, discodermolide, maytansine, DM-1, DM-4, and acanthopanaxgenin.

Antibody drug conjugates can be prepared by conjugating the anti-tubulin agent monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF) to an antigen-binding protein (e.g., an antibody). In the case of MMAE, the linker may consist of thiol-reactive maleimide, hexanoyl spacer, dipeptide valine-citrulline or p-aminobenzyloxycarbonyl (self-cleaving (self-immolative) cleavage group). In the case of MMAF, protease resistant maleimidocaproyl linkages can be used. The conjugation process results in heterogeneity of drug-antibody linkages, differing both in the number of drugs bound to each antibody molecule (drug-antibody ratio [ DAR ]) and the site of linkage. The most common category is dar=4 materials, with DAR being 0, 2, 6 and 8 materials being less common. The ensemble average drug to antibody ratio (DAR) is about 4.

The term "progression" of tumor growth or "progressive disease" ("PD") as used herein with respect to cancer status refers to an increase in the sum of the diameters of target lesions (tumors). In some embodiments, progressive disease is measured and defined according to the International Myeloma Working Group (IMWG) standard (see, e.g., kumar S, paiva B, anderson KC., et al International myeloma working group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328-46.). in some embodiments, tumor growth progression refers to an increase in the sum of diameters of target lesions of at least 20%, referenced to the minimum sum in the study (including the baseline sum, if the sum is the minimum in the study). In some embodiments, in addition to a relative increase of 20%, the sum of diameters of target lesions must exhibit an absolute increase of at least 5 mm.

As used herein, "about" refers to ±10% of the specified value.

As used herein, "treating" refers to alleviating one or more symptoms or effects associated with a disorder and/or slowing the progression of a disorder. For example, in some embodiments, the disclosed therapies reduce ocular toxicity. "eye toxicity" refers to any unintended exposure of a therapeutic agent to ocular tissue and includes alterations in corneal epithelium, dry eyes, irritation, redness, blurred vision, dry eyes, photophobia, and/or vision changes. The detection of ocular toxicity may be determined by an ophthalmic examination by an optician or optometrist prior to, during and/or after treatment.

The ophthalmic examination may include one or more of the following:

1. The vision is optimally corrected and the vision is well corrected,

2. Record manifest refraction and methods for obtaining optimal corrected vision,

3. Current eyeglass prescriptions (as applicable),

4. The measurement of the intraocular pressure is carried out,

5. Anterior ocular segment (slit lamp) examination, including corneal fluorescein staining and lens examination,

6. Mydriatic fundus examination, and/or

7. Ocular Surface Disease Index (OSDI), which is a visual function questionnaire that evaluates the impact of potential ocular changes in vision on function and health-related quality of life.

Therapeutic methods using Bei Lantuo monoclonal antibodies

Described herein are methods of treating a disease or disorder in a patient benefiting from the inhibition or blocking of B Cell Maturation Antigen (BCMA). The use of BCMA inhibition or blocking therapy in the treatment of a disease or disorder in a patient is also described. In one aspect, the present disclosure provides a method of treating a disease or disorder responsive to inhibiting or blocking B Cell Maturation Antigen (BCMA) in a patient, the method comprising administering Bei Lantuo mab to the patient. Bei Lantuo mab is the unconjugated monoclonal antibody component of the mar Bei Tuo mab targeting BCMA and thus lacks the cytotoxic payload of the mar Bei Tuo mab.

In embodiments, bei Lantuo mab is administered at a dose of about 300 mg to about 2000 mg. In embodiments, bei Lantuo mab is administered at a dose of about 300 mg to about 900 mg. In embodiments, bei Lantuo mab is administered at a dose of about 900 mg to about 2000 mg. In embodiments, bei Lantuo mab is administered at a dose of about 300: 300 mg. In embodiments, the administered dose of Bei Lantuo mab is administered at a dose of about 900: 900 mg. In embodiments, bei Lantuo mab is administered at a dose of about 2000 mg.

In embodiments, the dose of Bei Lantuo mab is administered at regular intervals for a period of time. In embodiments, the dose of Bei Lantuo mab is administered on day 1 at regular intervals. In embodiments, the regular intervals are at least every 8 weeks ± 3 days, at least every 6 weeks ± 3 days, at least every 4 weeks ± 3 days, at least every 3 weeks ± 3 days, at least every 2 weeks ± 3 days, at least every week ± 3 days, from every week ± 3 days to every 8 weeks ± 3 days, from every week ± 3 days to every 6 weeks ± 3 days, from every week ± 3 days to every 4 weeks ± 3 days, from every week ± 3 days to every 3 weeks ± 3 days, from every 2 weeks ± 3 days to every 3 weeks ± 3 days, from every 3 weeks ± 3 days to every 4 weeks ± 3 days, from every 4 weeks ± 3 days to every 5 weeks ± 3 days, from every 5 weeks ± 3 days to every 6 weeks ± 3 days, from every 6 weeks ± 3 days to every 7 weeks ± 3 days, and/or from every 7 weeks ± 3 days to 8 weeks ± 3 days. In embodiments, the period of time is until the progressive disease occurs.

In embodiments, the dosage of Bei Lantuo mab is administered at least once every 8 weeks ± 3 days, at least once every 6 weeks ± 3 days, at least once every 4 weeks ± 3 days, at least once every 3 weeks ± 3 days, at least once every 2 weeks ± 3 days, at least once every week ± 3 days, once every 8 weeks ± 3 days, once every week ± 3 days to every 6 weeks ± 3 days, once every week ± 3 days to every 4 weeks ± 3 days, once every week ± 3 days to every 3 weeks ± 3 days, once every 2 weeks ± 3 days to every 3 weeks ± 3 days, once every 3 weeks ± 3 days to every 4 weeks ± 3 days, once every 4 weeks ± 3 days to every 5 weeks ± 3 days, once every 5 weeks ± 3 days to every 6 weeks ± 3 days, once every 6 weeks ± 3 days to 7 weeks ± 3 days and/or once every 7 weeks ± 3 days to 8 weeks ± 3 days. In embodiments, the dosage of Bei Lantuo mab is administered once a week ± 3 days to once every 4 weeks ± 3 days. In embodiments, the dosage of Bei Lantuo mab is administered from once every 2 weeks ± 3 days to once every 4 weeks ± 3 days. In embodiments, the dosage of Bei Lantuo mab is administered once every 2 weeks ± 3 days. In embodiments, the dosage of Bei Lantuo mab is administered once every 3 weeks ± 3 days. In embodiments, the dosage of Bei Lantuo mab is administered once every 4 weeks ± 3 days.

In embodiments, the dose of Bei Lantuo mab is administered parenterally, i.e., subcutaneously (s.c. or SC), intrathecally, intraperitoneally, intramuscularly (i.m. or IM), or intravenously (i.v. or IV), including by intravenous infusion. In embodiments, the dose of Bei Lantuo mab is administered intravenously. In embodiments, the dose of Bei Lantuo mab is administered by intravenous infusion. In embodiments, the dose of Bei Lantuo mab is administered subcutaneously.

In embodiments, bei Lantuo mab is administered as a first line treatment for a disease or disorder. In embodiments, bei Lantuo mab is administered after treatment of one or more previous lines for the disease or disorder. In embodiments, bei Lantuo mab is administered after treatment of at least 1 previous line, after treatment of at least 2 previous lines, after treatment of at least 3 previous lines, after treatment of at least 4 previous lines, after treatment of 1 to 4 previous lines, after treatment of 2 to 4 previous lines, after treatment of 1 to 2 previous lines, after treatment of 2 to 3 previous lines, after treatment of 3 to 4 previous lines, after treatment of 1 previous line, after treatment of 2 previous lines, after treatment of 3 previous lines, or after treatment of 4 previous lines for a disease or disorder. In embodiments, bei Lantuo mab is administered as a first-line cancer treatment. In embodiments, bei Lantuo mab is administered after one or more previous lines of cancer treatment. In embodiments, bei Lantuo mab is administered after at least 1 previous line of cancer treatment, after at least 2 previous lines of cancer treatment, after at least 3 previous lines of cancer treatment, after at least 4 previous lines of cancer treatment, after 1 to 4 previous lines of cancer treatment, after 2 to 4 previous lines of cancer treatment, after 1 to 2 previous lines of cancer treatment, after 2 to 3 previous lines of cancer treatment, after 3 to 4 previous lines of cancer treatment, after 1 previous line of cancer treatment, after 2 previous lines of cancer treatment, after 3 previous lines of cancer treatment, or after 4 previous lines of cancer treatment. In embodiments, the patient is not treated with prior treatments for the disease or disorder. In embodiments, the patient has been treated with at least one prior treatment for the disease or disorder. In embodiments, the patient has been treated with at least 1 previous line treatment, at least 2 previous line treatments, at least 3 previous line treatments, at least 4 previous line treatments, 1 to 4 previous line treatments, 2 to 4 previous line treatments, 1 to 2 previous line treatments, 2 to 3 previous line treatments, 3 to 4 previous line treatments, 1 previous line treatment, 2 previous line treatments, 3 previous line treatments, or 4 previous line treatments for the disease or disorder.

In embodiments, the patient has relapsed or refractory multiple myeloma and has previously received at least four previous therapies to treat the multiple myeloma.

In embodiments, the previous line cancer treatment is selected from an anti-CD 38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or a combination thereof. For example, a patient who has been treated with 0,1, 2,3, or 4 or more previous lines prior to treatment as described herein may have been previously treated with an immunomodulatory agent (e.g., an immunomodulatory imide drug (ImiD)), a Proteasome Inhibitor (PI), an anti-CD 38 treatment, or a combination thereof. In embodiments, the previous line of cancer treatment includes anti-CD 38 monoclonal antibodies, proteasome inhibitors, and immunomodulators.

Examples of anti-CD 38 antibodies that can be used in the methods described herein include, but are not limited to Ai Shatuo or Ai Shatuo mab-irfc (e.g., SARCLISA um) and darimumab (e.g., DARZALEX um, DARZALEX FASPRO um). In embodiments, the anti-CD 38 monoclonal antibody is selected from darimumab or Ai Shatuo ximab.

Examples of proteasome inhibitors that may be used in the methods described herein include, but are not limited to, bortezomib (e.g., VELCADE), ib Sha Zuo meters (e.g., NINLARO), carfilzomib (e.g., KYPROLIS), oprozomib (oprozomib), and delazomib (delanzomib). In embodiments, the proteasome inhibitor is selected from bortezomib, carfilzomib, or ib Sha Zuomi. In embodiments, the proteasome inhibitor is bortezomib.

Examples of immunomodulatory imide drugs (ImiD) that may be used in the methods described herein include, but are not limited to, thalidomide (e.g., THALOMID cube), lenalidomide (e.g., REVLIMID cube), and pomalidomide (e.g., POMALYST cube). In embodiments, the immunomodulator is selected from thalidomide, lenalidomide, or pomalidomide. In embodiments, the immunomodulator is lenalidomide or pomalidomide. In embodiments, the immunomodulator is lenalidomide.

In embodiments, bei Lantuo mab is administered as monotherapy. In embodiments, bei Lantuo mab is administered in combination with at least one additional treatment. In embodiments, bei Lantuo mab is administered in combination with at least one additional cancer treatment. In embodiments, bei Lantuo mab is administered on day 1 of the treatment cycle. In embodiments, bei Lantuo mab is administered on day 1 of a 28-day treatment cycle. In embodiments, bei Lantuo mab is administered on days 1 and 15 of a 28 day treatment cycle. In embodiments, bei Lantuo mab is administered on day 1 of a 21-day treatment cycle.

In embodiments, the additional cancer treatment is selected from an anti-CD 38 monoclonal antibody, a gamma-secretase inhibitor, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody.

Examples of gamma secretase inhibitors useful in the methods described herein include, but are not limited to, ogestramustine Wei Ao (nirogacestat, PF-0308014), CRENIGACESTAT (LY 3039478), CB-103, tarenflurbil, simasite (SEMAGACESTAT, LY 450139), RG-4733, EVP-0962, celecoxib (avagacestat), MK-0752, and BMS-906024, as well as derivatives and polymorphs thereof.

Examples of proteasome inhibitors that may be used in the methods described herein include, but are not limited to, bortezomib (e.g., VELCADE), ib Sha Zuo meters (e.g., NINLARO), carfilzomib (e.g., KYPROLIS), oprozomib, and delazomib. In embodiments, the proteasome inhibitor is selected from bortezomib, carfilzomib, or ib Sha Zuomi. In embodiments, the proteasome inhibitor is bortezomib.

Examples of immunomodulatory imide drugs (ImiD) that may be used in the methods described herein include, but are not limited to, thalidomide (e.g., THALOMID cube), lenalidomide (e.g., REVLIMID cube), and pomalidomide (e.g., POMALYST cube). In embodiments, the immunomodulator is selected from thalidomide, lenalidomide, or pomalidomide. In embodiments, the immunomodulator is lenalidomide or pomalidomide. In embodiments, the immunomodulator is lenalidomide. In embodiments, the immunomodulator is pomalidomide.

Examples of anti-PD-1 monoclonal antibodies that can be used in the methods described herein include, but are not limited to, pembrolizumab (pembroluzimab) and rituximab (dostarlimab). In embodiments, the anti-PD-1 monoclonal antibody is selected from pembrolizumab or rituximab.

Other additional cancer treatments include corticosteroids. Examples of corticosteroids include, but are not limited to, dexamethasone (e.g., DECADRON, DEXASONE, DIODEX, HEXADROL, MAXIDEX), prednisone (e.g., deltaSONE) and methylprednisolone (e.g., MEDROL).

In embodiments, the additional cancer treatment is selected from lenalidomide, pomalidomide, dexamethasone, or a combination thereof. In embodiments, the additional cancer treatments are lenalidomide and dexamethasone. In embodiments, the additional cancer treatments are pomalidomide and dexamethasone. In embodiments, the additional cancer treatment is bortezomib and dexamethasone. In embodiments, the additional cancer treatments are pomalidomide, bortezomib, and dexamethasone. In embodiments, the additional cancer treatments are lenalidomide, bortezomib, and dexamethasone.

In embodiments, the additional cancer treatment is standard of care treatment.

In embodiments, the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg, once daily, for a period of time. In embodiments, the additional cancer treatment is lenalidomide, which is administered once daily at a dose of 10 mg to 25 mg on days 1-21 of the 28 day cycle.

In embodiments, the additional cancer treatment is dexamethasone. In embodiments, the additional cancer treatment is dexamethasone at a dose of 20 mg to 40 mg, once a week. In embodiments, if the patient is less than 75 years old, the additional cancer treatment is dexamethasone at a dose of 40 mg, once a week. In embodiments, if the patient is at least 75 years old, the additional cancer treatment is dexamethasone at a dose of 20 mg, once a week. In embodiments, if the patient's BMI is at least 18.5, the additional cancer treatment is dexamethasone at a dose of 40 mg, once a week. In embodiments, if the patient's BMI is less than 18.5, the additional cancer treatment is dexamethasone at a dose of 20 mg, once a week. In embodiments, dexamethasone is administered at days 1, 8, 15, and 22 of the 28 day cycle.

In embodiments, the additional cancer treatment is administration of 10 mg to 25 mg doses of lenalidomide once daily on days 1-21 of the 28 day cycle and 20mg to 40mg doses of dexamethasone on days 1, 8, 15, and 22 of the 28 day cycle. In embodiments, if the patient is less than 75 years old or the BMI is at least 18.5, the additional cancer treatment is to administer 10 mg to 25 mg doses of lenalidomide once daily on days 1-21 of the 28 day cycle and 40mg doses of dexamethasone on days 1, 8, 15, and 22 of the 28 day cycle. In embodiments, if the patient is at least 75 years old or the BMI is less than 18.5, the additional cancer treatment is to administer 10 mg to 25 mg doses of lenalidomide once daily on days 1-21 of the 28 day cycle and 20mg doses of dexamethasone on days 1, 8, 15, and 22 of the 28 day cycle.

Introduction of dosage period

In some cases, the patient is receiving an initial therapy or combination of initial therapies (referred to as an introduced dose) prior to administration of a subsequent therapy or combination of therapies. An "lead-in period" refers to a period of time in which a specified initial therapy or combination of initial therapies is administered prior to administration of a subsequent therapy or combination of therapies.

In embodiments, the method further comprises administering an introduced dose of mar Bei Tuoshan antibody prior to beginning administration of Bei Lantuo mab. In embodiments, the dose of MA Bei Tuo mab introduced is about 1.4 mg/kg to about 3.4 mg/kg, once during the introduction period. In embodiments, the dose of MA Bei Tuo mab introduced is about 1.4 mg/kg to about 1.9 mg/kg, once during the introduction period. In embodiments, the introduced dose of MA Bei Tuo mab is about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2.0 mg/kg, about 2.5 mg/kg, about 3.0 mg/kg, or about 3.4 mg/kg, once during the introduction period. In embodiments, the introduced dose of MA Bei Tuo mab is about 1.4 mg/kg, once during the introduction period. In embodiments, the introduced dose of MA Bei Tuo mab is about 1.9 mg/kg, once during the introduction period.

In embodiments, the induction period is four weeks ± 3 days, and the mar Bei Tuoshan antibody is administered on day 1 of the induction period.

In embodiments, the dose of MA Bei Tuo mab is administered parenterally, i.e., subcutaneously ((s.c. or SC), intrathecally, intraperitoneally, intramuscularly (i.m. or IM) or intravenously (i.v. or IV), including administration by intravenous infusion, in embodiments, the dose of MA Bei Tuo mab is administered intravenously, in embodiments, the dose of mab Bei Tuo was administered by intravenous infusion.

In embodiments, the mar Bei Tuoshan antibody is administered as monotherapy during the lead-in period. In embodiments, the mar Bei Tuoshan antibody is administered in combination with at least one additional treatment during the lead-in period. In embodiments, the mar Bei Tuoshan antibody is administered in combination with at least one additional cancer treatment during the lead-in period.

In embodiments, the additional cancer therapy for administration during the lead-in period is selected from the group consisting of an anti-CD 38 monoclonal antibody, a gamma-secretase inhibitor, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody.

Examples of anti-CD 38 antibodies that can be used in the methods described herein include, but are not limited to Ai Shatuo or Ai Shatuo mab-irfc (e.g., SARCLISA um) and darimumab (e.g., DARZALEX um, DARZALEX FASPRO um). In embodiments, the anti-CD 38 monoclonal antibody for administration during the lead-in period is selected from darimumab or Ai Shatuo mab.

Examples of gamma secretase inhibitors useful in the methods described herein include, but are not limited to, oginse Wei Ao (PF-0308014), CRENIGACESTAT (LY 3039478), CB-103, tarenflurbil, samadert (LY 450139), RG-4733, EVP-0962, celecoxib, MK-0752, and BMS-906024, and derivatives and polymorphs thereof.

Examples of proteasome inhibitors that may be used in the methods described herein include, but are not limited to, bortezomib (e.g., VELCADE), ib Sha Zuo meters (e.g., NINLARO), carfilzomib (e.g., KYPROLIS), oprozomib, and delazomib. In embodiments, the proteasome inhibitor for administration during the lead-in period is selected from bortezomib, carfilzomib, or ib Sha Zuomi. In embodiments, the proteasome inhibitor for administration during the lead-in period is bortezomib.

Examples of immunomodulatory imide drugs (ImiD) that may be used in the methods described herein include, but are not limited to, thalidomide (e.g., THALOMID cube), lenalidomide (e.g., REVLIMID cube), and pomalidomide (e.g., POMALYST cube). In embodiments, the immunomodulator for administration during the lead-in period is selected from thalidomide, lenalidomide or pomalidomide. In embodiments, the immunomodulator for administration during the lead-in period is lenalidomide or pomalidomide. In embodiments, the immunomodulatory agent for administration during the lead-in period is lenalidomide. In embodiments, the immunomodulatory agent for administration during the lead-in period is pomalidomide.

Examples of anti-PD-1 monoclonal antibodies that can be used in the methods described herein include, but are not limited to, pembrolizumab and rituximab. In embodiments, the anti-PD-1 monoclonal antibody is selected from pembrolizumab or rituximab.

In embodiments, the additional cancer treatment for administration during the lead-in period is selected from lenalidomide, pomalidomide, dexamethasone, or a combination thereof. In embodiments, additional cancer treatments for administration during the lead-in period are lenalidomide and dexamethasone. In embodiments, additional cancer treatments for administration during the lead-in period are pomalidomide and dexamethasone. In embodiments, additional cancer treatments for administration during the lead-in period are lenalidomide and dexamethasone. In embodiments, additional cancer treatments for administration during the lead-in period are bortezomib and dexamethasone. In embodiments, additional cancer treatments for administration during the lead-in period are pomalidomide, bortezomib, and dexamethasone. In embodiments, additional cancer treatments for administration during the lead-in period are lenalidomide, bortezomib, and dexamethasone.

In embodiments, the additional cancer therapy for administration during the lead-in period is standard of care therapy.

In embodiments, the additional cancer treatment for administration during the lead-in period is lenalidomide at a dose of 10 mg to 25 mg, once daily, for a period of time. In embodiments, the additional cancer treatment for administration during the lead-in period is lenalidomide, which is administered once daily at a dose of 10 mg to 25 mg on days 1-21 of the 28 day lead-in period.

In embodiments, the additional cancer treatment for administration during the lead-in period is dexamethasone. In embodiments, the additional cancer treatment for administration during the lead-in period is dexamethasone at a dose of 20 mg to 40 mg, once a week. In embodiments, if the patient is less than 75 years old, the additional cancer treatment for administration during the lead-in period is dexamethasone at a dose of 40 mg, once a week. In embodiments, if the patient is at least 75 years old, the additional cancer treatment for administration during the lead-in period is dexamethasone at a dose of 20 mg, once a week. In embodiments, if the patient's BMI is at least 18.5, then the additional cancer treatment for administration during the lead-in period is dexamethasone at a dose of 40 mg, once a week. In embodiments, if the patient's BMI is less than 18.5, then the additional cancer treatment for administration during the lead-in period is dexamethasone at a dose of 20 mg, once a week. In embodiments, dexamethasone is administered at days 1, 8, 15, and 22 of the 28 day introduction period.

In embodiments, additional cancer treatments for administration during the lead-in period are administration of 10 mg to 25 mg doses of lenalidomide once daily on days 1-21 of the 28 day lead-in period and 20 mg to 40 mg doses of dexamethasone on days 1, 8, 15 and 22 of the 28 day lead-in period. In embodiments, if the patient is less than 75 years old or the BMI is at least 18.5, then the additional cancer therapy for administration during the lead-in period is to administer 10 mg to 25 mg doses of lenalidomide once daily on days 1-21 of the 28 day lead-in period and 40 mg doses of dexamethasone on days 1, 8, 15 and 22 of the 28 day lead-in period. In embodiments, if the patient is at least 75 years old or the BMI is less than 18.5, then the additional cancer therapy for administration during the lead-in period is to administer 10 mg to 25 mg doses of lenalidomide once daily on days 1-21 of the 28 day lead-in period and 20 mg doses of dexamethasone on days 1, 8, 15 and 22 of the 28 day lead-in period.

In embodiments, the method comprises administering an introduced dose of mar Bei Tuo mab during an introduction period, followed by administration of Bei Lantuo mab during a subsequent treatment period. In embodiments, the method comprises administering an introduced dose of the mar Bei Tuoshan antibody (once during the introduction period) at a dose of about 1.4 mg/kg to about 3.4 mg/kg, followed by administration of Bei Lantuo mab at a dose of about 300 mg to about 2000 mg during a subsequent treatment period. In embodiments, the method comprises administering an introduced dose of the mar Bei Tuoshan antibody (once during the introduction period) at a dose of about 1.4 mg/kg, about 1.9 mg/kg, about 2.5 mg/kg, or about 3.4 mg/kg, followed by administration of the Bei Lantuo mab at a dose of about 300 mg, 900 mg, or about 2000 mg during a subsequent treatment period.

In some embodiments, the method further comprises applying a keratoscope (bandage contact lens) during the introduction period and/or the subsequent treatment period. Corneal bandaged lenses are therapeutic contact lenses made of soft, flexible plastic that allow oxygen to pass through to the cornea, which is worn in one or both eyes for a period of time to protect the cornea and/or treat ocular toxicity, such as that resulting from anti-treatment with a therapeutic agent such as mar Bei Tuoshan. In some embodiments, the keratology consists of N-carboxyvinyl ester (NCVE), N-vinyl pyrrolidone (NVE), poly [ dimethylsiloxy ] bis [ silylbutanol ] bis [ vinyl carbamate ] (PBVC), and/or tris- (trimethylsilyl) propylvinyl carbamate (TPVC). In some embodiments, the keratology consists of NCVE, NVE, PBVC and TPVC. In some embodiments, the keratology consists of NCVE, NVE, PBVC and TPVC, and has a moisture content of 30% to 40%, e.g., 30%, 32%, 34%, 36%, 38%, or 40%. In some embodiments, the keratology consists of NCVE, NVE, PBVC and TPVC, and has a moisture content of about 36%. In some embodiments, the keratoscope is made from silicone hydrogel a. Silicone hydrogel a is a copolymer of silicone vinyl urethane, N-vinyl-pyrrolidone, a siloxane crosslinking agent, and a vinyl alanine wetting monomer, and when immersed in a solution (e.g., saline solution), it is 36% water by weight.

Inlet Bei Lantuo monoclonal antibody

In embodiments, the method further comprises stopping administration of Bei Lantuo mab followed by administration of the mar Bei Tuoshan antibody. In embodiments, the MA Bei Tuo mab is administered at a dose of 2.5 mg/kg once every three weeks ± 3 days. In embodiments, the administration of Bei Lantuo mab is stopped after the patient exhibits progressive disease.

In embodiments, the method further comprises administering the mar Bei Tuo mab and then ceasing administration of the Bei Lantuo mab. In embodiments, the MA Bei Tuo mab is administered at a dose of 2.5 mg/kg once every three weeks ± 3 days. In embodiments, the administration of Bei Lantuo mab is stopped after the patient exhibits progressive disease.

Therapeutic methods using MA Bei Tuo mab

In one aspect, the present disclosure provides a method of treating a disease or disorder responsive to inhibiting or blocking B Cell Maturation Antigen (BCMA) in a patient, the method comprising administering to the patient a mar Bei Tuoshan antibody.

In embodiments, the mar Bei Tuoshan antibody is administered at a dose of about 1.4 mg/kg to about 3.4 mg/kg. In embodiments, the mar Bei Tuoshan antibody is administered at a dose of about 1.4 mg/kg to about 1.9 mg/kg. In embodiments, the marc Bei Tuoshan antibody is administered at a dose of about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2.0 mg/kg, about 2.5 mg/kg, about 3.0 mg/kg, or about 3.4 mg/kg. In embodiments, the mar Bei Tuoshan antibody is administered at a dose of about 1.4 mg/kg. In embodiments, the mar Bei Tuoshan antibody is administered at a dose of about 1.9 mg/kg. In embodiments, bei Lantuo mab is administered once every eight weeks ± 3 days.

In embodiments, the MA Bei Tuo mab is administered at a dose of about 1.4 mg/kg to about 3.4 mg/kg once every eight weeks ±3 days. In embodiments, the MA Bei Tuo mab is administered at a dose of about 1.4 mg/kg to about 1.9 mg/kg once every eight weeks ±3 days. In embodiments, the MA Bei Tuo mab is administered at a dose of about 1.4 mg/kg to about 1.9 mg/kg once every eight weeks ±3 days. In embodiments, the MA Bei Tuo mab is administered at a dose of about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2.0 mg/kg, about 2.5 mg/kg, about 3.0 mg/kg, or about 3.4 mg/kg once every eight weeks ± 3 days. In embodiments, the MA Bei Tuo mab is administered at a dose of about 1.4 mg/kg once every eight weeks ±3 days. In embodiments, the MA Bei Tuo mab is administered at a dose of about 1.9 mg/kg once every eight weeks ±3 days.

In some embodiments, the method further comprises applying a keratome.

Co-administration of BCMA antagonists

Described herein are methods of treating a disease or disorder in a patient benefiting from the inhibition or blocking of B Cell Maturation Antigen (BCMA). The use of BCMA inhibition or blocking therapy in the treatment of a disease or disorder in a patient is also described. In addition, described herein are kits comprising BCMA inhibition or blocking therapies and instructions for use.

In one aspect, the present disclosure provides a method of treating a disease or disorder responsive to inhibiting or blocking B Cell Maturation Antigen (BCMA) in a patient, the method comprising administering to the patient a therapeutically effective amount of a combination comprising a first BCMA antagonist and a second BCMA antagonist. The term "BCMA antagonist" refers to a molecule that specifically binds B Cell Maturation Antigen (BCMA) and inhibits BAFF and/or APRIL binding to BCMA receptor. Examples of BCMA antagonists include, but are not limited to, anti-BCMA antibodies or antigen binding fragments thereof, anti-BCMA antibody-drug conjugates, bispecific anti-BCMA antibodies or antigen binding fragments thereof, and chimeric antigen receptor T (CAR T) cell therapies targeting BCMA.

In embodiments, the first and second BCMA antagonists are independently selected from an anti-BCMA antibody or antigen binding fragment thereof, an anti-BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or antigen binding fragment thereof, and a chimeric antigen receptor T (CAR T) cell therapy targeting BCMA. The first BCMA antagonist is different from the second BCMA antagonist. In embodiments, the first and second BCMA antagonists are both anti-BCMA antibodies or fragments thereof, are both anti-BCMA antibody-drug conjugates, are both bispecific anti-BCMA antibodies or fragments thereof, or are chimeric antigen receptor T (CAR T) cell therapies that target BCMA. In embodiments, the first BCMA antagonist is an anti-BCMA antibody or antigen binding fragment thereof and the second BCMA antagonist is a different anti-BCMA antibody or antigen binding fragment thereof. In embodiments, the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is a different anti-BCMA antibody-drug conjugate. In embodiments, the first BCMA antagonist is a bispecific anti-BCMA antibody or antigen binding fragment thereof and the second BCMA antagonist is a different bispecific anti-BCMA antibody or antigen binding fragment thereof. In embodiments, the first BCMA antagonist is a BCMA-targeted chimeric antigen receptor T (CAR T) cell therapy and the second BCMA antagonist is a different BCMA-targeted chimeric antigen receptor T (CAR T) cell therapy.

In embodiments, the bispecific anti-BCMA antibody or antigen binding fragment thereof comprises an anti-BCMA antibody or antigen binding fragment thereof and an anti-CD 38 antibody or antigen binding fragment thereof. In embodiments, the bispecific anti-BCMA antibody or antigen binding fragment thereof specifically binds BCMA and CD3.

In embodiments, the first and second BCMA antagonists are independently selected from Ai Jiwei am, cildamascene, terituzumab, REGN5458, ma Bei Tuoshan antibody, bei Lantuo mab, SEA-BCMA, ABBV-383, elrantamab, pavurutumab, alnuctamab, MEDI2228, and CC99712.

In embodiments, the first BCMA antagonist is a mar Bei Tuoshan antibody. In embodiments, the first BCMA antagonist is Bei Lantuo mab.

In embodiments, the first BCMA antagonist is a mar Bei Tuo mab and the second BCMA antagonist is an anti-BCMA antibody or antigen binding fragment thereof. In embodiments, the first BCMA antagonist is a mar Bei Tuo mab and the second BCMA antagonist is an anti-BCMA antibody-drug conjugate. In embodiments, the first BCMA antagonist is a mar Bei Tuo mab and the second BCMA antagonist is a bispecific anti-BCMA antibody or antigen binding fragment thereof. In embodiments, the first BCMA antagonist is mar Bei Tuo mab and the second BCMA antagonist is a chimeric antigen receptor T (CAR T) cell therapy that targets BCMA.

In embodiments, the first BCMA antagonist is Bei Lantuo mab and the second BCMA antagonist is an anti-BCMA antibody or antigen binding fragment thereof. In embodiments, the first BCMA antagonist is Bei Lantuo mab and the second BCMA antagonist is an anti-BCMA antibody-drug conjugate. In embodiments, the first BCMA antagonist is Bei Lantuo mab and the second BCMA antagonist is a bispecific anti-BCMA antibody or antigen binding fragment thereof. In embodiments, the first BCMA antagonist is Bei Lantuo mab and the second BCMA antagonist is a chimeric antigen receptor T (CAR T) cell therapy targeting BCMA.

In embodiments, the first BCMA antagonist is mar Bei Tuo mab and the second BCMA antagonist is Ai Jiwei lamellate. In embodiments, the first BCMA antagonist is mar Bei Tuo mab and the second BCMA antagonist is sidaopranluki. In embodiments, the first BCMA antagonist is mar Bei Tuo mab and the second BCMA antagonist is territuximab. In embodiments, the first BCMA antagonist is mar Bei Tuo mab and the second BCMA antagonist is REGN5458. In embodiments, the first BCMA antagonist is mar Bei Tuo mab and the second BCMA antagonist is SEA-BCMA. In embodiments, the first BCMA antagonist is mar Bei Tuo mab and the second BCMA antagonist is ABBV-383. In embodiments, the first BCMA antagonist is mar Bei Tuo mab and the second BCMA antagonist is elrantamab. In embodiments, the first BCMA antagonist is mar Bei Tuo mab and the second BCMA antagonist is pavurutumab. In embodiments, the first BCMA antagonist is mar Bei Tuo mab and the second BCMA antagonist is alnuctamab. In embodiments, the first BCMA antagonist is mar Bei Tuo mab and the second BCMA antagonist is MEDI2228. In embodiments, the first BCMA antagonist is mar Bei Tuo mab and the second BCMA antagonist is CC99712.

In embodiments, the first BCMA antagonist is Bei Lantuo mab and the second BCMA antagonist is Ai Jiwei lamellate. In embodiments, the first BCMA antagonist is Bei Lantuo mab and the second BCMA antagonist is sidakyl olanexidine. In embodiments, the first BCMA antagonist is Bei Lantuo mab and the second BCMA antagonist is terituzumab. In embodiments, the first BCMA antagonist is Bei Lantuo mab and the second BCMA antagonist is REGN5458. In embodiments, the first BCMA antagonist is Bei Lantuo mab and the second BCMA antagonist is SEA-BCMA. In embodiments, the first BCMA antagonist is Bei Lantuo mab and the second BCMA antagonist is ABBV-383. In embodiments, the first BCMA antagonist is Bei Lantuo mab and the second BCMA antagonist is elrantamab. In embodiments, the first BCMA antagonist is Bei Lantuo mab and the second BCMA antagonist is pavurutumab. In embodiments, the first BCMA antagonist is Bei Lantuo mab and the second BCMA antagonist is alnuctamab. In embodiments, the first BCMA antagonist is Bei Lantuo mab and the second BCMA antagonist is MEDI2228. In embodiments, the first BCMA antagonist is Bei Lantuo mab and the second BCMA antagonist is CC99712.

In embodiments, the combination further comprises a third BCMA antagonist. In embodiments, the third BCMA antagonist is selected from the group consisting of an anti-BCMA antibody or antigen binding fragment thereof, an anti-BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or antigen binding fragment thereof, and a chimeric antigen receptor T (CAR T) cell therapy targeting BCMA. The third BCMA antagonist is different from the first and second BCMA antagonists. In embodiments, the third BCMA antagonist is selected from Ai Jiwei am, cilobronate, terituzumab, REGN5458, mar Bei Tuoshan, bei Lantuo mab, SEA-BCMA, ABBV-383, elrantamab, pavurutumab, alnuctamab, MEDI2228, and CC99712.

In embodiments, the combination comprises a mar Bei Tuoshan antibody, a Bei Lantuo mab, and an anti-BCMA antibody or antigen binding fragment thereof. In embodiments, the combination comprises a mar Bei Tuoshan antibody, a Bei Lantuo mab, and an anti-BCMA antibody-drug conjugate. In embodiments, the combination comprises a mar Bei Tuoshan antibody, a Bei Lantuo mab, and a bispecific anti-BCMA antibody or antigen binding fragment thereof. In embodiments, a chimeric antigen receptor T (CAR T) cell therapy comprising a mar Bei Tuoshan antibody, bei Lantuo mab, and a targeted BCMA is combined.

In embodiments, the combination comprises a mar Bei Tuoshan antibody, bei Lantuo mab, and Ai Jiwei lamellate. In embodiments, the combination comprises a mar Bei Tuoshan antibody, bei Lantuo mab, and a cetosteara. In embodiments, the combination comprises a mar Bei Tuoshan antibody, bei Lantuo mab, and teritumumab. In embodiments, the combination comprises a mar Bei Tuoshan antibody, bei Lantuo mab, and REGN5458. In embodiments, the combination comprises a mar Bei Tuoshan antibody, bei Lantuo mab, and SEA-BCMA. In an embodiment, the combination comprises a mar Bei Tuoshan antibody, bei Lantuo mab, and ABBV-383. In embodiments, the combination comprises a mar Bei Tuoshan antibody, bei Lantuo mab, and elrantamab. In embodiments, the combination comprises a mar Bei Tuoshan antibody, bei Lantuo mab, and pavurutumab. In embodiments, the combination comprises a mar Bei Tuoshan antibody, bei Lantuo mab, and alnuctamab. In embodiments, the combination comprises a mar Bei Tuoshan antibody, bei Lantuo mab, and MEDI2228. In embodiments, the combination comprises a mar Bei Tuoshan antibody, bei Lantuo mab, and CC99712.

In embodiments, the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is a corresponding unconjugated anti-BCMA antibody. In embodiments, the first BCMA antagonist is mar Bei Tuo mab and the second BCMA antagonist is Bei Lantuo mab. In embodiments, the first and second BCMA antagonists and the third BCMA antagonist (if present) are administered simultaneously, e.g., on the same day of the treatment cycle. In embodiments, the first and second BCMA antagonists and the third BCMA antagonist (if present) are administered on the same day of the treatment cycle. In embodiments, the first and second BCMA antagonists and the third BCMA antagonist (if present) are administered on different days of the treatment cycle during the same treatment cycle.

In embodiments, the first and second BCMA antagonists and the third BCMA antagonist (if present) are independently administered at least once every 8 weeks ± 3 days, at least once every 6 weeks ± 3 days, at least once every 4 weeks ± 3 days, at least once every 3 weeks ± 3 days, at least once every 2 weeks ± 3 days, at least once every week ± 3 days to every 8 weeks ± 3 days, once every week ± 3 days to every 6 weeks ± 3 days, once every week ± 3 days to every 4 weeks ± 3 days, once every week ± 3 days to every 3 weeks ± 3 days, once every week ± 3 days to every 2 weeks ± 3 days, once every 2 weeks ± 3 days to every 3 weeks ± 3 days, once every 3 weeks ± 3 days to every 4 weeks ± 3 days, once every 4 weeks ± 3 days to every 5 weeks ± 3 days, once every 5 weeks ± 3 days to every 6 weeks ± 3 days, once every 6 weeks ± 3 days to 7 weeks ± 3 days and/or once every 7 weeks ± 3 days to 8 days.

In some embodiments, the first and second BCMA antagonists and the third BCMA antagonist (if present) are administered in combination with the use of a keratology.

In embodiments, the first and second BCMA antagonists and the third BCMA antagonist (if present) are administered in combination with at least one additional treatment. In embodiments, the additional cancer treatment is selected from an anti-CD 38 monoclonal antibody, a gamma-secretase inhibitor, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody.

In embodiments, the additional cancer treatment is standard of care treatment.

In embodiments, the first and second BCMA antagonists and the third BCMA antagonist (if present) are administered on day 1 of the treatment cycle. In embodiments, the first and second BCMA antagonists and the third BCMA antagonist (if present) are administered on day 1 of a 28 day treatment cycle. In embodiments, the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg, once daily, for a period of time. In embodiments, the additional cancer treatment is lenalidomide, which is administered once daily at a dose of 10 mg to 25 mg on days 1-21 of the 28 day cycle. In embodiments, the additional cancer treatment is dexamethasone. In embodiments, the additional cancer treatment is dexamethasone at a dose of 20 mg to 40 mg, once a week. In embodiments, if the patient is less than 75 years old, the additional cancer treatment is dexamethasone at a dose of 40 mg, once a week. In embodiments, if the patient is at least 75 years old, the additional cancer treatment is dexamethasone at a dose of 20 mg, once a week. In embodiments, if the patient's BMI is at least 18.5, the additional cancer treatment is dexamethasone at a dose of 40 mg, once a week. In embodiments, if the patient's BMI is less than 18.5, the additional cancer treatment is dexamethasone at a dose of 20 mg, once a week. In embodiments, dexamethasone is administered at days 1, 8, 15, and 22 of the 28 day cycle. In embodiments, the additional cancer treatment is administration of 10 mg to 25 mg doses of lenalidomide once daily on days 1-21 of the 28 day cycle and 20 mg to 40 mg doses of dexamethasone on days 1, 8, 15, and 22 of the 28 day cycle. In embodiments, if the patient is less than 75 years old or the BMI is at least 18.5, the additional cancer treatment is to administer 10 mg to 25 mg doses of lenalidomide once daily on days 1-21 of the 28 day cycle and 40 mg doses of dexamethasone on days 1, 8, 15, and 22 of the 28 day cycle. In embodiments, if the patient is at least 75 years old or the BMI is less than 18.5, the additional cancer treatment is to administer 10 mg to 25 mg doses of lenalidomide once daily on days 1-21 of the 28 day cycle and 20 mg doses of dexamethasone on days 1, 8, 15, and 22 of the 28 day cycle.

In one aspect, the present disclosure provides a kit comprising (i) a first B Cell Maturation Antigen (BCMA) antagonist, and (ii) instructions for treating a disease or disorder responsive to inhibiting or blocking BCMA when combined with a second BCMA antagonist. In embodiments, the kit further comprises a third BCMA antagonist. In embodiments, the instructions further describe a method for treating a disease or disorder responsive to inhibiting or blocking BCMA when combined with a second and third BCMA antagonist.

In embodiments, the first, second, and third BCMA antagonists are independently selected from an anti-BCMA antibody or antigen binding fragment thereof, an anti-BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or antigen binding fragment thereof, and a chimeric antigen receptor T (CAR T) cell therapy targeting BCMA. In embodiments, the first, second, and third BCMA antagonists are independently selected from Ai Jiwei am, sidaoram, terituzumab, REGN5458, ma Bei Tuoshan, bei Lantuo mab, SEA-BCMA, ABBV-383, elrantamab, pavurutumab, alnuctamab, MEDI2228, and CC99712.

In one aspect, the disclosure provides a kit comprising (i) a mar Bei Tuoshan antibody, and (ii) instructions for treating a disease or disorder responsive to inhibiting or blocking BCMA when combined with Bei Lantuo mab.

In one aspect, the present disclosure provides a kit comprising (i) Bei Lantuo mab, and (ii) instructions for treating a disease or disorder responsive to inhibiting or blocking BCMA when combined with mar Bei Tuo mab.

Sequential use of BCMA antagonists

In one aspect, the present disclosure provides a method of treating a disease or disorder responsive to inhibiting or blocking B Cell Maturation Antigen (BCMA) in a patient previously treated with a first BCMA antagonist, the method comprising administering to the patient a therapeutically effective amount of a second BCMA antagonist, wherein the patient stops administration of the first BCMA antagonist before beginning administration of the second BCMA antagonist, and the second BCMA antagonist is different from the first BCMA antagonist.

In one aspect, the present disclosure provides a method of reducing corneal toxicity in a patient previously treated with a first B Cell Maturation Antigen (BCMA) antagonist, the method comprising administering to the patient a therapeutically effective amount of a second BCMA antagonist, wherein the patient stops administration of the first BCMA antagonist before beginning administration of the second BCMA antagonist, and the second BCMA antagonist is different from the first BCMA antagonist. "corneal toxicity" or "corneal adverse reaction" refers to changes in the cornea, including keratopathy (e.g., mild superficial keratopathy, moderate superficial keratopathy, severe superficial keratopathy) and corneal epithelial defects, such as corneal ulcers. In some embodiments, the corneal toxicity or corneal adverse reaction refers to keratopathy, and the severity or grade of such corneal adverse reaction can be determined according to the treatment-related corneal toxicity of table 2 using the Keratopathy Vision (KVA) scale. In some embodiments, the patient has grade 1 corneal adverse effects. In some embodiments, the patient has grade 2 corneal adverse effects. In some embodiments, the patient has grade 3 corneal adverse effects. In some embodiments, the patient has grade 4 corneal adverse effects. In some embodiments, reducing ocular toxicity refers to reducing the severity of a corneal adverse reaction or the grade of treatment-related corneal toxicity, as determined according to the KVA scale.

TABLE 2

Abbreviations BCVA = best corrected vision, KVA = keratopathy vision, logMAR = logarithm of minimum resolution angle, SPK = superficial punctate keratitis.

In embodiments, the first and second BCMA antagonists are independently selected from an anti-BCMA antibody or antigen binding fragment thereof, an anti-BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or antigen binding fragment thereof, and a chimeric antigen receptor T (CAR T) cell therapy targeting BCMA. The first BCMA antagonist is different from the second BCMA antagonist. In embodiments, the first and second BCMA antagonists are both anti-BCMA antibodies or fragments thereof, are both anti-BCMA antibody-drug conjugates, are both bispecific anti-BCMA antibodies or fragments thereof, or are both chimeric antigen receptor T (CAR T) cell therapies targeting BCMA. In embodiments, the first BCMA antagonist is an anti-BCMA antibody or antigen binding fragment thereof and the second BCMA antagonist is a different anti-BCMA antibody or antigen binding fragment thereof. In embodiments, the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is a different anti-BCMA antibody-drug conjugate. In embodiments, the first BCMA antagonist is a bispecific anti-BCMA antibody or antigen binding fragment thereof and the second BCMA antagonist is a different bispecific anti-BCMA antibody or antigen binding fragment thereof. In embodiments, the first BCMA antagonist is a BCMA-targeted chimeric antigen receptor T (CAR T) cell therapy and the second BCMA antagonist is a different BCMA-targeted chimeric antigen receptor T (CAR T) cell therapy.

In embodiments, the bispecific anti-BCMA antibody or antigen binding fragment thereof comprises an anti-BCMA antibody or antigen binding fragment thereof and an anti-CD 38 antibody or antigen binding fragment thereof. In embodiments, the bispecific anti-BCMA antibody or antigen binding fragment thereof comprises an anti-BCMA antibody or antigen binding fragment thereof and an anti-CD 3 antibody or antigen binding fragment thereof.

In embodiments, the first BCMA antagonist is a mar Bei Tuoshan antibody. In embodiments, the first BCMA antagonist is Bei Lantuo mab. In embodiments, the second BCMA antagonist is a mar Bei Tuoshan antibody. In embodiments, the second BCMA antagonist is Bei Lantuo mab.

In embodiments, the first BCMA antagonist is a mar Bei Tuo mab and the second BCMA antagonist is an anti-BCMA antibody or antigen binding fragment thereof. In embodiments, the first BCMA antagonist is a mar Bei Tuo mab and the second BCMA antagonist is an anti-BCMA antibody-drug conjugate. In embodiments, the first BCMA antagonist is a mar Bei Tuo mab and the second BCMA antagonist is a bispecific anti-BCMA antibody or antigen binding fragment thereof. In embodiments, the first BCMA antagonist is mar Bei Tuo mab and the second BCMA antagonist is a chimeric antigen receptor T (CAR T) cell therapy that targets BCMA. In embodiments, the first BCMA antagonist is an anti-BCMA antibody or antigen binding fragment thereof and the second BCMA antagonist is a mar Bei Tuoshan antibody. In embodiments, the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is a mar Bei Tuoshan antibody. In embodiments, the first BCMA antagonist is a bispecific anti-BCMA antibody or antigen binding fragment thereof and the second BCMA antagonist is a mar Bei Tuoshan antibody. In embodiments, the first BCMA antagonist is a chimeric antigen receptor T (CAR T) cell therapy targeting BCMA and the second BCMA antagonist is a mar Bei Tuoshan antibody.

In embodiments, the first BCMA antagonist is Bei Lantuo mab and the second BCMA antagonist is an anti-BCMA antibody or antigen binding fragment thereof. In embodiments, the first BCMA antagonist is Bei Lantuo mab and the second BCMA antagonist is an anti-BCMA antibody-drug conjugate. In embodiments, the first BCMA antagonist is Bei Lantuo mab and the second BCMA antagonist is a bispecific anti-BCMA antibody or antigen binding fragment thereof. In embodiments, the first BCMA antagonist is Bei Lantuo mab and the second BCMA antagonist is a chimeric antigen receptor T (CAR T) cell therapy targeting BCMA. In embodiments, the first BCMA antagonist is an anti-BCMA antibody or antigen binding fragment thereof and the second BCMA antagonist is Bei Lantuo mab. In embodiments, the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is Bei Lantuo mab. In embodiments, the first BCMA antagonist is a bispecific anti-BCMA antibody or antigen binding fragment thereof and the second BCMA antagonist is Bei Lantuo mab. In embodiments, the first BCMA antagonist is a chimeric antigen receptor T (CAR T) cell therapy targeting BCMA and the second BCMA antagonist is Bei Lantuo mab.

In embodiments, the first BCMA antagonist is mar Bei Tuo mab and the second BCMA antagonist is Ai Jiwei lamellate. In embodiments, the first BCMA antagonist is mar Bei Tuo mab and the second BCMA antagonist is sidaopranluki. In embodiments, the first BCMA antagonist is mar Bei Tuo mab and the second BCMA antagonist is territuximab. In embodiments, the first BCMA antagonist is mar Bei Tuo mab and the second BCMA antagonist is REGN5458. In embodiments, the first BCMA antagonist is mar Bei Tuo mab and the second BCMA antagonist is SEA-BCMA. In embodiments, the first BCMA antagonist is Ai Jiwei am and the second BCMA antagonist is a mar Bei Tuoshan antagonist. In embodiments, the first BCMA antagonist is sidaocloxel and the second BCMA antagonist is a mar Bei Tuoshan antagonist. In embodiments, the first BCMA antagonist is terituzumab and the second BCMA antagonist is mar Bei Tuoshan. In embodiments, the first BCMA antagonist is REGN5458 and the second BCMA antagonist is a mar Bei Tuoshan antagonist. In embodiments, the first BCMA antagonist is SEA-BCMA and the second BCMA antagonist is a mar Bei Tuoshan antagonist. In embodiments, the first BCMA antagonist is ABBV-383 and the second BCMA antagonist is a mar Bei Tuoshan antagonist. In embodiments, the first BCMA antagonist is elrantamab and the second BCMA antagonist is a mar Bei Tuoshan antagonist. In embodiments, the first BCMA antagonist is pavurutumab and the second BCMA antagonist is a mar Bei Tuoshan antagonist. In embodiments, the first BCMA antagonist is alnuctamab and the second BCMA antagonist is a mar Bei Tuoshan antagonist. In embodiments, the first BCMA antagonist is MEDI2228 and the second BCMA antagonist is mar Bei Tuoshan antagonist. In embodiments, the first BCMA antagonist is CC99712 and the second BCMA antagonist is a mar Bei Tuoshan antagonist.

In embodiments, the first BCMA antagonist is Bei Lantuo mab and the second BCMA antagonist is Ai Jiwei lamellate. In embodiments, the first BCMA antagonist is Bei Lantuo mab and the second BCMA antagonist is sidakyl olanexidine. In embodiments, the first BCMA antagonist is Bei Lantuo mab and the second BCMA antagonist is terituzumab. In embodiments, the first BCMA antagonist is Bei Lantuo mab and the second BCMA antagonist is REGN5458. In embodiments, the first BCMA antagonist is Bei Lantuo mab and the second BCMA antagonist is SEA-BCMA. In embodiments, the first BCMA antagonist is Ai Jiwei am and the second BCMA antagonist is Bei Lantuo mab. In embodiments, the first BCMA antagonist is sidaky olanexidine and the second BCMA antagonist is Bei Lantuo mab. In embodiments, the first BCMA antagonist is terituzumab and the second BCMA antagonist is Bei Lantuo mab. In embodiments, the first BCMA antagonist is REGN5458 and the second BCMA antagonist is Bei Lantuo mab. In embodiments, the first BCMA antagonist is SEA-BCMA and the second BCMA antagonist is Bei Lantuo mab. In embodiments, the first BCMA antagonist is ABBV-383 and the second BCMA antagonist is Bei Lantuo mab. In embodiments, the first BCMA antagonist is elrantamab and the second BCMA antagonist is Bei Lantuo mab. In embodiments, the first BCMA antagonist is pavurutumab and the second BCMA antagonist is Bei Lantuo mab. In embodiments, the first BCMA antagonist is alnuctamab and the second BCMA antagonist is Bei Lantuo mab. In embodiments, the first BCMA antagonist is MEDI2228 and the second BCMA antagonist is Bei Lantuo mab. In embodiments, the first BCMA antagonist is CC99712 and the second BCMA antagonist is Bei Lantuo mab.

In embodiments, the method further comprises administering to the patient a therapeutically effective amount of a combination of a third BCMA antagonist and a second BCMA antagonist, wherein the patient stops administration of the first BCMA antagonist before starting administration of the second and third BCMA antagonists, and the third BCMA antagonist is different from the first and second BCMA antagonists.

In embodiments, the first BCMA antagonist is an anti-BCMA antibody or antigen binding fragment thereof, the second BCMA antagonist is mar Bei Tuo mab, and the third BCMA antagonist is Bei Lantuo mab. In embodiments, the first BCMA antagonist is an anti-BCMA antibody-drug conjugate, the second BCMA antagonist is mar Bei Tuo mab, and the third BCMA antagonist is Bei Lantuo mab. In embodiments, the first BCMA antagonist is a bispecific anti-BCMA antibody or antigen binding fragment thereof, the second BCMA antagonist is mar Bei Tuo mab, and the third BCMA antagonist is Bei Lantuo mab. In embodiments, the first BCMA antagonist is a chimeric antigen receptor T (CAR T) cell therapy targeting BCMA, the second BCMA antagonist is mar Bei Tuo mab, and the third BCMA antagonist is Bei Lantuo mab.

In embodiments, the first BCMA antagonist is Ai Jiwei am, the second BCMA antagonist is mar Bei Tuo mab, and the third BCMA antagonist is Bei Lantuo mab. In embodiments, the first BCMA antagonist is cetosteara, the second BCMA antagonist is mar Bei Tuo mab, and the third BCMA antagonist is Bei Lantuo mab. In embodiments, the first BCMA antagonist is teritumumab, the second BCMA antagonist is mar Bei Tuo mab, and the third BCMA antagonist is Bei Lantuo mab. In embodiments, the first BCMA antagonist is REGN5458, the second BCMA antagonist is mar Bei Tuo mab, and the third BCMA antagonist is Bei Lantuo mab. In embodiments, the first BCMA antagonist is SEA-BCMA, the second BCMA antagonist is mar Bei Tuo mab, and the third BCMA antagonist is Bei Lantuo mab. In embodiments, the first BCMA antagonist is ABBV-383, the second BCMA antagonist is a mar Bei Tuo mab, and the third BCMA antagonist is a Bei Lantuo mab. In embodiments, the first BCMA antagonist is elrantamab, the second BCMA antagonist is a mar Bei Tuo mab, and the third BCMA antagonist is a Bei Lantuo mab. In embodiments, the first BCMA antagonist is pavurutumab, the second BCMA antagonist is a mar Bei Tuo mab, and the third BCMA antagonist is a Bei Lantuo mab. In embodiments, the first BCMA antagonist is alnuctamab, the second BCMA antagonist is a mar Bei Tuo mab, and the third BCMA antagonist is a Bei Lantuo mab. In embodiments, the first BCMA antagonist is MEDI2228, the second BCMA antagonist is mar Bei Tuo mab, and the third BCMA antagonist is Bei Lantuo mab. In embodiments, the first BCMA antagonist is CC99712, the second BCMA antagonist is a mar Bei Tuo mab, and the third BCMA antagonist is a Bei Lantuo mab.

In embodiments, the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is a corresponding unconjugated anti-BCMA antibody. In embodiments, the second BCMA antagonist is an anti-BCMA antibody-drug conjugate and the first BCMA antagonist is a corresponding unconjugated anti-BCMA antibody. In embodiments, the first BCMA antagonist is mar Bei Tuo mab and the second BCMA antagonist is Bei Lantuo mab. In embodiments, the first BCMA antagonist is Bei Lantuo mab and the second BCMA antagonist is a mar Bei Tuoshan antagonist.

In embodiments, the second BCMA antagonist and the third BCMA antagonist (if present) are independently administered at least once every 8 weeks ± 3 days, at least once every 6 weeks ± 3 days, at least once every 4 weeks ± 3 days, at least once every 3 weeks ± 3 days, at least once every 2 weeks ± 3 days, at least once every 3 days, once every week ± 3 days to every 8 weeks ± 3 days, once every 3 days to every 6 weeks ± 3 days, once every 4 weeks ± 3 days, once every 3 weeks ± 3 days, once every 2 weeks ± 3 days to every 3 weeks ± 3 days, once every 3 weeks ± 3 days to every 4 weeks ± 3 days, once every 4 weeks ± 3 days to every 5 weeks ± 3 days, once every 5 weeks ± 3 days to 6 weeks ± 3 days, once every 6 weeks ± 3 days to 7 weeks ± 3 days and/or once every 7 weeks ± 3 days to 8 ± 3 days.

In embodiments, the second BCMA antagonist and the third BCMA antagonist (if present) are administered in combination with the use of a keratometric.

In embodiments, the second BCMA antagonist and the third BCMA antagonist (if present) are administered in combination with at least one additional treatment. In embodiments, the additional cancer treatment is selected from an anti-CD 38 monoclonal antibody, a gamma-secretase inhibitor, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody.

In embodiments, the additional cancer treatment is standard of care treatment.

In embodiments, the second BCMA antagonist and the third BCMA antagonist (if present) are administered on day 1 of the treatment cycle. In embodiments, the second BCMA antagonist and the third BCMA antagonist (if present) are administered on day 1 of a 28 day treatment cycle. In embodiments, the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg, once daily, for a period of time. In embodiments, the additional cancer treatment is lenalidomide, which is administered once daily at a dose of 10 mg to 25 mg on days 1-21 of the 28 day cycle. In embodiments, the additional cancer treatment is dexamethasone. In embodiments, the additional cancer treatment is dexamethasone at a dose of 20 mg to 40 mg, once a week. In embodiments, if the patient is less than 75 years old, the additional cancer treatment is dexamethasone at a dose of 40 mg, once a week. In embodiments, if the patient is at least 75 years old, the additional cancer treatment is dexamethasone at a dose of 20 mg, once a week. In embodiments, if the patient's BMI is at least 18.5, then the additional cancer treatment is dexamethasone at a dose of 40 mg, once a week. In embodiments, if the patient's BMI is less than 18.5, the additional cancer treatment is dexamethasone at a dose of 20 mg, once a week. In embodiments, dexamethasone is administered at days 1, 8, 15, and 22 of the 28 day cycle. In embodiments, the additional cancer treatment is administration of 10 mg to 25 mg doses of lenalidomide once daily on days 1-21 of the 28 day cycle and 20 mg to 40 mg doses of dexamethasone on days 1, 8, 15, and 22 of the 28 day cycle. In embodiments, if the patient is less than 75 years old or the BMI is at least 18.5, an additional cancer treatment regimen is to administer 10 mg to 25 mg doses of lenalidomide once daily on days 1-21 of the 28 day cycle and 40 mg doses of dexamethasone on days 1, 8, 15, and 22 of the 28 day cycle. In embodiments, if the patient is at least 75 years old or the BMI is less than 18.5, then an additional cancer treatment is to administer once daily 10 mg to 25 mg doses of lenalidomide on days 1-21 of the 28 day cycle and 20 mg doses of dexamethasone on days 1, 8, 15, and 22 of the 28 day cycle.

In embodiments, the first BCMA antagonist is stopped after the patient exhibits progressive disease.

Combination of an antibody-drug conjugate with a corresponding unconjugated antibody

In some cases, an immunoconjugate or antibody-drug conjugate is used in combination with its corresponding unconjugated antibody. When used with reference to an immunoconjugate or antibody-drug conjugate (ADC), the corresponding unconjugated antibody refers to the antibody portion of the immunoconjugate or ADC that lacks the cytotoxic payload of the immunoconjugate or ADC and optionally any linker moiety. In one aspect, the present disclosure provides a method of treating a disease or disorder in a patient, the method comprising administering to the patient a therapeutically effective amount of a combination comprising an antibody-drug conjugate and a corresponding unconjugated antibody.

In one aspect, the present disclosure provides a method of reducing toxicity of an antibody-drug conjugate, the method comprising administering to a patient in need thereof a therapeutically effective amount of a combination comprising an antibody-drug conjugate and a corresponding unconjugated antibody to the patient.

In one aspect, the present disclosure provides a method of toxicity in a patient previously treated with an antibody-drug conjugate, the method comprising administering to the patient a therapeutically effective amount of a corresponding unconjugated antibody, wherein the patient ceases administration of the antibody-drug conjugate prior to commencing administration of the corresponding unconjugated antibody.

In embodiments, the antibody-drug conjugate is selected from the group consisting of gemtuzumab ozogamicin, vitamin b uzumab, enmetrastuzumab, oxepituzumab, polotouzumab, wien You Shan antibody, detrastuzumab, go Sha Tuozhu mab, ma Bei Tuoshan antibody, rituximab, tixostat, mositumomab, MEDI2228, or CC99712.

Diseases and disorders

Described herein are methods of treating a disease or disorder in a patient benefiting from the inhibition or blocking of B Cell Maturation Antigen (BCMA). The use of BCMA inhibition or blocking therapy in the treatment of a disease or disorder in a patient is also described.

In embodiments, the disease or disorder is a plasma cell disorder or a B cell disorder. B cell disorders can be categorized as defective B cell development/immunoglobulin production (immunodeficiency) and excessive/uncontrolled proliferation (lymphomas, leukemias). As used herein, B cell disorders refer to both types of disease and provide a method of treating B cell disorders. In some embodiments, the cancer may be a B-cell cancer (e.g., leukemia and lymphoma).

Examples of diseases or disorders that may be treated according to the methods described herein include Multiple Myeloma (MM), chronic Lymphocytic Leukemia (CLL), follicular Lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), non-secretory multiple myeloma, smoky multiple myeloma, monoclonal Gammaglobulopathy of Unknown Significance (MGUS), isolated plasma cell neoplasm (bone, extramedullary), lymphoplasmacytic lymphoma (LPL), waldenstrom macroglobulinemia (WALDENSTR m's Macroglobulinemia), plasma cell leukemia, primary Amyloidosis (AL), heavy chain disease, systemic Lupus Erythematosus (SLE), poe ms syndrome/bone sclerosis myeloma, type I and II cryoglobulinemia, light chain deposition disease, goodpasture's sydrome), idiopathic Thrombocytopenic Purpura (ITP), acute glomerulonephritis, pemphigus and pemphigoid, epidermoid and epidermolysis, or any other lymphomatosis (HL) and non-hodgkin's lymphoma. In some cases, the disease or disorder may be selected from Multiple Myeloma (MM), non-hodgkin's lymphoma B-cell leukemia (NHL), follicular Lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL). In embodiments, the disease may be multiple myeloma or non-hodgkin's lymphoma B-cell leukemia (NHL). In embodiments, the disease may be multiple myeloma.

In embodiments, the disease or disorder is BCMA-expressing cancer. In embodiments, the disease or disorder is Multiple Myeloma (MM). In embodiments, the MM is a relapsed and/or refractory MM, a newly diagnosed MM, a MM unsuitable for transplantation, or a newly diagnosed MM unsuitable for transplantation. In embodiments, the disease or disorder is multiple myeloma that was previously treated with at least one, at least two, at least three, or at least four therapeutic agents. In embodiments, the disease or disorder is relapsed and/or refractory multiple myeloma that was previously treated with at least one, at least two, at least three, or at least four therapeutic agents. In another embodiment, the disease or disorder is relapsed and/or refractory multiple myeloma previously treated with at least 3 previous lines of therapy, which may include immunomodulatory drugs (ImiD), proteasome Inhibitors (PI), and anti-CD 38 therapies (e.g., darimumab), or a combination thereof. The line of therapy may be defined by the consensus group of the international myeloma seminar (IMWG). In some embodiments, a patient receiving prior line treatment may have recurrent, and/or refractory cancer. In some cases, the cancer may be a primary cancer. In some cases, the cancer may be a metastatic cancer. In some cases, the cancer may be a chemically resistant cancer.

In embodiments, the disease or disorder is an autoimmune disease or disorder. In embodiments, the disease or disorder is Systemic Lupus Erythematosus (SLE), idiopathic Thrombocytopenic Purpura (ITP), rheumatoid arthritis, type 1 diabetes, multiple sclerosis, or psoriasis.

Antibody sequences

The term "Bei Lantuo mab" refers to a B Cell Maturation Antigen (BCMA) blocking antibody ("anti-BCMA antibody"), or a functional fragment or functional variant thereof, which specifically binds to BCMA and which inhibits the binding of BAFF and/or APRIL to BCMA receptor, comprising an immunoglobulin heavy chain variable domain (VH) comprising Complementarity Determining Region (CDR) H1 comprising the amino acid sequence of SEQ ID No. 5, CDRH2 comprising the amino acid sequence of SEQ ID No. 6, CDRH3 comprising the amino acid sequence of SEQ ID No. 7, and an immunoglobulin light chain variable domain (VL) comprising CDRL1 comprising the amino acid sequence of SEQ ID No. 8, CDRL2 comprising the amino acid sequence of SEQ ID No. 9, and CDRL3 comprising the amino acid sequence of SEQ ID No. 10. Exemplary antibody heavy chain variable region and light chain variable region sequences are provided in table 3 below. In certain embodiments, the VH comprises the amino acid sequence of SEQ ID NO. 3. In certain embodiments, the VL comprises the amino acid sequence of SEQ ID NO. 4. In certain embodiments, the heavy chain comprises the amino acid sequence of SEQ ID NO. 1. In certain embodiments, the light chain comprises the amino acid sequence of SEQ ID NO. 2. In certain other embodiments, bei Lantuo mab comprises a VH comprising the amino acid sequence of SEQ ID No. 3 and a VL comprising the amino acid sequence of SEQ ID No. 4. In other embodiments, bei Lantuo monoclonal antibodies comprise the heavy and light chain sequences of SEQ ID NO. 1 and SEQ ID NO. 2, respectively.

The terms "MA Bei Tuoshan anti" and "belamaf" are used interchangeably and refer to immunoconjugates comprising Bei Lantuo mab conjugated to monomethyl auristatin F (MMAF) via a 6-Maleimidocaproyl (MC) linker.

The term "biosimilar" refers to a biopharmaceutical or biological product that is highly similar to a reference biological product (e.g., bei Lantuo mab or mar Bei Tuoshan antibody), although there are subtle differences in clinically inactive ingredients, and there are no clinically significant differences between the biological product and the reference product in terms of safety, purity and potency of the product (public health services code 351 (i) section (42 u.s.c.262 (i)).

Thus, the term "biosimilar" refers to a biosystem that is highly similar to a reference product (e.g., bei Lantuo mab or mar Bei Tuoshan antibody) as approved by a regulatory agency (e.g., the U.S. Food and Drug Administration (FDA) or European Medicines Administration (EMA)) based on data from (a) analytical studies that indicate that, despite subtle differences in clinically inactive ingredients, the biosystem is highly similar to the reference product, (b) animal studies (including toxicity assessment), and/or (c) one or more clinical studies (including immunogenicity and pharmacokinetic or pharmacodynamic assessment) that are sufficient to demonstrate safety, purity, and efficacy (e.g., no clinically meaningful differences between the biosystem and the reference product in terms of safety, purity, and efficacy of the product) under one or more appropriate use conditions in which the reference product is approved and intended for approval is sought. In certain embodiments, the biosimilar product is an interchangeable product determined by regulatory authorities (e.g., FDA).

It will generally be appreciated that a biological analogue of MA Bei Tuo mab will comprise post-translational modifications critical to the function and efficacy of MA Bei Tuo mab (as disclosed in international patent application publication number WO 2021/024333). However, in certain embodiments, a biological analog (e.g., a biological analog of Bei Lantuo mab or mar Bei Tuo mab) may comprise one or more molecular differences, such as post-translational modifications, such as, but not limited to, glycosylation, oxidation, deamidation, and/or truncation, that differ from the post-translational modifications of a reference drug product (e.g., bei Lantuo mab or mar Bei Tuoshan antibody), provided that such differences do not result in significant changes in the safety and/or efficacy of the drug product. In certain embodiments, a biological analog (e.g., a biological analog of Bei Lantuo mab or mar Bei Tuo mab) may have the same or different glycosylation pattern as a reference drug product (e.g., bei Lantuo mab or mar Bei Tuoshan antibody). In particular, but not exclusively, a biological analogue (e.g., bei Lantuo mab or a biological analogue of the MA Bei Tuo mab) may have different glycosylation patterns, for example, if the difference is to address or aims at addressing the safety issues associated with a reference drug product (e.g., bei Lantuo mab or the MA Bei Tuoshan antibody). Furthermore, a biological analog (e.g., bei Lantuo mab or a biological analog of mar Bei Tuo mab) may deviate from a reference drug product (e.g., bei Lantuo mab or mar Bei Tuoshan antibody) in terms of, for example, its strength, pharmaceutical form, formulation, excipient, and/or presentation, provided that the safety and efficacy of the drug product are not compromised. In other embodiments, a biological analog (e.g., a biological analog of Bei Lantuo mab or mar Bei Tuo mab) may include differences in, for example, pharmacokinetic (PK) and/or Pharmacodynamic (PD) profiles as compared to a reference drug product (e.g., bei Lantuo mab or mar Bei Tuoshan mab), but still be considered similar enough to the reference drug product to be authorized or considered suitable for authorization. In certain embodiments, a biological analog (e.g., a biological analog of Bei Lantuo mab or mar Bei Tuo mab) may exhibit different binding characteristics as compared to a reference drug product (e.g., bei Lantuo mab or mar Bei Tuoshan mab), wherein the different binding characteristics are not considered by regulatory authorities (such as the FDA and/or EMA) to be an obstacle to authorization as a similar biological product. The term "biological analogue" is also synonymously used by other national and regional regulatory authorities.

It should be understood that the international non-proprietary name (INN) of a drug (e.g., bei Lantuo mab or mar Bei Tuoshan antibody) should be interpreted to include a simulated, bioequivalent, and/or bioequivalent version of the drug, including, but not limited to, any drug that achieves simplified regulatory approval by reference to the drug's earlier regulatory approval. Furthermore, the INN of the drug optionally includes, but is not limited to, a glycosylated variant of Bei Lantuo mab or mar Bei Tuo mab and biological analogs thereof.

TABLE 3 Table 3

Description of the embodiments

Embodiment 1 is a method of treating a disease or disorder responsive to inhibiting or blocking B Cell Maturation Antigen (BCMA) in a patient comprising administering Bei Lantuo mab to the patient at a dose of about 300 mg to about 2000 mg.

Embodiment 2 is the method of embodiment 1, wherein the dose is about 300 mg, about 900 mg, or about 2000 mg.

Embodiment 3 is the method of embodiment 1 or 2, wherein the dose is administered at regular intervals for a period of time.

Embodiment 4 is the method of embodiment 1 or 2, wherein the dose is administered once per week ± 3 days to once every four weeks ± 3 days.

Embodiment 5 is the method of embodiment 1 or 2, wherein the dose is administered once every two weeks ± 3 days.

Embodiment 6 is the method of embodiment 1 or 2, wherein the dose is administered once every three weeks ± 3 days.

Embodiment 7 is the method of embodiment 1 or 2, wherein the dose is administered once every four weeks ± 3 days.

Embodiment 8 is the method of embodiment 1 or 2, wherein the dose is administered on days 1 and 15 of a 28 day cycle.

Embodiment 9 is the method of embodiment 1 or 2, wherein the dose is administered on day 1 of the 21-day cycle.

Embodiment 10 is the method of any one of the preceding embodiments, wherein the patient has been treated with at least one previous line of cancer treatment.

Embodiment 11 is the method of any one of the preceding embodiments, wherein the patient has been treated with one, two, three, or four previous lines of cancer treatment.

Embodiment 12 is the method of embodiment 11, wherein the prior line of cancer treatment comprises an anti-CD 38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.

Embodiment 13 is the method of any one of the preceding embodiments, wherein Bei Lantuo mab is administered by intravenous infusion or subcutaneous injection.

Embodiment 14 is the method of any one of the preceding embodiments, wherein the patient is further receiving at least one additional cancer treatment, such as an anti-CD 38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody.

Embodiment 15 is the method of embodiment 14, wherein the additional cancer treatment is selected from lenalidomide, dexamethasone, darimumab, ai Shatuo ximab, pomalidomide, bortezomib, or a combination thereof, e.g., lenalidomide and dexamethasone.

Embodiment 16 is the method of embodiment 15, wherein the additional cancer treatment is lenalidomide at a dose of 10 mg to 25mg, once daily, for a period of time.

Embodiment 17 is the method of embodiment 16, wherein the patient receives lenalidomide on days 1-21 of a 28 day cycle.

Embodiment 18 is the method of any one of embodiments 14 to 17, wherein the additional cancer treatment is dexamethasone.

Embodiment 19 is the method of embodiment 18, wherein the additional cancer treatment is dexamethasone at a dose in the range of 20 mg to 40 mg, once per week.

Embodiment 20 is the method of embodiment 19, wherein the patient receives dexamethasone on days 1, 8, 15, and 22 of the 28 day cycle.

Embodiment 21 is the method of embodiment 19, wherein (i) the patient is less than 75 years old and is receiving dexamethasone at a dose of 40 mg a week, or (ii) the patient is at least 75 years old and is receiving dexamethasone at a dose of 20 a week mg.

Embodiment 22 is the method of embodiment 19, wherein (i) the patient has a BMI of at least 18.5 and is receiving dexamethasone at a dose of 40 mg a week, or (ii) the patient has a BMI of less than 18.5 and is receiving dexamethasone at a dose of 20 mg a week.

Embodiment 23 is the method of any one of the preceding embodiments, further comprising ceasing administration of Bei Lantuo mab and subsequently administering a mar Bei Tuoshan antibody.

Embodiment 24 is the method of any one of embodiments 1 to 22, further comprising administering a mar Bei Tuoshan antibody and then ceasing administration of Bei Lantuo mab.

Embodiment 25 is the method of embodiment 23 or 24, wherein the mar Bei Tuoshan antibody is administered at a dose of 2.5 mg/kg once every three weeks ± 3 days.

Embodiment 26 is the method of any one of the preceding embodiments, further comprising administering an introduced dose of mab Bei Tuo prior to beginning administration of Bei Lantuo mab, wherein the introduced dose of mab Bei Tuo is about 1.4 mg/kg to about 3.4 mg/kg once during the introduction period.

Embodiment 27 is the method of embodiment 26, wherein the introduced dose of the mar Bei Tuo mab is about 1.4 mg/kg to about 1.9 mg/kg once during the introduction period.

Embodiment 28 is the method of embodiment 26, wherein the introduced dose of the mar Bei Tuo mab is about 1.4 mg/kg, about 1.9 mg/kg, about 2.5 mg/kg, or about 3.4 mg/kg, once during the introduction period.

Embodiment 29 is the method of embodiment 26, wherein the introduced dose of the mar Bei Tuo mab is about 1.4 mg/kg, once during the introduction period.

Embodiment 30 is the method of any one of embodiments 26 to 29, wherein the induction period is four weeks ± 3 days, and the mar Bei Tuoshan antibody is administered on day 1 of the induction period.

Embodiment 31 is the method of any one of embodiments 26 to 30, further comprising administering at least one additional cancer treatment, such as an anti-CD 38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody, to the patient during the lead-in period.

Embodiment 32 is the method of embodiment 31, wherein the additional cancer treatment is selected from lenalidomide, dexamethasone, darimumab, ai Shatuo ximab, pomalidomide, bortezomib, or a combination thereof, e.g., lenalidomide and dexamethasone.

Embodiment 33 is the method of embodiment 32, wherein the additional cancer treatment is lenalidomide at a dose of 10 mg to 25mg, once daily, for a period of time.

Embodiment 34 is the method of embodiment 33, wherein lenalidomide is administered to the patient on days 1-21 of the lead-in period.

Embodiment 35 is the method of any one of embodiments 32 to 34, wherein the additional cancer treatment is dexamethasone.

Embodiment 36 is the method of embodiment 35, wherein the additional cancer treatment is dexamethasone at a dose in the range of 20 mg to 40 mg, once per week.

Embodiment 37 is the method of embodiment 36, wherein dexamethasone is administered to the patient at days 1, 8, 15, and 22 of the infusion period.

Embodiment 38 is the method of embodiment 36, wherein (i) the patient is less than 75 years old and dexamethasone is administered to the patient at a dose of 40 mg a week, or (ii) the patient is at least 75 years old and dexamethasone is administered to the patient at a dose of 20 mg a week.

Embodiment 39 is the method of embodiment 36, wherein (i) the patient has a BMI of at least 18.5 and is administered dexamethasone to the patient at a dose of 40mg a weekly, or (ii) the patient has a BMI of less than 18.5 and is administered to the patient at a dose of 20 mg a weekly.

Embodiment 40 is a method of treating a disease or disorder responsive to inhibiting or blocking B Cell Maturation Antigen (BCMA) in a patient, comprising administering to the patient a ma Bei Tuoshan antibody at a dose of about 1.4 mg/kg to about 3.4 mg/kg every eight weeks ± 3 days, for example about 1.4 mg/kg to about 1.9 mg/kg every eight weeks ± 3 days.

Embodiment 41 is the method of embodiment 40, wherein the dose is about 1.4 mg/kg, about 1.9 mg/kg, about 2.5 mg/kg, or about 3.4 mg/kg once every eight weeks ± 3 days.

Embodiment 42 is a method of treating a disease or disorder responsive to inhibiting or blocking B Cell Maturation Antigen (BCMA) in a patient, comprising administering to the patient a therapeutically effective amount of a combination comprising a first BCMA antagonist and a second BCMA antagonist.

Embodiment 43 is the method of embodiment 42, wherein the first and second BCMA antagonists are independently selected from the group consisting of an anti-BCMA antibody or antigen binding fragment thereof, an anti-BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or antigen binding fragment thereof, and a chimeric antigen receptor T (CAR T) cell therapy targeting BCMA.

Embodiment 44 is the method of embodiment 42 or 43, wherein the first and second BCMA antagonists are independently selected from Ai Jiwei am, sidaoram, terstuzumab, REGN5458, mar Bei Tuoshan antibody, bei Lantuo mab, SEA-BCMA, ABBV-383, elrantamab, pavurutumab, alnuctamab, MEDI2228, and CC99712.

Embodiment 45 is the method of any one of embodiments 42 to 44, wherein the first BCMA antagonist is a mar Bei Tuoshan antibody.

Embodiment 46 is the method of any one of embodiments 42 to 44, wherein the first BCMA antagonist is Bei Lantuo mab.

Embodiment 47 is the method of embodiment 42, wherein the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is a corresponding unconjugated anti-BCMA antibody.

Embodiment 48 is the method of embodiment 47, wherein the anti-BCMA antibody-drug conjugate is selected from the group consisting of mar Bei Tuoshan antibody, MEDI2228, and CC99712.

Embodiment 49 is the method of embodiment 48, wherein the first BCMA antagonist is mar Bei Tuo mab and the second BCMA antagonist is Bei Lantuo mab.

Embodiment 50 is a method of treating a disease or disorder responsive to inhibiting or blocking B Cell Maturation Antigen (BCMA) in a patient, comprising administering to the patient a therapeutically effective amount of a combination comprising a mar Bei Tuoshan antibody and Bei Lantuo mab.

Embodiment 51 is the method of any one of embodiments 42 to 50, further comprising administering to the patient at least one additional cancer treatment, such as an anti-CD 38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody.

Embodiment 52 is the method of embodiment 51, wherein the additional cancer treatment is selected from lenalidomide, dexamethasone, darimumab, ai Shatuo ximab, pomalidomide, bortezomib, or a combination thereof, e.g., lenalidomide and dexamethasone.

Embodiment 53 is a kit comprising (i) a first B Cell Maturation Antigen (BCMA) antagonist, and (ii) instructions for treating a disease or disorder responsive to inhibiting or blocking BCMA when combined with a second BCMA antagonist.

Embodiment 54 is a kit comprising (i) a marc Bei Tuoshan antibody, and (ii) instructions for treating a disease or disorder responsive to inhibiting or blocking B Cell Maturation Antigen (BCMA) when combined with Bei Lantuo mab.

Embodiment 55 is a kit comprising (i) Bei Lantuo mab, and (ii) instructions for treating a disease or disorder responsive to inhibiting or blocking B Cell Maturation Antigen (BCMA) when combined with mar Bei Tuo mab.

Embodiment 56 is a method of treating a disease or disorder responsive to inhibiting or blocking B Cell Maturation Antigen (BCMA) in a patient previously treated with a first BCMA antagonist, comprising administering to the patient a therapeutically effective amount of a second BCMA antagonist, wherein the patient stops administration of the first BCMA antagonist before starting administration of the second BCMA antagonist, and wherein the second BCMA antagonist is different from the first BCMA antagonist.

Embodiment 57 is the method of embodiment 56, wherein the first and second BCMA antagonists are independently selected from the group consisting of an anti-BCMA antibody or antigen binding fragment thereof, an anti-BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or antigen binding fragment thereof, and a chimeric antigen receptor T (CAR T) cell therapy targeting BCMA.

Embodiment 58 is the method of embodiment 56 or 57, wherein the first and second BCMA antagonists are independently selected from Ai Jiwei am, sidaoram, terstuzumab, REGN5458, mar Bei Tuoshan antibody, bei Lantuo mab, SEA-BCMA, ABBV-383, elrantamab, pavurutumab, alnuctamab, MEDI2228, and CC99712.

Embodiment 59 is the method of any one of embodiments 56-58, wherein the first BCMA antagonist is a mar Bei Tuoshan antibody.

Embodiment 60 is the method of any one of embodiments 56 to 58, wherein the first BCMA antagonist is Bei Lantuo mab.

Embodiment 61 is the method of any one of embodiments 56-58, wherein the second BCMA antagonist is a mar Bei Tuoshan antibody.

Embodiment 62 is the method of any one of embodiments 56 to 58, wherein said second BCMA antagonist is Bei Lantuo mab.

Embodiment 63 is the method of embodiment 56, wherein the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is a corresponding unconjugated anti-BCMA antibody.

Embodiment 64 is the method of embodiment 63, wherein the anti-BCMA antibody-drug conjugate is selected from the group consisting of mar Bei Tuoshan antibody, MEDI2228, and CC99712.

Embodiment 65 is the method of embodiment 63, wherein the first BCMA antagonist is mar Bei Tuo mab and the second BCMA antagonist is Bei Lantuo mab.

Embodiment 66 is the method of embodiment 56, wherein the second BCMA antagonist is an anti-BCMA antibody-drug conjugate and the first BCMA antagonist is a corresponding unconjugated anti-BCMA antibody.

Embodiment 67 is the method of embodiment 66, wherein the anti-BCMA antibody-drug conjugate is selected from the group consisting of mar Bei Tuoshan antibody, MEDI2228, and CC99712.

Embodiment 68 is the method of embodiment 66, wherein the second BCMA antagonist is mar Bei Tuo mab and the first BCMA antagonist is Bei Lantuo mab.

Embodiment 69 is a method of treating a disease or disorder responsive to inhibiting or blocking B Cell Maturation Antigen (BCMA) in a patient previously treated with a mar Bei Tuoshan antibody, comprising administering to the patient a therapeutically effective amount of Bei Lantuo mab, wherein the patient stops administration of the mar Bei Tuoshan antibody before administration of Bei Lantuo mab begins.

Embodiment 70 is a method of treating a disease or disorder responsive to inhibiting or blocking B Cell Maturation Antigen (BCMA) in a patient previously treated with Bei Lantuo mab, comprising administering to the patient a therapeutically effective amount of mar Bei Tuo mab, wherein the patient stops administration of Bei Lantuo mab before administration of mar Bei Tuo mab begins.

Embodiment 71 is the method of any one of embodiments 56-70, further comprising administering to the patient at least one additional cancer treatment, such as an anti-CD 38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody.

Embodiment 72 is the method of embodiment 71, wherein the additional cancer treatment is selected from lenalidomide, dexamethasone, darimumab, ai Shatuo ximab, pomalidomide, bortezomib, or a combination thereof, e.g., lenalidomide and dexamethasone.

Embodiment 73 is a method of reducing corneal toxicity in a patient previously treated with a first B Cell Maturation Antigen (BCMA) antagonist, comprising administering to the patient a therapeutically effective amount of a second BCMA antagonist, wherein the patient stops administration of the first BCMA antagonist before beginning administration of the second BCMA antagonist, and the second BCMA antagonist is different from the first BCMA antagonist.

Embodiment 74 is the method of embodiment 73, wherein the first and second BCMA antagonists are independently selected from the group consisting of an anti-BCMA antibody or antigen binding fragment thereof, an anti-BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or antigen binding fragment thereof, and a chimeric antigen receptor T (CAR T) cell therapy targeting BCMA.

Embodiment 75 is the method of embodiment 73 or 74, wherein the first and second BCMA antagonists are independently selected from Ai Jiwei am, sidaoram, terstuzumab, REGN5458, mar Bei Tuoshan antibody, bei Lantuo mab, SEA-BCMA, ABBV-383, elrantamab, pavurutumab, alnuctamab, MEDI2228, and CC99712.

Embodiment 76 is the method of any one of embodiments 73 to 75, wherein the first BCMA antagonist is a mar Bei Tuoshan antibody.

Embodiment 77 is the method of any one of embodiments 73 to 75, wherein said first BCMA antagonist is Bei Lantuo mab.

Embodiment 78 is the method of any one of embodiments 73 to 75, wherein the second BCMA antagonist is a mar Bei Tuoshan antibody.

Embodiment 79 is the method of any one of embodiments 73 to 75, wherein the second BCMA antagonist is Bei Lantuo mab.

Embodiment 80 is the method of embodiment 73, wherein the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is a corresponding unconjugated anti-BCMA antibody.

Embodiment 81 is the method of embodiment 80, wherein the anti-BCMA antibody-drug conjugate is selected from the group consisting of mar Bei Tuoshan antibody, MEDI2228, and CC99712.

Embodiment 82 is the method of embodiment 80, wherein the first BCMA antagonist is mar Bei Tuo mab and the second BCMA antagonist is Bei Lantuo mab.

Embodiment 83 is the method of embodiment 73, wherein the second BCMA antagonist is an anti-BCMA antibody-drug conjugate and the first BCMA antagonist is a corresponding unconjugated anti-BCMA antibody.

Embodiment 84 is the method of embodiment 83, wherein the anti-BCMA antibody-drug conjugate is selected from the group consisting of mar Bei Tuoshan antibody, MEDI2228, and CC99712.

Embodiment 85 is the method of embodiment 83, wherein the second BCMA antagonist is mar Bei Tuo mab and the first BCMA antagonist is Bei Lantuo mab.

Embodiment 86 is a method of reducing corneal toxicity in a patient previously treated with a mab Bei Tuoshan, the method comprising administering to the patient a therapeutically effective amount of Bei Lantuo mab, wherein the patient ceases administration of the mab Bei Tuoshan prior to beginning administration of Bei Lantuo mab.

Embodiment 87 is a method of reducing corneal toxicity in a patient previously treated with Bei Lantuo mab, the method comprising administering to the patient a therapeutically effective amount of mar Bei Tuo mab, wherein the patient ceases administration of Bei Lantuo mab before beginning administration of mar Bei Tuo mab.

Embodiment 88 is the method of any one of embodiments 73-87, further comprising administering to the patient at least one additional cancer treatment, such as an anti-CD 38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody.

Embodiment 89 is the method of embodiment 88, wherein the additional cancer treatment is selected from lenalidomide, dexamethasone, darimumab, ai Shatuo ximab, pomalidomide, bortezomib, or a combination thereof, e.g., lenalidomide and dexamethasone.

Embodiment 90 is a method of treating a disease or disorder in a patient, comprising administering a therapeutically effective amount of a combination comprising an antibody-drug conjugate and a corresponding unconjugated antibody.

Embodiment 91 is a method of treating a disease or disorder in a patient previously treated with an antibody-drug conjugate, the method comprising administering to the patient a therapeutically effective amount of a corresponding unconjugated antibody, wherein the patient ceases administration of the antibody-drug conjugate prior to beginning administration of the corresponding unconjugated antibody.

Embodiment 92 is the method of embodiment 90 or 91, wherein the antibody-drug conjugate is selected from the group consisting of gemtuzumab ozogamicin, vitamin b uzumab, enmetrastuzumab, oxepituzumab, poltuzumab, vintuzumab You Shan, detrastuzumab, 66andomized66 govitecan, ma Bei Tuoshan, rituximab, tixostat, mositumomab, MEDI2228, or CC99712.

Embodiment 93 is the method of any one of embodiments 1 to 52 or 56 to 92, or the kit of any one of embodiments 53 to 55, wherein the disease or disorder is a plasma cell disorder or a B cell disorder.

Embodiment 94 is the method of any one of embodiments 1 to 52 or 56 to 92, or the kit of any one of embodiments 53 to 55, wherein the disease or disorder is BCMA expressing cancer.

Embodiment 95 is the method of any one of embodiments 1 to 52 or 56 to 92, or the kit of any one of embodiments 53 to 55, wherein the disease or disorder is Multiple Myeloma (MM).

Embodiment 96 is the method of embodiment 95, wherein the MM is a relapsed and/or refractory MM, a newly diagnosed MM, a MM unsuitable for transplantation, or a newly diagnosed MM unsuitable for transplantation.

Embodiment 97 is the kit of embodiment 95, wherein the MM is a relapsed and/or refractory MM, a newly diagnosed MM, a MM unsuitable for transplantation, or a newly diagnosed MM unsuitable for transplantation.

Embodiment 98 is a method of treating cancer in a patient, wherein the patient has a grade 1 corneal adverse effect due to administration of MA Bei Tuo mab, comprising temporarily stopping administration of MA Bei Tuoshan mab, administering a therapeutically effective amount of Bei Lantuo mab to the patient for an introduction period, and resuming administration of MA Bei Tuoshan mab after the introduction period.

Embodiment 99 is a method of treating cancer in a patient, wherein the patient has a grade 2 or more corneal adverse effect due to administration of MA Bei Tuo mab, the method comprising temporarily stopping administration of MA Bei Tuoshan mab, administering a therapeutically effective amount of Bei Lantuo mab I I to the patient for an introduction period, and resuming administration of MA Bei Tuoshan mab after the introduction period.

Examples

The following examples are provided to illustrate but not limit the disclosure as claimed.

EXAMPLE 1 in vivo efficacy of Bei Lantuo mab in NOD/SCID mice treatment of subcutaneous NCI-H929 human multiple myeloma model.

A study was conducted to evaluate the in vivo therapeutic efficacy of Bei Lantuo mab (GSK 2857914) and a ma Bei Tuoshan antibody (GSK 2857916) in treating subcutaneous NCI-H929 human multiple myeloma models in NOD/SCID mice. Groups of 10 mice were dosed by intraperitoneal administration in the amounts, as well as frequency and duration, shown in table 4.

TABLE 4 Table 4

The method comprises culturing NCI-H929 tumor cells in vitro in RPMI1640 medium supplemented with 10% fetal bovine serum and 0.05mM beta-ME at 37℃in an atmosphere of 5% CO ₂/air. Cells in exponential growth phase were harvested and counted for tumor inoculation. Each mouse was inoculated subcutaneously with NCI-H929 tumor cells (5 x10 ⁶) in 0.1 ml of matrigel-mixed PBS (1:1) in the right anterior flank region for tumor development. Randomization begins when the average tumor size reaches 121 mm ³. 80 mice were enrolled in the group study. All animals were randomly assigned to 8 study groups. Randomization was based on a "matching distribution" method (Study Director ^TM software, version 3.1.399.19) random granule design. The randomization date is indicated as day 0. Treatment was started on the same day of randomization (day 0) according to study design.

Animals were checked daily for morbidity and mortality after tumor cell inoculation. During routine monitoring, animals were examined for any effect of tumor growth and treatment on behavior (e.g., activity, food and water consumption, weight gain/loss (body weight measured twice weekly after randomization), eye/hair tangles, and any other abnormal conditions). Mortality and observed clinical signs of individual animals were recorded in detail. After randomization, tumor volumes were measured twice a week in two dimensions using calipers, and volumes were expressed as mm ³ using the formula "v= (lxwxw) x 0.52", where V is tumor volume, L is tumor length (longest tumor size), and W is tumor width (longest tumor size perpendicular to L). Dosing and tumor and body weight measurements were all performed in a laminar flow cabinet. Both body weight and tumor volume were measured using StudyDirectorTM software (version 3.1.399.19).

Statistical analysis to compare tumor volumes of different groups on pre-specified days, the Bartlett test was first used to examine assumptions of variance alignment across all groups. When the Bartlett test p-value > = 0.05, one-way ANOVA was run to test the overall equality of the mean across all groups. If the p-value of one-way ANOVA is <0.05, a further post hoc test is performed by running Tukey's HSD (honest significant difference) test for all pairwise comparisons, and running Dunnett test for comparing each treatment group with the vehicle group. When the Bartlett test p-value was <0.05, the Kruskal-Wallis test was run to check the overall equality of the median of all groups. If the p-value of the Kruskal-Wallis test is <0.05, a further post-hoc test is performed by running Conover non-parametric tests for all pairwise comparisons or for comparing each treatment group with the vehicle group, both with a single step p-value adjustment.

In addition, pairwise comparisons were made without multiple comparison corrections, and nominal/uncorrected p-values were reported directly from the Welch t-test or Mann-Whitney U-test. Specifically, the Bartlett test is first used to check the assumption of variance alignment for a pair of groups. When the p value of the Bartlett test is more than or equal to 0.05, the Welch t test is run, otherwise the Mann-Whitney U test is run to obtain a nominal p value.

All statistical analyses were performed in the R-a language and environment (version 3.3.1) for statistical calculations and graphics. All assays were double-sided, unless otherwise indicated, and p-values <0.05 were considered statistically significant.

The survival time was analyzed by Kaplan-Meier method. The event of interest is death of the animal. Time to live is defined as the time from the date of randomization to the date when tumor volume reached 2500 mm ³. For each group, the median time to live (MST), the corresponding 95% confidence interval, and the increase In Lifetime (ILS) were calculated. Kaplan-Meier curves for each group were constructed and survival curves between groups were compared using a log rank test. All data were analyzed using SPSS 18.0.p < 0.05. P <0.05 is considered statistically significant.

As a result, tumor volume analysis showed that GSK2857916 of 4 mg/kg and GSK2857914 of 8 mg/kg exhibited significant anti-tumor efficacy in NCI-H929 xenograft models as a single agent or in combination with different dosing regimens (G2-G8) as compared to vehicle (G1). Furthermore, the combination of GSK2857916 with GSK2857914 (G4 and G6) showed significantly improved antitumor efficacy compared to the single agent of GSK2857916 (G2). The tumor volume increase curve between the random grouping and the termination of the study is shown in figure 1. Tumor Growth Inhibition (TGI) of the data collected on day 24 is provided in table 5.

TABLE 5

Survival analysis showed that 4 mg/kg of GSK2857916 and 8 mg/kg of GSK2857914 significantly increased the lifespan of mice in NCI-H929 xenograft models as single agents or in combination with different dosing regimens (G2-G8) compared to vehicle (G1). Furthermore, the combination of GSK2857916 with GSK2857914 (G4 and G6) may further increase the longevity of mice compared to the single agent (G2) of GSK 2857916. Figure 2 shows Kaplan-Meier survival curves for all treatment groups as a function of study day. Median days to survival for each group of mice are provided in table 6.

TABLE 6

Note that 1. A is relative to G1;

note 2G 2 relative to G4, p <0.001, G2 relative to G6, p=0.003, G2 relative to G7, p=0.122.

Example 2 phase 1/2 study to evaluate the safety and efficacy of Bei Lantuo mab in Multiple Myeloma (MM).

Studies were conducted to assess the safety and efficacy of Bei Lantuo mab in participants with relapsed or refractory multiple myeloma (RRMM).

Study design

Part 1, up-dosing phase in RRMM.

Part 1 is a phase I open label study evaluating the safety, tolerability, and clinical activity of ascending doses of single agent Bei Lantuo mab in participants with RRMM who have received at least 3 previous line treatments to determine the recommended part 2 dose. Bei Lantuo mab was administered twice per cycle on days 1 and 15 of the 28 day cycle, starting at a dose of 300 mg IV. Dose escalation was guided by modifying the probability of toxicity interval to 900 mg and then to the maximum dose 2000 mg according to the dose escalation plan and as directed by the dose escalation committee. Additional intermediate doses are allowed to be explored if the dose escalation committee suggests and agrees with medical supervisors and treatment researchers. The progression from one dose level to another and the recommended part 2 dose are based on all available data for part 1 of Bei Lantuo mab treatment, and the dose escalation committee recommends both dose levels for further characterization in part 2, taking into account, inter alia, the safety and tolerability of each dose level, the available PK and PD data, and preliminary efficacy.

Participants were dosed until Progressive Disease (PD) after which they were opted to receive treatment with 2.5 mg/kg Q3W of single agent mar Bei Tuoshan antibody (part 1B). Participants selected for treatment with the marc Bei Tuoshan anti-treatment after the first PD underwent an end-of-treatment (EOT) visit before starting the marc Bei Tuoshan anti-treatment, and then continued to monitor safety, tolerability, and disease response during the marc Bei Tuoshan anti-treatment until the next PD. After the second PD, participants underwent a second EOT mart Bei Tuoshan anti-visit (if available) and safety was monitored until at least 70 days after the last mart Bei Tuoshan anti-dose. Participants who opted out of the mar Bei Tuoshan anti-treatment after the first PD terminated the treatment and underwent EOT visit and subsequent safety monitoring.

Bei Lantuo mab treatment duration was up to the first PD (followed by optional mar Bei Tuoshan anti-treatment up to the second PD), unacceptable toxicity, or any other treatment termination criteria. For example, the duration of treatment may be as long as about 8 months.

The frequency of visit is once every 2 weeks from cycle 3 onwards. More visits are arranged in cycles 1 and 2.

Section 2, evaluation of combinations in RRMM.

Part 2 is a 2-arm safety study that assessed safety, tolerability, and clinical activity of 1 cycle of mar Bei Tuoshan anti-xRd (mar Bei Tuoshan antibody, treatment x, lenalidomide, and dexamethasone) followed by continuous treatment with Bei Lantuo mab-xRd (Bei Lantuo mab, treatment x, lenalidomide, and dexamethasone) in participants with recurrent MMs who received at least 1 previous line of treatment (2l+). In some cases, treatment x includes, but is not limited to, a combination of an anti-CD 38 antibody (e.g., darifenacin or Ai Shatuo ximab) and a gamma secretase inhibitor (e.g., oginse Wei Ao). In some cases, treatment x includes, but is not limited to, a proteasome inhibitor (e.g., bortezomib).

Combination therapy xRd includes lenalidomide (R) and dexamethasone (d). Treatment x was selected based on data from an ongoing marc Bei Tuoshan anti-clinical study and was the standard treatment regimen or emerging treatment for MM.

Bei Lantuo mab doses are based on the population of available part 1 data. Two different dose levels of Bei Lantuo mab (arm a and arm B) were administered once every 4 weeks. More frequent dosing is used if justified by part 1 data based on safety, tolerability, PK/PD models, or other data. Up to about 20 participants, who could assess safety and tolerability, were equally randomized into arm a and arm B after receiving one cycle (28 days) of ma Bei Tuoshan anti-xRd. Shan Jiliang M Bei Tuoshan anti 1.4 mg/kg is administered in combination with lenalidomide of treatment x, 25 or 10 mg once daily (on days 1-21 of the cycle), and 40 mg dexamethasone once daily (on days 1, 8, 15 and 22 of the cycle) (or 20mg if age > 75 years or BMI < 18.5).

The Bei Lantuo mab-xRd administration was continued until Progressive Disease (PD).

Study part 2 assessed the overall safety and tolerability of 10 participants/arm after 3 treatment cycles and corneal adverse events. A participant is considered to be evaluable for safety and tolerability if it completes at least 3 cycles of treatment (including 1 cycle of mar Bei Tuoshan anti-xRd followed by 2 cycles of Bei Lantuo mab-xRd). Participants may be replaced if they withdraw from a non-evaluable definition for reasons other than treatment-related adverse events, death, or PD. All data from parts 1 and 2 were used to determine the recommended phase 2 dose of Bei Lantuo mab to be used in part 3.

Participants who terminated treatment for reasons other than PD in study part 2 will continue follow-up for progression free and total survival.

The duration of treatment is up to PD, unacceptable toxic response, or any other treatment termination criteria. For example, the duration of treatment may be as long as about 15 months.

The frequency of visit was once every 4 weeks starting from cycle 3, unless data from part 1 and from the ongoing mar Bei Tuoshan anti-clinical trial suggest that Bei Lantuo mab-xRd be administered more frequently. More visits are scheduled during periods 1 and 2.

Part 3 combined evaluation in newly diagnosed multiple myeloma (TI-NDMM) unsuitable for transplantation.

Part 3 is a 4-arm phase 2 random open label study that evaluates the safety and efficacy of continuing Bei Lantuo mab-xRd in participants with TI-NDMM following treatment with 1 cycle of mar Bei Tuoshan anti-xRd. The cycle length was 4 weeks. Two different doses of Bei Lantuo mab (arm a and arm B) were administered every 4 weeks. The Bei Lantuo mab dose level was selected based on all available data from part 1 and part 2, and may be different from the dose level administered in part 2, the dose escalation committee selection process taking into account the overall safety and tolerability of the combination, available PK/PD data, and efficacy evidence of different dose levels. The drug administration with Bei Lantuo mab-xRd was continued until PD. The same doses of MA Bei Tuoshan antibody and xRd in arms A and B were used as Shan Jiliang MA Bei Tuoshan antibody 1.4 mg/kg in combination with treatment x, lenalidomide 25 or 10mg once daily (on days 1-21 of the cycle) and dexamethasone 40 mg once daily (on days 1, 8, 15 and 22 of the cycle) (or 20 mg if the age is > 75 years or BMI < 18.5).

Part 3 also tested the results of 1) treatment with serially administered MA Bei Tuoshan anti-xRd (arm C) and 2) treatment with serially administered Bei Lantuo mab-xRd in the absence of an initial dose of MA Bei Tuoshan anti-xRd (arm D).

In arm C, MA Bei Tuo mab was administered once every two 28-day cycles (Q8W) at a dose of 1.4 mg/kg in combination with treatment x, once daily (on days 1-21 of the cycle) with lenalidomide 25 or 10 mg and once daily (on days 1, 8, 15 and 22 of the cycle) with dexamethasone 40 mg (or 20mg if the age was > 75 years or BMI < 18.5).

In arm D Bei Lantuo mab was administered once every 28 day cycle in combination with combination x, lenalidomide 25 or 10 mg once daily (on days 1-21 of the cycle) and dexamethasone 40 mg once daily (on days 1, 8, 15 and 22 of the cycle) (or 20mg if age > 75 years or BMI < 18.5).

About 80 participants 1:1:1 were randomly assigned to arm a, arm B, arm C or arm D in order to obtain data for 20 evaluable participants per arm. Participants were considered evaluable if they had completed at least 4 cycles of treatment (including 1 cycle of mar Bei Tuoshan anti-xRd followed by 3 cycles of Bei Lantuo mab-xRd). Participants may be replaced if they withdraw from reasons other than treatment-related adverse events, death, or disease progression, which do not meet the evaluable definition.

The xRd dose was the same in all four arms studied, while the MA Bei Tuoshan antibody and Bei Lantuo mab doses and dosing frequency in arms C and D might be different compared to those in arms A and B.

The study was terminated 18 months after the first administration of the last subject. At that time, data collection was stopped for all enrolled participants no longer receiving study treatment and the clinical trial database was closed. If the disease does not progress as the study terminates, participants who continue to benefit from treatment according to the study recommendations will be transferred to the post-analysis-continued treatment study to continue to receive treatment. In this case, the duration of treatment by the part 3 participants up to the date of expiration of the data of the study was up to about 24 months.

The frequency of visit was once every 4 weeks starting from cycle 3, unless data from part 1 and part 2 and from the ongoing mar Bei Tuoshan anti-clinical trial suggested more frequent dosing of Bei Lantuo mab-xRd. More visits are scheduled during periods 1 and 2.

An overview of study treatments is provided in table 7.

TABLE 7

¹ Dose Limiting Toxicity (DLT)

² Bei Lantuo monoclonal antibody (bela)

³ Maca Bei Tuoshan (belamaf)

⁴ Bei Lantuo mab recommended part2 dose level 1 (bela RPart DL 1)

⁵ Bei Lantuo mab recommended part2 dose level 2 (bela RPart2 DL 2)

⁶ Bei Lantuo recommended phase 2 dose level 1 (bela RP2 DL 1)

⁷ Bei Lantuo recommended phase 2 dose level 2 (bela RP2 DL 2)

A summary of the therapeutic doses and frequency of administration is provided in table 8. Standard of care (SoC) treatment or emerging MM treatment was also administered as provided in table 8.

TABLE 8

Administration adjustment of MA Bei Tuoshan anti-tumor

In part 3 arm C, consecutive doses of marc Bei Tuoshan anti-1.4 mg/kg Q8W were administered, and based on emerging data from the ongoing marc Bei Tuo mab assay, dose levels could be increased to 1.9 mg/kg Q8W unless the data support more frequent administration. Initial doses were matched to parts a and B, and ongoing doses were selected based on consideration of clinical experience with respect to the ma Bei Tuoshan and from other study data.

And (3) drug administration adjustment: lenalidomide and dexamethasone

Lenalidomide was administered at 25 mg PO daily on days 1-21 of every 28-day cycle in participants with CLcr ≡60 mL/min (according to Cockcroft-Gault). The dose of lenalidomide in the participants with CLcr of 30-60 mL/min will be reduced to 10 mg daily on days 1 to 21. Lenalidomide is administered at a fixed dose level without the need for body weight or BSA adjustments. Lenalidomide should be administered as close as possible to the end of the rest period of 1-2 hours after administration of Bei Lantuo mab/mab Bei Tuo on the day of co-administration of lenalidomide and Bei Lantuo mab/mab Bei Tuoshan, and lenalidomide should be administered no later than 6 hours after the end of the rest period after Bei Lantuo mab/mab Bei Tuo administration on the PK day. Dexamethasone will be given at 40 mg (or 20 mg if age. Gtoreq.7.5 years or BMI <18.5 kg/m ²) PO weekly on days 1, 8, 15 and 22 of each cycle.

Qualification criteria

Inclusion criteria:

Participants were eligible for inclusion in the study only if all of the following criteria were met:

1. the participants are at least 18 years of age or have legal consent to age in the jurisdiction of the institute.

2. Participants had histologically or cytologically confirmed diagnosis of MM, as defined by the International Myeloma Working Group (IMWG).

Part 1, participants who have received at least 3 previous lines of anti-myeloma treatment, and who have received immunomodulators, proteasome inhibitors, and anti-CD 38 mabs (unless contraindicated or unavailable). The number of lines of therapy is defined by the international myeloma seminar consensus group.

Part 2 meets all participants (1) have undergone Autologous Stem Cell Transplantation (ASCT) or are considered unsuitable for transplantation, (2) have been previously treated with at least one previous line of MM therapy, and (3) have had disease progression recorded during or after their most recent therapy.

Part 3 participants meeting (1) NDMM with treatment requirements, as recorded according to the IMWG standard, and (2) co-morbid conditions that may negatively impact the tolerance of high-dose chemotherapy and ASCT, or refusing high-dose chemotherapy and ASCT as initial treatment, as a result of not being considered a candidate for high-dose chemotherapy and ASCT (a) age no less than 65 years, or (b) age 18-65 years.

3. Participants with an ASCT history were eligible to participate in the study provided that the eligibility criteria were met (a) that the transplantation was >100 days prior to screening, and (b) that there was no active infection.

4. Eastern tumor cooperative group-expression status (ECOG-PS) is 0-2.

5. Measurable disease is defined as at least one of (a) serum M protein concentration ∈0.5 g/dL (∈5 g/L); (b) urine M protein excretion ∈200. 200 mg/24 hours (. Gtoreq.0.2 g/24 hours), or (c) serum Free Light Chain (FLC) assay involving FLC levels ∈10 mg/dL (. Gtoreq.100 mg/L) and abnormal serum FLC ratios (< 0.26 or > 1.65).

6. Has sufficient organ system function as specified in table 9:

TABLE 9

7. Except for alopecia (any grade), neuropathy (≤2 grade) or endocrine lesions treated with alternative therapies (any grade), all prior treatment-related toxicities (defined by NCI-CTCAE, v5.0,2017) must be grade 1 at the time of screening.

8. Participants currently receiving physiological doses of oral steroids (< 10 mg/day), inhaled steroids or ophthalmic steroids were allowed to participate in the study.

Exclusion criteria:

Participants were excluded from the study if any of the following criteria were applicable:

Medical conditions:

1. Diagnosis of primary AL amyloidosis, active POEMS syndrome, primary plasma cell leukemia.

2. Any serious and/or unstable pre-existing medical, psychiatric or other condition (including laboratory abnormalities) that may affect the safety of the participants, gain informed consent or follow the study procedure.

3. Participants showed signs of MM meninges or central nervous system involvement.

4. There are currently corneal epithelial diseases, except for non-fusogenic SPKs.

5. According to the evaluation of researchers, the present unstable liver or biliary tract diseases are defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice or cirrhosis. Note that stable chronic liver disease (including gilbert syndrome or asymptomatic gallstones) is stable if the participants otherwise meet the entry criteria.

6. The presence of malignancy other than the disease in the study was excluded, except that the participants had been ill free for more than 2 years, and according to the opinion of the PI and GSK medical community, did not affect any other malignancy that would be evaluated for the effect of the present clinical trial treatment on the current target malignancy (MM). Note that participants with curative non-melanoma skin cancers are not excluded.

7. Evidence of cardiovascular risk, including any of (a) evidence of current clinically significant untreated arrhythmias, including but not limited to clinically significant ECG abnormalities such as second degree (Mobiz II-type) or third degree AV block, (b) QTcF interval >450 milliseconds (corrected QT interval for heart rate according to the friericia formula), and/or hypokalemia, and/or family history of long QT syndrome (for part 1), (c) history of MI, acute coronary syndrome (including unstable angina), coronary angioplasty, stent implantation or bypass grafting, all within three months of screening, (d) heart failure class III or IV as defined by the NYHA functional classification system, (e) uncontrolled hypertension.

8. Immediate or delayed hypersensitivity or idiosyncratic to drugs or any component of research therapy that are chemically related to Bei Lantuo mab/MA Bei Tuo mab are known. History of severe hypersensitivity to other mabs.

9. Active infections requiring antibiotic, antiviral or antifungal treatment.

10. HIV infection is known unless the participants are able to meet all of the criteria (a) establish ART for at least 4 weeks with HIV viral load <400 copies/mL, (b) CD4+ T cells (CD4+) count≥350 cells/uL, and (c) no history of AIDS-defined opportunistic infections in the past 12 months.

11. Recent (over the past 6 months) history of acute diverticulitis, inflammatory bowel disease, intraperitoneal abscesses, or gastrointestinal obstruction.

12. HBsAg or HBcAb was present at the screening. Note that the presence of HBsAb indicates that the previous vaccination does not exclude the participants.

13. Positive hepatitis c antibody detection results or positive hepatitis c RNA detection results within 3 months at the time of screening or prior to the first dose of study treatment unless the participants are able to meet the criteria of (a) RNA detection being negative, (b) requiring successful antiviral treatment (typically for a duration of 8 weeks), and HCV RNA detection being negative after a washout period of at least 4 weeks after completion of antiviral treatment.

14. Active kidney conditions (infection, need for dialysis or any other condition that may affect the safety of the participants) exist. Participants with isolated proteinuria caused by MM were eligible, provided that the criteria given in the table for adequate organ system function were met (table 9).

Previous/concomitant therapy:

15. Part 1 and part 2 refractory to MA Bei Tuo mab (PD as confirmed according to IMWG standard at the time of receiving MA Bei Tuoshan anti-therapy or within 60 days of completion of the therapy). If the mab Bei Tuo is stopped by toxicity, then the toxicity subsides, then the previous mab Bei Tuoshan is allowed. Note that previous treatments with other anti-BCMA drugs are permissible.

16. Part 2 and part 3 previous lenalidomide treatment was discontinued due to intolerable AE.

17. Part 1 and part 2 the refractoriness to the previous standard anti-myeloma therapies including lenalidomide allows for other mabs to be administered within 30 days of the first dose of study drug, or systemic anti-myeloma therapies to be administered within 14 days of the first dose of study drug.

18. Previous radiation therapies were within 2 weeks of starting the study therapy. The participants must have recovered from all radiation-related toxicities, do not require corticosteroids, and have not suffered from radiation pneumonitis. For palliative radiation of non-CNS disorders (≤2 weeks of radiation therapy), a1 week washout period is allowed.

19. Partial 3 only previous systemic therapy of MM.

Note that an urgent course of steroid treatment (defined as no more than 40 mg dexamethasone or equivalent per day for up to 4 days (i.e. 160 total mg) is permissible.

Note that focal palliative radiation is allowed prior to group entry, provided that it occurs at least 2 weeks prior to the first dose of study intervention, the participants have recovered from radiation-related toxicity, and the participants do not need corticosteroids for radiation-induced AEs.

20. Plasma separation was performed within 7 days prior to the first dose of study drug.

21. Previous allografts were prohibited.

22. Participants who received prior CAR-T therapy within 3 months of screening and who had lymphocyte clearance with chemotherapy.

23. Any major surgery (except bone stabilization surgery) within 2 weeks of the first dose, or not yet fully recovered from surgery.

24. Previous treatments with mAb within 30 days of receiving the first dose of study drug or treatment with study drug or approved systemic anti-myeloma therapies (including systemic steroids) within 14 days or 5 half-lives (whichever is longer) of receiving the first dose of study drug.

Other exclusions:

25. infusion of blood products (including platelets or erythrocytes) or administration of colony stimulating factors (including G-CSF, GMCSF, recombinant erythropoietin) or any thrombopoietin receptor agonist was received within 2 weeks prior to the first dose of study drug.

26. The participants were not vaccinated/live attenuated within 30 days prior to the first dose of study treatment, or at least 70 days after the last study treatment when receiving Bei Lantuo mab. Examples of live vaccines include, but are not limited to, measles vaccine, mumps vaccine, rubella vaccine, chicken pox/shingles (varicella) vaccine, yellow fever vaccine, rabies vaccine, BCG and typhoid vaccine. Seasonal influenza vaccines and COVID-19 vaccines for injection are not live or attenuated and are permissible, but intranasal influenza vaccines (e.g., flumix) are attenuated live and are not permissible.

27. Current drugs or alcohol abuse are known.

Diet and dietary restrictions (for parts 2 and 3 only)

The red wine, seville oranges (Seville oranges), grapefruit or grapefruit juice, grapefruit, exotic citrus fruits, grapefruit hybrids or fruit juice were avoided starting one day prior to each bela/belamaf dose and 1 day prior to study visit independent of Bei Lantuo mab/ma Bei Tuoshan dose until Bei Lantuo mab/ma Bei Tuoshan dose day or study visit day ended.

Water was not allowed until 2 hours after oral drug administration, and water was allowed ad libitum at all other times.

Lenalidomide capsules should be swallowed with water, and the capsules should not be opened, broken or chewed.

Lenalidomide should be taken orally at about the same time daily.

Lenalidomide capsules contain lactose. Risk-benefit should be assessed in lactose intolerant participants.

Caffeine, alcohol and tobacco (for parts 1,2 and 3)

Throughout the study, participants will refrain from ingesting caffeine-or xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) 24 hours prior to office visits on days of scheduled periodic PK and pharmacodynamic sample collection.

Throughout the course of the study, participants will abstain 24 hours before the visit of the clinic on the day of scheduled periodic PK and pharmacodynamic sample collection.

Participants using the tobacco product will be instructed not to allow use of the nicotine-containing product (including nicotine patches and other delivery devices, such as a vaporizer) while they are in the clinical unit.

Dose adjustment (dose reduction and dose delay)

Dose adjustments may be made to individual participants based on the participant's safety findings. Following cycle 1, the Bei Lantuo mab or the mar Bei Tuoshan antibody dose of the participants may be reduced or delayed due to toxicity (including corneal events/toxicity).

If the dose is delayed, the participant should wait for the next scheduled dose to resume treatment. In individual cases, if a researcher decides that waiting for an entire period after a delay associated with resolved toxicity (skipping the dose) to resume treatment would be detrimental to the health of the participants, the researcher should contact the medical inspector to discuss earlier restarting. Only participants recovering from toxicity to at most grade 1 can consider earlier restarts. The administration of the mar Bei Tuoshan antibody in parts 2 and 3 cannot be more frequent than every 28 days (+3 day window). In this case, efficacy and safety assessments must remain once every 4 weeks, consistent with the initial efficacy and safety assessments in the study, which may require 2 separate visits (1 for dosing, 1 for disease assessment). Only part IB participants selected to receive mab Bei Tuo after PD during treatment with Bei Lantuo mab therapy in part 1 will receive mab Bei Tuo once every 3 weeks (+3 day window), and efficacy and safety are assessed once every 3 weeks according to EMA and FDA approval. The dose related assessment will be entered into the electronic case report table (eCRF) for the next predetermined period.

Delayed dosing is allowed in the case of medical/surgical events or for logistical reasons unrelated to study therapy (e.g., chronosurgery, unrelated medical events, participant holidays and/or holidays, but not for decisions of participant delayed treatment). The reasons for any delay in administration must be recorded in the participant's eCRF and clinical records and discussed with the medical inspector.

In the absence of evidence of PD or significant toxicity associated with the study product, the maximum dose delay allowed for Bei Lantuo mab or mar Bei Tuo mab was 16 weeks unless written consent by the medical inspector.

In section 1, decisions to proceed to the next dose level (increase or decrease) of Bei Lantuo mab will be made by DEC based on safety, tolerability, and preliminary PK data obtained in participants at previous dose levels.

Example 3 analysis of the effect of GSK2857916 drug to antibody ratio (DAR) differences on anti-tumor activity in vivo.

The effect of drug to antibody ratio (DAR) on GSK2857916 in vitro and in vivo activity was evaluated. The results indicate that DAR differences have no significant effect on in vivo anti-tumor activity, and that activity is dependent on dose rather than DAR.

Experimental procedure

Female Severe Combined Immunodeficiency (SCID) mice were nine weeks of age at study day 1 and ranged in weight from 15.6 to 23.8 grams. The H929 human plasmacytoma cell line was obtained from the American Type Culture Collection (ATCC). Cells were maintained as exponentially growing suspension cultures in RPMI 1640 medium supplemented with 20% fetal bovine serum, 2mM glutamine, 50. Mu.M mercaptoethanol, 100 units/mL penicillin G sodium, 100. Mu.g/mL streptomycin sulfate and 25. Mu.g/mL gentamicin. Tumor cells were cultured in a humidified incubator at 37 ℃ under an atmosphere of 5% CO ₂ and 95% air in a tissue culture flask.

H929 cells for implantation were harvested during the log phase of growth and resuspended in 50% Matrigel (BD Biosciences) in cold PBS. Each mouse was subcutaneously injected with 1x10 ⁷ tumor cells (0.1 mL cell suspension) in the right flank. Mice bearing established H929 tumors were divided into four groups (n=10/group) 20 days after tumor implantation (this was designated as day 1 of the study). The individual tumor volumes ranged from 126 to 288 mm ³ for all groups, and the group average tumor volume ranged from 195 to 198 mm ³. Dosing was initiated according to the treatment schedule summarized in table 10, and the dosing volume was scaled to the body weight of the individual animals.

Results and discussion

The results of the study are shown in fig. 3. The results showed that 2 mg/kg of GSK2857916 DAR4.1 resulted in significant tumor growth delay, but no initial tumor regression. GSK2857916 DAR2.1 of 4 mg/kg is significantly more effective than GSK2857916 DAR4.1 of 2 mg/kg, even though the same dose of toxin is expected to be delivered under each condition. Furthermore, GSK2857916 DAR2.1 of 4 mg/kg is more effective than GSK2857916 DAR2.1 of 2 mg/kg, even though more toxin is expected to be delivered under the latter condition. These results indicate that the dosage of antibody is a more important determinant of antitumor activity than the molecular DAR.

In summary, the change in DAR from 2.1 to 5.7 had no effect on the antitumor activity of 2 mg/kg GSK 2857916. In contrast, the dose of ADC administered was the primary determinant of antitumor activity, as the activity of 4 mg/kg of GSK2857916 DAR2.1 was significantly higher than that of 2 mg/kg of GSK2857916 DAR4.1, even though the same amount of toxin was administered in both cases. Thus, this analysis shows that at a given drug concentration, DAR changes have no significant effect on anti-tumor activity in vivo.

TABLE 10 study treatment group

Example 4 evaluation of soluble BCMA (sBCMA) levels in relapsed/refractory multiple myeloma (RRMM) patients treated with MA Bei Tuoshan resistance

Soluble BCMA (sBCMA) levels were analyzed as exploratory endpoints in patients enrolled to evaluate the safety and efficacy of single agent mar Bei Tuoshan anti compared to the combination of pomalidomide dexamethasone in participants with RRMM (DREAMM-3 study; NCT 04162210) phase III open-label randomized clinical trial. Overall, the results indicate that the combined administration of unconjugated Bei Lantuo mab and mar Bei Tuo mab can affect sBCMA levels, thereby improving the efficacy of the mar Bei Tuoshan anti-treatment.

Experimental procedure

Study participants with RRMM were randomized at a 2:1 ratio to receive the single agent MA Bei Tuo mab or a combination of pomalidomide and dexamethasone (pom/dex). MA Bei Tuo mab was administered by Intravenous (IV) infusion at a dose of 2.5 mg/kg on day 1 of the 21 day cycle, i.e. once every three weeks (Q3W). Pomalidomide is administered daily on each of days 1 to 21 of the 28 day cycle, and dexamethasone is administered once weekly (i.e. on days 1, 8, 15 and 22 of each 28 day cycle). Participants in both arms received treatment until disease progression, death, unacceptable toxicity, withdrawal consent, and loss of visit or end of study (based on the prior occurrence).

Serum samples were obtained from patients in both study arms at the following time points relative to the MA Bei Tuoshan anti-infusion, pre-dose, at the end of infusion, 2 hours post-infusion, 24 hours post-infusion, 4 days post-infusion, and 8-15 days post-infusion. The level of sBCMA in the cell supernatant was measured using a validated electrochemiluminescence immunoassay.

Results and discussion

SBCMA levels are affected by anti-treatment with mar Bei Tuoshan. Analysis of sBCMA levels in patients treated with MA Bei Tuo mab versus pom/dex showed that there was a difference in sBCMA levels between the two treatment arms, and sBCMA levels were specifically affected by MA Bei Tuoshan versus pom/dex treatment. As shown in fig. 4, the Progression Free Survival (PFS) of the patient in the highest quartile (Q4) of baseline sBCMA levels (i.e., prior to administration of mar Bei Tuo mab) was lowest in both treatment arms, indicating poorer response to treatment. The response of patients in the highest quartile (Q3 and Q4) of baseline sBCMA levels in the pom/dex arm was substantially similar between the two quartiles (PFS about 4-5 months). However, the response of the patient in the highest quartile of baseline sBCMA levels (Q3 and Q4) in the mar Bei Tuoshan antibody arm was differentiated between the two quartiles, with observed PFS for Q4 and Q3 patients of about 7 months and 15 months, respectively. These data indicate that the response to the mar Bei Tuoshan anti-treatment was directly affected by sBCMA levels at baseline, which was not observed with the pom/dex treatment.

The MA Bei Tuo mab binds to sBCMA in the patient sample. At the end of the anti-infusion (EOI) of marc Bei Tuoshan, sBCMA levels were measured in participants of the anti-treatment arm of marc Bei Tuoshan. Patient samples were obtained within 30 minutes after the end of the mar Bei Tuoshan anti-infusion and sBCMA levels in the samples were measured. Based on sBCMA levels detected at EOI, it was determined that the mar Bei Tuoshan antibody bound substantially all sBCMA of the periphery at a dose level of 2.5 mg/kg. Referring to fig. 5, this figure shows a decrease in sBCMA from pre-administration to EOI levels with the marc Bei Tuoshan antibody for cycle 1, day 1 of the marc Bei Tuoshan antibody treatment, where the x-axis represents the pre-administration sBCMA level and the y-axis represents the difference from pre-infusion to EOI sBCMA level. The level of decrease at sBCMA at EOI was consistent during each cycle (data not shown). In the data shown, ELISA detected about 89% sBCMA binding, which may be the limit of detection for this assay, as there is no evidence that the amount of sBCMA exceeded the amount of study drug.

SBCMA bound immediately after the anti-infusion of mar Bei Tuoshan, but sBCMA levels rebound after 24 hours. Among participants treated with marc Bei Tuoshan anti-treatment, an increase in sBCMA levels was detected 24 hours after the end of the marc Bei Tuoshan anti-infusion (EOI). Although a linear decrease in sBCMA levels was observed, an exponential increase in sBCMA levels was observed after 24 hours, indicating that sBCMA rebound was non-linear with sBCMA baseline levels and followed a different pattern than sBCMA level decreases (fig. 6). However, the sBCMA levels observed 24 hours after EOI were not due solely to sBCMA being resistant to dissociation from ma Bei Tuoshan, as the half-life of sBCMA was about 24 hours, indicating that the increase in sBCMA levels was due in large part to fresh shedding of tumor cells. In addition, when evaluating the level of sBCMA in patients grouped in response to treatment with mar Bei Tuoshan, patients with Progressive Disease (PD) had the highest baseline sBCMA level, but a large overlap in baseline sBCMA levels was observed between responders and non-responders (fig. 7A). Although sBCMA level rebound was also greatest after infusion of the mar Bei Tuoshan resistance for the progressive disease group, the observed differences between responders (including patient groups with Complete Response (CR), very Good Partial Response (VGPR), and Partial Response (PR)) and non-responders (including patient groups with Stable Disease (SD) or Progressive Disease (PD)) were increased compared to baseline levels (fig. 7B). This suggests that the presence of sBCMA at the periphery and the rate/level of rebound of sBCMA after anti-infusion of mar Bei Tuoshan may have a direct impact on anti-treatment of mar Bei Tuoshan.

Taken together, these data indicate that elimination or binding to free sBCMA may be an advantageous strategy to increase the efficacy of MA Bei Tuo mab.

EXAMPLE 5 in vivo efficacy of Bei Lantuo mab and MA Bei Tuoshan against treatment of human multiple myeloma xenograft models in NOG mice

Studies were performed to evaluate the in vivo therapeutic efficacy of Bei Lantuo mab (GSK 2857914), ma Bei Tuoshan antibody (GSK 2857916), and oginseam Wei Ao as single agents and combination drugs for the treatment of mm.1s-Luc human multiple myeloma xenograft models in NOG mice.

Experimental procedure

And (5) culturing the cells. Mm.1s-Luc cancer cells were maintained in vitro in an atmosphere of 5% CO ₂ at 37 ℃ with RMPI1640 medium supplemented with 10% fetal bovine serum and 1% sodium pyruvate +1% L-glutamine +1% penicillin-streptomycin. Cells in exponential growth phase were collected and quantified by a cell counter prior to tumor inoculation.

Tumor inoculation. Each mouse was inoculated intravenously via the tail vein with mm.1s-Luc tumor cells (1 x10 ⁷) in 0.1 mL PBS for tumor development. Mice were imaged 7 days after tumor cell inoculation and randomly assigned to 7 study groups.

Therapeutic administration. Groups of ten (10) mice were dosed by intraperitoneal (ip) administration in the amounts, as well as frequency and duration, shown in table 11.

TABLE 11

Tumor monitoring. Tumor growth was imaged twice weekly by bioluminescence imaging. 15 minutes prior to imaging, mice were subcutaneously injected with 150 mg/kg of D-fluorescein (Perkinelmer, cat. No. 122799). Mice were imaged at PERKINELMER IVIS luminea SERIES III in vivo imaging system.

Results

Figure 8 shows the mean tumor volume curves for vehicle and treatment groups between randomization to study termination, and table 12 shows Tumor Growth Inhibition (TGI) from data collected on day 11. Figure 9 shows Kaplan-Meier survival curves for all treatment groups as a function of the study, and table 13 presents median day of survival and Kaplan-Meier statistical analysis. The results demonstrate that GSK2857916 single agent treatment (group 2), GSK2857916 in combination with GSK2857914 (groups 3 and 4) and GSK2857916 in combination with oginse Wei Ao (group 5) resulted in significant antitumor efficacy against MM1s-Luc models with TGI values of 98.87%, 99.19%, 97.88% and 99.19%, respectively, at day 11, with significant statistical differences (p < 0.01) compared to vehicle control. GSK2857916 in combination with GSK2857914 (groups 3 and 4) showed the strongest antitumor efficacy across all treatment groups during the course of the study. In addition, GSK2857916 in combination with GSK2857914 (groups 3 and 4) and GSK2857916 in combination with oginse Wei Ao (group 5) significantly prolonged survival of animals (median survival days 54.5, 58.00 and 53.50, respectively) compared to vehicle control (median survival day 25.00).

Table 12

TABLE 13

Unless otherwise indicated, all numbers expressing quantities of ingredients, properties (e.g., molecular weight), reaction conditions, and so forth in the specification and claims are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the disclosure are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

The use of the terms "a" and "an" and "the" and similar referents in the context of describing the disclosure (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the disclosure and does not pose a limitation on the scope of the disclosure otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure.

The grouping of alternative elements or embodiments of the present disclosure disclosed herein should not be construed as limiting. Each group member may be cited and claimed individually or in any combination with other members of the group or other elements found herein. It is contemplated that one or more members of a group may be included in or deleted from the group for convenience and/or patentability reasons. When any such inclusion or deletion occurs, the specification is considered to contain modified groups and thus satisfies the written description of all markush groups used in the appended claims.

Certain embodiments of the present disclosure are described herein, including the best mode known to the inventors for carrying out the present disclosure. Of course, variations on the described embodiments will become apparent to those skilled in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the disclosure to be practiced otherwise than as specifically described herein. Accordingly, this disclosure includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the disclosure unless otherwise indicated herein or otherwise clearly contradicted by context.

The specific embodiments disclosed herein may be further defined in the claims using a language "consisting of or consisting essentially of. The transitional term "consisting of" when used in a claim, whether submitted or added according to a modification, excludes any elements, steps, or components not specified in the claim. The transitional term "consisting essentially of" limits the scope of the claims to the specified materials or steps as well as those materials or steps that do not materially affect the basic and novel characteristics. The embodiments of the disclosure so claimed are inherently or explicitly described and implemented herein.

It should be understood that the embodiments of the present disclosure disclosed herein are illustrative of the principles of the present disclosure. Other modifications that may be employed are within the scope of this disclosure. Thus, by way of example, and not limitation, alternative configurations of the present disclosure may be utilized in accordance with the teachings herein. Accordingly, the present disclosure is not limited to what is precisely as shown and described.

Although the present disclosure has been described and illustrated herein with reference to various specific materials, procedures and embodiments, it is to be understood that the present disclosure is not limited to the particular combination of materials and procedures selected for this purpose. Many variations of these details may be implied as will be appreciated by one skilled in the art. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the disclosure being indicated by the following claims. All references, patents and patent applications mentioned in this application are incorporated herein by reference in their entirety.

Claims

1. A method of treating a disease or disorder responsive to inhibition or blockade of B-cell maturation antigen (BCMA) in a patient, the method comprising administering berantuzumab to the patient at a dose of about 300 mg to about 2000 mg.

2. The method of claim 1, wherein the dose is about 300 mg, about 900 mg, or about 2000 mg.

3. The method of any of the preceding claims, wherein the patient has been treated with one, two, three or four prior lines of cancer therapy, wherein the prior lines of cancer therapy include an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulator.

4. The method of any of the preceding claims, wherein the patient is further receiving at least one additional cancer treatment, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulator, or an anti-PD-1 monoclonal antibody.

5. The method of claim 4, wherein the additional cancer treatment is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone.

6. The method of any of the preceding claims, further comprising administering a lead-in dose of mabetuzumab prior to initiating administration of berantuzumab, wherein the lead-in dose of mabetuzumab is about 1.4 mg/kg to about 3.4 mg/kg once during the lead-in period.

7. The method of claim 6, wherein the lead-in dose of mabetuzumab is about 1.4 mg/kg, about 1.9 mg/kg, about 2.5 mg/kg, or about 3.4 mg/kg, once during the lead-in period.

8. The method of claim 6 or claim 7, wherein the run-in period is four weeks ± 3 days, and mabetuzumab is administered on day 1 of the run-in period.

9. The method of any one of claims 6 to 8, further comprising administering to the patient during the lead-in period at least one additional cancer treatment, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulator, or an anti-PD-1 monoclonal antibody.

10. The method of claim 9, wherein the additional cancer treatment is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone.

11. A method of treating a disease or disorder responsive to inhibition or blockade of B cell maturation antigen (BCMA) in a patient, the method comprising administering to the patient a therapeutically effective amount of a combination comprising a first BCMA antagonist and a second BCMA antagonist.

12. The method of claim 11, wherein the first and second BCMA antagonists are independently selected from an anti-BCMA antibody or an antigen-binding fragment thereof, an anti-BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or an antigen-binding fragment thereof, and a chimeric antigen receptor T (CAR T) cell therapy targeting BCMA.

13. The method of claim 11, wherein the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is a corresponding unconjugated anti-BCMA antibody.

14. A method of treating a disease or disorder responsive to inhibition or blockade of B-cell maturation antigen (BCMA) in a patient, the method comprising administering to the patient a therapeutically effective amount of a combination comprising mabetuzumab and berantuzumab.

15. The method of any one of claims 11 to 14, further comprising administering to the patient at least one additional cancer treatment, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulator, or an anti-PD-1 monoclonal antibody.

16. The method of claim 15, wherein the additional cancer treatment is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone.

17. A method for treating a disease or disorder responsive to inhibition or blockade of B-cell maturation antigen (BCMA) in a patient previously treated with a first BCMA antagonist, the method comprising administering to the patient a therapeutically effective amount of a second BCMA antagonist, wherein the patient ceased administration of the first BCMA antagonist prior to initiating administration of the second BCMA antagonist, and the second BCMA antagonist is different from the first BCMA antagonist.

18. The method of claim 17, wherein the first and second BCMA antagonists are independently selected from an anti-BCMA antibody or an antigen-binding fragment thereof, an anti-BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or an antigen-binding fragment thereof, and a chimeric antigen receptor T (CAR T) cell therapy targeting BCMA.

19. The method of claim 17, wherein the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is a corresponding unconjugated anti-BCMA antibody; or wherein the second BCMA antagonist is an anti-BCMA antibody-drug conjugate and the first BCMA antagonist is a corresponding unconjugated anti-BCMA antibody.

20. The method of claim 19, wherein the first BCMA antagonist is mabetuzumab and the second BCMA antagonist is belantuzumab; or wherein the second BCMA antagonist is mabetuzumab and the first BCMA antagonist is belantuzumab.

21. A method of reducing corneal toxicity in a patient previously treated with mabetuzumab, the method comprising administering to the patient a therapeutically effective amount of berantuzumab, wherein the patient discontinued administration of mabetuzumab prior to initiating administration of berantuzumab.

22. The method of any one of claims 17 to 21, further comprising administering to the patient at least one additional cancer treatment, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulator, or an anti-PD-1 monoclonal antibody.

23. The method of claim 22, wherein the additional cancer treatment is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone.

24. A method of treating a disease or disorder in a patient comprising administering a therapeutically effective amount of a combination comprising an antibody-drug conjugate and a corresponding unconjugated antibody.

25. A method of treating a disease or disorder in a patient previously treated with an antibody-drug conjugate, the method comprising administering to the patient a therapeutically effective amount of a corresponding unconjugated antibody, wherein the patient ceased administration of the antibody-drug conjugate prior to initiating administration of the corresponding unconjugated antibody.

26. The method of any one of claims 1 to 25, wherein the disease or disorder is a plasma cell disorder or a B cell disorder.

27. The method of any one of claims 1 to 25, wherein the disease or disorder is a BCMA-expressing cancer.

28. The method of any one of claims 1 to 25, wherein the disease or disorder is multiple myeloma (MM).

29. The method of claim 28, wherein the MM is relapsed and/or refractory MM, newly diagnosed MM, MM not suitable for transplantation, or newly diagnosed MM not suitable for transplantation.

30. A method for treating cancer in a patient, wherein the patient has a grade 2 or greater corneal adverse reaction due to administration of mabetuzumab, the method comprising temporarily stopping administration of mabetuzumab; administering to the patient a therapeutically effective amount of berantuzumab for a continued lead-in period; and resuming administration of mabetuzumab after the lead-in period.