Subcutaneous administration of anti-CD20 / anti-CD3 bispecific antibodies

Abstract

The present invention relates to the treatment of subjects with CD20-positive cell proliferative disorders (e.g., B-cell proliferative disorders such as non-Hodgkin's lymphoma). More specifically, the present invention relates to the treatment of subjects with B-cell proliferative disorders by subcutaneous administration of an anti-CD20 / anti-CD3 bispecific antibody.

Description

Technical Field

[0001] Sequence Listing This application includes a Sequence Listing submitted electronically in ASCII format, which is hereby incorporated by reference in its entirety. The name of the ASCII copy created on November 1, 2021 is 50474-235WO4_Sequence_Listing_11_1_21_ST25, and the size is 35,329 bytes.

[0002] Field of the Invention The present invention relates to the treatment of CD20-positive cell proliferative disorders. More specifically, the present invention relates to the treatment of a subject having a CD20-positive cell proliferative disorder by subcutaneous administration of a bispecific antibody that binds to cluster of differentiation 20 (CD20) and cluster of differentiation 3 (CD3).

Background Art

[0003] Background Cancer is characterized by the uncontrolled growth of cell subpopulations. Cancer is the leading cause of death in developed countries and the second most common cause of death in developing countries, with over 14 million new cancer cases diagnosed and over 8 million cancer deaths occurring each year. Therefore, cancer care represents a significant and growing societal burden.

[0004] CD20-positive cell proliferative disorders such as B-cell proliferative disorders are a major cause of cancer-related death. For example, non-Hodgkin lymphoma (NHL) progresses rapidly and is fatal if untreated. In the United States, B-cell lymphoma constitutes approximately 80% - 85% of all NHL cases. Diffuse large B-cell lymphoma (DLBCL) is the most common type of NHL, accounting for approximately 30% - 40% of all NHL diagnoses, followed by follicular lymphoma (FL; 20% - 25% of all NHL diagnoses) and mantle cell lymphoma (MCL; 6% - 10% of all NHL diagnoses). B-cell chronic lymphocytic leukemia (CLL) is the most common leukemia in adults, with approximately 15,000 new cases each year in the United States (American Cancer Society 2015).

[0005] Bispecific antibodies are capable of simultaneously binding cell surface antigens on cytotoxic cells (e.g., T cells via binding to cluster of differentiation 3 (CD3)) and cancer cells (e.g., B cells via binding to CD20) with the intent that the bound cytotoxic cells will destroy the bound cancer cells. However, antibody-based immunotherapies such as these can be limited by undesirable effects, including cytokine-driven toxicity (e.g., cytokine release syndrome (CRS)), infusion-related reactions (IRR), severe tumor lysis syndrome (TLS), and central nervous system (CNS) toxicity.

[0006] Thus, there is an unmet need in the art to develop effective methods of administering therapeutic bispecific antibodies (e.g., bispecific antibodies that bind to CD20 and CD3) for the treatment of CD20-positive cell proliferative disorders (e.g., B-cell proliferative disorders) that achieve a more favorable benefit-risk profile. Summary of the Invention

[0007] The present invention relates to a method of treating a subject with a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder) by subcutaneously administering a bispecific antibody that binds to cluster of differentiation 20 (CD20) and cluster of differentiation 3 (CD3).

[0008] In one aspect, the present invention is a method of treating a subject having a CD20-positive cell proliferative disorder (e.g., B-cell proliferative disorder), comprising subcutaneously administering to the subject a bispecific antibody that binds to CD20 and CD3 in a dosing schedule comprising at least a first dosing cycle and a second dosing cycle, wherein (a) the first dosing cycle comprises a first subcutaneous dose (C1D1), a second subcutaneous dose (C1D2), and a third subcutaneous dose (C1D3) of the bispecific antibody, and (i) C1D1 is less than or equal to C1D2 and less than C1D3, (ii) C1D2 is less than or equal to C1D3, and (iii) C1D1 is from about 0.1 mg to about 10 mg (e.g., from about 0.1 mg to about 7 mg, from about 0.2 mg to about 10 mg, from about 0.5 mg to about 10 mg, about 1 mg to about 9 mg, about 2 mg to about 8 mg, about 3 mg to about 7 mg, about 4 mg to about 6 mg; for example, about 5 mg), and C1D2 is about 5 mg to about 80 mg (for example, about 20 mg to about 75 mg, about 25 mg to about 75 mg, about 30 mg to about 75 mg, about 35 mg to about 75 mg, or about 40 mg to about 75 mg; for example, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg), and C1D3 is about 10 mg to about 300 mg (about 25 mg to about 300 mg, about 50 mg to about 300 mg, about 100 mg to about 300 mg, about 200 mg to about 300 mg, about 50 mg to about 250 mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, about 10 mg to about 250 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 150 (b) the second administration cycle comprises a single subcutaneous dose (2D1) of the bispecific antibody, C2D1 being equal to or greater than C1D3 and is between about 10 mg and about 300 mg (about 25 mg to about 300 mg, about 50 mg to about 300 mg, about 100 mg to about 300 mg, about 200 mg to about 300 mg, about 25 mg to about 300 mg, about 30 mg to about 300 mg, about 40 mg to about 100 mg, or about 25 mg to about 75 mg; for example, about 30 mg, about 45 mg, or about 60 mg); The dose is about 300 mg, about 50 mg to about 250 mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, about 10 mg to about 250 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 150 mg, about 10 mg to about 140 mg, about 20 mg to about 130 mg, about 30 mg to about 120 mg, or about 40 mg to about 100 mg, or about 25 mg to about 75 mg; for example, about 30 mg, about 45 mg, or about 60 mg).

[0009] In some embodiments, C1D1 is less than C1D2. In some embodiments, C1D2 is equivalent to C1D3. In some embodiments, (a) C1D1 is about 2 mg to about 8 mg, and C1D2 is about 10 mg to about 75 mg (e.g., about 20 mg to about 75 mg, about 25 mg to about 75 mg, about 30 mg to about 75 mg, about 35 mg to about 75 mg, or about 40 mg to about 75 mg; for example, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg). (b) C1D3 is about 20 mg to about 75 mg (e.g., about 25 mg to about 75 mg, about 30 mg to about 75 mg, about 35 mg to about 75 mg, or about 40 mg to about 75 mg; e.g., about 45 mg); and (b) C2D1 is about 20 mg to about 75 mg (e.g., about 25 mg to about 75 mg, about 30 mg to about 75 mg, about 35 mg to about 75 mg, or about 40 mg to about 75 mg; e.g., about 45 mg). In some embodiments, C1D1 is about 5 mg. In some embodiments, C1D3 is about 25 mg to about 75 mg. In some embodiments, C1D3 is about 30 mg, about 45 mg, or about 60 mg. In some embodiments, C2D1 is about 40 mg to about 75 mg. In some embodiments, C2D1 is about 30 mg, about 45 mg, or about 60 mg. In some embodiments, C1D2 is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 45 mg, or about 60 mg.

[0010] In some embodiments, C1D1 is about 5 mg, C1D2 is about 45 mg, C1D3 is about 45 mg, and C2D1 is about 45 mg; C1D1 is about 5 mg, C1D2 is about 10 mg, C1D3 is about 30 mg, and C2D1 is about 30 mg; C1D1 is about 5 mg, C1D2 is about 15 mg, C1D3 is about 45 mg, and C2D1 is about 45 mg; C1D1 is about 5 mg, C1D2 is about 20 mg, C1D3 is about 40 mg, and C2D1 is about 40 mg; or C1D1 is about 5 mg, C1D2 is about 20 mg, C1D3 is about 60 mg, and C2D1 is about 60 mg. In some embodiments, C1D1 is about 5 mg, C1D2 is about 20 mg, C1D3 is about 60 mg, and C2D1 is about 60 mg.

[0011] In some embodiments, C1D1 is equal to C1D2 (e.g., C1D1 is about 5 mg, C1D2 is about 5 mg, C1D3 is about 45 mg, and C2D1 is about 45 mg.). In some embodiments, C1D1 is equal to C1D2 (e.g., C1D1 is about 5 mg, C1D2 is about 5 mg, C1D3 is about 60 mg, and C2D1 is about 60 mg.). In other embodiments, C1D2 is equal to C1D3 (e.g., C1D1 is about 5 mg, C1D2 is about 60 mg, C1D3 is about 60 mg, and C2D1 is about 60 mg.). In other embodiments, C1D2 is equal to C1D3 (e.g., C1D1 is about 5 mg, C1D2 is about 45 mg, C1D3 is about 45 mg, and C2D1 is about 60 mg.).

[0012] In some embodiments, the method includes administering C1D2 to the subject about 7 days after C1D1. In some embodiments, the method includes administering C1D3 to the subject about 7 days after C1D2. In some embodiments, the method includes administering C2D1 to the subject about 7 days after C1D3. In some embodiments, the method includes administering C1D1, C1D2, and C1D3 to the subject on days 1, 8, and 15, or about days 1, 8, and 15, respectively, of a first administration cycle. In some embodiments, the method includes administering C2D1 to the subject on day 1 of a second administration cycle.

[0013] In some embodiments, the first and second dosing cycles are 21 day dosing cycles.

[0014] In some embodiments, the first and second administration cycles are 28-day administration cycles, hi some embodiments, the first administration cycle is a 21-day administration cycle and the second administration cycle is a 28-day administration cycle.

[0015] In another aspect, the invention provides a method of treating a subject with a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder), comprising subcutaneously administering to the subject a bispecific antibody that binds CD20 and CD3 in a dosing regimen comprising at least a first and a second dosing cycle, wherein (a) the first dosing cycle comprises a first subcutaneous dose (C1D1), a second subcutaneous dose (C1D2), and a third subcutaneous dose (C1D3) of the bispecific antibody, where (i) C1D1 is about 5 mg, (ii) C1D2 is equal to or greater than C1D1 and equal to or less than C1D3, and (iii) C1D3 is about 60 mg; and (b) the second dosing cycle comprises a single subcutaneous dose of the bispecific antibody (C2D1), where C2D1 is about 60 mg. In some embodiments, C1D3 is about 45 mg.

[0016] In some embodiments, C1D2 is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 45 mg, or about 60 mg. In some embodiments, C1D2 is about 15 mg. In some embodiments, C1D2 is about 45 mg. In some embodiments, the first dosing cycle and the second dosing cycle are 21-day dosing cycles. In some embodiments, the method comprises administering C1D1, C1D2, and C1D3 to a subject on days 1, 8, and 15, respectively, of the first dosing cycle, or on about day 1, about day 8, and about day 15. In some embodiments, the method comprises administering C2D1 to a subject on day 1 of the second dosing cycle. In some embodiments, the first dosing cycle and the second dosing cycle are 21-day dosing cycles. In some embodiments, the first dosing cycle and the second dosing cycle are 28-day dosing cycles. In some embodiments, the first dosing cycle is a 21-day dosing cycle and the second dosing cycle is a 28-day dosing cycle.

[0017] In another aspect, the invention is a method of treating a subject having a CD20-positive proliferative disorder (e.g., a B-cell proliferative disorder), the method comprising subcutaneously administering to the subject a bispecific antibody that binds to CD20 and CD3 in a dosing schedule comprising at least a first dosing cycle and a second dosing cycle, wherein: (a) the first dosing cycle comprises a first subcutaneous dose (C1D1) of the bispecific antibody on day 1 of the first dosing cycle, a second subcutaneous dose (C1D2) of the bispecific antibody on day 8 of the first dosing cycle, and a third subcutaneous dose (C1D3) of the bispecific antibody on day 15 of the first dosing cycle, wherein (i) C1D1 is about 5 mg, (ii) C1D2 is greater than or equal to C1D1 and less than or equal to C1D3, and (iii) C1D3 is about 45 mg; and (b) the second dosing cycle comprises a single subcutaneous dose (C2D1) of the bispecific antibody on day 1 of the second dosing cycle, and C2D1 is about 45 mg.

[0018] In another aspect, the invention features a method of treating a subject with a CD20-positive proliferative disorder (e.g., a B-cell proliferative disorder), comprising subcutaneously administering to the subject a bispecific antibody that binds CD20 and CD3 in a dosing regimen comprising at least a first and a second dosing cycle, wherein: (a) the first dosing cycle comprises a first subcutaneous dose of the bispecific antibody (C1D1) on day 1 of the first dosing cycle, a second subcutaneous dose of the bispecific antibody (C1D2) on day 8 of the first dosing cycle, and a third subcutaneous dose of the bispecific antibody (C1D3) on day 15 of the first dosing cycle, wherein (i) C1D1 is about 5 mg, (ii) C1D2 is greater than or equal to C1D1 and less than or equal to C1D3, and (iii) C1D3 is about 60 mg; and (b) the second dosing cycle comprises a single subcutaneous dose of the bispecific antibody (C2D1) on day 1 of the second dosing cycle, wherein C2D1 is about 60 mg. In some embodiments, the C1D3 is about 45 mg.

[0019] In some embodiments, C1D2 is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 45 mg, or about 60 mg. In some embodiments, C1D2 is about 15 mg. In some embodiments, C1D2 is about 45 mg. In some embodiments, each additional administration cycle is a 21-day administration cycle. In some embodiments, each additional administration cycle is a 28-day administration cycle.

[0020] In some embodiments, each of the one or more additional administration cycles comprises a single subcutaneous dose of the bispecific antibody. In some embodiments, the method comprises administering to the subject a single subcutaneous dose on day 1 of each of the one or more additional administration cycles.

[0021] In some embodiments of any of the foregoing methods, the CD20-positive cell proliferative disorder (e.g., B-cell proliferative disorder) is non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL). In some embodiments, the NHL is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), or primary mediastinal (thymic) large B-cell lymphoma (PMLBCL). In some embodiments, the NHL is previously untreated (1L) NHL. In some embodiments, the NHL is relapsed or refractory NHL (R / R NHL). In some embodiments, the DLBCL is 1L DLBCL. In some embodiments, the DLBCL is relapsed or refractory DLBCL. In some embodiments, the DLBCL is Richter transformation. In some embodiments, the FL is 1L FL. In some embodiments, the FL is relapsed or refractory FL. In some embodiments, the FL is transformed FL. In some embodiments, the NHL is high-grade B-cell lymphoma. In some embodiments, the NHL is Ann Arbor stage III or IV NHL. In some embodiments, the subject has previously received at least one (e.g., at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or more) prior lines of systemic therapy. In some embodiments, the subject has received between 1 and 9 (e.g., one, two, three, four, five, six, seven, eight, or nine) prior lines of systemic therapy. In some embodiments, the subject has received three prior lines of systemic therapy. In some embodiments, at least one (e.g., one, two, three, four, five, six, seven, eight, or nine) prior line of systemic therapy included an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is rituximab or obinutuzumab. In some embodiments, the prior line of systemic therapy that included an anti-CD20 antibody additionally included an alkylating agent or anthracycline. In some embodiments, the alkylating agent is cyclophosphamide or bendamustine.In some embodiments, the anthracycline is daunomycin or doxorubicin. In some embodiments, the prior line of systemic therapy comprising an anti-CD20 antibody additionally comprises: (i) cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); (ii) cyclophosphamide, vincristine, and prednisone (CVP); (iii) fludarabine; or (iv) bendamustine. In some embodiments, at least one (e.g., one, two, three, four, five, six, seven, eight, or nine) prior line of systemic therapy included a Bruton's tyrosine kinase (BTK) inhibitor.

[0022] In another aspect of the invention, there is provided a method of treating a subject with DLBCL, comprising subcutaneously administering to the subject a bispecific antibody that binds CD20 and CD3 in a dosing regimen comprising at least a first 21-day dosing cycle and a second 21-day dosing cycle, wherein: (a) the first 21-day dosing cycle comprises a first subcutaneous dose (C1D1), a second subcutaneous dose (C1D2), and a third subcutaneous dose (C1D3) of the bispecific antibody; (i) C1D2, C1D3, and C1D4; D1 is equal to or less than C1D2 and less than C1D3, (ii) C1D2 is equal to or less than C1D3, and (iii) C1D1 is about 0.1 mg to about 10 mg (e.g., about 0.1 mg to about 7 mg, about 0.2 mg to about 10 mg, about 0.5 mg to about 10 mg, about 1 mg to about 9 mg, about 2 mg to about 8 mg, about 3 mg to about 7 mg, about 4 mg to about 6 mg; e.g., about 5 mg), and C1D2 is about 5 mg to about 80 mg (e.g., about 20 mg to about 75 mg, about 25 mg). g to about 75 mg, about 30 mg to about 75 mg, about 35 mg to about 75 mg, or about 40 mg to about 75 mg; for example, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg), and C1D3 is about 10 mg to about 300 mg (about 25 mg to about 300 mg, about 50 mg to about 300 mg, about 100 mg to about 300 mg, about 200 mg to about 300 mg, about 50 mg to about 250 mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, about 10 mg to about 250 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 150 mg, about 10 mg to about 140 mg, about 20 mg to about 130 mg, about 30 mg to about 120 mg, or about 40 mg to about 100 mg, or about 25 mg to about 75 mg;For example, (a) the first 21-day dosing cycle comprises a single subcutaneous dose of a bispecific antibody (1D1), C1D1 is about 30 mg, about 45 mg, or about 60 mg, and (b) the second 21-day dosing cycle comprises a single subcutaneous dose of a bispecific antibody (2D1), C2D1 is greater than or equal to C1D3, and is about 10 mg to about 300 mg (about 25 mg to about 300 mg, about 50 mg to about 300 mg, about 100 mg to about 300 mg, about 200 mg to about 300 mg, about 50 mg to about 250 mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, about 10 mg to about 250 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 150 mg, about 10 mg to about 140 mg, about 20 mg to about 130 mg, about 30 mg to about 120 mg, or about 40 mg to about 100 mg, or about 25 mg to about 75 mg; for example, about 30 mg, about 45 mg, or about 60 mg). A method is provided. In some embodiments, the DLBCL is 1L DLBCL, or relapsed or refractory DLBCL. In some embodiments, the DLBCL is Richter's transformation. In some embodiments, the method comprises administering C1D2 to the subject about 7 days after C1D1. In some embodiments, the method comprises administering C1D3 to the subject about 7 days after C1D2. In some embodiments, the method comprises administering C2D1 to the subject about 7 days after C1D3. In some embodiments, the method comprises administering C1D1, C1D2, and C1D3 to the subject on days 1, 8, and 15, respectively, of the first dosing cycle, or on about day 1, about day 8, and about day 15.;

[0023] In another aspect, the invention provides a method of treating a subject with FL, comprising subcutaneously administering to the subject a bispecific antibody that binds CD20 and CD3 in a dosing regimen comprising at least a first 28-day dosing cycle and a second 28-day dosing cycle, wherein: (a) the first 28-day dosing cycle comprises a first subcutaneous dose (C1D1), a second subcutaneous dose (C1D2), and a third subcutaneous dose (C1D3) of the bispecific antibody, wherein: (i) C1D1 is equal to or less than C1D2 and less than C1D3; (ii) C1D2 is equal to or less than C1D3; and (iii) C1D1 is between about 0.1 mg and about 10 mg (e.g., between about 0.1 mg and about 7 mg, between about 0.2 mg and about 10 mg, between about 0.5 mg and about 15 mg, or between about 0.5 mg and about 15 mg).5 mg to about 10 mg, about 1 mg to about 9 mg, about 2 mg to about 8 mg, about 3 mg to about 7 mg, about 4 mg to about 6 mg; for example, about 5 mg), C1D2 is about 5 mg to about 80 mg (for example, about 20 mg to about 75 mg, about 25 mg to about 75 mg, about 30 mg to about 75 mg, about 35 mg to about 75 mg, or about 40 mg to about 75 mg; for example, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg), C1D3 is about 10 mg to about 300 mg (about 25 mg to about 300 mg, about 50 mg to about 300 mg, about 100 mg to about 300 mg, about 200 mg to about 300 mg, about 50 mg to about 250 mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, about 10 mg to about 250 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 150 mg, about 10 mg to about 140 mg, about 20 mg to about 130 mg, about 30 mg to about 120 mg, or about 40 mg to about 100 mg, or about 25 mg to about 75 mg; for example, about 30 mg, about 45 mg, or about 60 mg), (b) the second 28-day dosing cycle includes a single subcutaneous dose of the bispecific antibody (2D1), C2D1 is greater than or equal to C1D3, about 10 mg to about 300 mg (about 25 mg to about 300 mg, about 50 mg to about 300 mg, about 100 mg to about 300 mg, about 200 mg to about 300 mg, about 50 mg to about 250 mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, about 10 mg to about 250 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 150 mg, about 10 mg to about 140 mg, about 20 mg to about 130 mg, about 30 mg to about 120 mg, or about 40 mg to about 100 mg, or about 25 mg to about 75 mg; for example, about 30 mg, about 45 mg, or about 60 mg). In some embodiments, FL is previously untreated (1L) FL, or relapsed or refractory FL. In some embodiments, FL is previously untreated (1L) FL. In some embodiments, FL is transformed FL.

[0024] In another aspect, the invention provides a method of treating a subject with FL, comprising subcutaneously administering to the subject a bispecific antibody that binds CD20 and CD3 in a dosing regimen comprising at least a first 21-day dosing cycle and a second 28-day dosing cycle, wherein: (a) the first 21-day dosing cycle comprises a first subcutaneous dose (C1D1), a second subcutaneous dose (C1D2), and a third subcutaneous dose (C1D3) of the bispecific antibody, wherein: (i) C1D1 is equal to or less than C1D2 and less than C1D3; (ii) C1D2 is equal to or less than C1D3; and (iii) C1D1 is between about 0.1 mg and about 10 mg (e.g., between about 0.1 mg and about 7 mg, between about 0.2 mg and about 10 mg, between about 0.5 mg and about 15 mg, or between about 0.5 mg and about 15 mg).5 mg to about 10 mg, about 1 mg to about 9 mg, about 2 mg to about 8 mg, about 3 mg to about 7 mg, about 4 mg to about 6 mg; for example, about 5 mg), and C1D2 is about 5 mg to about 80 mg (for example, about 20 mg to about 75 mg, about 25 mg to about 75 mg, about 30 mg to about 75 mg, about 35 mg to about 75 mg, or about 40 mg to about 75 mg; for example, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg , about 60 mg, about 65 mg, about 70 mg, or about 75 mg), and C1D3 is about 10 mg to about 300 mg (about 25 mg to about 300 mg, about 50 mg to about 300 mg, about 100 mg to about 300 mg, about 200 mg to about 300 mg, about 50 mg to about 250 mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, about 10 mg to about 250 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 150 mg, about 10 mg (b) a second 28-day administration cycle comprising a single subcutaneous dose (C2D1) of bispecific antibody, C2D1 being equal to or greater than C1D3 and ranging from about 10 mg to about 300 mg (e.g., about 25 mg to about 300 mg, about 50 mg to about 300 mg, about 100 mg to about 300 mg, about 200 mg to about 300 mg, about 25 mg to about 300 mg, about 50 mg to about 300 mg, about 100 mg to about 300 mg, about 200 mg to about 300 mg); g, about 50 mg to about 250 mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, about 10 mg to about 250 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 150 mg, about 10 mg to about 140 mg, about 20 mg to about 130 mg, about 30 mg to about 120 mg, or about 40 mg to about 100 mg, or about 25 mg to about 75 mg; e.g., about 30 mg, about 45 mg, or about 60 mg). In some embodiments, the FL is previously untreated (1L) FL or relapsed or refractory FL. In some embodiments, the FL is previously untreated (1L) FL. In some embodiments, the FL is transformed FL.

[0025] In some embodiments, the method comprises administering C1D2 to the subject about 7-10 days after C1D1. In some embodiments, the method comprises administering C1D3 to the subject about 7-10 days after C1D2. In some embodiments, the method comprises administering C2D1 to the subject about 7-10 days after C1D3. In some embodiments, C1D1 is less than C1D2. In other embodiments, C1D2 is about equal to or less than C1D3. In some embodiments, (a) C1D1 is about 2 mg to about 8 mg (e.g., about 5 mg), and C1D2 is about 10 mg to about 75 mg (e.g., about 20 mg to about 75 mg, about 25 mg to about 75 mg, about 30 mg to about 75 mg, about 35 mg to about 75 mg, or about 40 mg to about 75 mg; for example, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg). g, about 65 mg, about 70 mg, or about 75 mg), C1D3 is about 20 mg to about 75 mg (e.g., about 25 mg to about 75 mg, about 30 mg to about 75 mg, about 35 mg to about 75 mg, or about 40 mg to about 75 mg; e.g., about 45 mg), and (b) C2D1 is about 20 mg to about 75 mg (e.g., about 25 mg to about 75 mg, about 30 mg to about 75 mg, about 35 mg to about 75 mg, or about 40 mg to about 75 mg; e.g., about 45 mg). In some embodiments, C1D1 is about 5 mg. In some embodiments, C1D3 is about 25 mg to about 75 mg. In some embodiments, C1D3 is about 30 mg, about 45 mg, or about 60 mg. In some embodiments, C2D1 is about 40 mg to about 75 mg (e.g., about 30 mg, about 45 mg, or about 60 mg), and C1D2 is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 45 mg, or about 60 mg.

[0026] In some embodiments, C1D1 is about 5 mg, C1D2 is about 10 mg, C1D3 is about 30 mg, and C2D1 is about 30 mg; C1D1 is about 5 mg, C1D2 is about 15 mg, C1D3 is about 45 mg, and C2D1 is about 45 mg; C1D1 is about 5 mg, C1D2 is about 20 mg, C1D3 is about 40 mg, and C2D1 is about 40 mg; C1D1 is about 5 mg, C1D2 is about 20 mg, C1D3 is about 45 mg, and C2D1 is about 60 mg; or C1D1 is about 5 mg, C1D2 is about 20 mg, C1D3 is about 60 mg, and C2D1 is about 60 mg. In some embodiments, C1D1 is about 5 mg, C1D2 is about 20 mg, C1D3 is about 45 mg, and C2D1 is about 60 mg. In some embodiments, C1D1 is about 5 mg, C1D2 is about 20 mg, C1D3 is about 60 mg, and C2D1 is about 60 mg. In some embodiments, C1D1 is equal to C1D2. In some embodiments, C1D1 is about 5 mg, C1D2 is about 5 mg, C1D3 is about 60 mg, and C2D1 is about 60 mg. In some embodiments, C1D1 is about 5 mg, C1D2 is about 5 mg, C1D3 is about 45 mg, and C2D1 is about 60 mg. In some embodiments, C1D2 is equal to C1D3 (e.g., C1D1 is about 5 mg, C1D2 is about 60 mg, C1D3 is about 60 mg, and C2D1 is about 60 mg, or e.g., C1D1 is about 5 mg, C1D2 is about 45 mg, C1D3 is about 45 mg, and C2D1 is about 60 mg). In some embodiments, the method comprises administering C2D1 to the subject on day 1 of a second administration cycle.

[0027] In some embodiments, the dosing schedule includes one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) additional dosing cycles (e.g., from 1 to 15 additional dosing cycles, from 8 to 17 additional dosing cycles, or from 6 to 15 additional dosing cycles). In some embodiments, the dosing schedule includes 6 additional dosing cycles. In some embodiments, the dosing schedule includes 15 additional dosing cycles. In some embodiments, the dosing schedule includes a total of from 2 to 17 (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17) dosing cycles. In some embodiments, the dosing schedule includes a total of 8 dosing cycles. In some embodiments, the dosing schedule includes a total of 17 dosing cycles. In some embodiments, each additional dosing cycle is a 21-day dosing cycle. In some embodiments, each additional dosing cycle is a 28-day dosing cycle. In some embodiments, each additional dosing cycle includes administration of an additional dose of the bispecific antibody. In some embodiments, each additional dose of the bispecific antibody is an amount substantially equal to C2D1. In some embodiments, each additional dose of the bispecific antibody is about 45 mg. In some embodiments, the method includes administering each additional dose of the bispecific antibody to the subject on day 1 of each respective additional dosing cycle.

[0028] In some embodiments of any of the preceding aspects, the bispecific antibody is administered as monotherapy to the subject.

[0029] In some other embodiments of any of the preceding aspects, the bispecific antibody is administered as a combination therapy to a subject. In some embodiments, the bispecific antibody is administered to the subject simultaneously with one or more additional therapeutic agents. In some embodiments, the bispecific antibody is administered to the subject prior to the administration of one or more additional therapeutic agents. In some embodiments, the bispecific antibody is administered to the subject after the administration of one or more additional therapeutic agents. In some embodiments, the additional therapeutic agent is a CD79b antibody-drug conjugate (ADC), such as polatuzumab vedotin or anti-CD79b-MC-vc-PAB-MMAE. In some embodiments, the additional therapeutic agent is a PD-1 axis-binding antagonist (e.g., a PD-L1 antagonist antibody). In some embodiments, the additional therapeutic agent is obinutuzumab (GAZYVA®). In some embodiments, the additional therapeutic agent is lenalidomide.

[0030] In some embodiments of any one of the preceding aspects, the subject has a cytokine release syndrome event and the method further comprises treating the symptoms of the cytokine release syndrome event while withholding treatment with the bispecific antibody. In some embodiments, the method further comprises administering to the subject an effective amount of tocilizumab to treat the cytokine release syndrome event. In some embodiments, tocilizumab is administered intravenously as a single dose of about 8 mg / kg to the subject. In some embodiments, the cytokine release syndrome event does not resolve or worsens within 24 hours after treating the symptoms of the cytokine release syndrome event, and the method further comprises administering to the subject one or more additional doses of tocilizumab to manage the cytokine release syndrome event. In some embodiments, the one or more additional doses of tocilizumab are administered intravenously to the subject at a dose of about 8 mg / kg. In some embodiments, each dose of tocilizumab does not exceed 800 mg / dose. In some embodiments, the method further comprises administering to the subject an effective amount of a corticosteroid (e.g., methylprednisolone or dexamethasone). In some embodiments, the corticosteroid (e.g., methylprednisolone or dexamethasone) is administered intravenously to the subject. In some embodiments, methylprednisolone is administered as a single dose of about 2 mg / kg per day. In some embodiments, dexamethasone is administered at a dose of about 10 mg to about 100 mg (e.g., about 10 mg).

[0031] In another aspect, the present invention is a method of treating a population of subjects having a CD20-positive cell proliferative disorder (e.g., B-cell proliferative disorder), comprising subcutaneously administering to one or more subjects a bispecific antibody that binds to CD20 and CD3 in a dosing schedule comprising at least a first dosing cycle and a second dosing cycle, wherein (a) the first dosing cycle comprises a first subcutaneous dose (C1D1), a second subcutaneous dose (C1D2), and a third subcutaneous dose (C1D3) of the bispecific antibody, (i) C1D1 is less than or equal to C1D2 and less than C1D3, (ii) C1D2 is less than or equal to C1D3, (iii) C1D1 is from about 0.1 mg to about 10 mg (e.g., from about 0.1 mg to about 7 mg, from about 0.2 mg to about 10 mg, from about 0.C1D2 is about 5 mg to about 80 mg (e.g., about 20 mg to about 75 mg, about 25 mg to about 75 mg, about 30 mg to about 75 mg, about 35 mg to about 75 mg, or about 40 mg to about 75 mg; for example, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg). g, about 60 mg, about 65 mg, about 70 mg, or about 75 mg), and C1D3 is about 10 mg to about 300 mg (about 25 mg to about 300 mg, about 50 mg to about 300 mg, about 100 mg to about 300 mg, about 200 mg to about 300 mg, about 50 mg to about 250 mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, about 10 mg to about 250 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 150 mg, about 1 (b) the second administration cycle comprises a single subcutaneous dose (C2D1) of the bispecific antibody, C2D1 being equal to or greater than C1D3 and ranging from about 10 mg to about 300 mg (about 25 mg to about 300 mg, about 50 mg to about 300 mg, about 100 mg to about 300 mg, about 200 mg to about 300 mg, about 25 mg to about 300 mg, about 50 mg to about 300 mg, about 100 mg to about 300 mg, about 200 mg to about 300 mg, The method is characterized in that the dose is about 50 mg to about 250 mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, about 10 mg to about 250 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 150 mg, about 10 mg to about 140 mg, about 20 mg to about 130 mg, about 30 mg to about 120 mg, or about 40 mg to about 100 mg, or about 25 mg to about 75 mg; for example, about 30 mg, about 45 mg, or about 60 mg).

[0032] In another aspect, the invention features a method of treating a population of subjects having a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder), comprising subcutaneously administering to the subject a bispecific antibody that binds CD20 and CD3 in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein: (a) the first dosing cycle comprises a first subcutaneous dose (C1D1), a second subcutaneous dose (C1D2), and a third subcutaneous dose (C1D3) of the bispecific antibody, where (i) C1D1 is about 5 mg, (ii) C1D2 is greater than or equal to C1D1 and less than or equal to C1D3, and (iii) C1D3 is about 45 mg; and (b) the second dosing cycle comprises a single subcutaneous dose of the bispecific antibody (C2D1), where C2D1 is about 45 mg.

[0033] In another aspect, the invention features a method of treating a population of subjects having a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder), comprising subcutaneously administering to the subject a bispecific antibody that binds CD20 and CD3 in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein: (a) the first dosing cycle comprises a first subcutaneous dose (C1D1), a second subcutaneous dose (C1D2), and a third subcutaneous dose (C1D3) of the bispecific antibody, where (i) C1D1 is about 5 mg, (ii) C1D2 is greater than or equal to C1D1 and less than or equal to C1D3, and (iii) C1D3 is about 45 mg or about 60 mg; and (b) the second dosing cycle comprises a single subcutaneous dose of the bispecific antibody (C2D1), where C2D1 is about 45 mg or 60 mg.

[0034] In another aspect, the invention provides a method of treating a population of subjects having a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder), comprising subcutaneously administering to the subject a bispecific antibody that binds CD20 and CD3 in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein: (a) the first dosing cycle comprises a first subcutaneous dose (C1D1) of the bispecific antibody on day 1 of the first dosing cycle, a second subcutaneous dose (C1D2) of the bispecific antibody on day 8 of the first dosing cycle, and a third subcutaneous dose (C1D3) of the bispecific antibody on day 8 of the first dosing cycle. and a third subcutaneous dose (C1D3) of the bispecific antibody on day 15 of the first administration cycle, wherein (i) C1D1 is about 5 mg, (ii) C1D2 is greater than or equal to C1D1 and less than or equal to C1D3, and (iii) C1D3 is about 45 mg or about 60 mg; and (b) the second administration cycle comprises a single subcutaneous dose of the bispecific antibody (C2D1) on day 1 of the second administration cycle, wherein C2D1 is about 45 mg or about 60 mg.

[0035] In some embodiments, the CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder) is non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL). In some embodiments, the NHL is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), or primary mediastinal (thymic) large B-cell lymphoma (PMLBCL). In some embodiments, the NHL is previously untreated (1L) NHL. In some embodiments, the NHL is CLL. In some embodiments, the DLBCL is 1L DLBCL. In some embodiments, the DLBCL is relapsed or refractory DLBCL. In some embodiments, the DLBCL is Richter's transformed. In some embodiments, the FL is 1L FL. In some embodiments, the FL is relapsed or refractory FL. In some embodiments, the FL is transformed FL. In some embodiments, the NHL is an aggressive B-cell lymphoma. In some embodiments, the NHL is Ann Arbor Stage III or IV NHL. In some embodiments, the subject has previously received at least one (e.g., at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or more) prior line of systemic therapy. In some embodiments, the subject has received between one and nine (e.g., one, two, three, four, five, six, seven, eight, or nine) prior lines of systemic therapy. In some embodiments, the subject has received three prior lines of systemic therapy. In some embodiments, at least one (e.g., one, two, three, four, five, six, seven, eight, or nine) prior line of systemic therapy included an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is rituximab or obinutuzumab. In some embodiments, the prior line of systemic therapy comprising an anti-CD20 antibody additionally comprises an alkylating agent or an anthracycline. In some embodiments, the alkylating agent is cyclophosphamide or bendamustine. In some embodiments, the anthracycline is daunomycin or doxorubicin.In some embodiments, the prior line of systemic therapy comprising an anti-CD20 antibody additionally comprises: (i) cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); (ii) cyclophosphamide, vincristine, and prednisone (CVP); (iii) fludarabine; or (iv) bendamustine. In some embodiments, at least one (e.g., one, two, three, four, five, six, seven, eight, or nine) prior line of systemic therapy included a Bruton's tyrosine kinase (BTK) inhibitor.

[0036] In another aspect, the invention provides a method of treating a population of subjects with DLBCL, comprising subcutaneously administering to one or more subjects a bispecific antibody that binds CD20 and CD3 (e.g., mosunetuzumab) in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein: (a) the first dosing cycle comprises a first subcutaneous dose (C1D1), a second subcutaneous dose (C1D2), and a third subcutaneous dose (C1D3) of the bispecific antibody; (i) C1D1 is equal to or less than C1D2 and less than C1D3, (ii) C1D2 is equal to or less than C1D3, and (iii) C1D1 is about 0.1 mg to about 10 mg (e.g., about 0.1 mg to about 7 mg, about 0.2 mg to about 10 mg, about 0.5 mg to about 10 mg, about 1 mg to about 9 mg, about 2 mg to about 8 mg, about 3 mg to about 7 mg, about 4 mg to about 6 mg; e.g., about 5 mg), and C1D2 is about 5 mg to about 80 mg (e.g., about 20 mg to about 75 mg). , about 25 mg to about 75 mg, about 30 mg to about 75 mg, about 35 mg to about 75 mg, or about 40 mg to about 75 mg; for example, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg), and C1D3 is about 10 mg to about 300 mg (about 25 mg to about 300 mg, about 50 mg to about 300 mg, about 1 00mg to about 300mg, about 200mg to about 300mg, about 50mg to about 250mg, about 100mg to about 250mg, about 100mg to about 200mg, about 10mg to about 250mg, about 10mg to about 200mg, about 10mg to about 180mg, about 10mg to about 160mg, about 10mg to about 150mg, about 10mg to about 140mg, about 20mg to about 130mg, about 30mg to about 120mg, about 40mg to about 100mg, or about 25mg to about 75mg;(b) the second administration cycle comprises a single subcutaneous dose (2D1) of the bispecific antibody, wherein C2D1 is equal to or greater than C1D3 and is between about 10 mg and about 300 mg (e.g., between about 25 mg and about 300 mg, between about 50 mg and about 300 mg, between about 100 mg and about 300 mg, between about 200 mg and about 300 mg, between about 50 mg and about 250 mg, between about 100 mg and about 250 mg, between about 100 mg and about 250 mg, between about 100 mg and about 100 mg), and In some embodiments, the dose is about 200 mg, about 10 mg to about 250 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 150 mg, about 10 mg to about 140 mg, about 20 mg to about 130 mg, about 30 mg to about 120 mg, or about 40 mg to about 100 mg, or about 25 mg to about 75 mg; e.g., about 30 mg, about 45 mg, or about 60 mg). In some embodiments, the DLBCL is relapsed or refractory DLBCL. In some embodiments, the DLBCL is previously untreated (1L) DLBCL. In some embodiments, the DLBCL is Richter's transformation. In some embodiments, the complete response rate is at least about 10% (e.g., at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, or at least about 65%; e.g., about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 10% to about 30%, about 10% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 20% to about 30%, about 30% to about 50%, about 30% to about 60%, or about 40% to about 60%; e.g., about 15%, about 20%, about 25%, about 30%, about 35%, or about 40%). In some embodiments, the complete response rate is about 10 to about 90% (e.g., about 10 to about 80%, about 10 to about 70%, about 10 to about 60%, about 10 to about 50%, about 10 to about 40%, about 10 to about 30%, about 20 to about 80%, about 30 to about 80%, about 40 to about 80%, about 50 to about 80%, about 30 to about 70%, about 30 to about 60%, about 40 to about 60%, about 30 to about 50%, about 15 to about 40%, about 20 to about 40%, about 60 to about 90%, about 45 to about 55%, or about 45 to about 50%;For example, it is about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%). In certain embodiments, the complete response rate for a population of subjects with 1L DLBCL is about 40%. In another particular embodiment, the complete response rate for a population of subjects with R / R DLBCL is about 20%.;

[0037] In some embodiments, the median progression-free survival is greater than about 4 months (e.g., at least about 4.5 months, at least about 5 months, at least about 5.5 months, at least about 6 months, at least about 6.5 months, at least about 7 months, at least about 7.5 months, at least about 8 months, at least about 8.5 months, at least about 9.0 months, at least about 9.5 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 20 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, at least about 48 months, at least about 54 months, or more; e.g., between about 4 months and about 48 months, between about 4 months and about 36 months, between about 4 months and about 24 months, between about 4 months and about 12 months, between about 4 months and about 10 months; between about 4 months and about 8 months, between about 8 months and about 24 months, between about 12 months and about 24 months, or between about 8 months and about 16 months; e.g., about 4.5 months, about 5 months, about 5.5 months, about 6 months, about 6.5 months, about 7 months, about 7.5 months, about 8 months, about 8.5 months, about 9.0 months, about 9.5 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 20 months, about 24 months, about 30 months, about 36 months, about 42 months, about 48 months, about 54 months, or more). In some embodiments, the median progression-free survival in a population of subjects with R / R FL is greater than about 4 months (e.g., at least about 4.5 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or at least about 12 months; e.g., between about 4 and about 12 months, between about 4 and about 10 months, between about 4 and about 8 months, between about 4 and about 6 months, between about 8 and about 12 months, between about 6 and about 10 months, between about 6 and about 12 months, or between about 5 and about 9 months; e.g., about 4 months, about 4.5 months, about 5 months, about 5.5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 12 months).In certain embodiments, the median progression-free survival in a population of subjects having R / R FL exceeds about 4 months.

[0038] In some embodiments, the median progression-free survival exceeds about 1 month (e.g., at least about 1.5 months, at least about 2 months, at least about 2.5 months, at least about 3 months, at least about 3.5 months, at least about 4 months, at least about 4.5 months, at least about 5 months, or at least 5 six months; e.g., between about 1 month and about 6 months, between about 1 month and about 5 months, between about 1 month and about 4 months, between about 1 month and about 3 months, between about 1 month and about 2 months, between about 2 months and about 4 months, between about 3 months and about 5 months, between about 4 months and about 6 months, or between about 3 months and about 6 months; e.g., about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, or about 6 months). In some embodiments, the median progression-free survival in a population of subjects having DLBCL exceeds about 2 months (e.g., more than about 2.5 months, more than about 3 months, more than about 3.5 months, more than about 4 months, more than about 4.5 months, more than about 5 months, or more than about 6 months; e.g., between about 2 months and about 12 months, between about 2 months and about 6 months, between about 2 months and about 5 months, between about 2 months and about 4 months, between about 2 months and about 3 months, between about 3 months and about 5 months, or between about 4 months and about 6 months; e.g., about 2.1 months, about 2.5 months, about 3 months, about 3.5 months, about 4 months, about 4.5 months, about 5 months, about 5.5 months, or about 6 months). In one embodiment, the median progression-free survival in a population of subjects having R / R DLBCL exceeds 2 months. In certain embodiments, the median progression-free survival in a population of subjects having R / R DLBCL is about 2.5 months.

[0039] In some embodiments, the median overall survival is greater than 9.5 months (e.g., at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 20 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, at least about 48 months, at least about 54 months, or more; e.g., between about 9 months and about 48 months, between about 9 months and about 36 months, between about 9 months and about 24 months, between about 9 months and about 12 months, between about 10 months and about 18 months; between about 12 months and about 24 months, between about 18 months and about 36 months, between about 12 months and about 36 months, or between about 24 months and about 48 months; e.g., about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 20 months, about 24 months, about 30 months, about 36 months, about 42 months, about 48 months, about 54 months, or more). In some embodiments, the first dosing cycle is a 21-day dosing cycle and the second dosing cycle is a 21-day dosing cycle.

[0040] In another aspect, the invention provides a method of treating a population of subjects with FL, comprising subcutaneously administering to the subject a bispecific antibody that binds CD20 and CD3 in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein: (a) the first dosing cycle comprises a first subcutaneous dose (C1D1), a second subcutaneous dose (C1D2), and a third subcutaneous dose (C1D3) of the bispecific antibody, and (i) C1D1 is less than or equal to C1D2; (ii) C1D2 is equal to or less than C1D3, and (iii) C1D1 is about 0.1 mg to about 10 mg (e.g., about 0.1 mg to about 7 mg, about 0.2 mg to about 10 mg, about 0.5 mg to about 10 mg, about 1 mg to about 9 mg, about 2 mg to about 8 mg, about 3 mg to about 7 mg, about 4 mg to about 6 mg; e.g., about 5 mg), and C1D2 is about 5 mg to about 80 mg (e.g., about 20 mg to about 75 mg, about 25 mg to about 75 mg). , about 30 mg to about 75 mg, about 35 mg to about 75 mg, or about 40 mg to about 75 mg; for example, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg), and C1D3 is about 10 mg to about 300 mg (about 25 mg to about 300 mg, about 50 mg to about 300 mg, about 100 mg to about 3 00 mg, about 200 mg to about 300 mg, about 50 mg to about 250 mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, about 10 mg to about 250 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 150 mg, about 10 mg to about 140 mg, about 20 mg to about 130 mg, about 30 mg to about 120 mg, or about 40 mg to about 100 mg, or about 25 mg to about 75 mg;For example, (a) the first administration cycle includes a single subcutaneous dose of a bispecific antibody (2D1), C1D3 is about 30 mg, about 45 mg, or about 60 mg, and (b) the second administration cycle includes a single subcutaneous dose of a bispecific antibody (2D1), C2D1 is greater than or equal to C1D3, and is about 10 mg to about 300 mg (about 25 mg to about 300 mg, about 50 mg to about 300 mg, about 100 mg to about 300 mg, about 200 mg to about 300 mg, about 50 mg to about 250 mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, about 10 mg to about 250 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 150 mg, about 10 mg to about 140 mg, about 20 mg to about 130 mg, about 30 mg to about 120 mg, or about 40 mg to about 100 mg, or about 25 mg to about 75 mg; for example, about 30 mg, about 45 mg, or about 60 mg). In some embodiments, FL is relapsed or refractory FL. In some embodiments, FL is transformed FL. In some embodiments, the complete response rate is at least about 40% (for example, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, or at least about 75%; for example, about 40% to about 80%, about 40% to about 70%, about 40% to about 60%, about 40% to about 50%, about 50% to about 70%, about 60% to about 80%, or about 50% to about 80%; for example, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or about 80%). In certain embodiments, the complete response rate of the population of subjects with R / R FL is about 45% to about 50%.;

[0041] In some embodiments, the objective response rate at about 20 months after starting treatment is at least about 70% (e.g., at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95%; e.g., about 70% to about 80%, about 70% to about 90%, about 70% to about 95%, or about 70% to about 100%; e.g., about 70%, about 75%, about 80%, about 85%, or about 90%). In some embodiments, the objective response rate at about 24 months after starting treatment is at least about 75% (e.g., at least about 80%, at least about 85%, at least about 90%, or at least about 95%; e.g., about 75% to about 80%, about 75% to about 90%, about 75% to about 95%, about 75% to about 100%, about 80% to about 100%, or about 90% to about 100%; e.g., about 75%, about 80%, about 85%, or about 90%). In some embodiments, the objective response rate at about 12 months after starting treatment is at least about 60% (e.g., at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95%; e.g., about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, or about 60% to about 100%; e.g., about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%).

[0042] In some embodiments, the population of interest has relapsed or refractory NHL, and the objective response rate is at least 34% (e.g., at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more; e.g., between 34% and 95%, between 34% and 85%, between 34% and 75%, between 34% and 65%, between 34% and 55%, between 35% and 60%, between 35% and 75%, between 55% and 95%, between 75% and 95%, between 40% and 50%, between 45% and 64%, between 34% and 45%, or between 34% and 40%; e.g., about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%). In some embodiments, the objective response rate is at least 44%. In some embodiments, the objective response rate is between 35% and 55%. In some embodiments, the objective response rate is about 45%.

[0043] In some embodiments, the population of interest has relapsed or refractory FL, and the objective response rate is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%; e.g., between 70% and 80%, between 70% and 90%, between 70% and 95%, or between 70% and 100%; e.g., about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, or about 95%). In some embodiments, the objective response rate is at least 80%. In some embodiments, the population of interest has relapsed or refractory FL, and the objective response rate is between 70% and 90%. In some embodiments, the objective response rate is about 80%.

[0044] In some embodiments, the population of interest has relapsed or refractory DLBCL or transformed FL, and the objective response rate is at least 25% (e.g., at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more; e.g., between 25% and 95%, between 25% and 75%, between 25% and 55%, between 25% and 50%, between 25% and 45%, between 25% and 40%, between 25% and 35%, between 25% and 30%, between 30% and 75%, between 35% and 75%, between 40% and 75%, between 30% and 40%, between 30% and 45%, between 30% and 50%, or between 50% and 70%; e.g., about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%). In some embodiments, the objective response rate is at least 35%. In some embodiments, the population of interest has relapsed or refractory DLBCL, and the objective response rate is between 25% and 45%. In some embodiments, the objective response rate is about 35%.

[0045] In some embodiments, a population of subjects exhibits cytokine release syndrome after administration of the bispecific antibody, and the rate of cytokine release syndrome in the population of subjects is about 40% or less (e.g., about 35% or less, about 30% or less, about 25% or less, about 20% or less, about 15% or less, about 10% or less, about 5% or less, or about 3% or less; e.g., between about 0% and about 40%, between about 0% and about 30%, about Between 0% and about 20%, between about 0% and about 10%, between about 0% and about 5%, between about 10% and about 20%, between about 10% and about 30%, between about 20% and about 40%, between about 15% and about 35%, or between about 5% and about 15%; for example, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, about 7%, about 5%, about 4%, about 3%, about 2%, about 1%, or about 0%). In some embodiments, the rate of cytokine release syndrome of Grade 2 or higher (as defined by the American Society for Transplantation and Cellular Therapy, 2018; ASTCT) is about 10% or less (e.g., about 7% or less, about 5% or less, about 3% or less, or about 1% or less; e.g., about 0% to about 10%, about 0% to about 7%, about 0% to about 5%, about 0% to about 3%, about 1% to about 3%, about 3% to about 5%, about 5% to about 7%, about 5% to about 10%, about 3% to about 7%; e.g., about 10%, about 7%, about 5%, about 4%, about 3%, about 2%, about 1%, or about 0%).

[0046] In another aspect of the invention, there is provided a method of reducing the rate of a particular adverse event in a population of subjects having a CD20-positive cell proliferative disorder (e.g., B-cell proliferative disorder) to which a bispecific antibody that binds to CD20 and CD3 is administered, the method comprising administering the bispecific antibody subcutaneously using a stepwise dosing schedule, wherein the rate of adverse events is reduced in the population of subjects as compared to a reference population of subjects administered the bispecific antibody intravenously. In some embodiments, the stepwise dosing schedule is selected from the group consisting of: (I) at least a first dosing cycle and a second dosing cycle, wherein (a) the first dosing cycle comprises a first subcutaneous dose (C1D1), a second subcutaneous dose (C1D2), and a third subcutaneous dose (C1D3) of the bispecific antibody, (i) C1D1 is less than or equal to C1D2 and less than C1D3, (ii) C1D2 is less than or equal to C1D3, (iii) C1D1 is from about 0.1 mg to about 10 mg (e.g., from about 0.1 mg to about 7 mg, from about 0.2 mg to about 10 mg, from about 0.5 mg to about 10 mg, from about 1 mg to about 9 mg, from about 2 mg to about 8 mg, from about 3 mg to about 7 mg, from about 4 mg to about 6 mg; e.g., about 5 mg), C1D2 is from about 5 mg to about 80 mg (e.g., from about 20 mg to about 75 mg, from about 25 mg to about 75 mg, from about 30 mg to about 75 mg, from about 35 mg to about 75 mg, or from about 40 mg to about 75 mg; e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg), and C1D3 is from about 10 mg to about 300 mg (from about 25 mg to about 300 mg, from about 50 mg to about 300 mg, from about 100 mg to about 300 mg, from about 200 mg to about 300 mg, from about 50 mg to about 250 mg, from about 100 mg to about 250 mg, from about 100 mg to about 200 mg, from about 10 mg to about 250 mg, from about 10 mg to about 200 mg, from about 10 mg to about 180 mg, from about 10 mg to about 160 mg, from about 10 mg to about 150 mg, from about 10 mg to about 140 mg, from about 20 mg to about 130 mg, from about 30 mg to about 120 mg, or from about 40 mg to about 100 mg, or from about 25 mg to about 75 mg;(b) the second administration cycle comprises a single subcutaneous dose (2D1) of the bispecific antibody, wherein C2D1 is equal to or greater than C1D3 and is between about 10 mg and about 300 mg (e.g., between about 25 mg and about 300 mg, between about 50 mg and about 300 mg, between about 100 mg and about 300 mg, between about 200 mg and about 300 mg, between about 50 mg and about 250 mg, between about 100 mg and about 250 mg, between about 100 mg and about 200 mg, between about 10 mg and about 250 mg, between about 10 mg and about 200 mg, between about 10 mg and about 180 mg, mg, about 10 mg to about 160 mg, about 10 mg to about 150 mg, about 10 mg to about 140 mg, about 20 mg to about 130 mg, about 30 mg to about 120 mg, or about 40 mg to about 100 mg, or about 25 mg to about 75 mg; for example, about 30 mg, about 45 mg, or about 60 mg); (II) at least a first administration cycle and a second administration cycle, wherein (a) the first administration cycle comprises a first subcutaneous dose (C1D1), a second subcutaneous dose (C1D2), and a third subcutaneous dose (C1D3) of the bispecific antibody; (i) C1D1 is about 5 mg, (ii) C1D2 is equal to or greater than C1D1 and equal to or less than C1D3; (iii) C1D3 is about 45 mg or about 60 mg, (b) the second administration cycle comprises a single subcutaneous dose of the bispecific antibody (C2D1), and C2D1 is 45 mg or about 60 mg; and (III) at least a first administration cycle and a second administration cycle, wherein (a) the first administration cycle comprises a first subcutaneous dose of the bispecific antibody (C1D1) on day 1 of the first administration cycle, a second subcutaneous dose of the bispecific antibody (C1D2) on day 8 of one administration cycle, and a third subcutaneous dose of the bispecific antibody (C1D3) on day 15 of the first administration cycle, where (i) C1D1 is about 5 mg, (ii) C1D2 is greater than or equal to C1D1 and less than or equal to C1D3, and (iii) C1D3 is about 45 mg or about 60 mg; and (b) the second administration cycle comprises a single subcutaneous dose of the bispecific antibody (C2D1) on day 1 of the second administration cycle, where C2D1 is about 45 mg or about 60 mg;

[0047] In some embodiments, the CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder) is non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL). In some embodiments, the NHL is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), or primary mediastinal (thymic) large B-cell lymphoma (PMLBCL). In some embodiments, the NHL is previously untreated (1L) NHL. In some embodiments, the NHL is CLL. In some embodiments, the DLBCL is 1L DLBCL. In some embodiments, the DLBCL is relapsed or refractory DLBCL. In some embodiments, the DLBCL is Richter's transformed. In some embodiments, the FL is 1L FL. In some embodiments, the FL is relapsed or refractory FL. In some embodiments, the FL is transformed FL. In some embodiments, the NHL is an aggressive B-cell lymphoma. In some embodiments, the NHL is Ann Arbor Stage III or IV NHL. In some embodiments, the subject has previously received at least one (e.g., at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or more) prior line of systemic therapy. In some embodiments, the subject has received between one and nine (e.g., one, two, three, four, five, six, seven, eight, or nine) prior lines of systemic therapy. In some embodiments, the subject has received three prior lines of systemic therapy. In some embodiments, at least one (e.g., one, two, three, four, five, six, seven, eight, or nine) prior line of systemic therapy included an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is rituximab or obinutuzumab. In some embodiments, the prior line of systemic therapy comprising an anti-CD20 antibody additionally comprises an alkylating agent or an anthracycline. In some embodiments, the alkylating agent is cyclophosphamide or bendamustine. In some embodiments, the anthracycline is daunomycin or doxorubicin.In some embodiments, the frontline systemic therapy comprising an anti-CD20 antibody further comprises (i) cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); (ii) cyclophosphamide, vincristine, and prednisone (CVP); (iii) fludarabine; or (iv) bendamustine. In some embodiments, at least one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) frontline lines of systemic therapy included a Bruton's tyrosine kinase (BTK) inhibitor.

[0048] In some embodiments, the population of subjects exhibits cytokine release syndrome following administration of the bispecific antibody, and the percentage of subjects in the population who exhibit cytokine release syndrome is about 40% or less (e.g., about 35% or less, about 30% or less, about 25% or less, about 20% or less, about 15% or less, about 10% or less, about 5% or less, or about 3% or less; e.g., between about 0% and about 40%, between about 0% and about 30%, between about 0% and about 20%, between about 0% and about 10%, between about 0% and about 5%, between about 10% and about 20%, between about 10% and about 30%, between about 20% and about 40%, between about 15% and about 35%, or between about 5% and about 15%; e.g., about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, about 7%, about 5%, about 4%, about 3%, about 2%, about 1%, or about 0%). In some embodiments, the percentage of subjects with grade 2 or higher cytokine release syndrome (as defined by the American Society for Transplantation and Cellular Therapy, 2018; ASTCT) is about 10% or less (e.g., about 7% or less, about 5% or less, about 3% or less, about 1% or less; e.g., between about 0% and about 10%, between about 0% and about 7%, between about 0% and about 5%, between about 0% and about 3%, between about 1% and about 3%, between about 3% and about 5%, between about 5% and about 7%, between about 5% and about 10%, between about 3% and about 7%; e.g., about 10%, about 7%, about 5%, about 4%, about 3%, about 2%, about 1% or about 0%).

[0049] In some embodiments, the complete response rate is at least about 10% (e.g., at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, or more; For example, about 10% to about 40%, about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 10% to about 30%, about 15% to about 30%, about 20% to about 40%, or more; for example, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 30%, about 35%, about 40%, or more). In some embodiments, the complete response rate is at least about 42% (e.g., at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or more; e.g., 42% to 45%, 45% to 50%, about 50% to about 55%, about 55% to about 60%, about 60% to about 65%, about 65% to about 70%, about 70% to about 75%, or more; e.g., about 42%, about 45%, about 50%, about 55%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or more). In some embodiments, the complete response rate is at least about 20%. In some embodiments, the complete response rate is at least about 40%. In some embodiments, the complete response rate is at least about 55%. In some embodiments, the objective response rate at about 24 months after initiation of treatment is at least about 75% (e.g., at least about 80%, at least about 85%, at least about 90%, or at least about 95%; e.g., about 75% to about 80%, about 75% to about 90%, about 75% to about 95%, about 75% to about 100%, about 80% to about 100%, or about 90% to about 100%; e.g., about 75%, about 80%, about 85%, or about 90%).In some embodiments, the objective response rate at about 20 months after initiation of treatment is at least about 70% (e.g., at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95%; e.g., 70% to 80%, 70% to 90%, 70% to 95%, or 70% to 100%; e.g., about 70%, about 75%, about 80%, about 85%, or about 90%). In some embodiments, the objective response rate at about 12 months after initiation of treatment is at least about 60% (e.g., at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95%; e.g., about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, or about 60% to about 100%; e.g., about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%).

[0050] In some embodiments, the subject population has relapsed or refractory NHL and the objective response rate is at least 34% (e.g., at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more; e.g., between 34% and 95%, between 34% and 85%, between 34% and 75%, between 34% and 65%, between 34% and 55%, between 35% and 65%). The objective response rate may be between 0%, 35% and 75%, 55% and 95%, 75% and 95%, 40% and 50%, 45% and 64%, 34% and 45%, or 34% and 40%, e.g., about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%. In some embodiments, the objective response rate is at least 44%. In some embodiments, the objective response rate is between 35% and 55%. In some embodiments, the objective response rate is about 45%.

[0051] In some embodiments, the subject population has relapsed or refractory FL and the objective response rate is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%; e.g., 70%-80%, 70%-90%, 70%-95%, or 70%-100%; e.g., about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, or about 95%). In some embodiments, the objective response rate is at least 80%. In some embodiments, the subject population has relapsed or refractory FL and the objective response rate is between 70% and 90%. In some embodiments, the objective response rate is about 80%.

[0052] In some embodiments, the population of interest has relapsed or refractory DLBCL or transformed FL, and the objective response rate is at least 25% (e.g., at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more; e.g., between 25% and 95%, between 25% and 75%, between 25% and 55%, between 25% and 50%, between 25% and 45%, between 25% and 40%, between 25% and 35%, between 25% and 30%, between 30% and 75%, between 35% and 75%, between 40% and 75%, between 30% and 40%, between 30% and 45%, between 30% and 50%, or between 50% and 70%; e.g., about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%). In some embodiments, the objective response rate is at least 35%. In some embodiments, the population of interest has relapsed or refractory DLBCL, and the objective response rate is between 25% and 45%. In some embodiments, the objective response rate is about 35%.

[0053] In some embodiments of any of the previous aspects, the bispecific antibody comprises an anti-CD20 arm comprising a first binding domain comprising the following six hypervariable regions (HVRs): (a) HVR-H1 comprising the amino acid sequence of GYTFTSYNMH (SEQ ID NO: 1); (b) HVR-H2 comprising the amino acid sequence of AIYPGNGDTSYNQKFKG (SEQ ID NO: 2); (c) HVR-H3 comprising the amino acid sequence of VVYYSNSYWYFDV (SEQ ID NO: 3); (d) HVR-L1 comprising the amino acid sequence of RASSSVSYMH (SEQ ID NO: 4); (e) HVR-L2 comprising the amino acid sequence of APSNLSAS (SEQ ID NO: 5); and (f) HVR-L3 comprising the amino acid sequence of QQWSFNPPT (SEQ ID NO: 6). In some embodiments, the bispecific antibody comprises an anti-CD20 arm comprising a first binding domain comprising (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 7; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the first binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 7 and a VL domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the bispecific antibody comprises an anti-CD3 arm having a second binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of NYYIH (SEQ ID NO: 9); (b) HVR-H2 comprising the amino acid sequence of WIYPGDGNTKYNEKFKG (SEQ ID NO: 10); (c) HVR-H3 comprising the amino acid sequence of DSYSNYYFDY (SEQ ID NO: 11); (d) HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 13); and (f) HVR-L3 comprising the amino acid sequence of TQSFILRT (SEQ ID NO: 14).In some embodiments, the bispecific antibody comprises an anti-CD3 arm that comprises a second binding domain that comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 15; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 16; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the second binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 15 and a VL domain comprising the amino acid sequence of SEQ ID NO: 16. In some embodiments, the bispecific antibody comprises (a) an anti-CD20 arm comprising a heavy chain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 51 and a light chain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 52, and (b) an anti-CD3 arm comprising a heavy chain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 53 and a light chain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 54. In some antibodies, (a) the anti-CD20 arm comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 51 and a light chain comprising the amino acid sequence of SEQ ID NO: 52, and (b) the anti-CD3 arm comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 53 and a light chain comprising the amino acid sequence of SEQ ID NO: 54.

[0054] In some embodiments of any of the previous aspects, the bispecific antibody is a humanized antibody. In some embodiments, the bispecific antibody is a chimeric antibody. In some embodiments, the bispecific antibody is an antibody fragment that binds to CD20 and CD3. In some embodiments, the antibody fragment is selected from the group consisting of Fab fragments, Fab’-SH fragments, Fv fragments, scFv fragments, and (Fab’)2 fragments.

[0055] In some embodiments, the bispecific antibody is a full-length antibody. In some embodiments, the bispecific antibody is an IgG antibody. In some embodiments, the IgG antibody is an IgG1 antibody. In some embodiments, the IgG antibody comprises a mutation at amino acid residue N297 (EU numbering) that results in the absence of glycosylation. In some embodiments, the mutation at amino acid residue N297 is a substitution mutation. In some embodiments, the mutation at amino acid residue N297 reduces the effector function of the Fc region. In some embodiments, the mutation is an N297G or N297A mutation. In some embodiments, the bispecific antibody comprises a mutation in the Fc region that reduces the effector function. In some embodiments, the mutation is a substitution mutation. In some embodiments, the substitution mutation is at amino acid residues L234, L235, D265, and / or P329 (EU numbering). In some embodiments, the substitution mutation is selected from the group consisting of L234A, L235A, D265A, and P329G. In some embodiments, the bispecific antibody comprises one or more heavy chain constant domains, and the one or more heavy chain constant domains are selected from a first CH1 (CH11) domain, a first CH2 (CH21) domain, a first CH3 (CH31) domain, a second CH1 (CH12) domain, a second CH2 (CH22) domain, and a second CH3 (CH32) domain. In some embodiments, at least one of the one or more heavy chain constant domains pairs with another heavy chain constant domain. In some embodiments, the CH31 domain and the CH32 domain each form a protrusion or a cavity, and the protrusion or cavity in the CH31 domain can be positioned in the cavity or protrusion in the CH32 domain, respectively. In some embodiments, the CH31 domain and the CH32 domain contact at the interface between the protrusion and the cavity. In some embodiments, the CH21 domain and the CH22 domain each comprise a protrusion or a cavity, and the protrusion or cavity of the CH21 domain can be disposed in the cavity or protrusion of the CH22 domain, respectively. In some embodiments, the CH21 and CH22 domains associate at the interface between the protrusion and the cavity.

[0056] In some embodiments, the anti-CD20 arm of the bispecific antibody further comprises the following substitution mutations (EU numbering): T366W and N297G. In some embodiments, the anti-CD3 arm of the bispecific antibody further comprises the following substitution mutations (EU numbering): T366S, L368A, Y407V, and N297G. In some embodiments, (a) the anti-CD20 arm further comprises the following substitution mutations (EU numbering): T366W and N297G, and (b) the anti-CD3 arm further comprises the following substitution mutations (EU numbering): T366S, L368A, Y407V, and N297G.

[0057] In some embodiments, the subjects are humans. In some embodiments, the population of subjects is a population of human subjects. [Brief explanation of the drawings]

[0058] The content of this application file contains at least one drawing executed in color. Copies of this patent or this patent application with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. [Figure 1] Figure 1 is a schematic diagram illustrating the design of the dose escalation portion of the GO29781 study. Initially, mosunetuzumab is given as a single, unfractionated intravenous (IV) dose on day 1 of each cycle (Group A). Cycle 1 dosing is then altered to stop the dose escalation for Group A and perform mosunetuzumab dose escalation as follows: Group B: mosunetuzumab dose escalation utilizing a cycle 1 step-up IV administration scheme; Group D: mosunetuzumab dose escalation utilizing a cycle 1 unfractionated subcutaneous (SC) dosing scheme; Group F: mosunetuzumab dose escalation utilizing a cycle 1 step-up SC dosing scheme. C = cycle; D = day; DL = dose level; MAD = maximum assessed dose. [Figure 2]Figure 2 is a schematic diagram showing the design of the expanded cohort of non-Hodgkin lymphoma (NHL) and the dose-escalation / expansion cohort of chronic lymphocytic leukemia (CLL) in the GO29781 study. DLBCL = diffuse large B-cell lymphoma; FL = follicular lymphoma; MCL = mantle cell lymphoma; NHL = non-Hodgkin lymphoma; RP2D = recommended phase II dose; R / R = relapsed / refractory; trFL = transformed follicular lymphoma. aMultiple expansion cohorts based on dose escalation in groups A, B, D, and F can be tested. bThe expansion cohort in R / R DLBCL / trFL enrolls up to approximately 80 patients, except for the expansion cohort based on the B-group RP2D that enrolls up to approximately 20 patients. cThe expansion cohort in R / R FL enrolls up to approximately 80 patients, except for the expansion cohort based on the B-group RP2D that enrolls up to approximately 20 patients. dAn expansion cohort based only on dose escalation in group B is tested. eDose escalation is performed as in the case of NHL (see Figure 1). fMultiple expansion cohorts based on dose escalation in groups B, D, and F can be tested. [Figure 3] Figure 3 is a schematic diagram showing the evaluation window in group B of the GO29781 study. [Figure 4] Figure 4 is a set of schematic diagrams showing three exemplary scenarios for the observation of DLTs in dose escalation (group F) in cycle 1 of the GO29781 study. The figure represents an example showing the timing of two DLTs in a dose-escalation cohort of six patients and does not represent all possible scenarios. [Figure 5] Figure 5 is a schematic diagram showing the duration of the initial study treatment and the options for retreatment or continued study treatment in the GO29781 study. CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease. aAdditional rounds of retreatment are possible according to the treatment flow for the first treatment. bScans must be scheduled to avoid / minimize any dose delays between cycle 8 and cycle 9 as much as possible. [Figure 6] Figure 6 is a schematic diagram showing the doses of SC mosunetuzumab tested in group D of the GO29781 study. D = dose. N = number of patients. [Figure 7]7 is a pair of graphs showing the concentration of mosunetuzumab (μg / mL) in patient serum samples at the indicated doses and time points. The left panel shows samples from Group B of the GO29781 study (IV step-up administration). The right panel shows samples from Group D of the GO29781 study (SC dosing). The dotted line indicates the Cmax of a 1 mg dose delivered by IV administration. [Figure 8] Figure 8 is a set of graphs showing the concentration of IL-6 (pg / mL) in patient peripheral blood samples at the indicated doses and time points. The left panel shows samples from Group A of the GO29781 study (IV dosing). The right panel shows samples from Group D of the GO29781 study (SC dosing). PD: Pre-dose. EoI: End of infusion. [Figure 9] Figure 9 is a set of graphs showing the concentration of IL-6 (pg / mL) in patient peripheral blood samples at the indicated time points. The left and center panels show samples from Group B of the GO29781 study (step-up IV dosing), which received a 1 mg dose of mosunetuzumab on Day 1 of Cycle 1 (C1D1) (left panel: data from the dose escalation phase; center panel: data from the dose expansion phase). The right panel shows samples from Group D of the GO29781 study (SC dosing), which received doses of 1.6 mg, 2.4 mg, 3.6 mg, or 7.2 mg. [Figure 10] 10 is a set of graphs showing the concentration of IL-6 (pg / mL) in peripheral blood samples of subcutaneously administered patients at the indicated doses and time points. Arrows indicate patient 1. PRE: Pre-dose. [Figure 11] Figure 11 is a set of graphs showing the concentrations (in pg / mL) of IL-2 (top left), IL-6 (top right), IFNγ (bottom left), and TNFα (bottom right) in the blood of cynomolgus monkeys that received vehicle intravenously, mosunetuzumab intravenously at doses ranging from 0.01 mg / kg to 1 mg / kg, or mosunetuzumab subcutaneously at a dose of 1 mg / kg. [Figure 12] Figure 12 is a set of graphs showing T cell activation after intravenous or subcutaneous administration of mosunetuzumab. Top panel: quantification of CD4+ / CD69+ / CD25+ T cells; bottom panel: quantification of CD8+ / CD69+ / CD25+ T cells. [Figure 13] Figure 13 is a set of graphs showing B cell depletion in cynomolgus monkeys after a single intravenous administration of 1 mg / mL of mosunetuzumab. Upper panel: circulating B cells (CD40+); lower panel: splenic B cells. [Figure 14] Figure 14 is a graph showing the kinetics of circulating B cell activating factor (BAFF) in serum. BAFF was evaluated up to day 8 in all dose groups and up to day 57 in the control and 1 mg / kg intravenous groups.

Mode for Carrying Out the Invention

[0059] Detailed Description The present invention relates to a method of treating a subject (or population of subjects) having a CD20-positive cell proliferative disorder, such as a B-cell proliferative disorder (e.g., non-Hodgkin lymphoma (NHL) (e.g., previously untreated (1L) NHL, diffuse large B-cell lymphoma (DLBCL) (e.g., 1L DLBCL, relapsed and / or refractory DLBCL, or Richter's transformation), follicular lymphoma (FL) (e.g., 1L FL, relapsed and / or refractory FL, or transformed FL), mantle cell lymphoma (MCL), high-grade B-cell lymphoma, or primary mediastinal (thymic) large B-cell lymphoma (PMLBCL)) or chronic lymphocytic leukemia (CLL) by subcutaneously administering to the subject a bispecific antibody that binds to CD20 and CD3 (e.g., mosunetuzumab) in a dosing schedule comprising at least a first dosing cycle and a second dosing cycle. The first dosing cycle comprises three subcutaneous administrations, wherein the first subcutaneous dose (C1D1) is less than or equal to the second subcutaneous dose (C1D2) and less than the third subcutaneous dose (C1D3), and C1D2 is less than or equal to C1D3.In some examples, C1D1 is from about 0.1 mg to about 10 mg (e.g., from about 0.1 mg to about 7 mg, from about 0.2 mg to about 10 mg, from about 0.5 mg to about 10 mg, from about 1 mg to about 9 mg, from about 2 mg to about 8 mg, from about 3 mg to about 7 mg, from about 4 mg to about 6 mg; e.g., about 5 mg), C1D2 is from about 5 mg to about 80 mg (e.g., from about 20 mg to about 75 mg, from about 25 mg to about 75 mg, from about 30 mg to about 75 mg, from about 35 mg to about 75 mg, or from about 40 mg to about 75 mg; e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg), and C1D3 is from about 10 mg to about 300 mg (from about 25 mg to about 300 mg, from about 50 mg to about 300 mg, from about 100 mg to about 300 mg, from about 200 mg to about 300 mg, from about 50 mg to about 250 mg, from about 100 mg to about 250 mg, from about 100 mg to about 200 mg, from about 10 mg to about 250 mg, from about 10 mg to about 200 mg, from about 10 mg to about 180 mg, from about 10 mg to about 160 mg, from about 10 mg to about 150 mg, from about 10 mg to about 140 mg, from about 20 mg to about 130 mg, from about 30 mg to about 120 mg, or from about 40 mg to about 100 mg, or from about 25 mg to about 75 mg; e.g., about 30 mg, about 45 mg, or about 60 mg). The second dosing cycle includes a single subcutaneous dose of the bispecific antibody (C2D1), and C2D1 is greater than or equal to C1D3 and is from about 10 mg to about 300 mg (from about 25 mg to about 300 mg, from about 50 mg to about 300 mg, from about 100 mg to about 300 mg, from about 200 mg to about 300 mg, from about 50 mg to about 250 mg, from about 100 mg to about 250 mg, from about 100 mg to about 200 mg, from about 10 mg to about 250 mg, from about 10 mg to about 200 mg, from about 10 mg to about 180 mg, from about 10 mg to about 160 mg, from about 10 mg to about 150 mg, from about 10 mg to about 140 mg, from about 20 mg to about 130 mg, from about 30 mg to about 120 mg, or from about 40 mg to about 100 mg, or from about 25 mg to about 75 mg; e.g., about 30 mg, about 45 mg, or about 60 mg).

[0060] The present invention is based in part on the discovery that a dosing regimen comprising subcutaneous administration of a bispecific antibody that binds to CD20 and CD3 (e.g., mosunetuzumab) over multiple dosing cycles (e.g., the first dosing cycle is a step-up divided dosing cycle) can effectively treat a subject having a CD20-positive cell proliferative disorder (e.g., B-cell proliferative disorder) while reducing toxicity (e.g., cytokine release syndrome or CNS toxicity).

[0061] I. General Technology The techniques and procedures described or referenced herein are generally well understood and can be found, for example, in Sambrook et al., Molecular Cloning: A Laboratory Manual 3rd edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Current Protocols in Molecular Biology (F.M.A.usubel, et al. eds., (2003)); the series Methods in Enzymology (Academic Press, Inc.): PCR 2: A Practical Approach (M.J. MacPherson, B.D. Hames and G.R. Taylor eds. (1995)), Harlow and Lane, eds. (1988); Antibodies, A Laboratory Manual, and Animal Cell Culture (R.I. Freshney, ed. (1987)); Oligonucleotide Synthesis (M.J. Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook(JECellis,ed.,1998)Academic Press;Animal Cell Culture(RIFreshney),ed.,1987);Introduction to Cell and Tissue Culture(JPMather and PERoberts,1998)Plenum Press;Cell and Tissue Culture:Laboratory Procedures(A.Doyle,JBGriffiths,and DGNewell,eds.,1993-8)J.Wiley and Sons; Handbook of Experimental Immunology (DM Weir and CC Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (JMMiller and MPCalos, eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994); Current Protocols in Immunology (JEColigan et al., eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (CA Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: A Practical Approach (D. Catty., ed., IRL Press, 1988-1989); Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using Antibodies: A Laboratory Manual (E. Harlow and D.Lane(Cold Spring Harbor Laboratory Press,1999);The Antibodies(M.Zanetti and These methods are commonly employed by those skilled in the art using conventional methodologies, such as the widely used methodologies described in J.D. Capra, eds., Harwood Academic Publishers, 1995; and Cancer: Principles and Practice of Oncology (VT DeVita et al., eds., J.B. Lippincott Company, 1993).

[0062] II. Definition It will be understood that aspects and embodiments of the invention described herein include "comprising," "consisting of," and "consisting essentially of" aspects and embodiments.

[0063] As used herein, the singular forms "a," "an," and "the" include plural referents unless otherwise indicated.

[0064] As used herein, the term "about" refers to a normal error range for the respective value, which would be readily understood by one of ordinary skill in the art. Reference herein to a value or parameter preceded by "about" includes (and describes) embodiments that are directed to that value or parameter itself.

[0065] The terms "cancer" and "cancerous" refer to or describe a physiological state in mammals typically characterized by uncontrolled cell growth. Examples of cancers include, but are not limited to, blood cancers such as mature B cell cancers, excluding Hodgkin lymphoma, but including non-Hodgkin lymphoma (NHL), such as diffuse large B cell lymphoma (DLBCL), which can be relapsed or refractory DLBCL or Richter transformation. Other specific examples of cancers include germinal center B cell-like (GCB) diffuse large B cell lymphoma (DLBCL), activated B cell-like (ABC) DLBCL, follicular lymphoma (FL), transformed FL, mantle cell lymphoma (MCL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), marginal zone lymphoma (MZL), transformed MZL, high-grade B cell lymphoma, primary mediastinal (thymic) large B cell lymphoma (PMLBCL), small lymphocytic leukemia (SLL), lymphoplasmacytic lymphoma (LL), transformed LL, Waldenström macroglobulinemia (WM), central nervous system lymphoma (CNSL), Burkitt lymphoma (BL), B cell prolymphocytic leukemia, splenic marginal zone lymphoma, hairy cell leukemia, splenic lymphoma / leukemia, unclassifiable, diffuse red pulp small B cell lymphoma, hairy cell leukemia variant, heavy chain disease, alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease, multiple myeloma, solitary plasmacytoma of bone, extramedullary plasmacytoma, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), nodal marginal zone lymphoma, pediatric nodal marginal zone lymphoma, pediatric follicular lymphoma, primary cutaneous follicle center lymphoma, T cell / histiocyte-rich large B cell lymphoma, primary CNS DLBCL, primary cutaneous DLBCL, leg type, EBV-positive DLBCL in the elderly, chronic inflammation-related DLBCL, lymphomatoid granulomatosis, intravascular large B cell lymphoma, ALK-positive large B cell lymphoma, plasmablastic lymphoma, large B cell lymphoma due to HHV8-related multicentric Castleman disease, primary effusion lymphoma: an unclassifiable B cell lymphoma with characteristics intermediate between DLBCL and Burkitt lymphoma, and an unclassifiable B cell lymphoma with characteristics intermediate between DLBCL and classical Hodgkin lymphoma.Further examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and lymphoid malignancies, including leukemia or B-cell lymphoma. More specific examples of such cancers include, but are not limited to, multiple myeloma (MM); low-grade / follicular NHL; small lymphocytic (SL) NHL; intermediate-grade / follicular NHL; intermediate-grade diffuse NHL; high-grade immunoblastic NHL; high-grade lymphocytic NHL; high-grade small non-dividing cell NHL; bulky mass disease NHL; AIDS-related lymphoma; and acute lymphocytic leukemia (ALL); chronic myeloblastic leukemia; and post-transplant lymphoproliferative disorder (PTLD).

[0066] "Tumor," as used herein, refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. The terms "cancer," "cancerous," "cell proliferative disorder," "proliferative disorder," and "tumor" are not mutually exclusive when referred to herein.

[0067] A "disorder" is any condition that would benefit from treatment, including, but not limited to, chronic and acute disorders or diseases, including conditions that predispose a mammal to the disorder in question.

[0068] The terms "cell proliferative disorder" and "proliferative disorder" refer to disorders associated with some degree of abnormal cell proliferation. In one embodiment, the cell proliferative disorder is cancer. In another embodiment, the cell proliferative disorder is a tumor.

[0069] The term "B cell proliferative disorder" or "B cell malignancy" refers to disorders associated with abnormal B cell proliferation to some extent, including, for example, diseases such as lymphoma, leukemia, myeloma, and myelodysplastic syndromes. In one embodiment, the B cell proliferative disorder is a lymphoma such as non-Hodgkin lymphoma (NHL), for example, diffuse large B cell lymphoma (DLBCL) (e.g., relapsed or refractory DLBCL or Richter's transformation), FL (e.g., relapsed and / or refractory FL or transformed FL), MCL, high-grade B cell lymphoma, or PMLBCL. In another embodiment, the B cell proliferative disorder is a leukemia such as chronic lymphocytic leukemia (CLL).

[0070] As used herein, "treatment" (and its grammatical variations such as "treat" or "treating") refers to a clinical intervention in an attempt to alter the natural course of the subject being treated, which can be carried out for prevention or during the clinical pathological course. Desired effects of treatment include, but are not limited to, preventing the onset or recurrence of a disease, alleviating symptoms, attenuating any direct or indirect pathological consequences of the disease, preventing metastasis, reducing the rate of disease progression, remission or alleviation of the disease state, and recovery or improvement of the prognosis. In some embodiments, the antibodies of the invention are used to delay the onset of a disease or to slow the progression of a disease.

[0071] As used herein, "delaying the progression of" a disorder or disease means deferring, hindering, decelerating, retarding, stabilizing, and / or delaying the development of a disease or disorder (e.g., a CD20-positive cell proliferative disorder, e.g., a B cell proliferative disorder, e.g., NHL, e.g., DLBCL or FL). This delay can be for various periods depending on the medical history and / or the individual being treated. As will be apparent to those skilled in the art, a sufficient or significant delay can in fact encompass prevention in the sense that the individual does not develop the disease. For example, the development of advanced cancer such as the occurrence of metastasis can be delayed.

[0072] "Reducing" or "inhibiting" refers to the ability to produce an overall decrease, e.g., of 20% or more, 50% or more, or 75%, 85%, 90%, 95%, or more. In certain embodiments, reducing or inhibiting refers to a reduction or inhibition of undesirable events such as cytokine-driven toxicity (e.g., cytokine release syndrome (CRS)), infusion-related reactions (IRR), macrophage activation syndrome (MAS), neurotoxicity, severe tumor lysis syndrome (TLS), neutropenia, thrombocytopenia, elevated liver enzymes, and / or central nervous system (CNS) toxicity following treatment with an anti-CD20 / anti-CD3 bispecific antibody using a split-escalating dose regimen of the invention compared to intravenous administration with the bispecific antibody. In other embodiments, reducing or inhibiting can refer to antibody effector functions mediated by the antibody Fc region, including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP).

[0073] As used herein, "administering" refers to a method of providing a dosage of a compound (e.g., a bispecific antibody) or composition (e.g., a pharmaceutical composition, e.g., a pharmaceutical composition comprising a bispecific antibody) to a subject. The compounds and / or compositions utilized in the methods described herein can be administered subcutaneously (e.g., by subcutaneous injection).

[0074] A "fixed" or "constant" dose of a therapeutic agent (e.g., a bispecific antibody) herein refers to a dose administered to a patient without regard to the patient's weight or body surface area (BSA). Thus, a fixed or flat dose can be expressed as a mg / kg dose or a mg / m 2 It is not provided as a dose, but as an absolute amount (eg, mg) of therapeutic agent.

[0075] The "subject" or "individual" is a mammal. Mammals include, but are not limited to, primates (e.g., humans and non-human primates such as monkeys), livestock (e.g., cows, sheep, cats, dogs, and horses), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the subject or individual is a human.

[0076] The "individual response" or "response" can be evaluated using any endpoint that indicates a benefit to the subject, including, but not limited to: (1) some inhibition of disease progression (e.g., of a CD20-positive cell proliferative disorder, such as a B-cell proliferative disorder (e.g., non-Hodgkin lymphoma (NHL) (e.g., previously untreated (1L) NHL, diffuse large B-cell lymphoma (DLBCL) (e.g., 1L DLBCL, relapsed and / or refractory DLBCL, or Richter's transformation), follicular lymphoma (FL) (e.g., 1L FL, relapsed and / or refractory FL, or transformed FL), mantle cell lymphoma (MCL), high-grade B-cell lymphoma, or primary mediastinal (thymic) large B-cell lymphoma (PMLBCL)) or chronic lymphocytic leukemia (CLL)), including slowing and complete cessation; (2) reduction in tumor size; (3) inhibition of cancer cell infiltration into adjacent peripheral organs and / or tissues (i.e., reduction, slowing, or complete cessation); (4) inhibition of metastasis (i.e., reduction, slowing, or complete cessation); (5) some alleviation of one or more symptoms associated with a CD20-positive cell proliferative disorder, such as a B-cell proliferative disorder (e.g., previously untreated (1L) NHL, diffuse large B-cell lymphoma (DLBCL) (e.g., 1L DLBCL, relapsed and / or refractory DLBCL, or Richter's transformation), follicular lymphoma (FL) (e.g., 1L FL, relapsed and / or refractory FL, or transformed FL), mantle cell lymphoma (MCL), high-grade B-cell lymphoma, or primary mediastinal (thymic) large B-cell lymphoma (PMLBCL)) or chronic lymphocytic leukemia (CLL)); (6) prolongation or extension of survival, including overall survival and progression-free survival; and / or (9) reduction in mortality at a given time point after treatment.

[0077] As used herein, "complete response" or "CR" refers to the disappearance of all target lesions (i.e., all evidence of disease).

[0078] As used herein, "partial response" or "PR" refers to at least a 30% reduction in the sum of the longest diameters (SLD) of target lesions referenced to a baseline SLD, or at least a 50% reduction in the product of diameters (SPD) of target lesions referenced to a baseline SPD.

[0079] As used herein, "objective response rate" (ORR) means the sum of the complete response (CR) rate and the partial response (PR) rate.

[0080] As used herein, "duration of objective response" (DOR) is defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause within 30 days of the last dose of treatment, whichever occurs first.

[0081] A "durable response" refers to a sustained effect on reducing tumor growth after cessation of treatment. For example, tumor size may remain the same or may be smaller compared to the size at the beginning of the administration phase. In some embodiments, the durable response has a duration at least equal to the treatment period, at least 1.5, 2.0, 2.5, or 3.0 times the treatment period.

[0082] A subject's "effective response" or subject "responsiveness," and similar words, to treatment with a pharmaceutical agent refers to a clinical or therapeutic benefit conferred on a subject at risk for or suffering from a disease or disorder, such as cancer. In one embodiment, such benefit includes any one or more of extending survival (including overall survival and progression-free survival), producing an objective response (including a complete or partial response), or ameliorating the signs or symptoms of cancer.

[0083] A subject who "does not respond effectively" to treatment refers to a subject who does not have any of the following: an extension of survival (including overall survival and progression-free survival), an objective response (including a complete or partial response), or an improvement in the signs or symptoms of cancer.

[0084] As used herein, the term "survival" refers to the patient being alive, and includes overall survival and progression-free survival.

[0085] As used herein, "overall survival" (OS) refers to the proportion of subjects in a group who are alive after a particular period of time, such as 1 year or 5 years from the time of diagnosis or treatment.

[0086] As used herein, "progression-free survival" (PFS) refers to the length of time during and after treatment that the disease being treated (e.g., a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder (e.g., an NHL (e.g., previously untreated (1L) NHL, DLBCL (e.g., 1L DLBCL, relapsed and / or refractory DLBCL, or Richter's transformation), FL (e.g., 1L FL, relapsed and / or refractory FL, or transformed FL), MCL, high-grade B-cell lymphoma or PMLBCL) or CLL)) does not worsen. Progression-free survival can include the amount of time a patient experiences a complete or partial remission, as well as the amount of time a patient experiences stable disease.

[0087] As used herein, "stable disease" or "SD" refers to neither sufficient shrinkage of target lesions to qualify as PR nor sufficient increase to qualify as PD, based on the smallest SLD since treatment initiation.

[0088] As used herein, "progressive disease" or "PD" refers to at least a 20% increase in the SLD of a target lesion, referenced to the smallest SLD, or at least a 50% increase in the SPD of a target lesion, referenced to the smallest SPD recorded after initiation of treatment or the presence of one or more new lesions.

[0089] As used herein, "delaying the progression" of a disorder or disease means impeding, delaying, stabilizing, and / or deferring the onset of a disease or disorder (e.g., a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder (e.g., an NHL (e.g., previously untreated (1L) NHL, DLBCL (e.g., 1L DLBCL, relapsed and / or refractory DLBCL, or Richter's transformation), FL (e.g., 1L FL, relapsed and / or refractory FL, or transformed FL), MCL, high-grade B-cell lymphoma or PMLBCL) or CLL))). This delay can be of various durations depending on the medical history and / or the subject being treated. As will be apparent to those skilled in the art, a sufficient or significant delay can effectively encompass prevention in that the subject does not develop the disease. For example, in advanced cancer, the occurrence of central nervous system (CNS) metastases can be delayed.

[0090] As used herein, the term "reducing or inhibiting cancer recurrence" means reducing or inhibiting the recurrence of a tumor or cancer, or the progression of a tumor or cancer.

[0091] "Reducing or inhibiting" means the ability to bring about an overall decrease of 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or more. The reduction or inhibition can refer to the symptoms of the disorder being treated (e.g., a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder (e.g., an NHL (e.g., previously untreated (1L) NHL, DLBCL (e.g., 1L DLBCL, relapsed and / or refractory DLBCL, or Richter's transformation), FL (e.g., 1L FL, relapsed and / or refractory FL, or transformed FL), MCL, high-grade B-cell lymphoma or PMLBCL) or CLL))), the presence or size of metastases, or the size of the primary tumor.

[0092] As used herein, the term "Ann Arbor staging" or "Ann Arbor stage" refers to a system for classifying the stage of lymphoma (e.g., non-Hodgkin lymphoma (NHL); e.g., DLBCL, FL, MCL, high-grade B-cell lymphoma, PMLBCL or CLL). Lymphoma (e.g., NHL) can be classified as one of four Ann Arbor stages. Stage I refers to lymphoma that shows involvement of a single lymph node region or a single extranodal organ or site. Stage II refers to lymphoma that shows involvement of two or more lymph node regions on the same side of the diaphragm. Stage III refers to lymphoma that shows involvement of lymph node regions on both sides of the diaphragm (III), which may be accompanied by limited involvement of an extranodal organ or site, or involvement of the spleen, or both. Stage IV refers to lymphoma that shows diffuse or disseminated lesions of one or more extranodal organs or tissues, with or without associated lymph node enlargement. Liver lesions are considered to be always diffuse and thus are always considered Ann Arbor stage IV. Lymphoid structures include lymph nodes, thymus, spleen, appendix, Waldeyer's ring, and Peyer's patches. See Carbone, P.P. et al., Cancer Res. 1971, 31(11):1860-1861.

[0093] By "survival prolongation" is meant an increase in the overall survival or progression-free survival in a treated patient compared to an untreated patient (e.g., a patient not treated with a medicament), or a patient not expressing a biomarker at a specified level, and / or a patient treated with an approved anti-tumor agent. An objective response refers to a measurable response that includes a complete response (CR) or a partial response (PR).

[0094] The term "antibody" is used herein in the broadest sense and includes, but is not limited to, various antibody structures, including monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, as long as they exhibit the desired antigen-binding activity.

[0095] "Antibody fragment" refers to a molecule other than an intact antibody that contains a portion of an intact antibody that binds to the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv); and multispecific antibodies formed from antibody fragments.

[0096] The terms "full length antibody," "intact antibody," and "whole antibody" are used interchangeably herein to refer to an antibody having a heavy chain that has a structure substantially similar to a native antibody structure or that contains an Fc region as defined herein.

[0097] "Binding domain" refers to a portion of a compound or molecule that specifically binds to a target epitope, antigen, ligand, or receptor. Binding domains include, but are not limited to, antibodies (e.g., monoclonal, polyclonal, recombinant, humanized, and chimeric antibodies), antibody fragments or portions thereof (e.g., Fab fragments, Fab'2, scFv antibodies, SMIPs, domain antibodies, diabodies, minibodies, scFv-Fc, affibodies, nanobodies, and antibody VH and / or VL domains), receptors, ligands, aptamers, and other molecules with identified binding partners.

[0098] The term "Fc region" is used herein to define the C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. This term includes native sequence Fc regions and variant Fc regions. In one embodiment, the human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present. Unless otherwise specified herein, the numbering of amino acid residues in the Fc region or constant region follows the EU numbering scheme (also referred to as the EU index) as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0099] The "class" of an antibody refers to the type of constant domain or constant region carried by its heavy chain. There are five major classes of antibodies, namely, IgA, IgD, IgE, IgG, and IgM, some of which can be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0100] As used herein, the term IgG "isotype" or "subclass" means any of the subclasses of immunoglobulins defined by the chemical and antigenic properties of their constant regions.

[0101] "Framework" or "FR" refers to variable domain residues other than hypervariable region (HVR) residues. The FR of the variable domain generally consists of four FR domains: an FR1 domain, an FR2 domain, an FR3 domain, and an FR4 domain. Thus, the HVR and FR sequences generally appear in the following sequence in VH (or VL): FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0102] "Human consensus framework" is a framework that represents the amino acid residues that most commonly occur in the selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup such as those in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda MD (1991), vols. 1-3. In one embodiment, for VL, the subgroup is subgroup kappa I in Kabat et al. (see above). In one embodiment, for VH, the subgroup is subgroup III in Kabat et al. (see above).

[0103] For purposes herein, an "acceptor human framework" is a framework that comprises the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or a human consensus framework, as defined below. An acceptor human framework "derived from" a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence, or may contain amino acid sequence changes. In some embodiments, the number of amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, the VL acceptor human framework is identical in sequence to the VL human immunoglobulin framework sequence or the human consensus framework sequence.

[0104] A "humanized" antibody refers to a chimeric antibody comprising amino acid residues from non-human HVRs and amino acid residues from human FRs. In certain embodiments, a humanized antibody comprises substantially all of at least one, and typically two, variable domains, in which all or substantially all of the HVRs (e.g., CDRs) correspond to those of a non-human antibody and all or substantially all of the FRs correspond to those of a human antibody. A humanized antibody may optionally comprise at least a portion of an antibody constant region derived from a human antibody. A "humanized form" of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization.

[0105] A "human antibody" is an antibody having an amino acid sequence of an antibody produced by a human or human cell, or an antibody derived from a non-human source that utilizes a human antibody repertoire, or an amino acid sequence corresponding to a sequence encoding another human antibody. This definition of a human antibody clearly excludes humanized antibodies that contain non-human antigen-binding residues. Human antibodies can be generated using a variety of techniques known in the art, including phage display libraries (Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991)). The methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al., J. Immunol., 147(1):86-95 (1991) can also be utilized for the preparation of human monoclonal antibodies (see also van Dijk and van de Winkel, Curr. Opin. Pharmacol., 5:368-74 (2001)). Human antibodies can be prepared, for example, by administering an antigen to a transgenic animal that has been modified to produce such antibodies in response to antigen administration but has an inactivated endogenous locus, such as an immunized xenomouse (see, for example, U.S. Patent Nos. 6,075,181 and 6,150,584 regarding the XENOMOUSE™ technology). See also, for example, Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006) regarding human antibodies generated by human B cell hybridoma technology.

[0106] The term "variable region" or "variable domain" refers to the domain of an antibody heavy chain or antibody light chain that is involved in binding of the antibody to an antigen. The variable domains of the heavy and light chains of a natural antibody (VH and VL, respectively) generally have similar structures, and each domain contains four conserved framework regions (FRs) and three hypervariable regions (HVRs). For example, Kindt et al., Kuby Immunology, 6th , W.H. Freeman and Co., page 91 (2007). A single VH or VL domain may be sufficient to confer antigen-binding specificity. Moreover, antibodies that bind to a specific antigen may be isolated by using the VH or VL domain of an antigen-binding antibody to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

[0107] The term "hypervariable region" or "HVR", as used herein, refers to each region of an antibody variable domain that is hypervariable in sequence ("complementarity determining region" or "CDR") and / or structurally forms defined loops ("hypervariable loops") and / or contains residues that contact the antigen ("antigen contacts"). Generally, antibodies contain six HVRs, three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3). Exemplary HVRs of the invention include the following: (a) hypervariable loops occurring at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)); (b) CDRs occurring at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)); (c) antigenic contacts occurring at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J. Mol. Biol. 262:732-745 (1996)); and (d) A combination of (a), (b) and / or (c) comprising HVR amino acid residues 46-56 (L2), 47-56 (L2), 48-56 (L2), 49-56 (L2), 26-35 (H1), 26-35b (H1), 49-65 (H2), 93-102 (H3) and 94-102 (H3).

[0108] Unless otherwise indicated, HVR residues and other residues in the variable domain (e.g., FR residues) are numbered herein according to Kabat et al., supra.

[0109] An "immunoconjugate" is an antibody conjugated to one or more heterologous molecules, including, but not limited to, cytotoxic agents.

[0110] The term "isolated antibody" as used herein to describe the various antibodies disclosed herein means an antibody that has been identified, separated and / or recovered from the cells or cell culture in which it is expressed. Contaminating components of its natural environment are materials that typically interfere with the diagnostic or therapeutic use of the polypeptide and can include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In some embodiments, the antibody is purified to greater than 95% or greater than 99% purity as determined, for example, by electrophoresis (e.g., SDS-PAGE, isoelectric focusing electrophoresis (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse phase HPLC). For a review of methods for assessing antibody purity, see, for example, Flatman et al., J. Chromatogr. B 848:79-87 (2007). In preferred embodiments, the antibody is purified to homogeneity by SDS-PAGE under non-reducing or reducing conditions using (1) a spinning cup sequenator to obtain at least 15 residues of the N-terminal or internal amino acid sequence to a sufficient extent, or (2) Coomassie blue or preferably silver staining. Isolated antibodies include antibodies in situ within recombinant cells because at least one component of the polypeptide's natural environment is absent. However, typically, an isolated polypeptide is prepared by at least one purification step.

[0111] The term "monoclonal antibody," as used herein, refers to an antibody obtained from a substantially homogeneous population of antibodies. That is, except for possible minor variant antibodies, including, for example, naturally occurring mutations or mutations that arise during the production of a monoclonal antibody preparation, the individual antibodies comprising the population are identical and / or bind the same epitope. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and should not be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies used in accordance with the present invention can be produced by a variety of techniques, including, but not limited to, hybridoma methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci; such methods and other exemplary methods for producing monoclonal antibodies are described herein.

[0112] "Affinity" refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (Kd). Affinity can be measured by methods common in the art, including those described herein. Specific illustrative explanations and exemplary embodiments for measuring binding affinity are described below.

[0113] An "affinity matured" antibody refers to an antibody that contains one or more alterations in one or more hypervariable regions (HVRs) compared to a parent antibody that does not contain such alterations, which alterations improve the affinity of the antibody for antigen.

[0114] The terms "anti-CD3 antibody" and "antibody that binds to CD3" refer to an antibody that can bind to CD3 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent targeting CD3. In one embodiment, the binding of an anti-CD3 antibody to an unrelated, non-CD3 protein is less than about 10% of the binding of the antibody to CD3, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, an antibody that binds to CD3 has an affinity of ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, ≦0.1 nM, ≦0.01 nM, or ≦0.001 nM (e.g., 10 -8 M or less, e.g. 10 -8 ~10 -13 M, e.g. 10 -9 M~10 -13 Dissociation constant (K D In certain embodiments, the anti-CD3 antibody binds to an epitope of CD3 that is conserved among CD3 from different species.

[0115] The term "cluster of differentiation 3" or "CD3," as used herein, unless otherwise indicated, refers to any native CD3 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), including, for example, the CD3ε, CD3γ, CD3α, and CD3β chains. The term encompasses "full-length" unprocessed CD3 (e.g., unprocessed or unmodified CD3ε or CD3γ) as well as any form of CD3 resulting from intracellular processing. The term also encompasses naturally occurring variants of CD3, including, for example, splice variants or allelic variants. CD3 includes, for example, the human CD3ε protein, which is 207 amino acids long (NCBI Reference SEQ ID NO: NP_000724), and the human CD3γ protein, which is 182 amino acids long (NCBI Reference SEQ ID NO: NP_000064).

[0116] The terms "anti-CD20 antibody" and "antibody that binds to CD20" refer to an antibody that can bind to CD20 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in the targeting of CD20. In one embodiment, the binding of the anti-CD20 antibody to irrelevant non-CD20 proteins is less than about 10% of the binding of the antibody to CD20 as measured, for example, by radioimmunoassay (RIA). In certain embodiments, the antibody that binds to CD20 has a dissociation constant (Kd) of ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, ≦0.1 nM, ≦0.01 nM or ≦0.001 nM (e.g., 10 -8 M or less, e.g., 10 -8 M to 10 -13 M, e.g., 10 -9 M to 10 -13 M). In certain embodiments, the anti-CD20 antibody binds to an epitope of CD20 that is conserved among CD20s from different species.

[0117] As used herein, the term "surface antigen classification 20" or "CD20" refers to any native CD20 derived from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. This term encompasses "full-length", unprocessed CD20, and any form of CD20 resulting from intracellular processing. This term also encompasses naturally occurring variants of CD20, including, for example, splice variants or allelic variants. CD20 includes, for example, the human CD20 protein (e.g., NCBI reference sequence numbers NP_068769.2 and NP_690605.1, see), which can be produced, for example, from a variant mRNA transcript that is 297 amino acids long and lacks a portion of the 5' UTR (e.g., NCBI reference sequence number NM_021950.3, see), or a longer variant mRNA transcript (e.g., NCBI reference sequence number NM_152866.2, see).

[0118] The terms "anti-CD20 / anti-CD3 bispecific antibody", "bispecific anti-CD20 / anti-CD3 antibody", and "antibody that binds to CD20 and CD3", or variants thereof, refer to multispecific antibodies (e.g., bispecific antibodies) that are capable of binding to CD20 and CD3 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent when targeting CD20 and / or CD3. In one embodiment, the degree of binding of a bispecific antibody that binds to CD20 and CD3 to unrelated non-CD3 proteins and / or non-CD20 proteins is less than about 10% of the binding of the antibody to CD3 and / or CD20, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, the bispecific antibody that binds to CD20 and CD3 has a dissociation constant (Kd) of 1 μM or less, 100 nM or less, 10 nM or less, 1 nM or less, 0.1 nM or less, 0.01 nM or less, or 0.001 nM or less (e.g., 10 -8 M or less, e.g., 10 -8 M to 10 -13 M, e.g., 10 -9 M to 10 -13 M). In certain embodiments, the bispecific antibody that binds to CD20 and CD3 binds to an epitope of CD3 that is conserved among CD3s from different species and / or an epitope of CD20 that is conserved among CD20s from different species. In one embodiment, the bispecific antibody that binds to CD20 and CD3 is mosunetuzumab.

[0119] As used herein, the term "mosunetuzumab" refers to an anti-CD20 / anti-CD3 bispecific antibody having the International Nonproprietary Name (INN) listed in List 117 (WHO Drug Information, Vol. 31, No. 2, 2017, p. 303) or the CAS Registry Number 1905409-39-3.

[0120] As used herein, the terms "bind", "specifically bind to", or "specific for" refer to a measurable and reproducible interaction, such as the binding between a target and an antibody, which determines the presence of the target in the presence of a heterogeneous population of molecules, including biomolecules. For example, an antibody that specifically binds to a target (which can be an epitope) is an antibody that binds to this target with higher affinity, binding strength, more readily, and / or for a longer duration than it binds to other targets. In one embodiment, the degree to which the antibody binds to an irrelevant target is less than about 10% of the binding of the antibody to the target as measured by radioimmunoassay (RIA). In certain embodiments, an antibody that specifically binds to a target has a dissociation constant (K D ) of ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, or ≦0.1 nM. In certain embodiments, the antibody specifically binds to an epitope on a protein that is conserved between proteins from different species. In another embodiment, specific binding can include, but does not require, exclusive binding. The terms used herein are, for example, 10 -4 M or less, or 10 -5 M or less, or 10 -6 M or less, or 10 -7 M or less, or 10 -8 M or less, or 10 -9 M or less, or 10 -10 M or less, or 10 -11 M or less, or 10 -12 M or less of K D , or can be indicated by a molecule having a K -4 in the range of 10 -6 M to 10 -6 M, or 10 -10 M to 10 -7 M, or 10 -9 M to 10 D . As will be appreciated by those skilled in the art, affinity and K D values are inversely correlated. High affinity for an antigen corresponds to low K DIn one embodiment, the term "specific binding" refers to binding when a molecule binds to a particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptides or polypeptide epitopes.

[0121] "Percent (%) amino acid sequence identity" with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to those in the reference polypeptide, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, without considering any conservative substitutions as part of the sequence identity. Alignment for determining percent amino acid sequence identity can be obtained by a variety of methods within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or MEGALIGN® (DNASTAR®) software. Those skilled in the art can determine appropriate parameters for sequence alignment, including any algorithms needed to achieve maximum alignment over the full length of the sequences being compared. However, for purposes herein, percent amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was written by Genentech, Inc., and the source code, together with user documentation, has been filed with the U.S. Copyright Office, Washington, DC 20559, where it is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc. (South San Francisco, California), or can be compiled from the source code. The ALIGN-2 program should be compiled for use on UNIX operating systems, including Digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.

[0122] In situations where ALIGN-2 is used for amino acid sequence comparison, the percent amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (alternatively, described as a given amino acid sequence A having or including a particular percent amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows: 100 × fraction X / Y

[0123] In this case, X is the number of amino acid residues scored as identical matches in the alignment of A and B by the sequence alignment program ALIGN-2, and Y is the total number of amino acid residues in B. It will be understood that if the length of amino acid sequence A differs from the length of amino acid sequence B, the percent amino acid sequence identity of A to B will be different from the percent amino acid sequence identity of B to A. Unless otherwise specified, all percent amino acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.

[0124] The term "pharmaceutical preparation" refers to a preparation in a form such that the biological activity of the active ingredient contained therein is effective and which does not contain additional constituents that are unacceptably toxic to the subject to which the preparation is administered.

[0125] "Pharmaceutically acceptable carrier" refers to components in a pharmaceutical preparation other than the active ingredient that are non-toxic to the subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0126] As used herein, the term "chemotherapeutic agent" refers to a compound useful for the treatment of cancers such as CD20-positive cell proliferative disorders (e.g., B-cell proliferative disorders (e.g., relapsed or refractory B-cell proliferative disorders), e.g., non-Hodgkin lymphoma (NHL; e.g., diffuse large B-cell lymphoma (DLBCL; e.g., Richter's transformation), follicular lymphoma (FL; e.g., grade 1 FL, grade 2 FL, grade 3 FL (e.g., grade 3a FL, grade 3b FL) or transformed FL), mantle cell lymphoma (MCL), or marginal zone lymphoma (MZL)), or chronic lymphocytic leukemia (CLL), e.g., relapsed or refractory NHL (e.g., relapsed or refractory DLBCL, relapsed or refractory FL, relapsed or refractory MCL or marginal zone lymphoma (MZL)), or relapsed or refractory CLL). Examples of chemotherapeutic agents include EGFR inhibitors (small molecule inhibitors (e.g., including erlotinib (TARCEVA®, Genentech / OSI Pharm.)); PD 183805 (CI 1033, 2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSA®) 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenylamino)-quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methylpiperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim); PKI-166 ((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol); (R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine); CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide);Dual EGFR / HER2 tyrosine kinase inhibitors such as EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide) (Wyeth); AG1478 (Pfizer); AG1571 (SU 5271; Pfizer); and lapatinib (TYKERB (registered trademark), GSK572016 or N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6[5[[[2-methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine)); tyrosine kinase inhibitors (e.g., EGFR inhibitors; small molecule HER2 tyrosine kinase inhibitors such as TAK165 (Takeda); oral selective inhibitors of ErbB2 receptor tyrosine kinase such as CP-724,714 (Pfizer and OSI); dual HER inhibitors such as EKB-569 (available from Wyeth) which preferentially binds to EGFR but inhibits both HER2 and EGFR overexpressing cells; PKI-166 (Novartis); pan-HER inhibitors such as canertinib (CI-1033; Pharmacia); Raf-1 inhibitors such as the antisense agent ISIS-5132 which inhibits Raf-1 signaling (ISIS Pharmaceuticals); non-HER target tyrosine kinase inhibitors such as imatinib mesylate (GLEEVEC (registered trademark), Glaxo SmithKline); multi-target tyrosine kinase inhibitors such as sunitinib (SUTENT (registered trademark), Pfizer); VEGF receptor tyrosine kinase inhibitors such as batatinib (PTK787 / ZK222584, Novartis / Schering AG); MAPK extracellular regulated kinase I inhibitor CI-1040 (Pharmacia); quinazolines such as PD153035, 4-(3-chloroanilino)quinazoline; pyridopyrimidines; pyridopyrimidines; pyrrolopyrimidines such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidine; curcumin (diferuloylmethane, 4,5-bis(4-fluoroanilino)phthalimide); tyrphostin containing a nitrothiophene moiety;PD-0183805 (Warner-Lambert); antisense molecules (e.g., those that bind to nucleic acids encoding HER); quinoxaline (U.S. Patent No. 5,804,396); triphosphostin (U.S. Patent No. 5,804,396); ZD6474 (Astra Zeneca); PTK-787 (Novartis / Schering AG); CI-1033 ((Pfizer), etc.) pan-HER inhibitors; Affinitac (ISIS 3521; Isis / Lilly); PKI 166 (Novartis); GW2016 (Glaxo SmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis / Schering AG); INC-1C11 (Imclone); and rapamycin (sirolimus, RAPAMUNE (registered trademark)); proteasome inhibitors such as bortezomib (VELCADE (registered trademark), Millennium Pharm.); disulfiram; epigallocatechin gallate; salinosporamide A; carfilzomib; 17-AAG (geldanamycin); radicicol; lactate dehydrogenase A (LDH-A); fulvestrant (FASLODEX (registered trademark), AstraZeneca); letrozole (Femara (registered trademark), Novartis), finasteride (VATALANIB (registered trademark), Novartis); oxaliplatin (ELOXATIN (registered trademark), Sanofi); 5-FU (5-fluorouracil); leucovorin; lonafarnib (SCH 66336); sorafenib (NEXAVAR (registered trademark), Bayer Labs); AG1478, thiotepa, and alkylating agents such as CYTOXAN (registered trademark) cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimelamamine; acetogenins (especially bullatacin and bullatacinone); camptothecin (including topotecan and irinotecan); bryostatin; calistatin;CC-1065 (including its adzelesin, carzelesin and bizelesin synthetic analogs); cryptophycin (especially cryptophycin 1 and cryptophycin 8); corticosteroids (including prednisone and prednisolone); cyproterone acetate; 5α-reductase including finasteride and dutasteride; vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat, dacostatins; aldosterone, duocarmycin talc (synthetic analogs, including KW-2189 and CB1-TM1); ellipticine; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chromafazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobenbine, phenesterine, prednimustine, trofosfamide, uracil mustard, etc.; nitrosoureas such as carmustine, chloroethylnitrosourea, fotemustine, lomustine, nimustine, and ranimustine; antibiotics such as enediyne antibiotics (e.g., calicheamicin, especially calicheamicin γ1 and calicheamicin ω1); dynemicin including dynemicin A; bisphosphonates such as clodronate; esperamicin; and neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomycin, actinomycin, authramycin, azaserine, cactinomycin, carabicin, caminomycin, cardinophilin, chromomycin, dactinomycin, detorubicin, 6-diazo-5-oxo-L-norleucine, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, keramycin, rhodomycin, streptozocin, streptozotocin, tubercidin, ubenimex, dinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU);Folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiampurine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, didoxyruridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, drostanolone propionate, epithiostanol, mepithiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as folic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; dexamethasone; diacron; elfornithine; elliptinium acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidamol; nitreleasin; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK (registered trademark) polysaccharide complex (JHS Natural Products); razoxane; rizoxin; sizofiran; spirogermanium; tenuazonic acid; triacron; 2,2’,2”-trichloroethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); thiotepa; chlorambucil; GEMZAR (registered trademark) (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; etoposide (VP-16); ifosfamide; mitoxantrone; novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA (registered trademark)); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid;and pharmaceutically acceptable salts, acids, prodrugs, and derivatives of any of the foregoing are included;

[0127] Chemotherapeutic agents also include: (i) antihormonal agents that act to regulate or inhibit the hormonal action on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs) (including tamoxifen (NOLVADEX®; including tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifene citrate)); (ii) aromatase inhibitors that inhibit the enzyme aromatase that regulates estrogen production in the adrenal glands, such as 4(5)-imidazole, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestane, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) antiandrogens such as flutamide, nilutamide, bicalutamide, leuprorelin, and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, Premarin, fluoxymesterone, all-trans retinoic acid, fenretinide, and troxacitabine (1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those that inhibit the expression of genes in signal transduction pathways involved in abnormal cell proliferation, such as PKC-alpha, Ralf, and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) gene therapy vaccines, such as ALLOVECTIN®, LEUVECTIN®, and VAXID®;(ix) Growth inhibitors including vinca (e.g., vincristine and vinblastine), NAVELBINE® (vinorelbine), taxanes (e.g., paclitaxel, nab-paclitaxel, and docetaxel), topoisomerase II inhibitors (e.g., doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin), and DNA alkylating agents (e.g., tamoxifen, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, and ara-C); (x) including any pharmaceutically acceptable salts, acids, prodrugs, and derivatives of the above.;

[0128] As used herein, the term "cytotoxic agent" refers to any agent that is harmful to cells (e.g., causes cell death, inhibits proliferation, or otherwise interferes with cell function). Cytotoxic agents include radioisotopes (e.g., At 211 、I 131 、I 125 、Y 90 、Re 186 、Re 188 、Sm 153 、Bi 212 、P 32 、Pb 212, and radioisotopes of Lu), chemotherapeutic agents, enzymes such as nucleolytic enzymes and fragments thereof, and low-molecular-weight toxins or enzymatically active toxins such as those derived from bacteria, fungi, plants or animals containing such fragments and / or variants, but are not limited thereto. Exemplary cytotoxic agents can be selected from antimicrotubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, apoptosis promoters, LDH-A inhibitors, fatty acid biosynthesis inhibitors, cell cycle signal transduction inhibitors, HDAC inhibitors, proteasome inhibitors, and cancer metabolism inhibitors. In one example, the cytotoxic agent is a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin). In one example, the cytotoxic agent is an antagonist of EGFR, for example, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (e.g., erlotinib). In one example, the cytotoxic agent is a RAF inhibitor, for example, a BRAF and / or CRAF inhibitor. In one example, the RAF inhibitor is vemurafenib. In one example, the cytotoxic agent is a PI3K inhibitor.

[0129] The term "PD-1 axis-binding antagonist" refers to a molecule that inhibits the interaction of either one or more of a PD-1 axis-binding partner and its binding partner so as to remove T cell dysfunction resulting from signal transduction on the PD-1 signal transduction axis, and as a result, restores or enhances T cell function (e.g., proliferation, cytokine production, target cell killing). As used herein, PD-1 axis-binding antagonists include PD-1 binding antagonists, PD-L1 binding antagonists, and PD-L2 binding antagonists.

[0130] The term "PD-1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, impairs, or interferes with the signal transduction resulting from the interaction of PD-1 with one or more binding partners such as PD-L1, PD-L2, etc. In some embodiments, a PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to one or more of its binding partners. In certain embodiments, a PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 and / or PD-L2. For example, PD-1 binding antagonists include anti-PD-1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, impair, or interfere with the signal transduction resulting from the interaction of PD-1 with PD-L1 and / or PD-L2. In one embodiment, a PD-1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes that mediate signal transduction via PD-1, and makes the dysfunction of dysfunctional T cells lower (for example, enhances the effector response to antigen recognition). In some embodiments, the PD-1 binding antagonist is an anti-PD-1 antibody. In certain embodiments, the PD-1 binding antagonist is MDX-1106 (nivolumab). In another specific embodiment, the PD-1 binding antagonist is pembrolizumab (previously lambrolizumab (MK-3475)). In another specific embodiment, the PD-1 binding antagonist is AMP-224. In some embodiments, the PD-1 binding antagonist is MDX-1106 (nivolumab). In some embodiments, the PD-1 binding antagonist is MK-3475 (pembrolizumab). In some embodiments, the PD-1 binding antagonist is MED1-0680. In some examples, the PD-1 binding antagonist is PDR001 (spartalizumab). In some examples, the PD-1 binding antagonist is REGN 2810 (semiplimab). In some examples, the PD-1 binding antagonist is BGB-108. In other examples, the PD-1 binding antagonist is prolegozumab, camrelizumab, sintilimab, tislelizumab, or tripalizumab.

[0131] As further examples of PD-1 axis-binding antagonists, there are semiprimab, prolgolimab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, retifanlimab, spartalizumab, sasanlimab, pembrolizumab, CS1003, HLX10, SCT-I10A, SHR-1316, CS1001, enobafolimab, TQB2450, ZKAB001, LP-002, zimberelimab, balstilimab, genolimuzumab, BI754091, cetrelimab, YBL-006, BAT1306, HX008, CX-072, IMC-001, KL-A167, budigalimab, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, APL-502, kcosiberelimab, rodapolimab, GS-4224, INCB086550, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, MAX-10181, RC98, BION-004, AM0001, CB201, ENUM 244C8, ENUM 388D4, AUNP-012, STI-1110, ADG104, AK-103, LBL-006, hAb21, AVA-004, PDL-GEX, INCB090244, KD036, KY1003, LYN192, MT-6035, VXM10, YBL-007, ABSK041, GB7003, JS-003, and HS-636.

[0132] The term "PD-L1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, suppresses, or interferes with signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners such as PD-1 or B7-1. In some embodiments, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partner. In certain aspects, a PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1 and / or B7-1. In some embodiments, a PD-L1 binding antagonist includes an anti-PD-L1 antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, and other molecules that reduce, block, inhibit, suppress, or interfere with signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners such as PD-1 or B7-1. In one embodiment, a PD-L1 binding antagonist reduces the negative co-stimulatory signal mediated by or through a cell surface protein expressed on T lymphocytes that is mediated by signal transduction through PD-L1, and alleviates the dysfunctional state of dysfunctional T cells (e.g., enhances the effector response to antigen recognition). In some embodiments, a PD-L1 binding antagonist is an anti-PD-L1 antibody. In certain embodiments, the anti-PD-L1 antibody is also known as MPDL3280A and is atezolizumab (CAS registration number: 1422185-06-5) described herein. In another specific embodiment, the anti-PD-L1 antibody is MDX-1105 described herein. In yet another specific aspect, the anti-PD-L1 antibody is MEDI4736 described herein.

[0133] As used herein, the term "atezolizumab" refers to an anti-PD-L1 antagonist antibody having the International Nonproprietary Name (INN) list 112 (WHO Drug Information, Vol. 28, No. 4, 2014, p. 488) or CAS registration number 1380723-44-3.

[0134] The term "PD-L2 binding antagonist" refers to a molecule that reduces, blocks, inhibits, suppresses, or interferes with the signaling resulting from the interaction of PD-L2 with any one or more of its binding partners, such as PD-1. In some embodiments, the PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to one or more of its binding partners. In certain aspects, the PD-L2 binding antagonist inhibits the binding of PD-L2 to PD-1. In some embodiments, the PD-L2 antagonist includes an anti-PD-L2 antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, and other molecules that reduce, block, inhibit, suppress, or interfere with the signaling resulting from the interaction of PD-L2 with any one or more of its binding partners, such as PD-1. In one embodiment, the PD-L2 binding antagonist reduces the negative co-stimulatory signal mediated by or through a cell surface protein expressed on T lymphocytes that mediates signaling through PD-L2, and reduces the dysfunctionality of dysfunctional T cells (e.g., enhances the effector response to antigen recognition). In some embodiments, the PD-L2 binding antagonist is an immunoadhesin.

[0135] The term "package insert" is used to refer to the instructions customarily included in the commercial package of a therapeutic product that contain information regarding indications, usage, dosage, administration, combination therapies, contraindications and / or warnings regarding the use of such therapeutic product.

[0136] III. Treatment Methods A method of treating a subject having a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder, e.g., NHL (e.g., DLBCL or FL) or CLL), comprising subcutaneous administration of a bispecific antibody that binds to CD20 and CD3 to the subject according to a dosing schedule comprising at least a first dosing cycle and a second dosing cycle. In some examples, the first dosing cycle comprises a first subcutaneous dose (C1D1), a second subcutaneous dose (C1D2), and a third subcutaneous dose (C1D3) of the bispecific antibody, and the second dosing cycle comprises a single subcutaneous dose (C2D1) of the bispecific antibody. In some examples, C1D1 is less than or equal to C1D2 and less than C1D3, and C1D2 is less than or equal to C1D3. In some examples, C1D1 is from about 0.1 mg to about 10 mg (e.g., from about 0.1 mg to about 7 mg, from about 0.2 mg to about 10 mg, from about 0.5 mg to about 10 mg, from about 1 mg to about 9 mg, from about 2 mg to about 8 mg, from about 3 mg to about 7 mg, from about 4 mg to about 6 mg; e.g., about 5 mg), C1D2 is from about 5 mg to about 80 mg (e.g., from about 20 mg to about 75 mg, from about 25 mg to about 75 mg, from about 30 mg to about 75 mg, from about 35 mg to about 75 mg, or from about 40 mg to about 75 mg; e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg), and C1D3 is from about 10 mg to about 300 mg (from about 25 mg to about 300 mg, from about 50 mg to about 300 mg, from about 100 mg to about 300 mg, from about 200 mg to about 300 mg, from about 50 mg to about 250 mg, from about 100 mg to about 250 mg, from about 100 mg to about 200 mg, from about 10 mg to about 250 mg, from about 10 mg to about 200 mg, from about 10 mg to about 180 mg, from about 10 mg to about 160 mg, from about 10 mg to about 150 mg, from about 10 mg to about 140 mg, from about 20 mg to about 130 mg, from about 30 mg to about 120 mg, or from about 40 mg to about 100 mg, or from about 25 mg to about 75 mg; e.g., about 30 mg, about 45 mg, or about 60 mg).In some examples, C2D1 is at least C1D3 and is from about 10 mg to about 300 mg (from about 25 mg to about 300 mg, from about 50 mg to about 300 mg, from about 100 mg to about 300 mg, from about 200 mg to about 300 mg, from about 50 mg to about 250 mg, from about 100 mg to about 250 mg, from about 100 mg to about 200 mg, from about 10 mg to about 250 mg, from about 10 mg to about 200 mg, from about 10 mg to about 180 mg, from about 10 mg to about 160 mg, from about 10 mg to about 150 mg, from about 10 mg to about 140 mg, from about 20 mg to about 130 mg, from about 30 mg to about 120 mg, or from about 40 mg to about 100 mg, or from about 25 mg to about 75 mg; for example, about 30 mg, about 45 mg, or about 60 mg). In some examples, the methods provided herein include treating a subject having CLL, the treatment including subcutaneously administering to the subject a bispecific antibody that binds CD20 and CD3 in a dosing regimen that includes 0.1 mg of C1D1.

[0137] A method of treating a population of subjects having a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder, e.g., NHL (e.g., DLBCL or FL) or CLL), the method comprising administering subcutaneously to the subject a bispecific antibody that binds to CD20 and CD3 in a dosing schedule comprising at least a first dosing cycle and a second dosing cycle. In some examples, the first dosing cycle comprises a first subcutaneous dose (C1D1), a second subcutaneous dose (C1D2), and a third subcutaneous dose (C1D3) of the bispecific antibody, and the second dosing cycle comprises a single subcutaneous dose (C2D1) of the bispecific antibody. In some examples, C1D1 is less than or equal to C1D2 and less than C1D3, and C1D2 is less than or equal to C1D3. In some examples, C1D1 is from about 0.1 mg to about 10 mg (e.g., from about 0.1 mg to about 7 mg, from about 0.2 mg to about 10 mg, from about 0.5 mg to about 10 mg, from about 1 mg to about 9 mg, from about 2 mg to about 8 mg, from about 3 mg to about 7 mg, or from about 4 mg to about 6 mg; e.g., about 5 mg), C1D2 is from about 5 mg to about 80 mg (e.g., from about 20 mg to about 75 mg, from about 25 mg to about 75 mg, from about 30 mg to about 75 mg, from about 35 mg to about 75 mg, or from about 40 mg to about 75 mg; e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg), and C1D3 is from about 10 mg to about 300 mg (from about 25 mg to about 300 mg, from about 50 mg to about 300 mg, from about 100 mg to about 300 mg, from about 200 mg to about 300 mg, from about 50 mg to about 250 mg, from about 100 mg to about 250 mg, from about 100 mg to about 200 mg, from about 10 mg to about 250 mg, from about 10 mg to about 200 mg, from about 10 mg to about 180 mg, from about 10 mg to about 160 mg, from about 10 mg to about 150 mg, from about 10 mg to about 140 mg, from about 20 mg to about 130 mg, from about 30 mg to about 120 mg, or from about 40 mg to about 100 mg, or from about 25 mg to about 75 mg; e.g., about 30 mg, about 45 mg, or about 60 mg).In some examples, C2D1 is at least C1D3 and is from about 10 mg to about 300 mg (about 25 mg to about 300 mg, about 50 mg to about 300 mg, about 100 mg to about 300 mg, about 200 mg to about 300 mg, about 50 mg to about 250 mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, about 10 mg to about 250 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 150 mg, about 10 mg to about 140 mg, about 20 mg to about 130 mg, about 30 mg to about 120 mg, about 40 mg to about 100 mg, or about 25 mg to about 75 mg; for example, about 30 mg, about 45 mg, or about 60 mg). In some examples, the methods provided herein include treating a population of subjects having CLL, the treatment including subcutaneously administering to the subject a bispecific antibody that binds CD20 and CD3 in a dosing regimen that includes 0.1 mg of C1D1.

[0138] A. Treatment method for dosing of anti-CD20 / anti-CD3 bispecific antibody The present invention provides a method of treating a subject having a CD20-positive cell proliferative disorder, such as a B-cell proliferative disorder (e.g., non-Hodgkin lymphoma (NHL) (e.g., previously untreated (1L) NHL, diffuse large B-cell lymphoma (DLBCL) (e.g., 1L DLBCL, relapsed and / or refractory DLBCL, or Richter's transformation), follicular lymphoma (FL) (e.g., 1L FL, relapsed and / or refractory FL, or transformed FL), mantle cell lymphoma (MCL), high-grade B-cell lymphoma, or primary mediastinal (thymic) large B-cell lymphoma (PMLBCL)) or chronic lymphocytic leukemia (CLL), comprising administering an anti-CD20 / anti-CD3 bispecific antibody (e.g., mosunetuzumab) to the subject, for example, in a divided-dose escalating dosing schedule, or for example, in a divided step-up dosing schedule of a first dosing cycle. In some examples, the method is used to treat a subject having relapsed and / or refractory NHL (e.g., aggressive NHL (e.g., relapsed and / or refractory DLBCL, or relapsed and / or refractory FL)). In some examples, the subject has a recorded history of at least 6 months of efficacy (e.g., complete response or partial response) during the period following completion of treatment and has relapsed after one or more (e.g., 1, 2, 3, or more) prior treatments (e.g., one or more prior systemic therapies, e.g., one or more prior systemic chemotherapy (e.g., one or more prior systemic therapies including administration of anthracycline), one or more previous stem cell therapies, or one or more prior CAR-T cell therapies). In some examples, the subject is refractory to any prior treatment (e.g., has no response to a prior treatment or has progressed within 6 months of completion of the last dose of treatment). Thus, in some embodiments, the dosing schedule is a second-line (2L) therapy. In some embodiments, the dosing schedule is a third-line (3L) therapy. In some embodiments, the subject has transformed FL, which is refractory to standard treatment for transformed FL. In some embodiments, the FL is graded FL (e.g., grade 1 FL, grade 2 FL, grade 3a FL, or grade 3b FL).In some embodiments, the method is used to treat subjects having non-recurrent and non-refractory NHL, and the dosing schedule is a first-line (1L) therapy.

[0139] In some examples, the invention includes subcutaneously administering to a subject a bispecific antibody that binds to CD20 and CD3 (e.g., mosunetuzumab) in a dosing schedule that includes at least a first dosing cycle and a second dosing cycle, for treating a subject having a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder (e.g., NHL (e.g., previously untreated (1L) NHL, DLBCL (e.g., 1L DLBCL, relapsed and / or refractory DLBCL, or Richter's transformation), FL (e.g., 1L FL, relapsed and / or refractory FL, or transformed FL), MCL, high-grade B-cell lymphoma or PMLBCL) or CLL)), wherein the first dosing cycle includes a first subcutaneous dose (C1D1), a second subcutaneous dose (C1D2), and a third subcutaneous dose (C1D3) of the bispecific antibody, C1D1 is less than or equal to C1D2 and less than C1D3, (ii) C1D2 is less than or equal to C1D3, (iii) C1D1 is from about 0.1 mg to about 10 mg (e.g., from about 0.1 mg to about 7 mg, from about 0.2 mg to about 10 mg, from about 0.5 mg to about 10 mg, from about 1 mg to about 9 mg, from about 2 mg to about 8 mg, from about 3 mg to about 7 mg, from about 4 mg to about 6 mg; e.g., about 5 mg), C1D2 is from about 5 mg to about 80 mg (e.g., from about 20 mg to about 75 mg, from about 25 mg to about 75 mg, from about 30 mg to about 75 mg, from about 35 mg to about 75 mg, or from about 40 mg to about 75 mg; e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg), and C1D3 is from about 10 mg to about 300 mg (from about 25 mg to about 300 mg, from about 50 mg to about 300 mg, from about 100 mg to about 300 mg, from about 200 mg to about 300 mg, from about 50 mg to about 250 mg, from about 100 mg to about 250 mg, from about 100 mg to about 200 mg, from about 10 mg to about 250 mg, from about 10 mg to about 200 mg, from about 10 mg to about 180 mg, from about 10 mg to about 160 mg, from about 10 mg to about 150 mg, from about 10 mg to about 140 mg, from about 20 mg to about 130 mg, from about 30 mg to about 120 mg, or from about 40 mg to about 100 mg, or from about 25 mg to about 75 mg; e.g., about 30 mg, about 45 mg, or about 60 mg).The second dosing cycle includes a single subcutaneous dose of the bispecific antibody (C2D1), where C2D1 is greater than or equal to C1D3 and is from about 10 mg to about 300 mg (e.g., from about 25 mg to about 300 mg, from about 50 mg to about 300 mg, from about 100 mg to about 300 mg, from about 200 mg to about 300 mg, from about 50 mg to about 250 mg, from about 100 mg to about 250 mg, from about 100 mg to about 200 mg, from about 10 mg to about 250 mg, from about 10 mg to about 200 mg, from about 10 mg to about 180 mg, from about 10 mg to about 160 mg, from about 10 mg to about 150 mg, from about 10 mg to about 140 mg, from about 20 mg to about 130 mg, from about 30 mg to about 120 mg, or from about 40 mg to about 100 mg, or from about 25 mg to about 75 mg; e.g., about 30 mg, about 45 mg, or about 60 mg). In some examples, C1D1 is less than C1D2. In some examples, C1D1 is approximately equal to C1D3. In some examples, C1D1 is from about 2 mg to about 8 mg (e.g., from about 3 mg to about 7 mg, from about 4 mg to about 6 mg; e.g., about 5 mg), C1D2 is from about 10 mg to about 75 mg (e.g., from about 20 mg to about 75 mg, from about 25 mg to about 75 mg, from about 30 mg to about 75 mg, from about 35 mg to about 75 mg, or from about 40 mg to about 75 mg; e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg), C1D3 is from about 20 mg to about 75 mg (e.g., from about 25 mg to about 75 mg, from about 30 mg to about 75 mg, from about 35 mg to about 75 mg, or from about 40 mg to about 75 mg; e.g., about 45 mg), and C2D1 is from about 20 mg to about 75 mg (e.g., from about 25 mg to about 75 mg, from about 30 mg to about 75 mg, from about 35 mg to about 75 mg, or from about 40 mg to about 75 mg; e.g., about 45 mg). In certain embodiments, C1D1 is about 5 mg, C1D2 is about 45 mg, C1D3 is about 45 mg, and C2D1 is about 45 mg. In other embodiments, C1D1 is about 5 mg, C1D2 is about 15 mg, C1D3 is about 45 mg, and C2D1 is about 45 mg. In other embodiments, C1D1 is about 5 mg, C1D2 is about 10 mg, C1D3 is about 30 mg, and C2D1 is about 30 mg.In other embodiments, C1D1 is about 5 mg, C1D2 is about 20 mg, C1D3 is about 40 mg, and C2D1 is about 40 mg. In still other embodiments, C1D1 is about 5 mg, C1D2 is about 20 mg, C1D3 is about 60 mg, and C2D1 is about 60 mg. In still other embodiments, C1D1 is about 5 mg, C1D2 is about 20 mg, C1D3 is about 45 mg, and C2D1 is about 60 mg.

[0140] In some examples, C1D1 is equal to C1D2 (e.g., C1D1 is about 5 mg, C1D2 is about 5 mg, C1D3 is about 45 mg or 60 mg, and C2D1 is about 45 mg or 60 mg).

[0141] In other examples, C1D2 is equal to C1D3 (e.g., C1D1 is about 5 mg, C1D2 is about 45 mg or 60 mg, C1D3 is about 45 mg or 60 mg, and C2D1 is about 45 mg or 60 mg). In some examples, the method includes administering C1D2 to the subject about 7 days after C1D1. In some examples, the method includes administering C1D3 to the subject about 7 days after C1D2. In some examples, the method includes administering C2D1 to the subject about 7 days after C1D3. For example, in some embodiments, the method of the invention includes administering C1D1, C1D2, and C1D3 to the subject on days 1, 8, and 15, respectively, of a first dosing cycle, or on about day 1, about day 8, and about day 15. In some examples, these methods include administering C2D1 to the subject on day 1 of a second dosing cycle. In some examples, the first dosing cycle and the second dosing cycle are 21-day dosing cycles. In some examples, the first dosing cycle is a 21-day dosing cycle and the second dosing cycle is a 28-day dosing cycle. Alternatively, in some examples, the first dosing cycle and the second dosing cycle are 28-day dosing cycles.

[0142] In some examples, the invention includes subcutaneously administering to a subject a bispecific antibody (e.g., mosunetuzumab) that binds to CD20 and CD3 in a dosing schedule that includes at least a first dosing cycle and a second dosing cycle, for treating a subject having a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder (e.g., NHL (e.g., previously untreated (1L) NHL, DLBCL (e.g., 1L DLBCL, relapsed and / or refractory DLBCL, or Richter's transformation), FL (e.g., 1L FL, relapsed and / or refractory FL, or transformed FL), MCL, high-grade B-cell lymphoma or PMLBCL) or CLL)), wherein the first dosing cycle includes a first subcutaneous dose (C1D1), a second subcutaneous dose (C1D2), and a third subcutaneous dose (C1D3) of the bispecific antibody, (i) C1D1 is about 5 mg, (ii) C1D2 is greater than or equal to C1D1 and less than or equal to C1D3, and (iii) C1D3 is about 45 mg. The second dosing cycle includes a single subcutaneous dose (C2D1) of the bispecific antibody, and C2D1 is about 45 mg. In some examples, C1D2 is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg or about 45 mg. In some examples, the first dosing cycle and the second dosing cycle are 21-day dosing cycles (e.g., C1D1, C1D2, and C1D3 are administered on days 1, 8, and 15, respectively, or about 1, about 8, and about 15 of the first dosing cycle, and C2D1 is administered on day 1 of the second dosing cycle in a 21-day dosing cycle). In some examples, the first dosing cycle is a 21-day dosing cycle and the second dosing cycle is a 28-day dosing cycle. In some examples, the first dosing cycle and the second dosing cycle are 28-day dosing cycles.

[0143] In some examples, the present invention involves subcutaneously administering to a subject a bispecific antibody (e.g., mosunetuzumab) that binds to CD20 and CD3, in a dosing schedule that includes at least a first dosing cycle and a second dosing cycle, for treating a subject having a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder (e.g., NHL (e.g., previously untreated (1L) NHL, DLBCL (e.g., 1L DLBCL, relapsed and / or refractory DLBCL, or Richter's transformation), FL (e.g., 1L FL, relapsed and / or refractory FL, or transformed FL), MCL, high-grade B-cell lymphoma or PMLBCL) or CLL)), wherein the first dosing cycle includes a first subcutaneous dose (C1D1) of the bispecific antibody on day 1 of the first dosing cycle, a second subcutaneous dose (C1D2) of the bispecific antibody on day 8 of the first dosing cycle, and a third subcutaneous dose (C1D3) of the bispecific antibody on day 15 of the first dosing cycle, and (i) C1D1 is about 5 mg, (ii) C1D2 is greater than or equal to C1D1 and less than or equal to C1D3, and (iii) C1D3 is about 45 mg. The second dosing cycle includes a single subcutaneous dose (C2D1) of the bispecific antibody on day 1 of the second dosing cycle, and C2D1 is about 45 mg. 31In some examples, C1D2 is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 45 mg or about 60 mg. In some embodiments, C1D2 is about 15 mg. In some embodiments, C1D2 is about 45 mg.

[0144] In some embodiments, the dosing schedule includes one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) additional dosing cycles (e.g., from 1 to 15 additional dosing cycles, from 8 to 17 additional dosing cycles, or from 6 to 15 additional dosing cycles). In some embodiments, the dosing schedule includes 6 additional dosing cycles. In some embodiments, the dosing schedule includes 15 additional dosing cycles. In some embodiments, the dosing schedule includes a total of from 2 to 17 (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17) dosing cycles. In some embodiments, the dosing schedule includes a total of 8 dosing cycles. In some embodiments, the dosing schedule includes a total of 17 dosing cycles. In some embodiments, each additional dosing cycle is a 21-day dosing cycle. In some embodiments, each additional dosing cycle is a 28-day dosing cycle. In some embodiments, each additional dosing cycle includes administration of an additional dose of the bispecific antibody. In some embodiments, each additional dose of the bispecific antibody is an amount substantially equal to C2D1. In some embodiments, each additional dose of the bispecific antibody is about 45 mg. In some embodiments, the method includes administering each additional dose of the bispecific antibody to the subject on day 1 of each respective additional dosing cycle.

[0145] In some examples, each additional dosing cycle is a 21-day dosing cycle. In some examples, the first dosing cycle is a 21-day dosing cycle and the second dosing cycle is a 28-day dosing cycle. Alternatively, each additional dosing cycle is a 28-day dosing cycle.

[0146] In some examples, each of one or more additional dosing cycles includes a single subcutaneous dose of the bispecific antibody, e.g., a single subcutaneous dose on day 1 of each of one or more additional dosing cycles.

[0147] In certain examples, the present invention provides a method of treating a subject having DLBCL (e.g., 1L DLBCL, relapsed and / or refractory DLBCL, or Richter's transformation) comprising subcutaneously administering to the subject a bispecific antibody that binds CD20 and CD3 (e.g., mosunetuzumab) in a dosing schedule comprising at least a first 21-day dosing cycle and a second 21-day dosing cycle, wherein the first 21-day dosing cycle comprises a first subcutaneous dose (C1D1), a second subcutaneous dose (C1D2), and a third subcutaneous dose (C1D3) of the bispecific antibody, and (i) C1D1 is less than or equal to C1D2 and less than C1D3, (ii) C1D2 is less than or equal to C1D3, (iii) C1D1 is from about 0.1 mg to about 10 mg (e.g., from about 0.1 mg to about 7 mg, from about 0.2 mg to about 10 mg, from about 0.5 mg to about 10 mg, from about 1 mg to about 9 mg, from about 2 mg to about 8 mg, from about 3 mg to about 7 mg, from about 4 mg to about 6 mg; e.g., about 5 mg), C1D2 is from about 5 mg to about 80 mg (e.g., from about 20 mg to about 75 mg, from about 25 mg to about 75 mg, from about 30 mg to about 75 mg, from about 35 mg to about 75 mg, or from about 40 mg to about 75 mg; e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg), and C1D3 is from about 10 mg to about 300 mg (from about 25 mg to about 300 mg, from about 50 mg to about 300 mg, from about 100 mg to about 300 mg, from about 200 mg to about 300 mg, from about 50 mg to about 250 mg, from about 100 mg to about 250 mg, from about 100 mg to about 200 mg, from about 10 mg to about 250 mg, from about 10 mg to about 200 mg, from about 10 mg to about 180 mg, from about 10 mg to about 160 mg, from about 10 mg to about 150 mg, from about 10 mg to about 140 mg, from about 20 mg to about 130 mg, from about 30 mg to about 120 mg, or from about 40 mg to about 100 mg, or from about 25 mg to about 75 mg; e.g., about 30 mg, about 45 mg, or about 60 mg).The second 21-day dosing cycle includes a single subcutaneous dose of the bispecific antibody (C2D1), where C2D1 is greater than or equal to C1D3 and is from about 10 mg to about 300 mg (from about 25 mg to about 300 mg, from about 50 mg to about 300 mg, from about 100 mg to about 300 mg, from about 200 mg to about 300 mg, from about 50 mg to about 250 mg, from about 100 mg to about 250 mg, from about 100 mg to about 200 mg, from about 10 mg to about 250 mg, from about 10 mg to about 200 mg, from about 10 mg to about 180 mg, from about 10 mg to about 160 mg, from about 10 mg to about 150 mg, from about 10 mg to about 140 mg, from about 20 mg to about 130 mg, from about 30 mg to about 120 mg, or from about 40 mg to about 100 mg, or from about 25 mg to about 75 mg; for example, about 30 mg, about 45 mg, or about 60 mg). In some examples, the method includes administering C1D2 to the subject at about 7 days after C1D1. In some examples, the method includes administering C1D3 to the subject at about 7 days after C1D2. In some examples, the method includes administering C2D1 to the subject at about 7 days after C1D3. In some examples, the method includes administering C1D1, C1D2, and C1D3 to the subject on days 1, 8, and 15 or about day 1, about day 8, and about day 15 of each of the first dosing cycles.

[0148] In certain examples, the present invention provides a method of treating a subject having FL (e.g., 1L FL, relapsed and / or refractory FL, or transformed FL) comprising subcutaneously administering to the subject a bispecific antibody that binds to CD20 and CD3 (e.g., mosunetuzumab) in a dosing schedule comprising at least a first 28-day dosing cycle and a second 28-day dosing cycle, wherein the first 28-day dosing cycle comprises a first subcutaneous dose (C1D1), a second subcutaneous dose (C1D2), and a third subcutaneous dose (C1D3) of the bispecific antibody, (i) C1D1 is less than or equal to C1D2 and less than C1D3, (ii) C1D2 is less than or equal to C1D3, (iii) C1D1 is from about 0.1 mg to about 10 mg (e.g., about 0.5 to about 10 mg), C1D2 is from about 5 mg to about 80 mg (e.g., about 20 mg to about 75 mg, about 25 mg to about 75 mg, about 30 mg to about 75 mg, about 35 mg to about 75 mg, or about 40 mg to about 75 mg; e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg), and C1D3 is from about 10 mg to about 300 mg (about 25 mg to about 300 mg, about 50 mg to about 300 mg, about 100 mg to about 300 mg, about 200 mg to about 300 mg, about 50 mg to about 250 mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, about 10 mg to about 250 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 150 mg, about 10 mg to about 140 mg, about 20 mg to about 130 mg, about 30 mg to about 120 mg, about 40 mg to about 100 mg, or about 25 mg to about 75 mg; e.g., about 30 mg, about 45 mg, or about 60 mg).The second 28-day dosing cycle includes a single subcutaneous dose of the bispecific antibody (C2D1), where C2D1 is equal to or greater than C1D3 and is from about 10 mg to about 300 mg (about 25 mg to about 300 mg, about 50 mg to about 300 mg, about 100 mg to about 300 mg, about 200 mg to about 300 mg, about 50 mg to about 250 mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, about 10 mg to about 250 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 150 mg, about 10 mg to about 140 mg, about 20 mg to about 130 mg, about 30 mg to about 120 mg, or about 40 mg to about 100 mg, or about 25 mg to about 75 mg; for example, about 30 mg, about 45 mg, or about 60 mg).

[0149] In certain examples, the present invention provides a method of treating a subject having FL (e.g., 1L FL, relapsed and / or refractory FL, or transformed FL) comprising subcutaneously administering to the subject a bispecific antibody that binds CD20 and CD3 (e.g., mosunetuzumab) according to a dosing schedule comprising at least a first 21-day dosing cycle and a second 28-day dosing cycle, wherein the first 21-day dosing cycle comprises a first subcutaneous dose (C1D1), a second subcutaneous dose (C1D2), and a third subcutaneous dose (C1D3) of the bispecific antibody, and (i) C1D1 is less than or equal to C1D2 and less than C1D3, (ii) C1D2 is less than or equal to C1D3, (iii) C1D1 is from about 0.1 mg to about 10 mg (e.g., from about 0.5 to about 10 mg), C1D2 is from about 5 mg to about 80 mg (e.g., from about 20 mg to about 75 mg, from about 25 mg to about 75 mg, from about 30 mg to about 75 mg, from about 35 mg to about 75 mg, or from about 40 mg to about 75 mg; e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg), and C1D3 is from about 10 mg to about 300 mg (from about 25 mg to about 300 mg, from about 50 mg to about 300 mg, from about 100 mg to about 300 mg, from about 200 mg to about 300 mg, from about 50 mg to about 250 mg, from about 100 mg to about 250 mg, from about 100 mg to about 200 mg, from about 10 mg to about 250 mg, from about 10 mg to about 200 mg, from about 10 mg to about 180 mg, from about 10 mg to about 160 mg, from about 10 mg to about 150 mg, from about 10 mg to about 140 mg, from about 20 mg to about 130 mg, from about 30 mg to about 120 mg, from about 40 mg to about 100 mg, or from about 25 mg to about 75 mg; e.g., about 30 mg, about 45 mg, or about 60 mg).The second 28-day dosing cycle includes a single subcutaneous dose of the bispecific antibody (C2D1), where C2D1 is greater than or equal to C1D3 and is from about 10 mg to about 300 mg (from about 25 mg to about 300 mg, from about 50 mg to about 300 mg, from about 100 mg to about 300 mg, from about 200 mg to about 300 mg, from about 50 mg to about 250 mg, from about 100 mg to about 250 mg, from about 100 mg to about 200 mg, from about 10 mg to about 250 mg, from about 10 mg to about 200 mg, from about 10 mg to about 180 mg, from about 10 mg to about 160 mg, from about 10 mg to about 150 mg, from about 10 mg to about 140 mg, from about 20 mg to about 130 mg, from about 30 mg to about 120 mg, or from about 40 mg to about 100 mg, or from about 25 mg to about 75 mg; for example, about 30 mg, about 45 mg, or about 60 mg).

[0150] In some examples, C1D1 is less than C1D2. In some examples, C1D2 is approximately equal in amount to C1D3. In some examples, C1D1 is from about 2 mg to about 8 mg (e.g., from about 3 mg to about 7 mg, from about 4 mg to about 6 mg; e.g., about 5 mg), C1D2 is from about 10 mg to about 75 mg (e.g., from about 20 mg to about 75 mg, from about 25 mg to about 75 mg, from about 30 mg to about 75 mg, from about 35 mg to about 75 mg, or from about 40 mg to about 75 mg; e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg), C1D3 is from about 20 mg to about 75 mg (e.g., from about 25 mg to about 75 mg, from about 30 mg to about 75 mg, from about 35 mg to about 75 mg, or from about 40 mg to about 75 mg; e.g., about 45 mg), and C2D1 is from about 20 mg to about 75 mg (e.g., from about 25 mg to about 75 mg, from about 30 mg to about 75 mg, from about 35 mg to about 75 mg, or from about 40 mg to about 75 mg; e.g., about 45 mg). In certain embodiments, C1D1 is about 5 mg. In some embodiments, C1D3 is from about 25 mg to about 75 mg. In some embodiments, C1D3 is about 30 mg, about 45 mg or about 60 mg. In some embodiments, C2D1 is from about 40 mg to about 75 mg. In some embodiments, C2D1 is about 30 mg, about 45 mg or about 60 mg. In some embodiments, C1D2 is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg or about 60 mg.In some examples, (a) C1D1 is about 5 mg, C1D2 is about 45 mg, C1D3 is about 45 mg, and C2D1 is about 45 mg; (b) C1D1 is about 5 mg, C1D2 is about 10 mg, C1D3 is about 30 mg, and C2D1 is about 30 mg; (c) C1D1 is about 5 mg, C1D2 is about 15 mg, C1D3 is about 45 mg, and C2D1 is about 45 mg; (d) C1D1 is about 5 mg, C1D2 is about 20 mg, C1D3 is about 40 mg, and C2D1 is about 40 mg; (e) C1D1 is about 5 mg, C1D2 is about 20 mg, C1D3 is about 45 mg, and C2D1 is about 60 mg; or (f) C1D1 is about 5 mg, C1D2 is about 20 mg, C1D3 is about 60 mg, and C2D1 is about 60 mg.

[0151] In certain embodiments, C1D1 is about 5 mg, C1D2 is about 45 mg, C1D3 is about 45 mg, and C2D1 is about 45 mg. In some embodiments, C1D1 is equal to C1D2. For example, C1D1 is about 5 mg, C1D2 is about 5 mg, C1D3 is about 45 mg or about 60 mg, and C2D1 is about 45 mg or about 60 mg.

[0152] In other examples, C1D2 is equal to C1D3. For example, C1D1 is about 5 mg, C1D2 is about 45 mg or about 60 mg, C1D3 is about 45 mg or about 60 mg, and C2D1 is about 45 mg or about 60 mg.

[0153] In some examples, these methods include administering C2D1 to the subject on day 1 of a second dosing cycle.

[0154] In some examples, the dosing schedule includes one or more additional dosing cycles (additional dosing cycles beyond the second dosing cycle) (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, or 17 or more additional dosing cycles, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 additional dosing cycles). In certain examples, the dosing schedule includes 8 to 17 additional dosing cycles (e.g., 10 to 19 total dosing cycles). In certain examples, the dosing schedule includes 6 to 15 additional dosing cycles (e.g., 8 to 17 total dosing cycles).

[0155] The present invention also provides a method of treating a population of subjects having a CD20-positive cell proliferative disorder by administering to one or more subjects a bispecific antibody that binds to CD20 and CD3 (e.g., mosunetuzumab) according to any of the dosing regimens described herein. In some examples, the present invention provides a method of treating a population of subjects having a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder (e.g., NHL (e.g., previously untreated (1L) NHL, DLBCL (e.g., 1L DLBCL, relapsed and / or refractory DLBCL, or Richter's transformation), FL (e.g., 1L FL, relapsed and / or refractory FL, or transformed FL), MCL, high-grade B-cell lymphoma or PMLBCL) or CLL)) comprising subcutaneously administering to one or more subjects a bispecific antibody that binds to CD20 and CD3 (e.g., mosunetuzumab) in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein the first dosing cycle comprises a first subcutaneous dose (C1D1), a second subcutaneous dose (C1D2) and a third subcutaneous dose (C1D3) of the bispecific antibody, (i) C1D1 is less than or equal to C1D2 and less than C1D3, (ii) C1D2 is less than or equal to C1D3, (iii) C1D1 is from about 0.1 mg to about 10 mg (e.g., from about 0.1 mg to about 7 mg, from about 0.2 mg to about 10 mg, about 0.5 mg to about 10 mg, about 1 mg to about 9 mg, about 2 mg to about 8 mg, about 3 mg to about 7 mg, about 4 mg to about 6 mg; for example, about 5 mg), C1D2 is about 5 mg to about 80 mg (for example, about 20 mg to about 75 mg, about 25 mg to about 75 mg, about 30 mg to about 75 mg, about 35 mg to about 75 mg, or about 40 mg to about 75 mg; for example, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg), and C1D3 is about 10 mg to about 300 mg (for example, about 25 mg to about 300 mg, about 50 mg to about 300 mg, about 100 mg to about 300 mg, about 200 mg to about 300 mg, about 50 mg to about 250 mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, about 10 mg to about 250 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 150 mg, about 10 mg to about 140 mg, about 20 mg to about 130 mg, about 30 mg to about 120 mg, about 40 mg to about 100 mg, about 20 mg to about 100 mg, about 25 mg to about 75 mg, about 30 mg to about 75 mg, about 35 mg to about 75 mg, or about 40 mg to about 75 mg; for example, about 45 mg). The second dosing cycle includes a single subcutaneous dose of the bispecific antibody (C2D1), and C2D1 is greater than or equal to C1D3 and is about 10 mg to about 300 mg (for example, about 25 mg to about 300 mg, about 50 mg to about 300 mg, about 100 mg to about 300 mg, about 200 mg to about 300 mg, about 50 mg to about 250 mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, about 10 mg to about 250 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 150 mg, about 10 mg to about 140 mg, about 20 mg to about 130 mg, about 30 mg to about 120 mg, about 40 mg to about 100 mg, about 20 mg to about 100 mg, about 25 mg to about 75 mg, from about 30 mg to about 75 mg, about 35 mg to about 75 mg, or about 40 mg to about 75 mg; for example, about 45 mg).

[0156] In some examples, the invention features a method of treating a population of subjects having a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder (e.g., NHL (e.g., previously untreated (1L) NHL, DLBCL (e.g., 1L DLBCL, relapsed and / or refractory DLBCL, or Richter's transformation), FL (e.g., 1L FL, relapsed and / or refractory FL, or transformed FL), MCL, high-grade B-cell lymphoma or PMLBCL) or CLL)), comprising subcutaneously administering to the subject a bispecific antibody that binds to CD20 and CD3 (e.g., mosunetuzumab) in a dosing schedule comprising at least a first dosing cycle and a second dosing cycle, wherein the first dosing cycle comprises a first subcutaneous dose (C1D1), a second subcutaneous dose (C1D2), and a third subcutaneous dose (C1D3) of the bispecific antibody, and (i) C1D1 is about 5 mg, (ii) C1D2 is greater than or equal to C1D1 and less than or equal to C1D3, and (iii) C1D3 is about 45 mg. In some examples, the second dosing cycle comprises a single subcutaneous dose (C2D1) of the bispecific antibody, and C2D1 is about 45 mg.

[0157] In some examples, the invention features a method of treating a population of subjects having a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder (e.g., NHL (e.g., previously untreated (1L) NHL, DLBCL (e.g., 1L DLBCL, relapsed and / or refractory DLBCL, or Richter's transformation), FL (e.g., 1L FL, relapsed and / or refractory FL, or transformed FL), MCL, high-grade B-cell lymphoma or PMLBCL) or CLL)) by subcutaneously administering to the subject a bispecific antibody that binds to CD20 and CD3 (e.g., mosunetuzumab) in a dosing schedule that includes at least a first dosing cycle and a second dosing cycle, wherein the first dosing cycle includes a first subcutaneous dose of the bispecific antibody (C1D1) on day 1 of the first dosing cycle, a second subcutaneous dose of the bispecific antibody (C1D2) on day 8 of the first dosing cycle, and a third subcutaneous dose of the bispecific antibody (C1D3) on day 15 of the first dosing cycle, and (i) C1D1 is about 5 mg, (ii) C1D2 is greater than or equal to C1D1 and less than or equal to C1D3, and (iii) C1D3 is about 45 mg. In some examples, the second dosing cycle includes a single subcutaneous dose of the bispecific antibody (C2D1) on day 1 of the second dosing cycle, and C2D1 is about 45 mg.

[0158] In some examples, the invention provides a method of treating a population of subjects having DLBCL (e.g., 1L DLBCL, relapsed and / or refractory DLBCL, or Richter's transformation) by subcutaneously administering to one or more subjects a bispecific antibody that binds to CD20 and CD3 (e.g., mosunetuzumab) in a dosing schedule comprising at least a first dosing cycle and a second dosing cycle, wherein the first dosing cycle comprises a first subcutaneous dose (C1D1), a second subcutaneous dose (C1D2), and a third subcutaneous dose (C1D3) of the bispecific antibody, (i) C1D1 is less than or equal to C1D2 and less than C1D3, (ii) C1D2 is less than or equal to C1D3, (iii) C1D1 is from about 0.1 mg to about 10 mg (e.g., from about 0.1 mg to about 7 mg, from about 0.2 mg to about 10 mg, from about 0.5 mg to about 10 mg, from about 1 mg to about 9 mg, from about 2 mg to about 8 mg, from about 3 mg to about 7 mg, from about 4 mg to about 6 mg; e.g., about 5 mg), C1D2 is from about 5 mg to about 80 mg (e.g., from about 20 mg to about 75 mg, from about 25 mg to about 75 mg, from about 30 mg to about 75 mg, from about 35 mg to about 75 mg, or from about 40 mg to about 75 mg; e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg), and C1D3 is from about 10 mg to about 300 mg (from about 25 mg to about 300 mg, from about 50 mg to about 300 mg, from about 100 mg to about 300 mg, from about 200 mg to about 300 mg, from about 50 mg to about 250 mg, from about 100 mg to about 250 mg, from about 100 mg to about 200 mg, from about 10 mg to about 250 mg, from about 10 mg to about 200 mg, from about 10 mg to about 180 mg, from about 10 mg to about 160 mg, from about 10 mg to about 150 mg, from about 10 mg to about 140 mg, from about 20 mg to about 130 mg, from about 30 mg to about 120 mg, from about 40 mg to about 100 mg, or from about 25 mg to about 75 mg; e.g., about 30 mg, about 45 mg, or about 60 mg).In some examples, the second dosing cycle comprises a single subcutaneous dose of the bispecific antibody (C2D1), where C2D1 is greater than or equal to C1D3 and is from about 10 mg to about 300 mg (about 25 mg to about 300 mg, about 50 mg to about 300 mg, about 100 mg to about 300 mg, about 200 mg to about 300 mg, about 50 mg to about 250 mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, about 10 mg to about 250 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 150 mg, about 10 mg to about 140 mg, about 20 mg to about 130 mg, about 30 mg to about 120 mg, or about 40 mg to about 100 mg, or about 25 mg to about 75 mg; for example, about 30 mg, about 45 mg, or about 60 mg).

[0159] In other examples, the invention provides a method of treating a population of subjects having FL (e.g., 1L FL, relapsed and / or refractory FL, or transformed FL) comprising subcutaneously administering to the subject a bispecific antibody that binds to CD20 and CD3 (e.g., mosunetuzumab) in a dosing schedule comprising at least a first dosing cycle and a second dosing cycle, wherein the first dosing cycle comprises a first subcutaneous dose (C1D1), a second subcutaneous dose (C1D2), and a third subcutaneous dose (C1D3) of the bispecific antibody, (i) C1D1 is less than or equal to C1D2 and less than C1D3, (ii) C1D2 is less than or equal to C1D3, (iii) C1D1 is from about 0.1 mg to about 10 mg (e.g., from about 0.1 mg to about 7 mg, from about 0.2 mg to about 10 mg, from about 0.5 mg to about 10 mg, from about 1 mg to about 9 mg, from about 2 mg to about 8 mg, from about 3 mg to about 7 mg, from about 4 mg to about 6 mg; e.g., about 5 mg), C1D2 is from about 5 mg to about 80 mg (e.g., from about 20 mg to about 75 mg, from about 25 mg to about 75 mg, from about 30 mg to about 75 mg, from about 35 mg to about 75 mg, or from about 40 mg to about 75 mg; e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg), and C1D3 is from about 10 mg to about 300 mg (from about 25 mg to about 300 mg, from about 50 mg to about 300 mg, from about 100 mg to about 300 mg, from about 200 mg to about 300 mg, from about 50 mg to about 250 mg, from about 100 mg to about 250 mg, from about 100 mg to about 200 mg, from about 10 mg to about 250 mg, from about 10 mg to about 200 mg, from about 10 mg to about 180 mg, from about 10 mg to about 160 mg, from about 10 mg to about 150 mg, from about 10 mg to about 140 mg, from about 20 mg to about 130 mg, from about 30 mg to about 120 mg, from about 40 mg to about 100 mg, or from about 25 mg to about 75 mg; e.g., about 30 mg, about 45 mg, or about 60 mg).The second dosing cycle includes a single subcutaneous dose of the bispecific antibody (C2D1), where C2D1 is equal to or greater than C1D3 and is from about 10 mg to about 300 mg (from about 25 mg to about 300 mg, from about 50 mg to about 300 mg, from about 100 mg to about 300 mg, from about 200 mg to about 300 mg, from about 50 mg to about 250 mg, from about 100 mg to about 250 mg, from about 100 mg to about 200 mg, from about 10 mg to about 250 mg, from about 10 mg to about 200 mg, from about 10 mg to about 180 mg, from about 10 mg to about 160 mg, from about 10 mg to about 150 mg, from about 10 mg to about 140 mg, from about 20 mg to about 130 mg, from about 30 mg to about 120 mg, or from about 40 mg to about 100 mg, or from about 25 mg to about 75 mg; for example, about 30 mg, about 45 mg, or about 60 mg).

[0160] The dosing regimens provided herein can also reduce the rate of certain adverse events in a population of subjects having a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder (e.g., NHL (e.g., previously untreated (1L) NHL, DLBCL (e.g., 1L DLBCL, relapsed and / or refractory DLBCL, or Richter's transformation), FL (e.g., 1L FL, relapsed and / or refractory FL, or transformed FL), MCL, high-grade B-cell lymphoma or PMLBCL) or CLL). For example, in some instances, the invention includes a method of reducing the rate of certain adverse events in a population of subjects having a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder (e.g., NHL (e.g., previously untreated (1L) NHL, DLBCL (e.g., 1L DLBCL, relapsed and / or refractory DLBCL, or Richter's transformation), FL (e.g., 1L FL, relapsed and / or refractory FL, or transformed FL), MCL, high-grade B-cell lymphoma or PMLBCL) or CLL)) administered a bispecific antibody that binds CD20 and CD3 (e.g., mosunetuzumab), the method comprising subcutaneously administering the bispecific antibody using a stepwise dosing regimen, wherein the rate of adverse events is reduced in the population of subjects as compared to a reference population of subjects administered the bispecific antibody intravenously or a reference population of subjects administered the bispecific antibody subcutaneously at a fixed dosing (i.e., not step-up dosing). In some instances, the stepwise dosing regimen includes at least a first dosing cycle and a second dosing cycle, (a) the first dosing cycle includes a first subcutaneous dose (C1D1), a second subcutaneous dose (C1D2) and a third subcutaneous dose (C1D3) of the bispecific antibody, (i) C1D1 is less than or equal to C1D2 and less than C1D3, (ii) C1D2 is less than or equal to C1D3, (iii) C1D1 is from about 0.1 mg to about 10 mg (e.g., from about 0.1 mg to about 7 mg, from about 0.2 mg to about 10 mg, from about 0.5 mg to about 10 mg, about 1 mg to about 9 mg, about 2 mg to about 8 mg, about 3 mg to about 7 mg, about 4 mg to about 6 mg; for example, about 5 mg), C1D2 is about 5 mg to about 80 mg (for example, about 20 mg to about 75 mg, about 25 mg to about 75 mg, about 30 mg to about 75 mg, about 35 mg to about 75 mg, or about 40 mg to about 75 mg, for example, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg), C1D3 is about 10 mg to about 300 mg (for example, about 25 mg to about 300 mg, about 50 mg to about 300 mg, about 100 mg to about 300 mg, about 200 mg to about 300 mg, about 50 mg to about 250 mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, about 10 mg to about 250 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 150 mg, about 10 mg to about 140 mg, about 20 mg to about 130 mg, about 30 mg to about 120 mg, about 40 mg to about 100 mg, about 20 mg to about 100 mg, about 25 mg to about 75 mg, about 30 mg to about 75 mg, about 35 mg to about 75 mg, or about 40 mg to about 75 mg; for example, about 45 mg), and (b) the second dosing cycle includes a single subcutaneous dose (C2D1) of the bispecific antibody, C2D1 is greater than or equal to C1D3, and is about 10 mg to about 300 mg (for example, about 25 mg to about 300 mg, about 50 mg to about 300 mg, about 100 mg to about 300 mg, about 200 mg to about 300 mg, about 50 mg to about 250 mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, about 10 mg to about 250 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 150 mg, about 10 mg to about 140 mg, about 20 mg to about 130 mg, about 30 mg to about 120 mg, about 40 mg to about 100 mg, about 20 mg to about 100 mg, about 25 mg to about 75 mg, about 30 mg to about 75 mg, about 35 mg to about 75 mg, or about 40 mg to about 75 mg; for example, about 45 mg).

[0161] In some examples, the stepwise dosing regimen includes at least a first dosing cycle and a second dosing cycle, wherein (a) the first dosing cycle includes a first subcutaneous dose (C1D1), a second subcutaneous dose (C1D2), and a third subcutaneous dose (C1D3) of the bispecific antibody, (i) C1D1 is about 5 mg, (ii) C1D2 is greater than or equal to C1D1 and less than or equal to C1D3, and (iii) C1D3 is about 45 mg, and (b) the second dosing cycle includes a single subcutaneous dose (C2D1) of the bispecific antibody, and C2D1 is about 45 mg.

[0162] In some examples, the stepwise dosing regimen includes at least a first dosing cycle and a second dosing cycle, wherein (a) the first dosing cycle includes a first subcutaneous dose (C1D1) of the bispecific antibody on day 1 of the first dosing cycle, a second subcutaneous dose (C1D2) of the bispecific antibody on day 8 of the first dosing cycle, and a third subcutaneous dose (C1D3) of the bispecific antibody on day 15 of the first dosing cycle, (i) C1D1 is about 5 mg, (ii) C1D2 is greater than or equal to C1D1 and less than or equal to C1D3, and (iii) C1D3 is about 45 mg, and (b) the second dosing cycle includes a single subcutaneous dose (C2D1) of the bispecific antibody on day 1 of the second dosing cycle, and C2D1 is about 45 mg.

[0163] Any of the methods described herein may include monitoring a subject for cytokine release syndrome (CRS) (e.g., a CRS event after initiation of any of the above methods). Current clinical responses focus on treating individual signs and symptoms, providing supportive therapy, and attempting to attenuate the inflammatory response using high doses of corticosteroids. However, this approach does not always succeed, especially in cases of late intervention. The CRS grading criteria used by the methods described herein define mild, moderate, severe, or life-threatening CRS and were published by the American Society for Transplantation and Cellular Therapy (ASTCT) (Lee et al. Biology of Blood and Marrow Transplantation. 25(4):625-638, 2019) to harmonize reporting across clinical trials and enable rapid recognition and treatment of CRS. The ASTCT criteria are objective, easy to apply, and intended to more accurately classify the severity of CRS. This revised CRS grading system is shown in Table 1 below.

Table 1

[0164] Fever is defined as a temperature of 38°C or higher not attributable to other causes. Subsequently, in a subject with CRS, once antipyretic or anti-cytokine therapy such as tocilizumab or steroids is received, fever is no longer required to grade subsequent CRS severity. In this case, CRS grading is determined by hypotension and / or hypoxemia.

[0165] The CRS grade is determined by more severe events not attributable to other causes, hypotension, or hypoxia. For example, a subject having a temperature of 39.5°C, hypotension requiring one pressor agent, and hypoxia requiring a low-flow nasal cannula is classified as grade 3 CRS.

[0166] A low-flow nasal cannula is defined as oxygen delivered at ≤6 L / min. Low flow also includes blow-by oxygen delivery sometimes used in pediatrics. A high-flow nasal cannula is defined as oxygen delivered at >6 L / min.

[0167] CRS is associated with an increase in various cytokines, with marked increases in IFNγ, IL-6, and TNF-α levels. The emerging evidence particularly associates CRS with IL-6 as a central mediator. IL-6 is a pro-inflammatory multifunctional cytokine produced by various cell types, and this cytokine has been shown to be involved in a wide variety of physiological processes with T cell activation. Regardless of the inducer, CRS has high IL-6 levels (Nagorsen et al. Cytokine. 25(1):31-5, 2004; Lee et al. Blood. 124(2):188-95, 2014; Doesegger et al. Clin. Transl. Immunol. 4(7):e39, 2015) and IL-6 correlates with the severity of CRS, and subjects experiencing grade 4 or 5 CRS events have much higher IL-6 levels compared to subjects not experiencing CRS or those experiencing milder CRS (grades 0-3) (Chen et al. J. Immunol. Methods. 434:1-8, 2016).

[0168] Therefore, using an agent that inhibits IL-6-mediated signaling to block the inflammatory effects of IL-6 and manage CRS observed in a subject during a two-stage split-dose escalation dosing regimen is an alternative to steroid treatment that is not expected to adversely affect T cell function or reduce the efficacy or clinical benefit of anti-CD20 / anti-CD3 bispecific antibody therapy in the treatment of CD20-positive cell proliferative disorders (e.g., B cell proliferative disorders).

[0169] Tocilizumab (ACTEMRA® / RoACTEMRA®) is a recombinant, humanized, anti-human monoclonal antibody made against soluble membrane-bound IL-6R that inhibits IL-6-mediated signaling (see, e.g., WO1992 / 019579, which is incorporated herein by reference in its entirety).

[0170] When a subject has a cytokine release syndrome (CRS) event after administration of a bispecific antibody, the method can further comprise administering to the subject an effective amount of an interleukin-6 receptor (IL-6R) antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab (ACTEMRA® / RoACTEMRA®)) to manage the event. In some examples, tocilizumab is administered intravenously as a single dose of about 8 mg / kg to the subject. In some examples, each dose of tocilizumab does not exceed 800 mg / dose. Other anti-IL-6R antibodies that can be used instead of or in combination with tocilizumab include sarilumab, balilimumab (ALX-0061), satralizumab (SA-237), and variants thereof.

[0171] If the subject has a CRS event that does not resolve or worsen within 24 hours after administration of an IL-6R antagonist to treat the symptoms of the CRS event, this method may further comprise administering one or more additional doses of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab) to the subject to manage the CRS event. If the CRS event is not managed through administration of the IL-6R antagonist, the subject may be administered a corticosteroid such as methylprednisolone or dexamethasone.

[0172] Management of the CRS event can be adjusted based on the stage of CRS and the presence of co-morbidities. For example, after administration of a bispecific antibody, if the subject has a grade 2 cytokine release syndrome (CRS) event in the absence of co-morbidities or in the presence of minimal co-morbidities, this method can further comprise treating the symptoms of the grade 2 CRS event while withholding treatment with the bispecific antibody. If, for at least 3 consecutive days, the grade 2 CRS event resolves to a grade ≤1 CRS event, this method can further include resuming treatment with the bispecific antibody without changing the dose. On the other hand, if the grade 2 CRS event does not resolve within 24 hours after treating the symptoms of the grade 2 CRS event or does not worsen to a grade ≥3 event, the method can further include administering an effective amount of an interleukin-6 receptor (IL-6R) antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab (ACTEMRA® / RoACTEMRA®)) to the subject to manage the grade 2 or grade ≥3 CRS event. In some examples, tocilizumab is administered intravenously as a single dose of about 8 mg / kg to the subject. In some examples, each dose of tocilizumab does not exceed 800 mg / dose. Other anti-IL-6R antibodies that can be used instead of tocilizumab or in combination with tocilizumab include sarilumab, bavalirizumab (ALX-0061), satralizumab (SA-237), and variants thereof.

[0173] If the subject has a grade 2, 3, or 4 CRS event in the presence of extensive complications after administration of the bispecific antibody, the method may further include methods understood in the art to reduce the CRS event, such as administering a first dose of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab (ACTEMRA® / RoACTEMRA®)) to the subject while interrupting treatment with the bispecific antibody. Other anti-IL-6R antibodies that can be used instead of tocilizumab or in combination with tocilizumab include sarilumab, balilimumab (ALX-0061), satralizumab (SA-237), and variants thereof. In some examples, the method further includes administering to the subject an effective amount of a corticosteroid, such as methylprednisolone or dexamethasone.

[0174] In some examples, the dosing schedule of the present invention results in a median progression-free survival (PFS) of a population of subjects that exceeds about 1 month (e.g., at least about 1.5 months, at least about 2 months, at least about 2.5 months, at least about 3 months, at least about 3.5 months or more; e.g., from about 1 month to about 5 months, from about 1 month to about 4 months, from about 1 month to about 3 months, from about 1 month to about 2 months, from about 3 months to about 5 months, from about 2 months to about 4 months, from about 2 months to about 5 months, or from about 2 months to about 3 months; e.g., about 1 month, about 1.5 months, about 2 months, about 2.5 months, about 3 months, about 3.5 months, about 4 months, or more). In some examples, the dosing schedule of the present invention results in a median progression-free survival (PFS) of a population of subjects that exceeds about 4 months (e.g., at least about 4.5 months, at least about 5 months, at least about 5.5 months, at least about 6 months, at least about 6.5 months, at least about 7 months, at least about 7.5 months, at least about 8 months, at least about 8.5 months, at least about 9.0 months, at least about 9.5 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 20 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, at least about 48 months, at least about 54 months, or more; e.g., from about 4 to about 60 months, from about 8 to about 60 months, from about 12 to about 60 months, from about 24 to about 60 months, from about 48 to about 60 months, from about 4 to about 48 months, from about 4 to about 24 months, from about 4 to about 18 months, from about 4 to about 12 months, from about 4 to about 8 months, from about 8 to about 24 months, from about 8 to about 18 months, from about 8 to about 12 months, from about 4 to about 6 months, from about 6 to about 8 months, from about 6 to about 12 months, or from about 6 to about 10 months; e.g., about 4.5 months, about 5 months, about 5.5 months, about 6 months, about 6.5 months, about 7 months, about 7.5 months, about 8 months, about 8.5 months, about 9.0 months, about 9.5 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 20 months, about 24 months, about 30 months, about 36 months, about 42 months, about 48 months, about 54 months, or more).

[0175] In some examples, the dosing schedule of the present invention provides a PFS for a population of subjects having FL (e.g., relapsed and / or refractory FL) that exceeds about 4 months (e.g., at least about 4.5 months, at least about 5 months, at least about 5.5 months, at least about 6 months, at least about 6.5 months, at least about 7 months, at least about 7.5 months, at least about 8 months, at least about 8.5 months, at least about 9.0 months, at least about 9.5 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 20 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, at least about 48 months, at least about 54 months, or more; e.g., about 4 to about 60 months, about 8 to about 60 months, about 12 to about 60 months, about 24 to about 60 months, about 48 to about 60 months, about 4 to about 48 months, about 4 to about 24 months, about 4 to about 18 months, about 4 to about 12 months, about 4 to about 8 months, about 8 to about 24 months, about 8 to about 18 months, about 8 to about 12 months, about 4 to about 6 months, about 6 to about 8 months, about 6 to about 12 months, or about 6 to about 10 months; e.g., about 4.5 months, about 5 months, about 5.5 months, about 6 months, about 6.5 months, about 7 months, about 7.5 months, about 8 months, about 8.5 months, about 9.0 months, about 9.5 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 20 months, about 24 months, about 30 months, about 36 months, about 42 months, about 48 months, about 54 months, or more).

[0176] In some examples, the dosing schedule of the present invention results in a median PFS for a population of subjects having DLBCL (e.g., relapsed and / or refractory DLBCL) that exceeds about 1 month (e.g., at least about 1.5 months, at least about 2 months, at least about 2.5 months, at least about 3 months, at least about 3.5 months or more; e.g., from about 1 month to about 5 months, from about 1 month to about 4 months, from about 1 month to about 3 months, from about 1 month to about 2 months, from about 3 months to about 5 months, from about 2 months to about 4 months, from about 2 months to about 5 months, or from about 2 months to about 3 months; e.g., about 1 month, about 1.5 months, about 2 months, about 2.5 months, about 3 months, about 3.5 months, about 4 months, or more).In some examples, the dosing schedule of the present invention results in a PFS in a population of subjects having DLBCL (e.g., relapsed and / or refractory DLBCL) that exceeds about 4 months (e.g., at least about 4.5 months, at least about 5 months, at least about 5.5 months, at least about 6 months, at least about 6.5 months, at least about 7 months, at least about 7.5 months, at least about 8 months, at least about 8.5 months, at least about 9.0 months, at least about 9.5 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 20 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, at least about 48 months, at least about 54 months, or more; e.g., about 4 to about 60 months, about 8 to about 60 months, about 12 to about 60 months, about 24 to about 60 months, about 48 to about 60 months, about 4 to about 48 months, about 4 to about 24 months, about 4 to about 18 months, about 4 to about 12 months, about 4 to about 8 months, about 8 to about 24 months, about 8 to about 18 months, about 8 to about 12 months, about 4 to about 6 months, about 6 to about 8 months, about 6 to about 12 months, or about 6 to about 10 months; e.g., about 4.5 months, about 5 months, about 5.5 months, about 6 months, about 6.5 months, about 7 months, about 7.5 months, about 8 months, about 8.5 months, about 9.0 months, about 9.5 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 20 months, about 24 months, about 30 months, about 36 months, about 42 months, about 48 months, about 54 months, or more).

[0177] In some examples, the dosing schedule of the present invention results in a median PFS for a population of subjects having DLBCL (e.g., relapsed and / or refractory DLBCL) that exceeds about 1 month (e.g., at least about 1.5 months, at least about 2 months, at least about 2.5 months, at least about 3 months, at least about 3.5 months or more; e.g., about 1 month to about 5 months, about 1 month to about 4 months, about 1 month to about 3 months, about 1 month to about 2 months, about 3 months to about 5 months, about 2 months to about 4 months, about 2 months to about 5 months, or about 2 months to about 3 months; e.g., about 1 month, about 1.5 months, about 2 months, about 2.5 months, about 3 months, about 3.5 months, about 4 months, or more). In some examples, the dosing schedule of the present invention results in a median PFS for a population of subjects having DLBCL (e.g., relapsed and / or refractory DLBCL) of at least 1 month. In some examples, the dosing schedule of the present invention results in a median PFS for a population of subjects having DLBCL (e.g., relapsed and / or refractory DLBCL) of at least 1.5 months. In some examples, the dosing schedule of the present invention results in a median PFS for a population of subjects having DLBCL (e.g., relapsed and / or refractory DLBCL) of at least 2 months. In some examples, the dosing schedule of the present invention results in a median PFS for a population of subjects having DLBCL (e.g., relapsed and / or refractory DLBCL) of at least 2.5 months. In some examples, the dosing schedule of the present invention results in a median PFS for a population of subjects having DLBCL (e.g., relapsed and / or refractory DLBCL) of at least 3 months.In some examples, the dosing schedule of the present invention provides a median PFS for a population of subjects having DLBCL (e.g., relapsed and / or refractory DLBCL) that exceeds about 6.3 months (e.g., at least about 6.5 months, at least about 6.7 months, at least about 7 months, at least about 7.3 months, at least about 7.5 months, at least about 8 months, at least about 8.5 months, at least about 9.0 months, at least about 9.5 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 20 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, at least about 48 months, at least about 54 months, or more; e.g., between about 6 months and about 48 months, between about 6 months and about 36 months, between about 6 months and about 24 months, between about 6 months and about 12 months, between about 6 months and about 10 months; between about 6 months and about 8 months, between about 8 months and about 24 months, between about 12 months and about 24 months, or between about 8 months and about 16 months; e.g., about 6.3 months, about 6.5 months, about 7 months, about 7.5 months, about 8 months, about 8.5 months, about 9.0 months, about 9.5 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 20 months, about 24 months, about 30 months, about 36 months, about 42 months, about 48 months, about 54 months, or more). In some examples, the dosing schedule of the present invention provides a median PFS for a population of subjects having DLBCL (e.g., relapsed and / or refractory DLBCL) of at least 6.7 months. In some examples, the dosing schedule of the present invention provides a median PFS for a population of subjects having DLBCL (e.g., relapsed and / or refractory DLBCL) of at least 7.3 months. In some examples, the dosing schedule of the present invention provides a median PFS for a population of subjects having DLBCL (e.g., relapsed and / or refractory DLBCL) of at least 8.0 months.

[0178] In some examples, the dosing schedule of the present invention results in a median overall survival (OS) of a population of subjects that exceeds 9.5 months (e.g., at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 20 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, at least about 48 months, at least about 54 months, or more; e.g., between about 9 months and about 48 months, between about 9 months and about 36 months, between about 9 months and about 24 months, between about 9 months and about 12 months, between about 10 months and about 18 months; between about 12 months and about 24 months, between about 18 months and about 36 months, between about 12 months and about 36 months, or between about 24 months and about 48 months; e.g., about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 20 months, about 24 months, about 30 months, about 36 months, about 42 months, about 48 months, about 54 months, or more).

[0179] In some examples, the dosing schedule of the present invention results in a median OS for a population of subjects having FL (e.g., relapsed and / or refractory FL) that exceeds 9.5 months (e.g., at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 20 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, at least about 48 months, at least about 54 months, or more; e.g., between about 9 months and about 48 months, between about 9 months and about 36 months, between about 9 months and about 24 months, between about 9 months and about 12 months, between about 10 months and about 18 months; between about 12 months and about 24 months, between about 18 months and about 36 months, between about 12 months and about 36 months, or between about 24 months and about 48 months; e.g., about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 20 months, about 24 months, about 30 months, about 36 months, about 42 months, about 48 months, about 54 months, or more).

[0180] In some examples, the dosing schedule of the present invention results in a median OS for a population of subjects having DLBCL (e.g., relapsed and / or refractory DLBCL) that exceeds 9.5 months (e.g., at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 20 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, at least about 48 months, at least about 54 months, or more; e.g., between about 9 months and about 48 months, between about 9 months and about 36 months, between about 9 months and about 24 months, between about 9 months and about 12 months, between about 10 months and about 18 months; between about 12 months and about 24 months, between about 18 months and about 36 months, between about 12 months and about 36 months, or between about 24 months and about 48 months; e.g., about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 20 months, about 24 months, about 30 months, about 36 months, about 42 months, about 48 months, about 54 months, or more).

[0181] In some examples, the dosing schedule of the present invention results in a median OS for a population of subjects with DLBCL (e.g., relapsed and / or refractory DLBCL) that exceeds 12.5 months (e.g., at least about 13 months, at least about 14 months, at least about 14.6 months, at least about 15 months, at least about 15.8 months, at least about 16 months, at least about 17 months, at least about 17.3 months, at least about 18 months, at least about 20 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, at least about 48 months, at least about 54 months, or more; e.g., between about 13 months and about 48 months, between about 13 months and about 36 months, between about 13 months and about 24 months, between about 16 months and about 60 months, between about 24 months and about 36 months; between about 12 months and about 24 months, between about 18 months and about 36 months, between about 24 months and about 36 months, or between about 24 months and about 48 months; e.g., about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 20 months, about 24 months, about 30 months, about 36 months, about 42 months, about 48 months, about 54 months, or more). In some examples, the dosing schedule of the present invention results in a median OS for a population of subjects with DLBCL (e.g., relapsed and / or refractory DLBCL) that exceeds about 14.6 months. In some examples, the dosing schedule of the present invention results in a median OS for a population of subjects with DLBCL (e.g., relapsed and / or refractory DLBCL) that exceeds about 15.8 months. In some examples, the dosing schedule of the present invention results in a median OS for a population of subjects with DLBCL (e.g., relapsed and / or refractory DLBCL) that exceeds about 17.3 months.

[0182] In some examples, the dosing regimen of the present invention results in a complete response (CR) in at least about 10% (e.g., at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, or more; e.g., about 10% to about 40%, about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 10% to about 30%, about 15% to about 30%, about 20% to about 40%, or more; e.g., about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 30%, about 35%, about 40%, or more) of the population of subjects. In some examples, the dosing regimen of the present invention results in a CR in at least about 42% (e.g., at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or more, e.g., about 42% to about 45%, about 45% to about 50%, about 50% to about 55%, about 55% to about 60%, about 60% to about 65%, about 65% to about 70%, about 70% to about 75%, or more, e.g., about 42%, about 45%, about 50%, about 55%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or more) of the population of subjects.

[0183] In some examples, the dosing regimen of the present invention results in a CR rate of at least about 20% (e.g., at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or more; e.g., about 20% to about 50%, about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 20% to about 40%, about 30% to about 50%, or more; e.g., about 20%, about 25%, about 30%, about 35%, about 45%, about 50%, or more) in a population of subjects having FL (e.g., 1L FL, or relapsed and / or refractory FL). In some examples, the dosing regimen of the present invention results in a CR rate of at least about 55% (e.g., at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or more; e.g., about 55% to about 60%, about 60% to about 65%, about 65% to about 70%, about 70% to about 75%, or more; e.g., about 42%, about 45%, about 50%, about 55%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or more) in a population of subjects having FL (e.g., 1L FL, or relapsed and / or refractory FL). In certain embodiments, the complete response rate in a population of subjects having R / R FL is about 45% to about 50%.

[0184] In some examples, the dosing regimen of the present invention results in a complete response (CR) in at least about 10% (e.g., at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, or more; e.g., about 10% to about 40%, about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 10% to about 30%, about 15% to about 30%, about 20% to about 40%, or more; e.g., about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 30%, about 35%, about 40%, or more) of a population of subjects having DLBCL (e.g., 1L DLBCL, or relapsed and / or refractory DLBCL). In some examples, the dosing regimen of the present invention results in a CR in at least about 42% (e.g., at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or more, e.g., about 42% to about 45%, about 45% to about 50%, about 50% to about 55%, about 55% to about 60%, about 60% to about 65%, about 65% to about 70%, about 70% to about 75%, or more, e.g., about 42%, about 45%, about 50%, about 55%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or more) of a population of subjects with DLBCL (e.g., 1L DLBCL, or relapsed and / or refractory DLBCL).

[0185] In some embodiments, the population of interest has relapsed or refractory FL, and the objective response rate is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%; e.g., 70% - 80%, 70% - 90%, 70% - 95%, or 70% - 100%; e.g., about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, or about 95%). In some embodiments, the objective response rate is at least 80%. In some embodiments, the population of interest has relapsed or refractory FL, and the objective response rate is between 70% and 90%. In some embodiments, the objective response rate is about 80%.

[0186] In some examples, the dosing regimen of the present invention results in a CR rate of at least about 50% (e.g., at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or more, e.g., 50% - 55%, 55% - 60%, 60% - 65%, 65% - 70%, 70% - 75%, or more, e.g., about 42%, about 45%, about 50%, about 55%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or more) in a population of subjects having DLBCL (e.g., 1L DLBCL, or relapsed and / or refractory DLBCL). In some examples, the dosing regimen of the present invention results in a CR rate of at least about 15% in a population of subjects having DLBCL (e.g., 1L DLBCL, or relapsed and / or refractory DLBCL). In some examples, the dosing regimen of the present invention results in a CR rate of at least about 20% in a population of subjects having DLBCL (e.g., 1L DLBCL, or relapsed and / or refractory DLBCL). In some examples, the dosing regimen of the present invention results in a CR rate of at least about 25% in a population of subjects having DLBCL (e.g., 1L DLBCL, or relapsed and / or refractory DLBCL). In some examples, the dosing regimen of the present invention results in a CR rate of at least about 30% in a population of subjects having DLBCL (e.g., 1L DLBCL, or relapsed and / or refractory DLBCL). In some examples, the dosing regimen of the present invention results in a CR rate of at least about 35% in a population of subjects having DLBCL (e.g., 1L DLBCL, or relapsed and / or refractory DLBCL). In some examples, the dosing regimen of the present invention results in a CR rate of at least about 40% in a population of subjects having DLBCL (e.g., 1L DLBCL, or relapsed and / or refractory DLBCL). In some examples, the dosing regimen of the present invention results in a CR rate of at least about 45% in a population of subjects having DLBCL (e.g., 1L DLBCL, or relapsed and / or refractory DLBCL).In some examples, the dosing regimen of the present invention results in a CR at a rate of at least about 50% in a population of subjects having DLBCL (e.g., 1L DLBCL, or relapsed and / or refractory DLBCL). In some examples, the dosing regimen of the present invention results in a CR at a rate of at least about 55% in a population of subjects having DLBCL (e.g., 1L DLBCL, or relapsed and / or refractory DLBCL). In some examples, the dosing regimen of the present invention results in a CR at a rate of at least about 60% in a population of subjects having DLBCL (e.g., 1L DLBCL, or relapsed and / or refractory DLBCL). In some examples, the dosing regimen of the present invention results in a CR at a rate of at least about 65% in a population of subjects having DLBCL (e.g., 1L DLBCL, or relapsed and / or refractory DLBCL).

[0187] In some embodiments, the population of interest has relapsed or refractory DLBCL or transformed FL, and the objective response rate is at least 25% (e.g., at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more; e.g., between 25% and 95%, between 25% and 75%, between 25% and 55%, between 25% and 50%, between 25% and 45%, between 25% and 40%, between 25% and 35%, between 25% and 30%, between 30% and 75%, between 35% and 75%, between 40% and 75%, between 30% and 40%, between 30% and 45%, between 30% and 50%, or between 50% and 70%; e.g., about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%). In some embodiments, the objective response rate is at least 35%. In some embodiments, the population of interest has relapsed or refractory DLBCL, and the objective response rate is between 25% and 45%. In some embodiments, the objective response rate is about 35%.

[0188] In some embodiments, the population of interest has relapsed or refractory NHL, and the objective response rate is at least 34% (e.g., at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more; e.g., between 34% and 95%, between 34% and 85%, between 34% and 75%, between 34% and 65%, between 34% and 55%, between 35% and 60%, between 35% and 75%, between 55% and 95%, between 75% and 95%, between 40% and 50%, between 45% and 64%, between 34% and 45%, or between 34% and 40%; e.g., about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%). In some embodiments, the objective response rate is at least 44%. In some embodiments, the objective response rate is between 35% and 55%. In some embodiments, the objective response rate is about 45%.

[0189] B. Bispecific antibody that binds to CD20 and CD3 The present invention provides a bispecific antibody that binds to CD20 and CD3 (i.e., anti-CD20 / anti-CD3 antibody) useful for the treatment of CD20-positive cell proliferative disorders, such as B-cell proliferative disorders (e.g., non-Hodgkin lymphoma (NHL) (e.g., previously untreated (1L) NHL, diffuse large B-cell lymphoma (DLBCL) (e.g., 1L DLBCL, relapsed and / or refractory DLBCL, or Richter transformation), follicular lymphoma (FL) (e.g., 1L FL, relapsed and / or refractory FL, or transformed FL), mantle cell lymphoma (MCL), high-grade B-cell lymphoma, or primary mediastinal (thymic) large B-cell lymphoma (PMLBCL)) or chronic lymphocytic leukemia (CLL).

[0190] In some examples, the invention provides a bispecific antibody comprising an anti-CD20 arm having a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of GYTFTSYNMH (SEQ ID NO: 1); (b) HVR-H2 comprising the amino acid sequence of AIYPGNGDTSYNQKFKG (SEQ ID NO: 2); (c) HVR-H3 comprising the amino acid sequence of VVYYSNSYWYFDV (SEQ ID NO: 3); (d) HVR-L1 comprising the amino acid sequence of RASSSVSYMH (SEQ ID NO: 4); (e) HVR-L2 comprising the amino acid sequence of APSNLAS (SEQ ID NO: 5); and (f) HVR-L3 comprising the amino acid sequence of QQWSFNPPT (SEQ ID NO: 6). In some examples, the anti-CD20 / anti-CD3 antibody comprises at least 1 (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 each comprising the sequences of SEQ ID NOs: 17-20, and / or at least 1 (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 each comprising the sequences of SEQ ID NOs: 21-24. In some examples, the bispecific antibody comprises an anti-CD20 arm having a first binding domain comprising: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 7 or the amino acid sequence of SEQ ID NO: 7; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 8, or the amino acid sequence of SEQ ID NO: 8; or (c) a first binding domain comprising a VH domain as in (a) and a VL domain as in (b). Thus, in some examples, the first binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 7 and a VL domain comprising the amino acid sequence of SEQ ID NO: 8.

[0191] In some examples, the invention provides a bispecific antibody comprising an anti-CD3 arm having a second binding domain comprising at least one, two, three, four, five, or six HVRS selected from: (a) HVR-H1 comprising the amino acid sequence of NYYIH (SEQ ID NO: 9); (b) HVR-H2 comprising the amino acid sequence of WIYPGDGNTKYNEKFKG (SEQ ID NO: 10); (c) HVR-H3 comprising the amino acid sequence of DSYSNYYFDY (SEQ ID NO: 11); (d) HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 13); and (f) HVR-L3 comprising the amino acid sequence of TQSFILRT (SEQ ID NO: 14). In some examples, the anti-CD20 / anti-CD3 antibody comprises at least one (e.g., one, two, three, or four) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 each comprising the sequences of SEQ ID NOs: 25-28, and / or at least one (e.g., one, two, three, or four) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 each comprising the sequences of SEQ ID NOs: 29-32. In some examples, the bispecific antibody comprises an anti-CD3 arm having a second binding domain comprising: (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 15, or the amino acid sequence of SEQ ID NO: 15; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 16, or the amino acid sequence of SEQ ID NO: 16; or (c) a VH domain as in (a) and a VL domain as in (b). Thus, in some examples, the second binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 15 and a VL domain comprising the amino acid sequence of SEQ ID NO: 16.

[0192] In some examples, the invention provides an anti-CD20 arm having a first binding domain comprising at least one, two, three, four, five, or six HVRs selected from: (1) HVR-H1 comprising the amino acid sequence of GYTFTSYNMH (SEQ ID NO: 1); (b) HVR-H2 comprising the amino acid sequence of AIYPGNGDTSYNQKFKG (SEQ ID NO: 2); (c) HVR-H3 comprising the amino acid sequence of VVYYSNSYWYFDV (SEQ ID NO: 3); (d) HVR-L1 comprising the amino acid sequence of RASSSVSYMH (SEQ ID NO: 4); (e) HVR-L2 comprising the amino acid sequence of APSNLSAS (SEQ ID NO: 5); and (f) HVR-L3 comprising the amino acid sequence of QQWSFNPPT (SEQ ID NO: 6), and an anti-CD3 arm having a second binding domain comprising at least one, two, three, four, five, or six HVRs selected from: (2) (a) HVR-H1 comprising the amino acid sequence of NYYIH (SEQ ID NO: 9); (b) HVR-H2 comprising the amino acid sequence of WIYPGDGNTKYNEKFKG (SEQ ID NO: 10); (c) HVR-H3 comprising the amino acid sequence of DSYSNYYFDY (SEQ ID NO: 11); (d) HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 13); and (f) HVR-L3 comprising the amino acid sequence of TQSFILRT (SEQ ID NO: 14). In some examples, the anti-CD20 / anti-CD3 bispecific antibody comprises (1) at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 each comprising the sequences of SEQ ID NOs: 17-20, and / or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 each comprising the sequences of SEQ ID NOs: 21-24, and (2) at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 each comprising the sequences of SEQ ID NOs: 25-28, and / or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 each comprising the sequences of SEQ ID NOs: 29-32.In some examples, the anti-CD20 / anti-CD3 bispecific antibody comprises (1) an anti-CD20 arm comprising a first binding domain comprising (a) an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity) to SEQ ID NO: 7, or an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 7, as the VH domain; (b) an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity) to SEQ ID NO: 8, or an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 8, as the VL domain; (c) a VH as in (a) and a VL as in (b); and (2) an anti-CD3 arm comprising a second binding domain comprising (a) an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity) to SEQ ID NO: 15, or an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 15, as the VH domain; (b) an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity) to SEQ ID NO: 16, or an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 16, as the VL domain; or (c) a VH as in (a) and a VL as in (b). In some examples, the anti-CD20 / anti-CD3 bispecific antibody comprises (1) a first binding domain comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 7 and a VL domain comprising the amino acid sequence of SEQ ID NO: 8, and (2) a second binding domain comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 15 and a VL domain comprising the amino acid sequence of SEQ ID NO: 16.

[0193] In some examples, the anti-CD20 / anti-CD3 bispecific antibody is mosunetuzumab, which has the International Nonproprietary Name (INN) listed in List 117 of the World Health Organization (WHO Drug Information, Vol. 31, No. 2, 2017, p. 303) or the CAS registration number 1905409-39-3, and has (1) an anti-CD20 arm comprising a heavy chain sequence and a light chain sequence of SEQ ID NO: 51 and SEQ ID NO: 52, respectively, and (2) an anti-CD3 arm comprising a heavy chain and a light chain sequence of SEQ ID NO: 53 and SEQ ID NO: 54, respectively. In some examples, the anti-CD20 / anti-CD3 bispecific antibody comprises (1) an anti-CD20 arm comprising a first binding domain comprising (a) a heavy chain having an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 51 (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) or the amino acid sequence of SEQ ID NO: 51; (b) a light chain having an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 52 (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) or the amino acid sequence of SEQ ID NO: 52; (c) a heavy chain as in (a) and a light chain as in (b); and (2) an anti-CD3 arm comprising a second binding domain comprising (a) a heavy chain having an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 53 (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) or the amino acid sequence of SEQ ID NO: 53; (b) a light chain having an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 54 (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) or the amino acid sequence of SEQ ID NO: 54; or (c) a heavy chain as in (a) and a light chain as in (b). In some examples, the anti-CD20 / anti-CD3 bispecific antibody comprises (1) an anti-CD20 arm comprising a first binding domain comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 51 and a light chain comprising the amino acid sequence of SEQ ID NO: 52, and (2) an anti-CD3 arm comprising a second binding domain comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 53 and a light chain comprising the amino acid sequence of SEQ ID NO: 54.

[0194] The amino acid sequence of mosunetuzumab is summarized in Table 2 below. [Table 2]

[0195] The anti-CD20 / anti-CD3 bispecific antibody can be produced using recombinant methods and compositions, for example, as described in U.S. Patent No. 4,816,567.

[0196] In some examples, the anti-CD20 / anti-CD3 bispecific antibody according to any of the above embodiments may incorporate any of the features as described in Section C below, either alone or in combination.

[0197] C. Antibody Format and Characteristics The methods described herein may further include any of the above antibodies, in which case the antibody includes any of the features as described below, either alone or in combination.

[0198] 1. Antibody Affinity In certain examples, the anti-CD20 / anti-CD3 bispecific antibody has a dissociation constant (K D ) of ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM or ≤0.001 nM (e.g., 10 -8 M or less, e.g., 10 -8 M to 10 -13 M, e.g., 10 -9 M to 10 -13 M).

[0199] In one example, K D is measured by a radiolabeled antigen binding assay (RIA). In one example, the RIA is performed using the Fab version of the antibody of interest and its antigen. For example, the solution binding affinity of the Fab for the antigen is determined in the presence of a titration series of unlabeled antigen at the minimum concentration of ( 125I) It is measured by equilibrating Fab with the labeled antigen and then capturing the bound antigen on a plate coated with an anti-Fab antibody (see, for example, Chen et al., "J. Mol. Biol." Vol. 293, pp. 865-881 (1999)). To establish the assay conditions, a MICROTITER® multiwell plate (Thermo Scientific) is coated overnight with 5 μg / mL of the capture anti-Fab antibody (Cappel Labs) in 50 mM sodium carbonate (pH 9.6), and then blocked with 2% (w / v) bovine serum albumin in PBS for 2-5 hours at room temperature (approximately 23°C). In a non-adsorbent plate (Nunc number 269620), 100 pM or 26 pM of 125 I]-antigen is mixed with a serial dilution of the Fab of interest (consistent with, for example, the evaluation of anti-VEGF antibody Fab-12 in Presta et al., Cancer Res. 57:4593-4599 (1997)). The Fab of interest is then incubated overnight; however, the incubation may be continued for a longer period (e.g., about 65 hours) to reach equilibrium. The mixture is then transferred to the capture plate for incubation at room temperature (e.g., 1 hour). The solution is then removed and the plate is washed 8 times with 0.1% polysorbate 20 (TWEEN-20®) in PBS. When the plate is dry, 150 μL / well of scintillant (MICROSCINT-20™; Packard) is added and the plate is counted on a TOPCOUNT® gamma counter (Packard) for 10 minutes. The concentration of each Fab that results in 20% or less of the maximum binding is selected for use in the competitive binding assay.

[0200] According to another example, K DIt is measured using a BIACORE (registered trademark) surface plasmon resonance assay. For example, an assay using BIACORE (registered trademark)-2000 or BIACORE (registered trademark)-3000 (BIACORE (registered trademark), Inc., Piscataway, NJ) is performed at 25 °C using an immobilized antigen CM5 chip at approximately 10 response units (RU). In one example, a carboxymethylated dextran biosensor chip (CM5, BIACORE (registered trademark), Inc.) is activated using N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) according to the supplier's instructions. The antigen is diluted to 5 μg / ml (approximately 0.2 μM) with 10 mM sodium acetate at pH 4.8 and then injected at a flow rate of 5 μl / min to achieve approximately 10 response units (RU) of the coupled protein. After injection of the antigen, 1 M ethanolamine is injected to block unreacted groups. For kinetic measurements, two-fold dilutions of Fab (0.78 nM to 500 nM) are injected at 25 °C at a flow rate of approximately 25 μl / min into PBS containing 0.05% polysorbate 20 (TWEEN-20 (registered trademark)) surfactant (PBST). The association rate (k on ) and dissociation rate (k off ) are calculated by simultaneously fitting the association sensorgram and dissociation sensorgram using a simple 1:1 Langmuir binding model (BIACORE (registered trademark) Evaluation Software version 3.2). The equilibrium dissociation constant (K D ) is calculated as the k off / k on ratio. See, for example, Chen et al., J. Mol. Biol. 293:865-881 (1999). The on-rate by the above surface plasmon resonance assay is 10 6 M- 1 s- 1When exceeding, the on-rate can be determined using a fluorescence quenching technique that measures the increase or decrease in the fluorescence emission intensity (excitation = 295 nm, emission = 340 nm, 16 nm bandpass) of 20 nM anti-antigen antibody (Fab type) (pH 7.2) in PBS at 25°C in the presence of increasing antigen concentrations, when measured with a spectrophotometer such as a spectrophotometer with stop flow (Aviv Instruments) or an 8000 series SLM-AMINCO (trademark) spectrophotometer (ThermoSpectronic) equipped with a stirred cuvette.

[0201] 2. Antibody fragments In certain examples, the anti-CD20 / anti-CD3 bispecific antibodies provided herein are antibody fragments. Antibody fragments include, but are not limited to, Fab fragments, Fab’ fragments, Fab’-SH fragments, F(ab’)2 fragments, Fv fragments, and scFv fragments, and other fragments described below. For a general review of specific antibody fragments, see Hudson et al. Nat. Med. 9:129-134 (2003). For references on scFv fragments, see, for example, Pluckthuen, in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenberg and Moore eds., (Springer-Verlag, New York), pp. 269-315 (1994); also see International Publication No. 93 / 16185; and U.S. Patent Nos. 5,571,894 and 5,587,458. For discussions of Fab and F(ab’)2 fragments that constitute salvage receptor binding epitope residues and increase in vivo half-life, see U.S. Patent No. 5,869,046.

[0202] A diabody is an antibody fragment having two antigen-binding sites that can be bivalent or bispecific. See, for example, European Patent No. 404,097, International Publication No. 1993 / 01161, Hudson et al. Nat. Med. 9:129-134 (2003); and Hollinger et al. Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al. Nat. Med. 9:129-134 (2003).

[0203] A single-domain antibody is an antibody fragment that includes all or part of the heavy-chain variable domain of an antibody or all or part of the light-chain variable domain of an antibody. In certain examples, the single-domain antibody is a human single-domain antibody (see Domantis, Inc., Waltham, Massachusetts, e.g., U.S. Patent No. 6,248,516 B1).

[0204] Antibody fragments can be produced by a variety of techniques including, but not limited to, proteolysis and production of intact antibodies by recombinant host cells (e.g., E. coli or phage) as described herein.

[0205] 3. Chimeric and Humanized Antibodies In certain examples, the anti-CD20 / anti-CD3 bispecific antibodies provided herein are chimeric antibodies. Certain chimeric antibodies are described, for example, in U.S. Patent No. 4,816,567; and Morrison et al. Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984). In one example, a chimeric antibody includes a non-human variable region (e.g., a variable region derived from a non-human primate such as a mouse, rat, hamster, rabbit, or monkey) and a human constant region. In a further example, a chimeric antibody is a "class-switch" antibody in which the class or subclass has been changed from that of the parent antibody. A chimeric antibody includes its antigen-binding fragment.

[0206] In certain examples, the chimeric antibody is a humanized antibody. Typically, non-human antibodies are humanized to reduce immunogenicity in humans while retaining the specificity and affinity of the parental non-human antibody. Generally, a humanized antibody comprises one or more variable domains in which the HVRs, e.g., CDRs (or a portion thereof) are derived from a non-human antibody and the FRs (or a portion thereof) are derived from human antibody sequences. A humanized antibody also optionally comprises at least a portion of a human constant region. In some examples, some FR residues in the humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the HVR residues are derived) to, for example, restore or improve antibody specificity or affinity.

[0207] Humanized antibodies and methods of making them are reviewed in Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008) and further described below: Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Natl Acad. Sci. USA 86:10029-10033 (1989); U.S. Pat. Nos. 5,821,337, 7,527,791, 6,982,321 and 7,087,409; Kashmiri et al., Methods 36:25-34 (2005) (describing specific determinant region (SDR) grafting); Padlan, Mol. Immunol. 28:489-498 (1991) (describing resurfacing); Dall’Acqua et al., Methods 36:43-60 (2005) (describing “FR shuffling”); and Osbourn et al., Methods 36:61-68 (2005) and Klimka et al., Br. J. Cancer, 83:252-260 (2000) (describing a “guided selection approach” to FR shuffling).

[0208] Human framework regions that can be used for humanization include, but are not limited to, the following: framework regions selected using the "best fit" method (see, e.g., Sims et al. J. Immunol. 151:2296 (1993)); framework regions derived from the consensus sequences of human antibodies of certain subgroups of the light or heavy chain variable regions (see, e.g., Carter et al. Proc. Natl. Acad. Sci. USA, 89:4285 (1992); and Presta et al. J. Immunol., 151:2623 (1993)); human mature (somatic mutated) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008)); and framework regions derived from screening of FR libraries (see, e.g., Baca et al., J. Biol. Chem. 272:10678-10684 (1997) and Rosok et al., J. Biol. Chem. 271:22611-22618 (1996)).

[0209] 4. Human Antibodies In certain examples, the anti-CD20 / anti-CD3 bispecific antibody is a human antibody. Human antibodies can be made using a variety of techniques known in the art. Human antibodies are generally described in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5:368-74 (2001) and Lonberg, Curr. Opin. Immunol. 20:450-459 (2008).

[0210] Human antibodies may be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies having human variable regions in response to an antigen challenge. Such animals typically contain all or part of a human immunoglobulin locus that replaces the endogenous immunoglobulin locus, is present episomally, or is randomly integrated into the chromosomes of the animal. In such transgenic mice, the endogenous immunoglobulin locus is generally inactivated. For a review of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23:1117-1125 (2005). See also, for example, U.S. Patent Nos. 6,075,181 and 6,150,584, which describe XENOMOUSE™ technology; U.S. Patent No. 5,770,429, which describes HuMab® technology; U.S. Patent No. 7,041,870, which describes K-M MOUSE® technology; and U.S. Patent Application Publication No. 2007 / 0061900, which describes VelociMouse® technology. The human variable regions from intact antibodies produced by such animals may be further modified, for example, by combining them with different human constant regions.

[0211] Human antibodies can also be made by methods based on hybridomas. Human myelomas and mouse-human heteromyeloma cell lines for the production of human monoclonal antibodies have been described. (See, e.g., Kozbor J. Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987); and Boerner et al., J. Immunol., 147:86 (1991).) Human antibodies generated via human B-cell hybridoma technology are also described in Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006). Additional methods include, for example, U.S. Patent No. 7,189,826 (describing the production of monoclonal human IgM antibodies from hybridoma cell lines), and Ni, Xiandai Mianyixue, 26(4):265-268 (2006) (describing human-human hybridomas). Human hybridoma technology (triooma technology) is also described in Histology and Histopathology, 20(3):927-937 (2005) and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology, 27(3):185-91 (2005).

[0212] Human antibodies can also be made by isolating Fv clone variable domain sequences selected from human-derived phage display libraries. Such variable domain sequences can then be combined with desired human constant domains. Techniques for selecting human antibodies from antibody libraries are described below.

[0213] 5. Antibodies from Libraries The anti-CD20 / anti-CD3 bispecific antibody of the present invention can be isolated by screening a combinatorial library against an antibody having a desired activity(ies). For example, phage display libraries can be created and various methods for screening such libraries for antibodies having desired binding properties are known in the art. Such methods are reviewed, for example, in Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O’Brien et al., ed., Human Press, Totowa, NJ, 2001), and further described in McCafferty et al., Nature 348:552-554; Clackson et al., Nature 352:624-628 (1991); Marks et al., J. Mol. Biol. 222:581-597 (1992); Marks and Bradbury, in Methods in Molecular Biology 248:161-175 (Lo, ed., Human Press, Totowa, NJ, 2003); Sidhu et al., J. Mol. Biol. 338(2):299-310 (2004); Lee et al., J. Mol. Biol. 340(5):1073-1093 (2004); Fellouse, Proc. Natl. Acad. Sci. USA 101(34):12467-12472 (2004); and Lee et al., J. Immunol. Methods 284(1-2):119-132 (2004).

[0214] In certain phage display methods, the repertoires of VH and VL genes are cloned separately by polymerase chain reaction (PCR), randomly recombined in a phage library, and then screened for antigen-binding phages as described in Winter et al., Ann. Rev. Immunol., 12:433-455 (1994). Phages typically display antibody fragments as either single-chain Fv (scFv) fragments or Fab fragments. Libraries from immunogens provide high-affinity antibodies to the immunogen without the need to construct hybridomas. Alternatively, naive repertoires can be cloned (e.g., from humans) to provide a single source of antibodies to a wide range of non-self and also self-antigens without immunization, as described by Griffiths et al., EMBO J, 12:725-734 (1993). Finally, naive libraries can also be made synthetically by cloning unrearranged V gene segments from stem cells and achieving rearrangement in vitro using PCR primers containing random sequences to encode highly variable CDR3 regions, as described in Hoogenboom and Winter, J. Mol. Biol., 227:381-388 (1992). Patent publications describing human antibody phage libraries include, for example: U.S. Patent No. 5,750,373, and U.S. Patent Application Publication Nos. 2005 / 0079574, 2005 / 0119455, 2005 / 0266000, 2007 / 0117126, 2007 / 0160598, 2007 / 0237764, 2007 / 0292936, and 2009 / 0002360.

[0215] An anti-CD20 / anti-CD3 bispecific antibody or antibody fragment isolated from a human antibody library is considered herein a human antibody or human antibody fragment.

[0216] 6. Antibody Variants In certain examples, amino acid sequence variants of the anti-CD20 / anti-CD3 bispecific antibodies of the invention are contemplated. As described in detail herein, anti-TIGIT antagonist antibodies, PD-1 axis binding antagonist antibodies (e.g., anti-PD-L1 antagonist antibodies), and / or anti-VEGF antibodies can be optimized based on desired structural and functional properties. For example, it may be desirable to improve the binding affinity of the antibody and / or other biological properties. Amino acid sequence variants of the antibody may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody or by peptide synthesis. Such modifications include, for example, deletions from residues within the amino acid sequence of the antibody and / or insertions into residues within the amino acid sequence of the antibody and / or substitutions of residues within the amino acid sequence of the antibody. Any combination of deletions, insertions, and substitutions can be made to reach the final construct, provided that the final construct possesses the desired characteristics, such as antigen binding.

[0217] a. Substitution, insertion, and deletion variants In certain examples, anti-CD20 / anti-CD3 bispecific antibody variants having one or more amino acid substitutions are provided. Target sites for mutagenesis by substitution include HVRs and FRs. Conservative substitutions are shown in Table 3 under the heading "Preferred Substitutions". More substantial changes are provided in Table 3 under the heading "Exemplary Substitutions" and are further described below with reference to amino acid side chain classes. Amino acid substitutions can be introduced into the antibody of interest and the product screened for the desired activity, e.g., retained / improved antigen binding, reduced immunogenicity, or improved ADCC or CDC. [Table 3]

[0218] Amino acids can be classified according to common side chain properties. (1) Hydrophobic: norleucine, Met, Ala, Val, Leu, Ile; (2) Neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; (3) Acidic: Asp, Glu; (4) Basic: His, Lys, Arg; (5) Residues affecting chain orientation: Gly, Pro; (6) Aromatic: Trp, Tyr, Phe.

[0219] Non-conservative substitutions involve exchanging a member of one of these classes for another.

[0220] Certain substitution variants involve substituting one or more hypervariable region residues of a parental antibody (e.g., a humanized antibody or a human antibody). Generally, the resulting variant(s) selected for further study will have a modification (e.g., improvement) in a particular biological property (e.g., increased affinity, decreased immunogenicity) compared to the parental antibody and / or will substantially retain a particular biological property of the parental antibody. Exemplary substitution variants are affinity matured antibodies and can be readily generated, for example, using phage display-based affinity maturation techniques as described herein. Briefly, one or more HVR residues are mutated, the variant antibody is displayed on phage, and screened for a particular biological activity (e.g., binding affinity).

[0221] Modifications (e.g., substitutions) may be made, for example, in the HVRs to improve antibody affinity. Such modifications can be made in HVR “hot spots,” i.e., residues encoded by codons that mutate frequently during somatic maturation (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)), and / or within residues that contact the antigen, and the resulting variant VH or VL is tested for binding affinity. Affinity maturation by construction of a secondary library and reselection therefrom is described, for example, in Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O’Brien et al., ed., Human Press, Totowa, NJ, (2001)). In some examples of affinity maturation, diversity is introduced into the variable genes selected for maturation by any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis). A secondary library is then created. The library is then screened to identify any antibody variants having the desired affinity. Another method for introducing diversity includes an HVR-directed approach in which some HVR residues (e.g., 4-6 residues at a time) are randomized. HVR residues involved in antigen binding can be specifically identified, for example, using alanine scanning mutagenesis or modeling. CDR-H3 and CDR-L3 are particularly often targeted.

[0222] In certain examples, substitutions, insertions, or deletions can occur in one or more HVRs so long as such changes do not substantially reduce the ability of the antibody to bind to its antigen. For example, conservative modifications (e.g., conservative substitutions provided herein) that do not substantially reduce binding affinity may be made in the HVRs. Such modifications can be, for example, outside of antigen contact residues within the HVRs. In certain examples of the variant VH and VL sequences described above, each HVR is either unmodified or has one, two, or three or fewer amino acid substitutions.

[0223] A useful method for identifying residues or regions of an antibody that can be targets for mutagenesis is what is called "alanine scanning mutagenesis" as described in Cunningham and Wells (1989) Science, 244:1081-1085. In this method, residues or groups of target residues (e.g., charged residues such as Arg, Asp, His, Lys, and Glu) are identified and replaced with neutral or negatively charged amino acids (e.g., alanine or polyalanine) to determine whether the interaction between the antibody and the antigen is affected. Further substitutions may be introduced at amino acid positions that show functional sensitivity to the initial substitution. Alternatively, or in addition, the crystal structure of the antigen-antibody complex to identify the contact points between the antibody and the antigen. Such contact residues and adjacent residues may be targeted or excluded as candidates for substitution. Variants may be screened to determine whether they have the desired properties.

[0224] Amino acid sequence insertions include amino-terminal and / or carboxyl-terminal fusions ranging in length from a single residue to polypeptides containing more than 100 residues, as well as in-sequence insertions of one or more amino acid residues. Examples of terminal insertions include antibodies having an N-terminal methionyl residue. Other insertion variants of the antibody molecule include the fusion of an enzyme (e.g., for ADEPT) or polypeptide that increases the serum half-life of the antibody to the N-terminus or C-terminus of the antibody.

[0225] b. Glycosylation variants In certain examples, the anti-CD20 / anti-CD3 bispecific antibodies of the invention can be modified to increase or decrease the degree to which the antibody is glycosylated. Addition or deletion of glycosylation sites to the anti-CD20 / anti-CD3 bispecific antibodies of the invention can be readily achieved by altering the amino acid sequence to create or remove one or more glycosylation sites.

[0226] When the antibody contains an Fc region, the carbohydrates attached thereto can be modified. Native antibodies produced by mammalian cells typically contain branched biantennary oligosaccharides that are generally attached by N-linkage to Asn297 of the CH2 domain of the Fc region. See, for example, Wright et al. TIBTECH 15:26-32 (1997). The oligosaccharides can include various carbohydrates such as mannose, N-acetylglucosamine (GlcNAc), galactose, and sialic acid, as well as fucose attached to the GlcNAc of the “stem” of the biantennary oligosaccharide structure. In some instances, modification of the oligosaccharides in the antibodies of the invention is carried out to produce antibody variants with improved specific properties.

[0227] In one example, an anti-CD20 / anti-CD3 bispecific antibody variant is provided that has a carbohydrate structure lacking fucose attached (directly or indirectly) to the Fc region. For example, the amount of fucose in such an antibody can be 1% to 80%, 1% to 65%, 5% to 65% or 20% to 40%. The amount of fucose is determined, for example, as described in WO 2008 / 077546, by calculating the average amount of fucose in the sugar chain at Asn297 relative to the total of all sugar chain structures attached to Asn297 (e.g., complex structures, hybrid structures, and high-mannose structures). Asn297 refers to the asparagine residue located at approximately position 297 of the Fc region (EU numbering of Fc region residues); however, Asn297 may also be located about ±3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to minor sequence variations in the antibody. Such fucosylation variants can have improved ADCC function. See, for example, US 2003 / 0157108 A1 (Presta, L.); US 2004 / 0093621 A1 (Kyowa Hakko Kogyo Co., Ltd). Examples of publications regarding "defucosylated" or "fucose-deficient" antibody variants include: US 2003 / 0157108 A1; WO 2000 / 61739 A2; WO 2001 / 29246 A2; US 2003 / 0115614 A1; US 2002 / 0164328 A1; US 2004 / 0093621 A1; US 2004 / 0132140 A1; US 2004 / 0110704 A1; US 2004 / 0110282 A1; US 2004 / 0109865 A1; WO 2003 / 085119 A2; WO 2003 / 084570 A2; WO 2005 / 035586 A2; WO 2005 / 035778 A2; WO 2005 / 053742 A2; US 2002 / 031140 A1; Okazaki et al. J. Mol. Biol. 336:1239-1249 (2004); Yamane-Ohnuki et al. Biotech. Bioeng. 87:614 (2004).Examples of cell lines capable of producing defucosylated antibodies include Lec13 CHO cells that are deficient in protein fucosylation (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); US Patent Application Publication No. 2003 / 0157108 A1, Presta, L; and International Publication No. 2004 / 056312 A1, Adams et al., particularly Example 11), and knockout cell lines such as the α-1,6-fucosyltransferase gene, FUT8, knockout CHO cells (see, for example, Yamane-Ohnuki et al. Biotech. Bioeng. 87:614 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94(4):680-688 (2006); and International Publication No. 2003 / 085107).

[0228] From the above perspective, in some examples, the method of the present invention comprises administering to a subject a variant of an anti-CD20 / anti-CD3 bispecific antibody having a mutation at the aglycosylation site according to a split-dose escalation dosing schedule. In some examples, the aglycosylation site mutation reduces the effector function of the antibody. In some examples, the aglycosylation site mutation is a substitution mutation. In some examples, the antibody comprises a substitution mutation in the Fc region that reduces the effector function. In some examples, the substitution mutation is at amino acid residues N297, L234, L235, and / or D265 (EU numbering). In some examples, the substitution mutation is selected from the group consisting of N297G, N297A, L234A, L235A, D265A, and P329G (EU numbering). In some examples, the substitution mutation is at amino acid residue N297 (EU numbering). In a preferred example, the substitution mutation is N297A (EU numbering). In some embodiments, the anti-CD20 arm of the anti-CD20 / anti-CD3 bispecific antibody further comprises substitution mutations of T366W and N297G (EU numbering). In some embodiments, the anti-CD3 arm of the anti-CD20 / anti-CD3 bispecific antibody further comprises substitution mutations of T366S, L368A, Y407V, and N297G (EU numbering). In some embodiments, (a) the anti-CD20 arm further comprises substitution mutations of T366W and N297G, and (b) the anti-CD3 arm further comprises substitution mutations of T366S, L368A, Y407V, and N297G (EU numbering).

[0229] There is further provided an anti-CD20 / anti-CD3 bispecific antibody variant having a bisected oligosaccharide, for example, a branched oligosaccharide attached to the Fc region of an antibody bisected by GlcNAc. Such antibody variants may have reduced fucosylation and / or improved ADCC function. Examples of such antibody variants are described, for example, in International Publication No. WO 2003 / 011878 (Jean-Mairet et al.); U.S. Patent No. 6,602,684 (Umana et al.); and U.S. Patent Application Publication No. 2005 / 0123546 (Umana et al). There is also provided an antibody variant having at least one galactose residue in the oligosaccharide attached to the Fc region. Such antibody variants may have improved CDC function. Examples of such antibody variants are described, for example, in International Publication No. WO 1997 / 30087 (Patel et al.); International Publication No. WO 1998 / 58964 (Raju, S.); and International Publication No. WO 1999 / 22764 (Raju, S).

[0230] c. Fc region variant In certain examples, one or more amino acid modifications are introduced into the Fc region of the anti-CD20 / anti-CD3 bispecific antibody of the invention, thereby creating an Fc region variant (see, for example, U.S. Patent Application Publication No. 2012 / 0251531). The Fc region variant may comprise a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3, or IgG4 Fc region) containing an amino acid modification (e.g., substitution) at one or more amino acid positions.

[0231] In certain instances, the present invention contemplates anti-CD20 / anti-CD3 bispecific antibody variants that have some, but not all, effector functions, thereby making them desirable candidates for applications where in vivo antibody half-life is important but certain effector functions (such as complement and ADCC) are unnecessary or detrimental. To confirm a decrease / loss of CDC and / or ADCC activity, in vitro and / or in vivo cytotoxicity assays can be performed. For example, an Fc receptor (FcR) binding assay can be carried out to confirm that the antibody lacks FcγR binding (and thus is likely to lack ADCC activity), but retains FcRn binding ability. NK cells, which are the major cells mediating ADCC, express only Fc(RIII, while monocytes express Fc(RI, Fc(RII, and Fc(RIII. The expression of FcRs in hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991). Non-limiting examples of in vitro assays for evaluating the ADCC activity of a molecule of interest are described in U.S. Patent No. 5,500,362 (see, e.g., Hellstrom, I. et al. Proc. Natl Acad. Sci. USA 83:7059-7063 (1986)) and Hellstrom, I. et al., Proc. Natl Acad. Sci. USA 82:1499-1502 (1985); 5,821,337 (see Bruggemann, M. et al., J. Exp. Med. 166:1351-1361 (1987)). Alternatively, non-radioactive assay methods may be used (see, e.g., ACTI (trademark) non-radioactive cytotoxicity assay for flow cytometry (CellTechnology, Inc., Mountain View, Calif.; and CYTOTOX 96 (registered trademark) non-radioactive cytotoxicity assay (PROMEGA (registered trademark), Madison, Wis.)). Effector cells useful in such assays include peripheral blood mononuclear cells (PBMC) and natural killer (NK) cells.Alternatively or additionally, the ADCC activity of the molecule of interest may be evaluated in vivo in an animal model, such as that disclosed in Clynes et al. Proc. Natl Acad. Sci. USA 95:652-656 (1998). Also, a C1q binding assay may be performed to confirm that the antibody is unable to bind C1q and lacks CDC activity. See, for example, C1q and C3c binding ELISAs in WO 2006 / 029879 and WO 2005 / 100402. A CDC assay may be performed to assess complement activation (see, for example, Gazzano-Santoro et al. J. Immunol. Methods 202:163 (1996); Cragg, M. S. et al. Blood. 101:1045-1052 (2003); and Cragg, M. S. and M. J. Glennie Blood. 103:2738-2743 (2004)). FcRn binding and in vivo clearance / half-life determination can also be performed using methods known in the art (see, for example, Petkova, S. B. et al. Int’l. Immunol. 18(12):1759-1769 (2006)).

[0232] Antibodies having reduced effector function include antibodies having one or more substitutions among Fc region residues 238, 265, 269, 270, 297, 327, and 329 (U.S. Patent Nos. 6,737,056 and 8,219,149). Such Fc mutants include Fc mutants having substitutions at two or more of amino acid positions 265, 269, 270, 297, and 327, including the so-called “DANA” Fc mutant in which residues 265 and 297 are substituted with alanine (U.S. Patent Nos. 7,332,581 and 8,219,149).

[0233] In certain examples, the proline at position 329 of the wild-type human Fc region in an antibody is replaced with an amino acid residue large enough to disrupt the proline sandwich within the Fc / Fcγ receptor interface formed between proline 329 of the Fc and tryptophan residues Trp87 and Trp110 of FcγRIII (Sondermann et al.: Nature 406, 267-273 (20 Jul. 2000)), or with glycine or arginine. In certain examples, the antibody further comprises at least one amino acid substitution. In one example, the further amino acid substitution is S228P, E233P, L234A, L235A, L235E, N297A, N297D, or P331S, and in yet another example, at least one further amino acid substitution is L234A and L235A of the human IgG1 Fc region, or S228P and L235E of the human IgG4 Fc region (see, e.g., U.S. Patent Application Publication No. 2012 / 0251531), and in yet another example, at least one further amino acid substitution is L234A and L235A and P329G of the human IgG1 Fc region.

[0234] Certain antibody variants with improved or decreased binding to FcR are described. (See, e.g., U.S. Patent No. 6,737,056; International Publication No. 2004 / 056312, and Shields et al., J. Biol. Chem. 9(2): 6591-6604 (2001).)

[0235] In certain examples, the antibody variant comprises an Fc region having one or more amino acid substitutions that improve ADCC, such as substitutions at positions 298, 333, and / or 334 (EU numbering of residues) of the Fc region.

[0236] In some examples, changes that result in an alteration (i.e., either an improvement or a decrease) in C1q binding and / or complement-dependent cytotoxicity (CDC), as described, for example, in U.S. Patent No. 6,194,551, International Publication No. 99 / 51642, and Idusogie et al. J. Immunol. 164: 4178-4184 (2000), are made within the Fc region.

[0237] Antibodies with increased half-life and improved binding to the neonatal Fc receptor (FcRn) that plays a role in transferring maternal IgG to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)) are described in U.S. Patent Application Publication No. 2005 / 0014934 A1 (Hinton et al.). Those antibodies contain an Fc region having one or more substitutions that improve the binding between the Fc region and FcRn. Such Fc variants include substitutions at one or more of the Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424 or 434, for example, variants having a substitution at Fc region residue 434 (U.S. Patent No. 7,371,826).

[0238] For other examples of Fc region variants, see also Duncan & Winter, Nature 322:738-40 (1988); U.S. Patent No. 5,648,260; U.S. Patent No. 5,624,821; and International Publication No. 94 / 29351.

[0239] In some embodiments, the anti-CD20 / anti-CD3 bispecific antibody contains an Fc region that includes the N297G mutation (EU numbering).

[0240] In some examples, the anti-CD20 / anti-CD3 bispecific antibody comprises one or more heavy chain constant domains, and the one or more heavy chain constant domains are selected from a first CH1 (CH11) domain, a first CH2 (CH21) domain, a first CH3 (CH31) domain, a second CH1 (CH12) domain, a second CH2 (CH22) domain, and a second CH3 (CH32) domain. In some examples, at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain. In some examples, the CH31 domain and the CH32 domain each comprise a protrusion or a cavity, and the protrusion or cavity within the CH31 domain can be disposed within the cavity or protrusion within the CH32 domain, respectively. In some examples, the CH31 domain and the CH32 domain associate at the interface between the protrusion and the cavity. In some examples, the CH21 domain and the CH22 domain each constitute a protrusion or a cavity, and the protrusion or cavity in the CH21 domain can be positioned in the cavity or protrusion in the CH22 domain, respectively. In other examples, the CH21 domain and the CH22 domain contact at the interface between the protrusion and the cavity. In some examples, the anti-CD20 / anti-CD3 bispecific antibody is an IgG1 antibody.

[0241] d. Cysteine-engineered antibody variants In certain examples, it is desirable to generate anti-CD20 / anti-CD3 bispecific antibodies engineered with cysteine, such as "thioMAbs" in which one or more residues of the antibody are replaced by cysteine residues. In certain examples, the substituted residues occur at accessible sites of the antibody. By substituting these residues with cysteine, reactive thiol groups are thereby positioned at accessible sites of the antibody and may be used to conjugate the antibody to other sites, such as drug sites or linker-drug sites, to generate immunoconjugates, as further described herein. In certain examples, any one or more of the following residues are replaced with cysteine: V205 (Kabat numbering) of the light chain, A118 (EU numbering) of the heavy chain, and S400 (EU numbering) of the heavy chain Fc region. Cysteine-engineered antibodies can be generated, for example, as described in U.S. Patent No. 7,521,541.

[0242] e. Antibody derivatives In certain examples, the anti-CD20 / anti-CD3 bispecific antibodies provided herein are further modified to contain additional non-proteinaceous moieties that are known in the art and readily available. Suitable sites for derivatization of the antibody include, but are not limited to, water-soluble polymers. Non-limiting examples of water-soluble polymers include polyethylene glycol (PEG), copolymers of ethylene glycol / propropylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene / maleic anhydride copolymer, polyamino acids (either homopolymers or random copolymers), and dextran or poly(n-vinylpyrrolidone) polyethylene glycol, propylene glycol homopolymer, polypropylene oxide / ethylene oxide copolymer, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof, but are not limited thereto. Polyethylene glycol propionaldehyde may be advantageous during production due to its stability in water. The polymer may be of any molecular weight and may be branched or unbranched. The number of polymers attached to the antibody may vary, and if multiple polymers are attached, they may be the same molecule or different molecules. In general, the number and / or type of polymer used for derivatization can be determined based on considerations including, but not limited to, the particular properties or functions of the antibody to be improved, whether the antibody derivative is to be used therapeutically under the defined conditions, and the like.

[0243] In another example, conjugates of antibodies and non-proteinaceous moieties that can be selectively heated by exposure to radiation are provided. In one example, the non-proteinaceous moiety is a carbon nanotube (Kam et al., Proc. Natl. Acad. Sci. USA 102:11600-11605 (2005)). The radiation can be of any wavelength and includes, but is not limited to, wavelengths that heat the non-protective moiety to a temperature at which cells proximal to the non-protective site of the antibody are killed, but that do not harm normal cells.

[0244] 7. Recombinant production method The anti-CD20 / anti-CD3 bispecific antibodies of the present invention can be produced using recombinant methods and compositions such as those described in U.S. Patent No. 4,816,567, which is hereby incorporated by reference in its entirety.

[0245] For the recombinant production of anti-CD20 / anti-CD3 bispecific antibodies, nucleic acids encoding the antibodies are isolated and inserted into one or more vectors for further cloning and / or expression in host cells. Such nucleic acids can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that can specifically bind to genes encoding the heavy and light chains of the antibody).

[0246] Suitable host cells for the cloning or expression of antibody-encoding vectors include prokaryotic or eukaryotic cells as described herein. For example, antibodies may be produced in bacteria, particularly when glycosylation and Fc effector functions are not required. For the expression of antibody fragments and polypeptides in bacteria, see, for example, U.S. Patent Nos. 5,648,237, 5,789,199, and 5,840,523. (See also Charlton, Methods in Molecular Biology, Vol. 248 (B.K.C. Lo, ed., Humana Press, Totowa, NJ, 2003), pp. 245-254, which describes the expression of antibody fragments in E. coli.) After expression, the antibodies of the invention may be isolated from the soluble fraction of the bacterial cell paste and further purified.

[0247] In addition to prokaryotes, eukaryotes such as filamentous fungi and yeast are suitable as cloning or expression hosts for vectors encoding antibodies, including strains and yeast strains in which the glycosylation pathway has been "humanized," resulting in the production of antibodies having a partially or fully human glycosylation pattern. See Gerngross, Nat. Biotech. 22:1409-1414 (2004) and Li et al., Nat. Biotech. 24:210-215 (2006).

[0248] Also, host cells suitable for expressing glycosylated antibodies are derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant cells and insect cells. A number of baculovirus strains have been identified and can be used in combination with insect cells, particularly for the transfection of Spodoptera frugiperda cells.

[0249] Plant cell cultures can also be used as hosts. See, for example, U.S. Pat. Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (PLANTIBODIES™ technology for producing antibodies in transgenic plants).

[0250] Vertebrate cells are also used as hosts. For example, mammalian cell lines adapted to grow in suspension can be useful. Other examples of useful mammalian host cell lines include monkey kidney CV1 cell line transformed by SV40 (COS-7), human embryonic kidney cell lines (e.g., 293 cells or 293 cells as described in Graham et al., J. Gen Virol. 36:59 (1977)), baby hamster kidney cells (BHK), mouse Sertoli cells (e.g., TM4 cells as described in Mather, Biol. Reprod. 23:243-251 (1980)), monkey kidney cells (CV1), African green monkey kidney cells (VERO-76), human cervical carcinoma cells (HELA), dog kidney cells (MDCK), buffalo rat liver cells (BRL 3A), human lung cells (W138), human liver cells (Hep G2), mouse mammary tumor cells (MMT 060562), TRI cells (e.g., cells described in Mather et al., Annals N.Y. Acad. Sci. 383:44-68 (1982); MRC5 cells; and FS4 cells. Other useful mammalian host cell lines include DHFR - Chinese hamster ovary (CHO) cells including DHFR CHO cells (Urlaub et al., Proc. Natl. Acad. Sci. USA 77:4216 (1980)), as well as myeloma cell lines such as Y0, NS0, and Sp2 / 0. For an overview of specific mammalian host cell lines suitable for antibody production, see, for example, Yazaki and Wu, Methods in Molecular Biology, Vol. 248 (B.K.C. Lo, ed., Humana Press, Totowa, NJ), pp. 255-268 (2003),

[0251] 8. Immunoconjugate The present invention also provides an immunoconjugate comprising the anti-CD20 / anti-CD3 bispecific antibody of the present invention conjugated to one or more cytotoxic agents, such as chemotherapeutic agents or drugs, growth inhibitors, toxins (e.g., protein toxins, enzymatically active toxins derived from bacteria, fungi, plants or animals, or fragments thereof), or radioisotopes.

[0252] In some instances, the immunoconjugate is an antibody-drug conjugate (ADC), and the antibody is conjugated to one or more agents including, but not limited to, maytansinoids (see U.S. Pat. Nos. 5,208,020, 5,416,064, and European Patent No. 0425235B1); auristatins such as monomethyl auristatin drug moieties DE and DF (MMAE and MMAF) (see U.S. Pat. Nos. 5,635,483, 5,780,588, and 7,498,298); dolastatin; calicheamicin or a derivative thereof (see U.S. Pat. Nos. 5,712,374, 5,714,586, 5,739,116, 5,767,285, 5,770,701, 5,770,710, 5,773,001, and 5,877,296; Hinman et al., Cancer Res. 53:3336-3342 (1993); and Lode et al., Cancer Res. 58:2925-2928 (1998)); anthracyclines such as daunomycin and doxorubicin (e.g., see Kratz et al., Current Med. Chem. 13:477-523 (2006); Jeffrey et al., Bioorganic & Med. Chem. Letters 16:358-362 (2006); Torgov et al., Bioconj. Chem. 16:717-721 (2005); Nagy et al., Proc. Natl. Acad. Sci. USA 97:829-834 (2000); Dubowchik et al., Bioorg. & Med. Chem. Letters 12:1529-1532 (2002); King et al., J. Med. Chem. 45:4336-4343 (2002); and U.S. Pat. No. 6,630,579); methotrexate; vindesine; taxanes such as docetaxel, paclitaxel, larotaxel, tesetaxel, and ortataxel; trichothecene; and CC1065.

[0253] In another example, the immunoconjugate comprises an anti-CD20 / anti-CD3 bispecific antibody conjugated to an enzymatically active toxin or a fragment thereof, including but not limited to diphtheria A chain, a non-binding active fragment of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii protein, dianthin protein, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), Momordica charantia inhibitor, curcin, crocin, Sapaonaria officinalis inhibitor, gelonin, mitogelin, restrictocin, phenomycin, enomycin, and trichothecene.

[0254] In another example, the immunoconjugate comprises an anti-CD20 / anti-CD3 bispecific antibody conjugated to a radioactive atom to form a radioactive conjugate. Various radioisotopes are available for the production of radioactive conjugates. Examples include 211 At, 131 I, 125 I, 90 Y, 186 Re, 188 Re, 153 Sm, 212 Bi, 32 P, 212 radioisotopes of Pb and Lu. When a radioactive substance is used for detection, it may contain a radioactive atom for scintigraphic studies, such as 99m Tc or 123 I, or a spin label for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, MRI), such as again iodine 123, iodine 131, indium 111, fluorine 19, carbon 13, nitrogen 15, oxygen 17, gadolinium, manganese, or iron.

[0255] Conjugates of antibodies and cytotoxic agents can be prepared, for example, using various bifunctional protein coupling agents, N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCl), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azide compounds (such as bis(p-azidobenzoyl)hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and di-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene), etc. For example, as described in Vitetta et al., Science 238:1098 (1987), ricin immunotoxins can be prepared. Carbon-14 labeled 1-isothiocyanatobenzyl-3-methyldiethylenetriaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugating radionuclides to antibodies. See International Publication No. 94 / 11026. The linker may be a "cleavable linker" that promotes the release of the cytotoxic drug intracellularly. For example, acid-labile linkers, protease-sensitive linkers, photolabile linkers, dimethyl linkers or disulfide-containing linkers (Chari et al., Cancer Res. 52:127-131 (1992); U.S. Patent No. 5,208,020) can be used.

[0256] The immunoconjugates or ADCs herein are clearly intended to include conjugates prepared using crosslinking reagents including, but not limited to, BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfo-EMCS, sulfo-GMBS, sulfo-KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC, and sulfo-SMPB, and SVSB (succinimidyl-(4-vinylsulfone)benzoate), which are commercially available (e.g., from Pierce Biotechnology, Rockford, IL, USA).

[0257] D. Additional Therapeutic Agents In some examples, the methods described herein include administering a bispecific anti-CD20 / anti-CD3 antibody in combination with one or more additional therapeutic agents (e.g., an antibody-drug conjugate (ADC) and / or a further chemotherapeutic agent and / or). In some examples, the bispecific anti-CD20 / anti-CD3 antibody is co-administered with one or more additional chemotherapeutic agents selected from cyclophosphamide, doxorubicin, rituximab, and prednisone. In some examples, the bispecific anti-CD20 / anti-CD3 antibody is co-administered with CHOP, in which case vincristine is replaced with an ADC. In some examples, the bispecific anti-CD20 / anti-CD3 antibody is co-administered with an anti-CD19 antibody, an anti-CD19 antibody-drug conjugate, an anti-CD22 antibody-drug conjugate, an anti-CD45 antibody-drug conjugate, and an anti-CD32 antibody-drug conjugate.

[0258] In some examples, the additional therapeutic agent is an anti-CD79b ADC, such as any of the anti-CD79b antibody-drug conjugates described in U.S. Patent No. 8,088,378, which is incorporated herein by reference in its entirety. In some examples, the anti-CD79b antibody-drug conjugate comprises an anti-79b binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 33; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 34; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 35; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 36; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 37; (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 38. In some examples, the anti-CD79b antibody-drug conjugate comprises an anti-79b binding domain comprising all 6 of the following HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 33, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 34, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 35, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 36, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 37, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 38. In some examples, the anti-CD79b antibody-drug conjugate comprises at least 1 (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4, each comprising the sequences of SEQ ID NOs: 39-42, and / or at least 1 (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4, each comprising the sequences of SEQ ID NOs: 43-46.In some examples, an anti-CD79b antibody-drug conjugate comprises: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 47 or the sequence of SEQ ID NO: 47; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 48 or the sequence of SEQ ID NO: 48; or (c) a VH domain as in (a) and a VL domain as in (b). Thus, in some examples, the first binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 47 and a VL domain comprising the amino acid sequence of SEQ ID NO: 48.

[0259] In some examples, the anti-CD79b antibody is conjugated to a toxin such as monomethyl auristatin E (MMAE, i.e., vedotin). In some examples, the anti-CD79b antibody-drug conjugate is polatuzumab vedotin (immunoglobulin G1-kappa auristatin E conjugate, anti-[Homo sapiens CD79b (immunoglobulin associated CD79 beta)], humanized monoclonal antibody conjugated to auristatin E; gamma 1 heavy chain (1-447) [humanized VH (Homo sapiens IGHV3-23 * 04(76.50%)-(IGHD)-IGHJ4 * 01)[8.8.10](1-117)-Homo sapiens IGHG1 *03(CH1 R120>K(214)(118 - 215), hinge (216 - 230), CH2(231 - 340), C...

Claims

Claim 1 A medicament for treating a subject having a B-cell proliferative disorder, comprising mosunetuzumab, wherein in a dosing schedule comprising at least a first dosing cycle and a second dosing cycle, the mosunetuzumab is to be administered subcutaneously to the subject, wherein (a) the first dosing cycle comprises a first subcutaneous dose (C1D1), a second subcutaneous dose (C1D2) and a third subcutaneous dose (C1D3) of the mosunetuzumab, wherein (i) the C1D1 is about 5 mg, wherein (ii) the C1D2 is about 15 mg or about 45 mg, wherein (iii) the C1D3 is about 45 mg; and wherein (b) the second dosing cycle comprises a single subcutaneous dose (C2D1) of the mosunetuzumab, and the C2D1 is about 45 mg; and wherein the B-cell proliferative disorder is non-Hodgkin lymphoma (NHL). The medicament. Claim 2 The medicament according to claim 1, wherein the C1D1 is about 5 mg, the C1D2 is about 15 mg, the C1D3 is about 45 mg, and the C2D1 is about 45 mg. Claim 3 The medicament according to claim 1, wherein the C1D1 is about 5 mg, the C1D2 is about 45 mg, the C1D3 is about 45 mg, and the C2D1 is about 45 mg. Claim 4 The medicament according to any one of claims 1 to 3, wherein the C1D2 is to be administered to the subject about 7 days after the C1D1. Claim 5 The medicament according to any one of claims 1 to 4, wherein the C1D3 is to be administered to the subject about 7 days after the C1D2. Claim 6 The medicament according to any one of claims 1 to 5, wherein the C2D1 is to be administered to the subject about 7 days after the C1D3. Claim 7 The medicament according to any one of claims 1 to 6, wherein the C1D1, the C1D2, and the C1D3 are to be administered to the subject on about day 1, about day 8, and about day 15, respectively, of the first dosing cycle. Claim 8 The medicament according to any one of claims 1 to 7, wherein the C2D1 is to be administered to the subject on day 1 of the second dosing cycle. Claim 9 The medicament according to any one of claims 1 to 8, wherein the first dosing cycle and the second dosing cycle are 21-day dosing cycles. Claim 10 The medicament according to any one of claims 1 to 8, wherein the first administration cycle is a 21-day administration cycle and the second administration cycle is a 28-day administration cycle.

11. A medicament for treating a subject having a B-cell proliferative disorder, comprising mosunetuzumab, wherein in an administration schedule comprising at least a first administration cycle and a second administration cycle, the mosunetuzumab is to be administered subcutaneously, (a) the first administration cycle comprises a first subcutaneous dose (C1D1) of the mosunetuzumab on day 1 of the first administration cycle, a second subcutaneous dose (C1D2) of the mosunetuzumab on day 8 of the first administration cycle, and a third subcutaneous dose (C1D3) of the mosunetuzumab on day 15 of the first administration cycle, (i) the C1D1 is about 5 mg, (ii) the C1D2 is about 15 mg or about 45 mg, (iii) the C1D3 is about 45 mg; and (b) the second administration cycle comprises a single subcutaneous dose (C2D1) of the mosunetuzumab on day 1 of the second administration cycle, the C2D1 is about 45 mg; and the B-cell proliferative disorder is NHL, medicament.

12. The medicament according to claim 11, wherein the C1D2 is about 15 mg.

13. The medicament according to claim 11, wherein the C1D2 is about 45 mg.

14. The medicament according to any one of claims 11 to 13, wherein each of the administration cycles is a 21-day administration cycle.

15. The medicament according to any one of claims 11 to 13, wherein the first administration cycle is a 21-day administration cycle and the second administration cycle is a 28-day administration cycle.

16. The medicament according to any one of claims 1 to 15, wherein the NHL is previously untreated NHL, relapsed or refractory NHL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), or primary mediastinal (thymic) large B-cell lymphoma (PMBCL).

17. The medicament according to claim 16, wherein the DLBCL is previously untreated DLBCL, or relapsed or refractory DLBCL.

18. The medicament according to claim 16, wherein the DLBCL is Richter transformation.

19. The medicament according to claim 16, wherein the FL is previously untreated FL, or relapsed or refractory FL.

20. The medicament according to claim 16, wherein the FL is transformed FL.

21. The medicament according to claim 16, wherein the NHL is high-grade B-cell lymphoma.

22. The medicament according to claim 16, wherein the NHL is Ann Arbor stage III or IV NHL.

23. The medicament according to any one of claims 1 to 22, wherein the subject has previously received at least one prior line of systemic therapy.

24. The medicament according to claim 23, wherein the subject has received 1 to 9 prior lines of systemic therapy.

25. The medicament according to claim 24, wherein the subject has received 3 prior lines of systemic therapy.

26. The medicament according to any one of claims 23 to 25, wherein at least one prior line of systemic therapy included an anti-CD20 antibody.

27. The medicament according to claim 26, wherein the anti-CD20 antibody is rituximab or obinutuzumab.

28. The medicament according to claim 26 or 27, wherein the prior line of systemic therapy comprising the anti-CD20 antibody additionally comprises an alkylating agent or anthracycline.

29. The medicament according to claim 28, wherein the alkylating agent is cyclophosphamide or bendamustine.

30. The medicament according to claim 28, wherein the anthracycline is daunomycin or doxorubicin.

31. The prior line of systemic therapy comprising the anti-CD20 antibody (i)cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), (ii)cyclophosphamide, vincristine and prednisone (CVP), (iii)fludarabine, or (iv)bendamustine The medicament according to claim 26, which additionally comprises.

32. The medicament according to any one of claims 23 to 25, wherein at least one prior line of systemic therapy included a Bruton's tyrosine kinase (BTK) inhibitor.

33. [[ID= (a) The first dosing cycle is a 21-day dosing cycle comprising a first subcutaneous dose (C1D1), a second subcutaneous dose (C1D2), and a third subcutaneous dose (C1D3) of the mosunetuzumab, (i) the C1D1 is about 5 mg, (ii) the C1D2 is about 15 mg or about 45 mg, (iii) the C1D3 is about 45 mg; and (b) the second dosing cycle is a 21-day dosing cycle comprising a single subcutaneous dose (C2D1) of the mosunetuzumab, the C2D1 being about 45 mg, Pharmaceutical.

34. The pharmaceutical according to claim 33, wherein the DLBCL is untreated DLBCL, or relapsed or refractory DLBCL.

35. The pharmaceutical according to claim 33 or 34, wherein the DLBCL is Richter's transformation.

36. The pharmaceutical according to any one of claims 33 to 35, wherein the C1D2 is to be administered to the subject about 7 days after the C1D1.

37. The pharmaceutical according to any one of claims 33 to 36, wherein the C1D3 is to be administered to the subject about 7 days after the C1D2.

38. The pharmaceutical according to any one of claims 33 to 37, wherein the C2D1 is to be administered to the subject about 7 days after the C1D3.

39. The pharmaceutical according to any one of claims 33 to 38, wherein the C1D1, the C1D2, and the C1D3 are to be administered to the subject on about day 1, about day 8, and about day 15, respectively, of the first dosing cycle.

40. A pharmaceutical for treating a subject with FL, comprising mosunetuzumab, wherein in a dosing schedule comprising at least a first dosing cycle and a second dosing cycle, the mosunetuzumab is to be administered subcutaneously, (a) the first dosing cycle is a 21-day dosing cycle comprising a first subcutaneous dose (C1D1), a second subcutaneous dose (C1D2), and a third subcutaneous dose (C1D3) of the mosunetuzumab, (i) the C1D1 is about 5 mg, (ii) the C1D2 is about 15 mg or about 45 mg, (iii) the C1D3 is about 45 mg; and (b) the second dosing cycle is a 28-day dosing cycle comprising a single subcutaneous dose (C2D1) of the mosunetuzumab, the C2D1 being about 45 mg, Pharmaceutical.

41. The medicament according to claim 40, wherein the FL is previously untreated FL, or relapsed or refractory FL.

42. The medicament according to claim 40 or 41, wherein the FL is transformed FL.

43. The medicament according to any one of claims 33 to 42, wherein C1D1 is about 5 mg, C1D2 is about 15 mg, C1D3 is about 45 mg, and C2D1 is about 45 mg.

44. The medicament according to any one of claims 33 to 42, wherein C1D1 is about 5 mg, C1D2 is about 45 mg, C1D3 is about 45 mg, and C2D1 is about 45 mg.

45. The medicament according to any one of claims 33 to 44, wherein C2D1 is to be administered to the subject on the first day of the second dosing cycle.

46. The medicament according to any one of claims 1 to 45, wherein the dosing schedule includes one or more additional dosing cycles.

47. The medicament according to claim 46, wherein the dosing schedule includes 1 to 15 additional dosing cycles.

48. The medicament according to claim 46 or 47, wherein the dosing schedule includes 6 additional dosing cycles.

49. The medicament according to claim 46 or 47, wherein the dosing schedule includes 15 additional dosing cycles.

50. The medicament according to any one of claims 46 to 49, wherein each additional dosing cycle is a 21-day dosing cycle.

51. The medicament according to any one of claims 46 to 49, wherein each additional dosing cycle is a 28-day dosing cycle.

52. The medicament according to any one of claims 46 to 51, wherein each additional dosing cycle includes administration of an additional dose of the mosunetuzumab.

53. The medicament according to claim 52, wherein each additional dose of the mosunetuzumab is about 45 mg.

54. The medicament according to claim 52, wherein each additional dose of the mosunetuzumab is to be administered to the subject on the first day of each respective additional dosing cycle.

55. The medicament according to any one of claims 1 to 54, wherein the mosunetuzumab is to be administered to the subject as a monotherapy.

56. The medicament according to any one of claims 1 to 54, wherein the mosunetuzumab is to be administered to the subject as a combination therapy.

57. The pharmaceutical according to claim 56, wherein the mosunetuzumab is to be administered to the subject simultaneously with an additional therapeutic agent.

58. The pharmaceutical according to claim 56, wherein the mosunetuzumab is to be administered to the subject prior to the administration of the additional therapeutic agent.

59. The pharmaceutical according to claim 56, wherein the mosunetuzumab is to be administered to the subject after the administration of one or more additional therapeutic agents.

60. The pharmaceutical according to claim 59, wherein the additional therapeutic agent is obinutuzumab (GAZYVA (registered trademark)).

61. The pharmaceutical according to claim 59, wherein the additional therapeutic agent is tocilizumab.

62. The pharmaceutical according to any one of claims 1 to 61, wherein the subject has cytokine release syndrome events and the symptoms of the cytokine release syndrome events are to be treated while withholding treatment with the mosunetuzumab.

63. The pharmaceutical according to claim 62, wherein the subject is to be administered an effective amount of tocilizumab to treat the cytokine release syndrome events.

64. The pharmaceutical according to claim 63, wherein tocilizumab is to be intravenously administered to the subject as a single dose of about 8 mg / kg, and the single dose does not exceed 800 mg.

65. The pharmaceutical according to claim 64, wherein the cytokine release syndrome events do not resolve or deteriorate within 24 hours after treating the symptoms of the cytokine release syndrome events, and one or more additional doses of tocilizumab are to be administered to the subject to manage the cytokine release syndrome events.

66. The pharmaceutical according to claim 65, wherein the one or more additional doses of tocilizumab are to be intravenously administered to the subject at a dose of about 8 mg / kg, and the dose does not exceed 800 mg.

67. The pharmaceutical according to claim 65 or 66, wherein the subject is to be further administered an effective amount of corticosteroid.

68. The pharmaceutical according to claim 67, wherein the corticosteroid is to be intravenously administered to the subject.

69. The pharmaceutical according to claim 67 or 68, wherein the corticosteroid is methylprednisolone.

70. The pharmaceutical according to claim 69, wherein methylprednisolone is to be administered to the subject at a dose of about 2 mg / kg per day.

71. The pharmaceutical according to claim 67 or 68, wherein the corticosteroid is dexamethasone.

72. The pharmaceutical according to claim 71, wherein dexamethasone is to be administered to the subject in a dose of 10 mg to 100 mg.

73. The pharmaceutical according to claim 72, wherein dexamethasone is to be administered to the subject in a dose of about 10 mg.

74. The pharmaceutical according to claim 72, wherein the dexamethasone is to be administered to the subject in a dose of about 20 mg.

75. A pharmaceutical for treating a population of subjects having a B-cell proliferative disorder, comprising mosunetuzumab, wherein in a dosing schedule comprising at least a first dosing cycle and a second dosing cycle, the mosunetuzumab is to be administered subcutaneously to each subject in the population, (a) the first dosing cycle comprises a first subcutaneous dose (C1D1), a second subcutaneous dose (C1D2) and a third subcutaneous dose (C1D3) of the mosunetuzumab, (i) the C1D1 is about 5 mg, (ii) the C1D2 is about 15 mg or about 45 mg, (iii) the C1D3 is about 45 mg; and (b) the second dosing cycle comprises a single subcutaneous dose (C2D1) of the mosunetuzumab, the C2D1 is about 45 mg; and the B-cell proliferative disorder is NHL, pharmaceutical.

76. A pharmaceutical for treating a population of subjects having a B-cell proliferative disorder, comprising mosunetuzumab, wherein in a dosing schedule comprising at least a first dosing cycle and a second dosing cycle, the mosunetuzumab is to be administered subcutaneously to each subject in the population, (a) the first dosing cycle comprises a first subcutaneous dose (C1D1) of the mosunetuzumab on day 1 of the first dosing cycle, a second subcutaneous dose (C1D2) of the mosunetuzumab on day 8 of the first dosing cycle, and a third subcutaneous dose (C1D3) of the mosunetuzumab on day 15 of the first dosing cycle, (i) the C1D1 is about 5 mg, (ii) the C1D2 is about 15 mg or about 45 mg, (iii) the C1D3 is about 45 mg; and (b) the second dosing cycle comprises a single subcutaneous dose (C2D1) of the mosunetuzumab on day 1 of the second dosing cycle, the C2D1 is about 45 mg, and the B-cell proliferative disorder is NHL, pharmaceutical.

77. The pharmaceutical according to claim 75 or 76, wherein the NHL is untreated NHL, recurrent or refractory NHL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), high-grade B-cell lymphoma, or primary mediastinal (thymic) large B-cell lymphoma (PMBCL).

78. The pharmaceutical according to claim 77, wherein the DLBCL is untreated DLBCL or recurrent or refractory DLBCL.

79. The pharmaceutical according to claim 77 or 78, wherein the DLBCL is Richter transformation.

80. The pharmaceutical according to claim 77, wherein the FL is untreated FL or recurrent or refractory FL.

81. The pharmaceutical according to claim 77 or 80, wherein the FL is transformed FL.

82. The pharmaceutical according to claim 77, wherein the NHL is high-grade B-cell lymphoma.

83. A pharmaceutical for treating a population of subjects having DLBCL, comprising mosunetuzumab, wherein in a dosing schedule comprising at least a first dosing cycle and a second dosing cycle, the mosunetuzumab is to be administered subcutaneously to each subject in the population, (a) the first dosing cycle comprises a first subcutaneous dose (C1D1), a second subcutaneous dose (C1D2) and a third subcutaneous dose (C1D3) of the mosunetuzumab, (i) the C1D1 is about 5 mg, (ii) the C1D2 is about 15 mg or about 45 mg, (iii) the C1D3 is about 45 mg; and (b) the second dosing cycle comprises a single subcutaneous dose (C2D1) of the mosunetuzumab, and the C2D1 is about 45 mg. A pharmaceutical.

84. The pharmaceutical according to claim 83, wherein the DLBCL is untreated DLBCL or recurrent or refractory DLBCL.

85. The pharmaceutical according to claim 83 or 84, wherein the DLBCL is Richter transformation.

86. A pharmaceutical for treating a population of subjects having FL, comprising mosunetuzumab, wherein in a dosing schedule comprising at least a first dosing cycle and a second dosing cycle, the mosunetuzumab is to be administered subcutaneously to each subject in the population, (a) The first dosing cycle includes a first subcutaneous dose (C1D1), a second subcutaneous dose (C1D2), and a third subcutaneous dose (C1D3) of the mosunetuzumab, (i) The C1D1 is about 5 mg, (ii) The C1D2 is about 15 mg or about 45 mg, (iii) The C1D3 is about 45 mg, (b) The second dosing cycle includes a single subcutaneous dose (C2D1) of the mosunetuzumab, and the C2D1 is about 45 mg, Pharmaceutical.

87. The pharmaceutical according to claim 86, wherein the FL is previously untreated FL, or relapsed or refractory FL.

88. The pharmaceutical according to claim 86 or 87, wherein the FL is transformed FL.

89. The pharmaceutical according to any one of claims 75 to 88, wherein the first dosing cycle and the second dosing cycle are 21-day dosing cycles.

90. The pharmaceutical according to any one of claims 75 to 88, wherein the first dosing cycle is a 21-day dosing cycle and the second dosing cycle is a 28-day dosing cycle.

91. The pharmaceutical according to any one of claims 75 to 90, wherein the dosing schedule includes one or more additional dosing cycles.

92. The pharmaceutical according to claim 91, wherein the dosing schedule includes 1 to 15 additional dosing cycles.

93. The pharmaceutical according to claim 91 or 92, wherein the dosing schedule includes 6 additional dosing cycles.

94. The pharmaceutical according to claim 91 or 92, wherein the dosing schedule includes 15 additional dosing cycles.

95. The pharmaceutical according to any one of claims 91 to 94, wherein each additional dosing cycle is a 21-day dosing cycle.

96. The pharmaceutical according to any one of claims 91 to 94, wherein each additional dosing cycle is a 28-day dosing cycle.

97. The pharmaceutical according to any one of claims 91 to 96, wherein each additional dosing cycle includes administration of an additional dose of the mosunetuzumab.

98. The pharmaceutical according to claim 97, wherein each additional dose of the mosunetuzumab is about 45 mg.

99. The pharmaceutical according to claim 97 or 98, wherein each additional dose of the mosunetuzumab is to be administered to each subject in the population on day 1 of each respective additional dosing cycle.

100. The pharmaceutical according to any one of claims 75 to 99, wherein the complete response rate is at least 20%.

101. The medicament according to any one of claims 75 to 100, wherein the complete response rate exceeds 40%.

102. The medicament according to any one of claims 75 to 101, wherein the complete response rate exceeds 55%.

103. The medicament according to any one of claims 75 to 102, wherein the median progression-free survival period exceeds 2 months.

104. The medicament according to any one of claims 75 to 103, wherein the median overall survival period exceeds 9.5 months.

105. The medicament according to any one of claims 75 to 102, wherein the objective response rate at about 20 months after the start of treatment is at least 70%.

106. The medicament according to any one of claims 75 to 102, wherein the objective response rate at 12 months after the start of treatment is at least 60%.

107. The medicament according to any one of claims 75 to 99, wherein the population of the subjects has relapsed or refractory NHL and the objective response rate is at least 34%.

108. The medicament according to claim 107, wherein the objective response rate is at least 44%.

109. The medicament according to any one of claims 75 to 99, wherein the population of the subjects has relapsed or refractory NHL and the objective response rate is between 35% and 55%.

110. The medicament according to claim 109, wherein the objective response rate is about 45%.

111. The medicament according to any one of claims 75 to 77 and 86 to 99, wherein the population of the subjects has relapsed or refractory FL and the objective response rate is at least 70%.

112. The medicament according to claim 111, wherein the objective response rate is at least 80%.

113. The medicament according to any one of claims 75 to 77 and 96 to 99, wherein the population of the subjects has relapsed or refractory FL and the objective response rate is between 70% and 90%.

114. The medicament according to claim 113, wherein the objective response rate is about 80%.

115. The medicament according to any one of claims 75 to 77, 83 to 85, and 89 to 99, wherein the population of the subjects has relapsed or refractory DLBCL, or transformed FL and the objective response rate is at least 25%.

116. The medicament according to claim 115, wherein the objective response rate is at least 35%.

117. The medicament according to any one of claims 75 to 77, 83 to 85, and 89 to 99, wherein the target population has relapsed or refractory DLBCL and the objective response rate is between 25% and 45%.

118. The medicament according to claim 117, wherein the objective response rate is about 35%.

119. The medicament according to any one of claims 75 to 118, wherein the target population shows a cytokine release syndrome after administration of the mosunetuzumab, and the proportion of the cytokine release syndrome in the target population is 30% or less.

120. The medicament according to claim 119, wherein the proportion of the cytokine release syndrome in the target population is 25% or less.

121. The medicament according to claim 120, wherein the proportion of the cytokine release syndrome in the target population is 10% or less.

122. The medicament according to claim 121, wherein the proportion of the cytokine release syndrome in the target population is 5% or less.

123. The medicament according to claim 122, wherein the proportion of the cytokine release syndrome in the target population is 3% or less.

124. The medicament according to any one of claims 75 to 123, wherein the proportion of the cytokine release syndrome having grade 2 or higher is about 10% or less, and the grade is defined by the American Society for Transplantation and Cellular Therapy, 2018.

125. The medicament according to claim 124, wherein the proportion of the cytokine release syndrome having grade 2 or higher is 5% or less, and the grade is defined by the American Society for Transplantation and Cellular Therapy, 2018.

126. The medicament according to claim 125, wherein the proportion of the cytokine release syndrome having grade 2 or higher is 3% or less, and the grade is defined by the American Society for Transplantation and Cellular Therapy, 2018.

127. The medicament according to any one of claims 75 to 126, wherein the proportion of the cytokine release syndrome having grade 3 or higher is 1% or less, and the grade is defined by the American Society for Transplantation and Cellular Therapy, 2018.

128. The medicament according to claim 127, wherein the proportion of the cytokine release syndrome having grade 3 or higher is about 0%, and the grade is defined by the American Society for Transplantation and Cellular Therapy, 2018.

129. A medicament for treating a subject having non-Hodgkin lymphoma (NHL) comprising mosunetuzumab, wherein the mosunetuzumab is to be administered subcutaneously using a stepwise dosing schedule, and the proportion of specific adverse events is reduced in the population of subjects to whom the mosunetuzumab is administered subcutaneously as compared to a reference population of subjects to whom the mosunetuzumab has been administered intravenously, and wherein the stepwise dosing schedule is (I) at least a first dosing cycle and a second dosing cycle, wherein (a) the first dosing cycle comprises a first subcutaneous dose (C1D1), a second subcutaneous dose (C1D2) and a third subcutaneous dose (C1D3) of the mosunetuzumab, (i) the C1D1 is about 5 mg, (ii) the C1D2 is about 15 mg or about 45 mg, (iii) the C1D3 is about 45 mg; and (b) the second dosing cycle comprises a single subcutaneous dose (C_{2}D_{1}) of the mosunetuzumab, and the C_{2}D_{1} is about 45 mg; at least a first dosing cycle and a second dosing cycle; or (II) at least a first dosing cycle and a second dosing cycle, wherein (a) the first dosing cycle comprises a first subcutaneous dose (C1D1), a second subcutaneous dose (C1D2) and a third subcutaneous dose (C1D3) of the mosunetuzumab, (i) the C1D1 is about 5 mg, (ii) the C1D2 is about 15 mg or about 45 mg, (iii) the C1D3 is about 45 mg; and (b) the second dosing cycle comprises a single subcutaneous dose (C_{2}D_{1}) of the mosunetuzumab, and the C_{2}D_{1} is about 45 mg, at least a first dosing cycle and a second dosing cycle comprising a medicament.

130. The medicament according to claim 129, wherein the first dosing cycle and the second dosing cycle are 21-day dosing cycles.

131. The medicament according to claim 129, wherein the first dosing cycle is a 21-day dosing cycle and the second dosing cycle is a 28-day dosing cycle.

132. The medicament according to any one of claims 129 to 131, wherein the dosing schedule comprises one or more additional dosing cycles.

133. The medicament according to claim 132, wherein the dosing schedule comprises from 1 to 15 additional dosing cycles.

134. The medicament according to claim 132 or 133, wherein the dosing schedule comprises 6 additional dosing cycles.

135. The medicament according to claim 132 or 133, wherein the administration plan includes 15 additional administration cycles.

136. The medicament according to any one of claims 132 to 135, wherein each additional administration cycle is a 21-day administration cycle.

137. The medicament according to any one of claims 132 to 135, wherein each additional administration cycle is a 28-day administration cycle.

138. The medicament according to any one of claims 132 to 137, wherein each additional administration cycle includes administration of an additional dose of said mosunetuzumab.

139. The medicament according to claim 138, wherein each additional dose of said mosunetuzumab is about 45 mg.

140. The medicament according to any one of claims 138 or 139, wherein each additional dose of said mosunetuzumab is to be administered to each subject in the population on the first day of each respective additional administration cycle.

141. The medicament according to any one of claims 129 to 140, wherein the subjects in the population and the subjects in the reference population have a B-cell proliferative disorder, and the B-cell proliferative disorder is NHL.

142. The medicament according to claim 141, wherein the NHL is previously untreated NHL, relapsed or refractory R / R NHL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), high-grade B-cell lymphoma, or primary mediastinal (thymic) large B-cell lymphoma (PMBCL).

143. The medicament according to claim 142, wherein the DLBCL is previously untreated DLBCL, or relapsed or refractory DLBCL.

144. The medicament according to claim 142 or 143, wherein the DLBCL is Richter transformation.

145. The medicament according to claim 142, wherein the FL is previously untreated FL, or relapsed or refractory FL.

146. The medicament according to claim 142 or 145, wherein the FL is transformed FL.

147. The medicament according to claim 142, wherein the NHL is high-grade B-cell lymphoma.

148. The medicament according to any one of claims 129 to 147, wherein the population of subjects exhibits cytokine release syndrome after administration of said mosunetuzumab, and the percentage of the cytokine release syndrome in the population of subjects is 25% or less.

149. The pharmaceutical according to any one of claims 129 to 147, wherein the target population exhibits cytokine release syndrome after administration of the mosunetuzumab, and the proportion of cytokine release syndrome in the target population is 30% or less.

150. The pharmaceutical according to claim 149, wherein the proportion of cytokine release syndrome in the target population is 10% or less.

151. The pharmaceutical according to claim 150, wherein the proportion of cytokine release syndrome in the target population is 5% or less.

152. The pharmaceutical according to claim 151, wherein the proportion of cytokine release syndrome in the target population is 3% or less.

153. The pharmaceutical according to any one of claims 129 to 147, wherein the proportion of cytokine release syndrome having grade 2 or higher is 10% or less, and the grade is defined by the American Society for Transplantation and Cellular Therapy in 2018.

154. The pharmaceutical according to claim 153, wherein the proportion of cytokine release syndrome having grade 2 or higher is 5% or less, and the grade is defined by the American Society for Transplantation and Cellular Therapy in 2018.

155. The pharmaceutical according to claim 154, wherein the proportion of cytokine release syndrome having grade 2 or higher is 3% or less, and the grade is defined by the American Society for Transplantation and Cellular Therapy in 2018.

156. The pharmaceutical according to any one of claims 129 to 155, wherein the proportion of cytokine release syndrome having grade 3 or higher is 1% or less, and the grade is defined by the American Society for Transplantation and Cellular Therapy in 2018.

157. The pharmaceutical according to claim 156, wherein the proportion of cytokine release syndrome having grade 3 or higher is approximately 0%, and the grade is defined by the American Society for Transplantation and Cellular Therapy in 2018.

158. The pharmaceutical according to any one of claims 129 to 157, wherein the complete response rate is at least 20%.

159. The pharmaceutical according to any one of claims 129 to 158, wherein the complete response rate is at least 40%.

160. The pharmaceutical according to any one of claims 129 to 159, wherein the median progression-free survival period exceeds 4 months.

161. The pharmaceutical according to any one of claims 129 to 159, wherein the median overall survival period exceeds 9.5 months.

162. The medicament according to any one of claims 129 to 161, wherein the objective response rate at about 24 months after the start of treatment is at least 75%.

163. The medicament according to any one of claims 129 to 161, wherein the objective response rate at about 24 months after the start of treatment is at least 70%.

164. The medicament according to any one of claims 129 to 161, wherein the objective response rate at about 12 months after the start of treatment is at least 60%.

165. The medicament according to any one of claims 129 to 142, wherein the population of interest has relapsed or refractory NHL and the objective response rate is at least 34%.

166. The medicament according to claim 165, wherein the objective response rate is at least 44%.

167. The medicament according to any one of claims 129 to 142, wherein the population of interest has relapsed or refractory NHL and the objective response rate is between 35% and 55%.

168. The medicament according to claim 167, wherein the objective response rate is about 45%.

169. The medicament according to any one of claims 129 to 142, wherein the population of interest has relapsed or refractory FL and the objective response rate is at least 70%.

170. The medicament according to claim 169, wherein the objective response rate is at least 80%.

171. The medicament according to any one of claims 129 to 142, wherein the population of interest has relapsed or refractory FL and the objective response rate is between 7% and 90%.

172. The medicament according to claim 171, wherein the objective response rate is about 80%.

173. The medicament according to any one of claims 129 to 142, wherein the population of interest has relapsed or refractory DLBCL, or transformed FL and the objective response rate is at least 25%.

174. The medicament according to claim 173, wherein the objective response rate is at least 35%.

175. The medicament according to any one of claims 129 to 142, wherein the population of interest has relapsed or refractory DLBCL and the objective response rate is between 25% and 45%.

176. The medicament according to claim 175, wherein the objective response rate is about 35%.

177. The medicament according to any one of claims 1 to 74, wherein the subject is a human.

178. The medicament according to any one of claims 75 to 176, wherein the subject is a human.

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