Administration for treatment with anti-CD20 / anti-CD3 bispecific antibody and anti-CD79B antibody drug conjugate

Abstract

The present invention relates to the treatment of a subject with a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder, e.g., non-Hodgkin's lymphoma). More specifically, the present invention relates to the treatment of a subject with a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder) by administering a combination of an anti-CD20 / anti-CD3 bispecific antibody and an anti-CD79b antibody-drug conjugate.

Description

[Technical Field]

[0001] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format, the entire contents of which are incorporated herein by reference. The ASCII copy created on October 28, 2021, has the title 50474-227WO3_Sequence_Listing_10_28_21_ST25 and is 36,330 bytes in size.

[0002] FIELD OF THE INVENTION The present invention relates to the treatment of B-cell proliferative disorders. More specifically, the present invention relates to the specific treatment of human subjects with CD20-positive cell proliferative disorders (e.g., B-cell proliferative disorders) using an anti-cluster of differentiation 20 (CD20) / anti-cluster of differentiation 3 (CD3) bispecific antibody in combination with an anti-cluster of differentiation 79b (CD79b) antibody-drug conjugate. [Background technology]

[0003] background Cancer is characterized by the uncontrolled proliferation of a cell subpopulation. It is the leading cause of death in developed countries and the second leading cause of death in developing countries, with over 14 million new cancer cases diagnosed and over 8 million cancer deaths occurring annually. As the elderly population grows, the incidence of cancer also rises concomitantly, as the likelihood of developing cancer more than doubles after age 70. Therefore, cancer care represents a significant and ever-increasing societal burden.

[0004] Hematological cancers, in particular, are the second leading cause of cancer-related deaths. Hematological cancers include B-cell proliferative disorders, such as non-Hodgkin's lymphoma (NHL) (e.g., diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL)), which are rapidly progressive and fatal if left untreated. Although treatment with the monoclonal CD20 antibody rituximab has reduced the number of relapsed DLBCL patients, it has become increasingly difficult to treat these patients with relapsed or refractory DLBCL. For such patients, alternative or secondary treatment methods, such as bispecific antibody-based immunotherapy, may be particularly effective. Bispecific antibodies can simultaneously bind cell surface antigens on cytotoxic cells (e.g., T cells via binding to 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. Antibody-drug conjugates can bind to cell surface epitopes (e.g., target CD79b) to promote internalization of the bound drug conjugate for targeted delivery of cytotoxic agents. However, antibody- and antibody-drug conjugate-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 hepatotoxicity.

[0005] Thus, there is an unmet need in the art for the development of effective combination administration methods using therapeutic bispecific antibodies (e.g., anti-CD20 / anti-CD3 bispecific antibodies) and antibody drug conjugates (e.g., anti-CD79b antibody drug conjugates) for the treatment of B cell proliferative disorders that achieve a more favorable benefit-risk profile. Summary of the Invention

[0006] The present invention provides methods of treating a subject with a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder (e.g., NHL, e.g., DLBCL, FL, or MCL)) by administering a combination of an anti-CD79b antibody drug conjugate and a bispecific antibody that binds CD20 and CD3 in a multi-cycle dosing regimen comprising fractional escalating doses of the bispecific antibody in a first dosing cycle.

[0007] In one aspect, the invention features a method of treating a subject having a CD20-positive cell proliferative disorder (e.g., a B cell proliferative disorder), comprising administering to the subject an anti-CD79b antibody drug conjugate and a bispecific antibody that binds CD20 and CD3 in a dosing regimen including at least a first dosing cycle and a second dosing cycle, wherein: (a) the first dosing cycle includes a first dose of the bispecific antibody (C1D1), a second dose of the bispecific antibody (C1D2), and a third dose of the bispecific antibody (C1D3); ), wherein C1D1 of the bispecific antibody is between about 0.02 mg and about 5.0 mg (for example, about 0.05 mg to about 5 mg, about 0.1 mg to about 5.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 2 mg to about 5.0 mg, about 3 mg to about 5.0 mg, about 0.05 mg to about 4.0 mg, about 0.05 mg to about 3.0 mg, about 0.05 mg to about 2.0 mg, about 0.1 mg to about 2.0 mg, about 0.5 mg to about 2.0 mg, about 2 mg to about 4.0 mg, about 1 mg to about 3.0 mg, about 1 mg g, about 2 mg, or about 5 mg), and C1D2 of the bispecific antibody is between about 0.05 mg and about 10.0 mg (for example, about 0.1 mg to about 10.0 mg, about 0.5 mg to about 10.0 mg, 1 mg to about 10.0 mg, about 2 mg to about 3.0 mg, about 5 mg to about 10.0 mg, about 8 mg to about 10.0 mg, about 0.5 mg to about 7.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 1 mg to about 3.0 mg, about 3 mg to about 8.0 mg, about 1 mg, about 2 mg, about 5 mg) or about 10 The bispecific antibody C1D3 is between about 9 mg and about 13 mg (e.g., about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 20 mg to about 50 mg, about 30 mg to about 50 mg, about 40 mg to about 50 mg, about 45 mg to about 50 mg, about 13 mg to about 17 mg, about 43 mg to about 48 mg, about 15 mg to about 35 mg, about 25 mg to about 45 mg, about 15 mg, about 30 mg, or about 45 mg).(b) a second administration cycle comprising a first dose of bispecific antibody (C1D1), a second dose of bispecific antibody (C1D2), and a third dose of bispecific antibody (C1D3), each of which is about 5 mg, about 20 mg, about 40 mg, about 45 mg, or about 60 mg; and (b) a second administration cycle comprising a single dose of bispecific antibody (C2D1), wherein C2D1 of the bispecific antibody is equal to or greater than C1D3.

[0008] In some embodiments, bispecific antibody C1D1 is about 1 mg, bispecific antibody C1D2 is about 2 mg, and bispecific antibody C1D3 is about 9 mg. In some embodiments, bispecific antibody C2D1 is about 9 mg.

[0009] In some embodiments, bispecific antibody C1D1 is about 1 mg, bispecific antibody C1D2 is about 2 mg, and bispecific antibody C1D3 is about 13.5 mg. In some embodiments, bispecific antibody C2D1 is about 13.5 mg.

[0010] In some embodiments, bispecific antibody C1D1 is about 1 mg, bispecific antibody C1D2 is about 2 mg, and bispecific antibody C1D3 is about 20 mg. In some embodiments, bispecific antibody C2D1 is about 20 mg.

[0011] In some embodiments, bispecific antibody C1D1 is about 1 mg, bispecific antibody C1D2 is about 2 mg, and bispecific antibody C1D3 is about 40 mg. In some embodiments, bispecific antibody C2D1 is about 40 mg.

[0012] In some embodiments, the first administration cycle comprises a single dose C1D1 of the anti-CD79b antibody drug conjugate. In some embodiments, the single dose C1D1 of the anti-CD79b antibody drug conjugate is about 0.5 mg / kg to about 10 mg / kg (e.g., between about 0.5 mg / kg to about 9 mg / kg, between about 0.5 mg / kg to about 8 mg / kg, between about 0.5 mg / kg to about 7 mg / kg, between about 0.5 mg / kg to about 6 mg / kg, between about 0.5 mg / kg to about 5 mg / kg, between about 0.5 mg / kg to about 4 mg / kg, about 0.5 mg In some embodiments, the single dose C1D1 of the anti-CD79b antibody drug conjugate is about 1.8 mg / kg. In some embodiments, the second administration cycle comprises a single dose C2D1 of the anti-CD79b antibody drug conjugate. In some embodiments, a single dose C2D1 of an anti-CD79b antibody drug conjugate is from about 0.5 mg / kg to about 10 mg / kg (e.g., between about 0.5 mg / kg to about 9 mg / kg, between about 0.5 mg / kg to about 8 mg / kg, between about 0.5 mg / kg to about 7 mg / kg, between about 0.5 mg / kg to about 6 mg / kg, between about 0.5 mg / kg to about 5 mg / kg, between about 0.5 mg / kg to about 4 mg / kg, between about 0.5 mg In some embodiments, a single dose of anti-CD79b antibody-drug conjugate C2D1 is about 1.8 mg / kg.

[0013] In some embodiments, bispecific antibody C1D1, bispecific antibody C1D2, and bispecific antibody C1D3 are administered to a subject on, or about, days 1, 8, and 15, respectively, of a first administration cycle. In some embodiments, bispecific antibody C2D1 is administered to a subject on day 1 of a second administration cycle. In some embodiments, anti-CD79b antibody drug conjugate C1D1 is administered to a subject on day 1 of a first administration cycle and / or anti-CD79b antibody drug conjugate C2D1 is administered to a subject on day 1 of a second administration cycle. In some embodiments, the first administration cycle and the second administration cycle are 21-day administration cycles. In some embodiments, the administration regimen includes one or more additional administration cycles. In some embodiments, the dosing regimen includes 4 to 15 additional dosing cycles (e.g., 4 to 10 additional dosing cycles (e.g., 4 additional dosing cycles, 5 additional dosing cycles, 6 additional dosing cycles, 7 additional dosing cycles, 8 additional dosing cycles, 9 additional dosing cycles, or 10 additional dosing cycles) or 11 to 15 additional dosing cycles (e.g., 11 additional dosing cycles, 12 additional dosing cycles, 13 additional dosing cycles, 14 additional dosing cycles, or 15 additional dosing cycles)). In certain embodiments, the dosing regimen includes 4 additional dosing cycles. In some embodiments, the additional dosing cycle is a 21-day dosing cycle.

[0014] In some embodiments, one or more of the additional administration cycles comprises an additional single dose of the bispecific antibody and an additional single dose of the anti-CD79b antibody drug conjugate. In some embodiments, the additional single dose of the anti-CD79b antibody drug conjugate is equivalent to the C2D1 of the anti-CD79b antibody drug conjugate. In some embodiments, the additional single dose of the anti-CD79b antibody drug conjugate is administered to the subject on day 1 of each additional administration cycle comprising an additional dose of the anti-CD79b antibody drug conjugate. In some embodiments, one or more of the additional administration cycles comprises an additional single dose of the bispecific antibody and does not comprise administration of the anti-CD79b antibody drug conjugate. In some embodiments, the additional single dose of the bispecific antibody is equivalent to the C2D1 of the bispecific antibody. In some embodiments, the additional single dose of the bispecific antibody is administered to the subject on day 1 of each additional administration cycle comprising an additional dose of the bispecific antibody. In some embodiments, the dosing regimen comprises six or more additional administration cycles, wherein each of the six or more additional administration cycles comprises a single dose of the bispecific antibody, and wherein no more than four of the six or more additional administration cycles comprise administration of the anti-CD79b antibody drug conjugate.

[0015] In another aspect, the invention features a method of treating a subject with a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder), comprising administering to the subject an anti-CD79b antibody drug conjugate and a bispecific antibody that binds CD20 and CD3 in a dosing regimen including at least a first administration cycle and a second administration cycle, wherein: (a) the first administration cycle comprises: (i) a single dose of the anti-CD79b antibody drug conjugate (C1D1); and (ii) a first dose of the bispecific antibody (C1D1) and a second dose of the bispecific antibody (C1D2), wherein C1D1 and C1D2 of the bispecific antibody are each administered to the subject after C1D1 of the anti-CD79b antibody drug conjugate, and wherein C1D1 of the bispecific antibody is administered at a dose between about 0.02 mg and about 5.0 mg (e.g., about 0.05 mg to about 5 mg, about 0.1 mg to about 5.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 2 mg to about 5.0 mg, about 3 mg to about 5.0 mg, about 0.05 mg to about 4.0 mg, about 0.05 mg to about 3.0 mg, about 0.05 mg to about 2.0 mg, about 0.1 mg to about 2.0 mg, about 0.5 mg to about 2.0 mg, about 2 mg to about 4.0 mg, about 1 mg to about 3.0 mg, about 1 mg, about 2 mg, or about 5 mg , the C1D2 of the bispecific antibody is between about 0.05 mg and about 10.0 mg (for example, about 0.1 mg to about 10.0 mg, about 0.5 mg to about 10.0 mg, 1 mg to about 10.0 mg, about 2 mg to about 3.0 mg, about 5 mg to about 10.0 mg, about 8 mg to about 10.0 mg, about 0.5 mg to about 7.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 1 mg to about 3.0 mg, about 3 mg to about 8.0 mg).0 mg, about 1 mg, about 2 mg, or about 5 mg) or between about 10 mg and about 60 mg (e.g., about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 20 mg to about 50 mg, about 30 mg to about 50 mg, about 40 mg to about 50 mg, about 45 mg to about 50 mg, about 13 mg to about 17 mg, about 43 mg to about 48 mg, about 15 mg to about 35 mg, about 25 mg to about (b) the second administration cycle comprises (i) a single dose of the anti-CD79b antibody-drug conjugate (C2D1); and (ii) a single dose of the bispecific antibody (C2D1), wherein the C2D1 of the bispecific antibody is equal to or greater than the C1D2. In some embodiments, the C1D1 of the bispecific antibody is about 1 mg and the C1D2 of the bispecific antibody is about 2 mg. In some embodiments, the C2D1 of the bispecific antibody is about 9 mg, about 13.5 mg, about 20 mg, about 40 mg, about 45 mg, or about 60 mg.

[0016] In some embodiments, the first administration cycle comprises a single dose C1D1 of the anti-CD79b antibody drug conjugate. In some embodiments, the single dose C1D1 of the anti-CD79b antibody drug conjugate is about 0.5 mg / kg to about 10 mg / kg. In some embodiments, the single dose C1D1 of the anti-CD79b antibody drug conjugate is about 1.8 mg / kg. In some embodiments, the second administration cycle comprises a single dose C2D1 of the anti-CD79b antibody drug conjugate. In some embodiments, the single dose C2D1 of the anti-CD79b antibody drug conjugate is about 0.5 mg / kg to about 10 mg / kg. In some embodiments, the single dose C2D1 of the anti-CD79b antibody drug conjugate is about 1.8 mg / kg.

[0017] In some embodiments, bispecific antibody C1D1 and bispecific antibody C1D2 are administered to the subject on, or about, days 8 and 15, respectively, of the first administration cycle. In some embodiments, bispecific antibody C2D1 is administered to the subject on day 1 of the second administration cycle. In some embodiments, anti-CD79b antibody drug conjugate C1D1 is administered to the subject on day 1 of the first administration cycle, and anti-CD79b antibody drug conjugate C2D1 is administered to the subject on day 1 of the second administration cycle. In some embodiments, the first administration cycle and the second administration cycle are 21-day administration cycles.

[0018] In some embodiments, the dosing regimen comprises one or more additional administration cycles. In some embodiments, the dosing regimen comprises 4 to 15 additional administration cycles (e.g., 4 to 10 additional administration cycles (e.g., 4 additional administration cycles, 5 additional administration cycles, 6 additional administration cycles, 7 additional administration cycles, 8 additional administration cycles, 9 additional administration cycles, or 10 additional administration cycles) or 11 to 15 additional administration cycles (e.g., 11 additional administration cycles, 12 additional administration cycles, 13 additional administration cycles, 14 additional administration cycles, or 15 additional administration cycles)). In specific embodiments, the dosing regimen comprises 4 additional administration cycles. In some embodiments, the additional administration cycle is a 21-day administration cycle. In some embodiments, one or more of the additional administration cycles comprises a single additional dose of the bispecific antibody and a single additional dose of the anti-CD79b antibody drug conjugate. In some embodiments, the additional single dose of the anti-CD79b antibody drug conjugate is equivalent to C2D1 of the anti-CD79b antibody drug conjugate. In some embodiments, the additional single dose of the anti-CD79b antibody drug conjugate is administered to the subject on day 1 of each additional administration cycle comprising an additional dose of the anti-CD79b antibody drug conjugate. In some embodiments, one or more of the additional administration cycles comprises an additional single dose of the bispecific antibody and does not comprise administration of an anti-CD79b antibody drug conjugate. In some embodiments, the additional single dose of the bispecific antibody is equivalent to C2D1 of the bispecific antibody. In some embodiments, the additional single dose of the bispecific antibody is administered to the subject on day 1 of each additional administration cycle comprising an additional dose of the bispecific antibody. In some embodiments, the administration regimen comprises six or more additional administration cycles, each of the six or more additional administration cycles comprising a single dose of the bispecific antibody, and no more than four of the six or more additional administration cycles comprising administration of an anti-CD79b antibody drug conjugate.

[0019] In yet another aspect, the invention features a method of treating a subject having a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder), comprising administering to the subject an anti-CD79b antibody drug conjugate and a bispecific antibody that binds CD20 and CD3 in a dosing regimen including eight or more dosing cycles, wherein: (a) the first dosing cycle includes: (i) a first dose of the bispecific antibody (C1D1), a second dose of the bispecific antibody (C1D2), and a third dose of the bispecific antibody (C1D3), , the C1D1 of the bispecific antibody is between about 0.02 mg and about 5.0 mg (e.g., about 0.05 mg to about 5 mg, about 0.1 mg to about 5.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 2 mg to about 5.0 mg, about 3 mg to about 5.0 mg, about 0.05 mg to about 4.0 mg, about 0.05 mg to about 3.0 mg, about 0.05 mg to about 2.0 mg, about 0.1 mg to about 2.0 mg, about 0.5 mg to about 2.0 mg, about 2 mg to about 4.0 mg, about 1 mg to about 3.0 mg, about 1 mg, about 2 mg mg, or about 5 mg), and C1D2 of the bispecific antibody is between about 0.05 mg and about 10.0 mg (for example, about 0.1 mg to about 10.0 mg, about 0.5 mg to about 10.0 mg, 1 mg to about 10.0 mg, about 2 mg to about 3.0 mg, about 5 mg to about 10.0 mg, about 8 mg to about 10.0 mg, about 0.5 mg to about 7.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 1 mg to about 3.0 mg, about 3 mg to about 8.0 mg, about 1 mg, about 2 mg, or about 5 mg) or about 10 mg The bispecific antibody C1D3 is between about 9 mg and about 13 mg (e.g., about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 20 mg to about 50 mg, about 30 mg to about 50 mg, about 40 mg to about 50 mg, about 45 mg to about 50 mg, about 13 mg to about 17 mg, about 43 mg to about 48 mg, about 15 mg to about 35 mg, about 25 mg to about 45 mg, about 15 mg, about 30 mg, or about 45 mg).(b) a first dose of the bispecific antibody (C1D1), a second dose of the bispecific antibody (C1D2), and a third dose of the bispecific antibody (C1D3), each of which is about 5 mg, about 20 mg, about 40 mg, about 45 mg, or about 60 mg; and (ii) a single dose of the anti-CD79b antibody drug conjugate (C1D1); (b) a second administration cycle comprising a single dose of the bispecific antibody (C2D1) and a single dose of the anti-CD79b antibody drug conjugate (C2D1); (c) a third administration cycle comprising a single dose of the bispecific antibody (C3D1) and a single dose of the anti-CD79b antibody drug conjugate (C3D1); (d) a fourth administration cycle comprising a single dose of the bispecific antibody (C4D1) and a single dose of the anti-CD79b antibody drug conjugate (C4D1). (e) the fifth administration cycle comprises a single dose of the bispecific antibody (C5D1) and a single dose of the anti-CD79b antibody drug conjugate (C5D1); (f) the sixth administration cycle comprises a single dose of the bispecific antibody (C6D1) and a single dose of the anti-CD79b antibody drug conjugate (C6D1); (g) the seventh administration cycle comprises a single dose of the bispecific antibody (C7D1) and does not include administration of the anti-CD79b antibody drug conjugate; and (h) the eighth administration cycle comprises a single dose of the bispecific antibody (C8D1) and does not include administration of the anti-CD79b antibody drug conjugate, wherein each single dose C2D1 through C8D1 of the bispecific antibody is equal to or greater than C1D3.

[0020] In some embodiments, C1D3 and C2D1 to C8D1 of the bispecific antibody are present in approximately equal amounts. In some embodiments, C1D1 to C6D1 of the anti-CD79b antibody drug conjugate are present in approximately equal amounts.

[0021] In yet another aspect, the invention features a method of treating a subject having a CD20-positive cell proliferative disorder (e.g., a B cell proliferative disorder), comprising administering to the subject an anti-CD79b antibody drug conjugate and a bispecific antibody that binds CD20 and CD3 in a dosing regimen including eight or more dosing cycles, wherein: (a) the first dosing cycle includes: (i) a first dose of the bispecific antibody (C1D1), a second dose of the bispecific antibody (C1D2), and a third dose of the bispecific antibody (C1D3), , the C1D1 of the bispecific antibody is between about 0.02 mg and about 5.0 mg (e.g., about 0.05 mg to about 5 mg, about 0.1 mg to about 5.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 2 mg to about 5.0 mg, about 3 mg to about 5.0 mg, about 0.05 mg to about 4.0 mg, about 0.05 mg to about 3.0 mg, about 0.05 mg to about 2.0 mg, about 0.1 mg to about 2.0 mg, about 0.5 mg to about 2.0 mg, about 2 mg to about 4.0 mg, about 1 mg to about 3.0 mg, about 1 mg, about 2 mg mg, or about 5 mg), and C1D2 of the bispecific antibody is between about 0.05 mg and about 10.0 mg (for example, about 0.1 mg to about 10.0 mg, about 0.5 mg to about 10.0 mg, 1 mg to about 10.0 mg, about 2 mg to about 3.0 mg, about 5 mg to about 10.0 mg, about 8 mg to about 10.0 mg, about 0.5 mg to about 7.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 1 mg to about 3.0 mg, about 3 mg to about 8.0 mg, about 1 mg, about 2 mg, or about 5 mg) or about 10 mg The bispecific antibody C1D3 is between about 9 mg and about 13 mg (e.g., about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 20 mg to about 50 mg, about 30 mg to about 50 mg, about 40 mg to about 50 mg, about 45 mg to about 50 mg, about 13 mg to about 17 mg, about 43 mg to about 48 mg, about 15 mg to about 35 mg, about 25 mg to about 45 mg, about 15 mg, about 30 mg, or about 45 mg).(b) a first dose of the bispecific antibody (C1D1), a second dose of the bispecific antibody (C1D2), and a third dose of the bispecific antibody (C1D3), each of which is about 5 mg, about 20 mg, about 40 mg, about 45 mg, or about 60 mg; and (ii) a single dose of an anti-CD79b antibody drug conjugate (C1D1); (b) a second administration cycle comprising a single dose of the bispecific antibody (C2D1) and a single dose of the anti-CD79b antibody drug conjugate (C2D1); (c) a third administration cycle comprising a single dose of the bispecific antibody (C3D1) and a single dose of the anti-CD79b antibody drug conjugate (C3D1); (d) a fourth administration cycle comprising a single dose of the bispecific antibody (C4D1) and a single dose of the anti-CD79b antibody drug conjugate (C4D1). (e) a fifth administration cycle comprises a single dose of the bispecific antibody (C5D1) and a single dose of the anti-CD79b antibody drug conjugate (C5D1); (f) a sixth administration cycle comprises a single dose of the bispecific antibody (C6D1) and a single dose of the anti-CD79b antibody drug conjugate (C6D1); (g) a seventh administration cycle comprises a single dose of the bispecific antibody (C7D1) and does not include administration of the anti-CD79b antibody drug conjugate; and (h) an eighth administration cycle comprises a single dose of the bispecific antibody (C8D1) and does not include administration of the anti-CD79b antibody drug conjugate, wherein the single dose C2D1 is approximately equivalent to C1D3, and each of the single doses C3D1-C8D1 of the bispecific antibody is less than C1D3. In some embodiments, each single dose of bispecific antibody C3D1-C8D1 is between about 10 mg and about 45 mg (e.g., between about 10 mg and about 40 mg, between about 10 mg and about 35 mg, between about 15 mg and about 45 mg, between about 20 mg and about 45 mg, or between about 25 mg and about 45 mg; e.g., about 30 mg).

[0022] In some embodiments, each of C1D1 to C6D1 of the anti-CD79b antibody drug conjugate is administered at a dose of about 0.5 mg / kg to about 10 mg / kg (e.g., between about 0.5 mg / kg to about 9 mg / kg, between about 0.5 mg / kg to about 8 mg / kg, between about 0.5 mg / kg to about 7 mg / kg, between about 0.5 mg / kg to about 6 mg / kg, between about 0.5 mg / kg to about 5 mg / kg, between about 0.5 mg / kg to about 4 mg / kg, or about 0.5 mg / kg to about 10 mg / kg). In some embodiments, each of C1D1 to C6D1 of the anti-CD79b antibody-drug conjugate is about 1.8 mg / kg.

[0023] In some embodiments, bispecific antibody C1D1, bispecific antibody C1D2, and bispecific antibody C1D3 are administered to a subject on, or about, days 1, 8, and 15, respectively, of a first administration cycle. In some embodiments, bispecific antibodies C1D1-C8D1 are administered to a subject on day 1 of each administration cycle. In some embodiments, anti-CD79b antibody drug conjugates C1D1-C6D1 are administered to a subject on day 1 of each administration cycle. In some embodiments, each administration cycle is a 21-day administration cycle.

[0024] In yet another aspect, the invention provides a method of treating a subject having a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder), comprising administering to the subject an anti-CD79b antibody drug conjugate and a bispecific antibody that binds CD20 and CD3 in a dosing regimen comprising eight or more dosing cycles, wherein: (a) the first dosing cycle comprises a first dose of the bispecific antibody (C1D1) and a second dose of the bispecific antibody (C1D2), wherein C1D1 of the bispecific antibody is , about 0.02 mg to about 5.0 mg (for example, about 0.05 mg to about 5 mg, about 0.1 mg to about 5.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 2 mg to about 5.0 mg, about 3 mg to about 5.0 mg, about 0.05 mg to about 4.0 mg, about 0.05 mg to about 3.0 mg, about 0.05 mg to about 2.0 mg, about 0.1 mg to about 2.0 mg, about 0.5 mg to about 2.0 mg, about 2 mg to about 4.0 mg, about 1 mg to about 3.0 mg, about 1 mg, about 2 mg, or and C1D2 is between about 0.05 mg and about 10.0 mg (e.g., about 0.1 mg to about 10.0 mg, about 0.5 mg to about 10.0 mg, 1 mg to about 10.0 mg, about 2 mg to about 3.0 mg, about 5 mg to about 10.0 mg, about 8 mg to about 10.0 mg, about 0.5 mg to about 7.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 1 mg to about 3.0 mg, about 3 mg to about 8.0 mg, about 1 mg, about 2 mg, or about 5 mg) or about 10 mg to Between about 60 mg (e.g., about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 20 mg to about 50 mg, about 30 mg to about 50 mg, about 40 mg to about 50 mg, about 45 mg to about 50 mg, about 13 mg to about 17 mg, about 43 mg to about 48 mg, about 15 mg to about 35 mg, about 25 mg to about 45 mg, about 15 mg, about 30 mg, or about 45 mg), and C1D3 is about 9 mg, about 13 mg, or about 17 mg.(b) a first dose of the bispecific antibody (C1D1) and a second dose of the bispecific antibody (C1D2) that are about 5 mg, about 20 mg, about 40 mg, about 45 mg, or about 60 mg; (b) a second administration cycle that includes a single dose of the bispecific antibody (C2D1) and a single dose of the anti-CD79b antibody drug conjugate (C2D1); (c) a third administration cycle that includes a single dose of the bispecific antibody (C3D1) and a single dose of the anti-CD79b antibody drug conjugate (C3D1); (d) a fourth administration cycle that includes a single dose of the bispecific antibody (C4D1) and a single dose of the anti-CD79b antibody drug conjugate (C4D1); (e) a fifth administration cycle that includes a single dose of the bispecific antibody (C4D1) and a single dose of the anti-CD79b antibody drug conjugate (C4D1); (f) the sixth administration cycle comprises a single dose of the bispecific antibody (C5D1) and a single dose of the anti-CD79b antibody drug conjugate (C5D1); (g) the seventh administration cycle comprises a single dose of the bispecific antibody (C7D1) and does not include administration of the anti-CD79b antibody drug conjugate; and (h) the eighth administration cycle comprises a single dose of the bispecific antibody (C8D1) and does not include administration of the anti-CD79b antibody drug conjugate, wherein each single dose of the bispecific antibody, C2D1 through C8D1, is equal to or greater than C1D3.

[0025] In some embodiments, the C1D3 and C2D1 to C8D1 of the bispecific antibody are present in approximately equal amounts.

[0026] In some embodiments, C2D1 to C6D1 of the anti-CD79b antibody-drug conjugate are present in approximately equal amounts. In some embodiments, each of C2D1 to C6D1 of the anti-CD79b antibody-drug conjugate is present in a concentration of about 0.5 mg / kg to about 10 mg / kg (e.g., between about 0.5 mg / kg to about 9 mg / kg, between about 0.5 mg / kg to about 8 mg / kg, between about 0.5 mg / kg to about 7 mg / kg, between about 0.5 mg / kg to about 6 mg / kg, between about 0.5 mg / kg to about 5 mg / kg, between about 0.5 mg / kg to about 4 mg / kg, or about 0.5 mg / kg to about 10 mg / kg). In some embodiments, each of C2D1 to C6D1 of the anti-CD79b antibody-drug conjugate is about 1.8 mg / kg.

[0027] In some embodiments, bispecific antibody C1D1, bispecific antibody C1D2, and bispecific antibody C1D3 are administered to a subject on, or about, days 1, 8, and 15, respectively, of a first administration cycle. In some embodiments, bispecific antibodies C1D1 and C2D1-C8D1 are administered to a subject on day 1 of each administration cycle. In some embodiments, anti-CD79b antibody drug conjugates C2D1-C6D1 are administered to a subject on day 1 of each administration cycle. In some embodiments, each administration cycle is a 21-day administration cycle.

[0028] In another aspect, the present invention provides a method of treating a subject having a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder), comprising administering to the subject an anti-CD79b antibody drug conjugate and a bispecific antibody that binds CD20 and CD3 in a dosing regimen comprising eight or more dosing cycles, wherein (a) the first dosing cycle comprises (i) a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody, wherein C1D1 of the bispecific antibody is between about 0.02 mg and about 5.0 mg (e.g., about 0.05 mg to about 5 mg, 0.1 mg to about 5.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 2 mg to about 5.0 mg, about 3 mg to about 5.0 mg, about 0.05 mg to about 4.0 mg, about 0.05 mg to about 3.0 mg, about 0.05 mg to about 2.0 mg, about 0.1 mg to about 2.0 mg, about 0.5 mg to about 2.0 mg, about 2 mg to about 4.0 mg, about 1 mg to about 3.0 mg, about 1 mg, about 2 mg, or about 5 mg), and C1D2 is between about 0.05 mg and about 10.0 mg (e.g., about 0.1 mg to about 10.0 mg, about 0.5 mg to about 10. 0 mg, 1 mg to about 10.0 mg, about 2 mg to about 3.0 mg, about 5 mg to about 10.0 mg, about 8 mg to about 10.0 mg, about 0.5 mg to about 7.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 1 mg to about 3.0 mg, about 3 mg to about 8.0 mg, about 1 mg, about 2 mg, or about 5 mg) or between about 10 mg and about 60 mg (e.g., about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 20 mg to about 50 mg, about 30 mg to about 5 (b) a second administration cycle comprising (i) a single dose (C2D1) of the bispecific antibody, wherein the C2D1 of the bispecific antibody is about 9 mg, about 13 mg, about 40 mg to about 50 mg, about 45 mg to about 50 mg, about 13 mg to about 17 mg, about 43 mg to about 48 mg, about 15 mg to about 35 mg, about 25 mg to about 45 mg, about 15 mg, about 30 mg, or about 45 mg; and (ii) a single dose (C1D1) of the anti-CD79b antibody-drug conjugate; (b) a second administration cycle comprising (i) a single dose (C2D1) of the bispecific antibody, wherein the C2D1 of the bispecific antibody is about 9 mg, about 13 mg, about 17 mg, about 43 mg to about 48 mg, about 15 mg, about 35 mg, about 25 mg to about 45 mg, about 15 mg, about 30 mg, or about 45 mg;(c) a third administration cycle comprising a single dose of the bispecific antibody (C3D1) and a single dose of the anti-CD79b antibody drug conjugate (C3D1); (d) a fourth administration cycle comprising a single dose of the bispecific antibody (C4D1) and a single dose of the anti-CD79b antibody drug conjugate (C4D1); (e) a fifth administration cycle comprising a single dose of the bispecific antibody (C5D1) and a single dose of the anti-CD79b antibody drug conjugate (C5D1); (f) a sixth administration cycle comprises a single dose of the bispecific antibody (C6D1) and a single dose of the anti-CD79b antibody drug conjugate (C6D1); (g) a seventh administration cycle comprises a single dose of the bispecific antibody (C7D1) and does not include administration of the anti-CD79b antibody drug conjugate; and (h) an eighth administration cycle comprises a single dose of the bispecific antibody (C8D1) and does not include administration of the anti-CD79b antibody drug conjugate, and each single dose of the bispecific antibody, C2D1 to C8D1, is greater than C1D2.

[0029] In some embodiments, C2D1 to C8D1 of the bispecific antibody are present in approximately equal amounts. In some embodiments, C1D1 to C6D1 of the anti-CD79b antibody-drug conjugate are present in approximately equal amounts. In some embodiments, each of C1D1 to C6D1 of the anti-CD79b antibody-drug conjugate is present in approximately equal amounts. In some embodiments, C1D1 to C6D1 are present in approximately equal amounts. In some embodiments, each of C1D1 to C6D1 of the anti-CD79b antibody-drug conjugate is present in approximately equal amounts (e.g., between about 0.5 mg / kg and about 9 mg / kg, between about 0.5 mg / kg and about 8 mg / kg, between about 0.5 mg / kg and about 7 mg / kg, between about 0.5 mg / kg and about 6 mg / kg, between about 0.5 mg / kg and about 5 mg / kg, between about 0.5 mg / kg and about 4 mg / kg, or about 0.5 mg / kg. The dose is typically between about 5 mg / kg and about 3 mg / kg, between about 0.5 mg / kg and about 2 mg / kg, between about 0.75 mg / kg and about 10 mg / kg, between about 1 mg / kg and about 10 mg / kg, between about 1.5 mg / kg and about 10 mg / kg, between about 1 mg / kg and about 5 mg / kg, between about 1 mg / kg and about 3 mg / kg, between about 1.5 mg / kg and about 2.5 mg / kg, between about 1.5 mg / kg and about 2 mg / kg, or about 1.8 mg / kg. In some embodiments, each of C1D1 to C6D1 of the anti-CD79b antibody-drug conjugates is about 1.8 mg / kg. In some embodiments, C1D1 of the bispecific antibody is administered after C1D1 of the anti-CD79b antibody-drug conjugate. In some embodiments, the bispecific antibody C1D1 is administered about 7 days after the anti-CD79b antibody drug conjugate C1D1.

[0030] In some embodiments, bispecific antibody C1D1 and bispecific antibody C1D2 are administered to a subject on, or about, days 8 and 15, respectively, of a first administration cycle. In some embodiments, bispecific antibodies C2D1-C8D1 are administered to a subject on day 1 of each administration cycle. In some embodiments, anti-CD79b antibody drug conjugates C1D1-C6D1 are administered to a subject on day 1 of each administration cycle. In some embodiments, each administration cycle is a 21-day administration cycle. In some embodiments, the administration regimen includes one or more additional administration cycles comprising a single dose of the bispecific antibody. In some embodiments, the administration regimen includes one to nine additional administration cycles comprising a single dose of the bispecific antibody. In some embodiments, each of the additional administration cycles does not include administration of an anti-CD79b antibody drug conjugate. In some embodiments, each of the additional administration cycles is a 21-day administration cycle.

[0031] In some embodiments, the bispecific antibody and the anti-CD79b antibody drug conjugate have a synergistic effect in a mouse NSG:human WSU-DLCL2 model system when compared to either the bispecific antibody or the anti-CD79b antibody drug conjugate alone.

[0032] In some embodiments of any of the above aspects, the method further includes administering one or more additional therapeutic agents to the subject. In some embodiments, the one or more additional therapeutic agents are a corticosteroid or an IL-R6 antagonist. In some embodiments, the IL-R6 antagonist is tocilizumab. In some embodiments, tocilizumab is administered intravenously to the subject as a single dose of about 8 mg / kg, the single dose not exceeding 800 mg. In some embodiments, the one or more additional therapeutic agents are corticosteroids. In some embodiments, the corticosteroid is dexamethasone, prednisone, or methylprednisolone. In some embodiments, the one or more additional therapeutic agents comprise one or more chemotherapeutic agents. In some embodiments, the one or more chemotherapeutic agents comprise cyclophosphamide or doxorubicin.

[0033] In another aspect, the invention provides a method of reducing the rate of cytokine release syndrome in a population of subjects with a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder) administered an anti-CD79b antibody drug conjugate and a bispecific antibody that binds CD20 and CD3, the method comprising administering to one or more subjects of the population an anti-CD79b antibody drug conjugate and a bispecific antibody that binds CD20 and CD3 according to the method of any one of the embodiments described herein.

[0034] In another aspect, the invention provides a method of reducing the rate of cytokine release syndrome in a population of subjects having a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder) administered an anti-CD79b antibody drug conjugate and a bispecific antibody that binds CD20 and CD3, comprising administering to one or more subjects of the population an anti-CD79b antibody drug conjugate and 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 , a first dose of the bispecific antibody (C1D1), a second dose of the bispecific antibody (C1D2), and a third dose of the bispecific antibody (C1D3), wherein C1D1 of the bispecific antibody is between about 0.02 mg and about 5.0 mg (for example, about 0.05 mg to about 5 mg, about 0.1 mg to about 5.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 2 mg to about 5.0 mg, about 3 mg to about 5.0 mg, about 0.05 mg to about 4.0 mg, about 0.05 mg to about 3.0 mg, about 0.05 mg to about 2.0 mg, about 0.1 mg to about 2 ... and C1D2 of the bispecific antibody is between about 0.05 mg and about 10.0 mg (for example, about 0.1 mg to about 10.0 mg, about 0.5 mg to about 10.0 mg, 1 mg to about 10.0 mg, about 2 mg to about 3.0 mg, about 5 mg to about 10.0 mg, about 8 mg to about 10.0 mg, about 0.5 mg to about 7.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 1 mg to about 3.0 mg, about 3 mg to about 8.0 mg, about The bispecific antibody C1D3 is about 9 mg, about 13 mg, about 2 mg, or about 5 mg) or between about 10 mg and about 60 mg (e.g., about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 20 mg to about 50 mg, about 30 mg to about 50 mg, about 40 mg to about 50 mg, about 45 mg to about 50 mg, about 13 mg to about 17 mg, about 43 mg to about 48 mg, about 15 mg to about 35 mg, about 25 mg to about 45 mg, about 15 mg, about 30 mg, or about 45 mg).(b) a second administration cycle comprising a first dose of the bispecific antibody (C1D1), a second dose of the bispecific antibody (C1D2), and a third dose of the bispecific antibody (C1D3), each dose being about 5 mg, about 20 mg, about 40 mg, about 45 mg, or about 60 mg; and (b) a second administration cycle comprising a single dose of the bispecific antibody (C2D1), wherein the C2D1 of the bispecific antibody is equal to or greater than the C1D3, and wherein the rate of adverse events is reduced in the population of subjects compared to a reference population of subjects not administered the anti-CD79b antibody-drug conjugate.

[0035] In a further aspect, the invention provides a method of reducing the rate of cytokine release syndrome in a population of subjects with a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder) administered an anti-CD79b antibody drug conjugate and a bispecific antibody that binds CD20 and CD3, comprising administering to one or more subjects of the population the anti-CD79b antibody drug conjugate and the 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: (i) a single dose of the anti-CD79b antibody drug conjugate (C1D1); and (ii) a first dose of the bispecific antibody (C1D1) and a second dose of the bispecific antibody (C1D2), wherein C1D1 and C1D2 of the bispecific antibody, respectively, are administered to the subject after C1D1 of the anti-CD79b antibody drug conjugate; is between about 0.02 mg and about 5.0 mg (e.g., about 0.05 mg to about 5 mg, about 0.1 mg to about 5.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 2 mg to about 5.0 mg, about 3 mg to about 5.0 mg, about 0.05 mg to about 4.0 mg, about 0.05 mg to about 3.0 mg, about 0.05 mg to about 2.0 mg, about 0.1 mg to about 2.0 mg, about 0.5 mg to about 2.0 mg, about 2 mg to about 4.0 mg, about 1 mg to about 3.0 mg, about 1 mg, about 2 mg, or about 5 mg), and C1D2 of the bispecific antibody is between about 0.05 mg and about 10.0 mg (for example, about 0.1 mg to about 10.0 mg, about 0.5 mg to about 10.0 mg, 1 mg to about 10.0 mg, about 2 mg to about 3.0 mg, about 5 mg to about 10.0 mg, about 8 mg to about 10.0 mg, about 0.5 mg to about 7.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 1 mg to about 3.0 mg, about 3 mg to about 8.about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 20 mg to about 50 mg, about 30 mg to about 50 mg, about 40 mg to about 50 mg, about 45 mg to about 50 mg, about 13 mg to about 17 mg, about 43 mg to about 48 mg, about 15 mg to about 35 mg, about 25 mg to about 45 mg, about 15 mg, about 30 mg, or about 45 mg) of a bispecific antibody. (b) a second administration cycle comprising: (i) a single dose of an anti-CD79b antibody drug conjugate (C2D1); and (ii) a single dose of a bispecific antibody (C2D1), wherein C2D1 of the bispecific antibody is greater than or equal to C1D2 of the bispecific antibody, and wherein the rate of adverse events is reduced in the population of subjects compared to a reference population of subjects not administered the anti-CD79b antibody drug conjugate.

[0036] In yet another aspect, the invention provides a method of reducing the rate of cytokine release syndrome in a population of subjects having a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder) administered an anti-CD79b antibody drug conjugate and a bispecific antibody that binds CD20 and CD3, comprising administering to one or more subjects of the population an anti-CD79b antibody drug conjugate and a bispecific antibody that binds CD20 and CD3 in a dosing regimen comprising eight or more dosing cycles, wherein (a) the first dosing cycle comprises: (i) administering to one or more subjects of the population an anti-CD79b antibody drug conjugate and a bispecific antibody that binds CD20 and CD3 in a dosing regimen comprising eight or more dosing cycles; The first dose of the antibody (C1D1), the second dose of the bispecific antibody (C1D2), and the third dose of the bispecific antibody (C1D3) are each between about 0.02 mg and about 5.0 mg (e.g., between about 0.05 mg and about 5 mg, between about 0.1 mg and about 5.0 mg, between about 0.5 mg and about 5.0 mg, between about 1 mg and about 5.0 mg, between about 2 mg and about 5.0 mg, between about 3 mg and about 5.0 mg, between about 0.05 mg and about 4.0 mg, between about 0.05 mg and about 3.0 mg, between about 0.05 mg and about 2.0 mg, between about 0.1 mg and about 2.0 mg, between about 0.5 mg and about 5.0 mg, and C1D2 of the bispecific antibody is between about 0.05 mg and about 10.0 mg (for example, about 0.1 mg to about 10.0 mg, about 0.5 mg to about 10.0 mg, 1 mg to about 10.0 mg, about 2 mg to about 3.0 mg, about 5 mg to about 10.0 mg, about 8 mg to about 10.0 mg, about 0.5 mg to about 7.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 1 mg to about 3.0 mg, about 3 mg to about 8.0 mg, about 1 mg g, about 2 mg, or about 5 mg) or between about 10 mg and about 60 mg (e.g., about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 20 mg to about 50 mg, about 30 mg to about 50 mg, about 40 mg to about 50 mg, about 45 mg to about 50 mg, about 13 mg to about 17 mg, about 43 mg to about 48 mg, about 15 mg to about 35 mg, about 25 mg to about 45 mg, about 15 mg, about 30 mg, or about 45 mg), and the C1D3 of the bispecific antibody is about 9 mg, about 13 mg, or about 5 mg.(b) a first dose of the bispecific antibody (C1D1), a second dose of the bispecific antibody (C1D2), and a third dose of the bispecific antibody (C1D3), each dose being about 5 mg, about 20 mg, about 40 mg, about 45 mg, or about 60 mg; and (ii) a single dose of an anti-CD79b antibody drug conjugate (C1D1); (b) a second administration cycle comprising a single dose of the bispecific antibody (C2D1) and a single dose of the anti-CD79b antibody drug conjugate (C2D1); (c) a third administration cycle comprising a single dose of the bispecific antibody (C3D1) and a single dose of the anti-CD79b antibody drug conjugate (C3D1); (d) a fourth administration cycle comprising a single dose of the bispecific antibody (C4D1) and a single dose of the anti-CD79b antibody drug conjugate (C4D1); (e) a fifth administration cycle comprising a single dose of the bispecific antibody (C4D1) and a single dose of the anti-CD79b antibody drug conjugate (C4D1); (f) a sixth administration cycle comprises a single dose of the bispecific antibody (C5D1) and a single dose of the anti-CD79b antibody drug conjugate (C5D1); (f) a sixth administration cycle comprises a single dose of the bispecific antibody (C6D1) and a single dose of the anti-CD79b antibody drug conjugate (C6D1); (g) a seventh administration cycle comprises a single dose of the bispecific antibody (C7D1) and does not include administration of the anti-CD79b antibody drug conjugate; and (h) an eighth administration cycle comprises a single dose of the bispecific antibody (C8D1) and does not include administration of the anti-CD79b antibody drug conjugate, wherein each single dose of the bispecific antibody, C2D1 through C8D1, is equal to or greater than C1D3, and the rate of adverse events is reduced in the population of subjects compared to a reference population of subjects not administered the anti-CD79b antibody drug conjugate.

[0037] In yet another aspect, the invention provides a method of reducing the rate of cytokine release syndrome in a population of subjects having a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder) administered an anti-CD79b antibody drug conjugate and a bispecific antibody that binds CD20 and CD3, comprising administering to one or more subjects of the population an anti-CD79b antibody drug conjugate and a bispecific antibody that binds CD20 and CD3 in a dosing regimen comprising eight or more dosing cycles, wherein (a) the first dosing cycle comprises: (i) administering to one or more subjects of the population an anti-CD79b antibody drug conjugate and a bispecific antibody that binds CD20 and CD3 in a dosing regimen comprising eight or more dosing cycles; The first dose of the antibody (C1D1), the second dose of the bispecific antibody (C1D2), and the third dose of the bispecific antibody (C1D3) are each between about 0.02 mg and about 5.0 mg (e.g., between about 0.05 mg and about 5 mg, between about 0.1 mg and about 5.0 mg, between about 0.5 mg and about 5.0 mg, between about 1 mg and about 5.0 mg, between about 2 mg and about 5.0 mg, between about 3 mg and about 5.0 mg, between about 0.05 mg and about 4.0 mg, between about 0.05 mg and about 3.0 mg, between about 0.05 mg and about 2.0 mg, between about 0.1 mg and about 2.0 mg, between about 0.5 mg and about 5.0 mg, and C1D2 of the bispecific antibody is between about 0.05 mg and about 10.0 mg (for example, about 0.1 mg to about 10.0 mg, about 0.5 mg to about 10.0 mg, 1 mg to about 10.0 mg, about 2 mg to about 3.0 mg, about 5 mg to about 10.0 mg, about 8 mg to about 10.0 mg, about 0.5 mg to about 7.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 1 mg to about 3.0 mg, about 3 mg to about 8.0 mg, about 1 mg g, about 2 mg, or about 5 mg) or between about 10 mg and about 60 mg (e.g., about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 20 mg to about 50 mg, about 30 mg to about 50 mg, about 40 mg to about 50 mg, about 45 mg to about 50 mg, about 13 mg to about 17 mg, about 43 mg to about 48 mg, about 15 mg to about 35 mg, about 25 mg to about 45 mg, about 15 mg, about 30 mg, or about 45 mg), and the C1D3 of the bispecific antibody is about 9 mg, about 13 mg, or about 5 mg.(b) a first dose of the bispecific antibody (C1D1), a second dose of the bispecific antibody (C1D2), and a third dose of the bispecific antibody (C1D3), each dose being about 5 mg, about 20 mg, about 40 mg, about 45 mg, or about 60 mg; and (ii) a single dose of the anti-CD79b antibody drug conjugate (C1D1); (b) a second administration cycle comprising a single dose of the bispecific antibody (C2D1) and an anti-CD79b antibody drug conjugate (C2D3). (c) a third administration cycle comprising a single dose of the bispecific antibody (C3D1) and a single dose of the anti-CD79b antibody drug conjugate (C3D1); (d) a fourth administration cycle comprising a single dose of the bispecific antibody (C4D1) and a single dose of the anti-CD79b antibody drug conjugate (C4D1); (e) a fifth administration cycle comprising a single dose of the bispecific antibody (C4D1) and a single dose of the anti-CD79b antibody drug conjugate (C4D1). (f) a sixth administration cycle comprises a single dose of the bispecific antibody (C6D1) and a single dose of the anti-CD79b antibody drug conjugate (C6D1); (g) a seventh administration cycle comprises a single dose of the bispecific antibody (C7D1) and no administration of the anti-CD79b antibody drug conjugate; and (h) an eighth administration cycle comprises a single dose of the bispecific antibody (C8D1) and no administration of the anti-CD79b antibody drug conjugate, wherein the single dose C2D1 is approximately equivalent to C1D3 and each of the single doses C3D1 through C8D1 of the bispecific antibody is less than C1D3, and the rate of adverse events is reduced in the population of subjects compared to a reference population of subjects not administered the anti-CD79b antibody drug conjugate. In some embodiments, each single dose of bispecific antibody C3D1-C8D1 is between about 10 mg and about 45 mg (e.g., between about 10 mg and about 40 mg, between about 10 mg and about 35 mg, between about 15 mg and about 45 mg, between about 20 mg and about 45 mg, or between about 25 mg and about 45 mg; e.g., about 30 mg).

[0038] In a further aspect, the invention provides a method of reducing the rate of cytokine release syndrome in a population of subjects having a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder) administered an anti-CD79b antibody drug conjugate and a bispecific antibody that binds CD20 and CD3, comprising administering to one or more subjects of the population an anti-CD79b antibody drug conjugate and a bispecific antibody that binds CD20 and CD3 in a dosing regimen comprising eight or more dosing cycles, wherein (a) the first dosing cycle , a first dose of the bispecific antibody (C1D1) and a second dose of the bispecific antibody (C1D2), wherein C1D1 of the bispecific antibody is between about 0.02 mg and about 5.0 mg (e.g., about 0.05 mg to about 5 mg, about 0.1 mg to about 5.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 2 mg to about 5.0 mg, about 3 mg to about 5.0 mg, about 0.05 mg to about 4.0 mg, about 0.05 mg to about 3.0 mg, about 0.05 mg to about 2.0 mg, about 0.1 mg to about 2.0 mg, about 0.5 mg to about 2. 0 mg, about 2 mg to about 4.0 mg, about 1 mg to about 3.0 mg, about 1 mg, about 2 mg, or about 5 mg), and C1D2 is between about 0.05 mg to about 10.0 mg (for example, about 0.1 mg to about 10.0 mg, about 0.5 mg to about 10.0 mg, 1 mg to about 10.0 mg, about 2 mg to about 3.0 mg, about 5 mg to about 10.0 mg, about 8 mg to about 10.0 mg, about 0.5 mg to about 7.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 1 mg to about 3.0 mg, about 3 mg to about 8.0 mg, about 1 mg, about 2 mg, or about 5 mg) or between about 10 mg and about 60 mg (e.g., about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 20 mg to about 50 mg, about 30 mg to about 50 mg, about 40 mg to about 50 mg, about 45 mg to about 50 mg, about 13 mg to about 17 mg, about 43 mg to about 48 mg, about 15 mg to about 35 mg, about 25 mg to about 45 mg, about 15 mg, about 30 mg, or about 45 mg), and C1D3 is about 9 mg, about 13 mg, or about 17 mg.(b) a first dose of the bispecific antibody (C1D1) and a second dose of the bispecific antibody (C1D2), each of which is about 5 mg, about 20 mg, about 40 mg, about 45 mg, or about 60 mg; (b) a second administration cycle comprising a single dose of the bispecific antibody (C2D1) and a single dose of the anti-CD79b antibody drug conjugate (C2D1); (c) a third administration cycle comprising a single dose of the bispecific antibody (C3D1) and a single dose of the anti-CD79b antibody drug conjugate (C3D1); (d) a fourth administration cycle comprising a single dose of the bispecific antibody (C4D1) and a single dose of the anti-CD79b antibody drug conjugate (C4D1); (e) a fifth administration cycle comprising a single dose of the bispecific antibody (C5D1) and a single dose of the anti-CD79b antibody drug conjugate (C5D1). (f) a sixth administration cycle comprises a single dose of the bispecific antibody (C6D1) and a single dose of the anti-CD79b antibody drug conjugate (C6D1); (g) a seventh administration cycle comprises a single dose of the bispecific antibody (C7D1) and does not include administration of the anti-CD79b antibody drug conjugate; and (h) an eighth administration cycle comprises a single dose of the bispecific antibody (C8D1) and does not include administration of the anti-CD79b antibody drug conjugate, wherein each single dose of the bispecific antibody, C2D1 through C8D1, is equal to or greater than C1D2, and the rate of adverse events is reduced in the population of subjects compared to a reference population of subjects not administered the anti-CD79b antibody drug conjugate.

[0039] In another aspect, the invention provides a method of reducing the rate of cytokine release syndrome in a population of subjects with a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder) administered an anti-CD79b antibody drug conjugate and a bispecific antibody that binds CD20 and CD3, comprising administering to one or more subjects of the population the anti-CD79b antibody drug conjugate and the bispecific antibody that binds CD20 and CD3 in a dosing regimen comprising eight or more administration cycles, wherein (a) the first administration cycle comprises (i) a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody, wherein C1D1 of the bispecific antibody is between about 0.02 mg and about 5.0 mg (e.g., about 0.05 mg to about 5 mg, about 0.1 mg to about 5.0 mg, about 0.5 mg to about 5.0 mg, mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 2 mg to about 5.0 mg, about 3 mg to about 5.0 mg, about 0.05 mg to about 4.0 mg, about 0.05 mg to about 3.0 mg, about 0.05 mg to about 2.0 mg, about 0.1 mg to about 2.0 mg, about 0.5 mg to about 2.0 mg, about 2 mg to about 4.0 mg, about 1 mg to about 3.0 mg, about 1 mg, about 2 mg, or about 5 mg), and C1 D2 is between about 0.05 mg and about 10.0 mg (e.g., about 0.1 mg to about 10.0 mg, about 0.5 mg to about 10.0 mg, 1 mg to about 10.0 mg, about 2 mg to about 3.0 mg, about 5 mg to about 10.0 mg, about 8 mg to about 10.0 mg, about 0.5 mg to about 7.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 1 mg to about 3.0 mg, about 3 mg to about 8.the first dose of the bispecific antibody is about 0 mg, about 1 mg, about 2 mg, or about 5 mg) or between about 10 mg and about 60 mg (e.g., about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 20 mg to about 50 mg, about 30 mg to about 50 mg, about 40 mg to about 50 mg, about 45 mg to about 50 mg, about 13 mg to about 17 mg, about 43 mg to about 48 mg, about 15 mg to about 35 mg, about 25 mg to about 45 mg, about 15 mg, about 30 mg, or about 45 mg). (b) a second administration cycle comprising (i) a single dose of the bispecific antibody (C2D1), wherein the C2D1 of the bispecific antibody is about 9 mg, about 13.5 mg, about 20 mg, about 40 mg, about 45 mg, or about 60 mg; and (ii) a single dose of the anti-CD79b antibody drug conjugate (C2D1); (c) a third administration cycle comprising (i) a single dose of the bispecific antibody (C2D1), wherein the C2D1 of the bispecific antibody is about 9 mg, about 13.5 mg, about 20 mg, about 40 mg, about 45 mg, or about 60 mg; and (ii) a single dose of the anti-CD79b antibody drug conjugate (C2D1); (d) a fourth administration cycle comprising a single dose of the bispecific antibody (C3D1) and a single dose of the anti-CD79b antibody drug conjugate (C3D1); (d) a fourth administration cycle comprising a single dose of the bispecific antibody (C4D1) and a single dose of the anti-CD79b antibody drug conjugate (C4D1); (e) a fifth administration cycle comprising a single dose of the bispecific antibody (C5D1) and a single dose of the anti-CD79b antibody drug conjugate (C5D1); (f) a sixth administration cycle comprising a single dose of the bispecific antibody (C6D1) and a single dose of the anti-CD79b antibody drug conjugate. (g) a seventh administration cycle comprises a single dose of the bispecific antibody (C7D1) and does not include administration of an anti-CD79b antibody drug conjugate; and (h) an eighth administration cycle comprises a single dose of the bispecific antibody (C8D1) and does not include administration of an anti-CD79b antibody drug conjugate, wherein each single dose of the bispecific antibody, C2D1 through C8D1, is equal to or greater than C1D2, and the rate of adverse events is reduced in the population of subjects compared to a reference population of subjects not administered the anti-CD79b antibody drug conjugate.

[0040] In some embodiments, the rate of cytokine release syndrome in a population of subjects is about 20% or less (e.g., about 18% or less, about 15% or less, about 14% or less, about 13% or less, about 12% or less, about 11% or less, about 10% or less, about 9% or less, about 8% or less, about 7% or less, about 6% or less, about 5% or less, about 4% or less, about 3% or less, about 2% or less, about 1% or less; e.g., between about 0% and about 20%, Between about 1% and about 20%, between about 5% and about 20%, between about 10% and about 20%, between about 15% and about 20%, between about 0% and about 5%, between about 1% and about 5%, between about 1% and about 10%, between about 5% and about 10%, between about 10% and about 15%, or between about 5% and about 15%; for example, 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 in a population of subjects is about 10% or less (e.g., about 9% or less, about 8% or less, about 7% or less, about 6% or less, about 5% or less, about 4% or less, about 3% or less, about 2% or less, or about 1% or less; e.g., between about 0.1% and about 10%, between about 0.5% and about 10%, between about 1% and about 10%, between about 1% and about 7%, between about 1% and about 5%, between about 1% and about 3%, or between about 5% and about 10%; e.g., 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 in a population of subjects is about 5% or less (e.g., about 1% to about 5%, about 2% to about 5%, about 3% to about 5%, about 4% to about 5%, about 0% to about 4%, about 1% to about 4%, about 2% to about 4%, about 3% to about 4%, about 0% to about 3%, about 1% to about 3%, about 2% to about 3%, about 0% to about 2%, about 1% to about 2%, or about 0% to about 1%; e.g., about 5%, about 4%, about 3%, about 2%, about 1%, or about 0%). In some embodiments, the rate of cytokine release syndrome in a population of subjects is about 3% or less.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, 2019; ASTCT) is about 20% or less (e.g., about 18% or less, about 15% or less, about 14% or less, about 13% or less, about 12% or less, about 11% or less, about 10% or less, about 9% or less, about 8% or less, about 7% or less, about 6% or less, about 5% or less, about 4% or less, about 3% or less, about 2% or less, about 1% or less; e.g., about 0% to about 20%. %, between about 1% and about 20%, between about 5% and about 20%, between about 10% and about 20%, between about 15% and about 20%, between about 0% and about 5%, between about 1% and about 5%, between about 1% and about 10%, between about 5% and about 10%, between about 10% and about 15%, or between about 5% and about 15%; for example, 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 having Grade 2 or higher (as defined by ASTCT) is about 5% or less (e.g., between about 1% and about 5%, between about 2% and about 5%, between about 3% and about 5%, between about 4% and about 5%, between about 0% and about 4%, between about 1% and about 4%, between about 2% and about 4%, between about 3% and about 4%, between about 0% and about 3%, between about 1% and about 3%, between about 2% and about 3%, between about 0% and about 2%, between about 1% and about 2%, or between about 0% and about 1%; e.g., about 5%, about 4%, about 3%, about 2%, about 1%, or about 0%). In some embodiments, the rate of cytokine release syndrome having Grade 2 or higher (as defined by ASTCT) is about 0%.

[0041] In some embodiments, the CD20-positive cell proliferative disorder is a B-cell proliferative disorder. In some embodiments, the B-cell proliferative disorder is non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), or central nervous system lymphoma (CNSL). In some embodiments, the NHL is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma (PMLBCL), diffuse B-cell lymphoma, small lymphocytic lymphoma, marginal zone lymphoma, Burkitt's lymphoma, or lymphoplasmacytic lymphoma. In some embodiments, the NHL is relapsed or refractory NHL. In some embodiments, the NHL is FL. In some embodiments, the NHL is DLBCL. In some embodiments, the NHL is MCL. 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 relapsed or refractory FL. In some embodiments, the FL is transformed FL. In some embodiments, the MCL is relapsed or refractory MCL. In some embodiments, the B-cell proliferative disorder is relapsed and / or refractory.

[0042] In some embodiments of any of the above aspects, the anti-CD79b antibody drug conjugate is polatuzumab vedotin or anti-CD79b-MC-vc-PAB-MMAE, hi some embodiments, the anti-CD79b antibody drug conjugate is polatuzumab vedotin.

[0043] In some embodiments of any of the above 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 APSNLAS (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) 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 first binding domain comprising the VH domain described in (a) and the VL domain described 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.

[0044] In some embodiments of any of the above aspects, the bispecific antibody comprises an anti-CD3 arm comprising a second binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of NYYIH (SEQ ID NO: 17); (b) HVR-H2 comprising the amino acid sequence of WIYPGDGNTKYNEKFKG (SEQ ID NO: 18); (c) HVR-H3 comprising the amino acid sequence of DSYSNYYFDY (SEQ ID NO: 19); (d) HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 20); (e) HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 21); and (f) HVR-L3 comprising the amino acid sequence of TQSFILRT (SEQ ID NO: 22). In some embodiments, the bispecific antibody comprises an anti-CD3 arm comprising: (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 23; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 24; or (c) a second binding domain comprising the VH domain of (a) and the VL domain of (b). In some embodiments, the second binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 23 and a VL domain comprising the amino acid sequence of SEQ ID NO: 24.

[0045] In some embodiments, the bispecific antibody comprises (a) an anti-CD20 arm comprising (i) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 85 and (ii) a light chain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 86, and (b) an anti-CD3 arm comprising (i) a heavy chain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 83 and (ii) a light chain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 84. In some antibodies, (a) the anti-CD20 arm comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 85 and a light chain comprising the amino acid sequence of SEQ ID NO: 86, and (b) the anti-CD3 arm comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 83 and a light chain comprising the amino acid sequence of SEQ ID NO: 84.

[0046] In some embodiments of any of the above 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 CD20 and CD3. In some embodiments, the antibody fragment is selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab')2 fragments. 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 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 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.

[0047] In some embodiments of any of the above aspects, the bispecific antibody comprises one or more heavy chain constant domains, wherein 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 is paired with another heavy chain constant domain. In some embodiments, the CH31 domain and the CH32 domain each comprise a protrusion or a cavity, and the protrusion or cavity of the CH31 domain is positionable in the cavity or protrusion of the CH32 domain, respectively. In some embodiments, the CH31 and CH32 domains associate 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 positioned 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.

[0048] In some embodiments, the anti-CD20 arm of the bispecific antibody further comprises T366W and N297G substitution mutations (EU numbering). In some embodiments, the anti-CD3 arm of the bispecific antibody further comprises T366S, L368A, Y407V, and N297G substitution mutations (EU numbering). In some embodiments, (a) the anti-CD20 arm further comprises T366W and N297G substitution mutations, and (b) the anti-CD3 arm further comprises T366S, L368A, Y407V, and N297G substitution mutations (EU numbering).

[0049] In another aspect, the invention provides a method of treating a subject with NHL, comprising administering to the subject polatuzumab vedotin and 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 dose of mosunetuzumab (C1D1), a second dose of mosunetuzumab (C1D2), and a third dose of mosunetuzumab (C1D3), wherein C1D1 of mosunetuzumab is about 1 mg and C1D2 of mosunetuzumab is about 1 mg. (b) a second administration cycle comprising a first dose of mosunetuzumab (C1D1), a second dose of mosunetuzumab (C1D2), and a third dose of mosunetuzumab (C1D3), wherein C1D1 of mosunetuzumab is about 2 mg, and C1D3 of mosunetuzumab is about 9 mg, about 13.5 mg, about 20 mg, about 40 mg, about 45 mg, or about 60 mg; and (b) a second administration cycle comprising a single dose of mosunetuzumab (C2D1), wherein C2D1 of mosunetuzumab is equal to or greater than C1D3.

[0050] In yet another aspect, the invention provides a method of treating a subject with NHL (e.g., relapsed and / or refractory NHL), comprising administering to the subject polatuzumab vedotin and mosunetuzumab in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein (a) the first dosing cycle comprises: (i) a single dose (C1D1) of polatuzumab vedotin; and (ii) a first dose (C1D1) of mosunetuzumab and a second dose (C1D2) of mosunetuzumab, wherein C1D1 and C1D2 of mosunetuzumab, respectively, are administered to the subject after C1D1 of polatuzumab vedotin; and (b) a second administration cycle comprising: (i) a single dose of polatuzumab vedotin (C2D1); and (ii) a single dose of mosunetuzumab (C2D1) wherein C2D1 of mosunetuzumab is about 9 mg, about 13.5 mg, about 20 mg, about 40 mg, about 45 mg, or about 60 mg, and C1D1 and C2D2 of mosunetuzumab vedotin are each about 1.8 mg / kg.

[0051] In a further aspect, the invention provides a method of treating a subject with NHL (e.g., relapsed and / or refractory NHL), comprising administering to the subject polatuzumab vedotin and mosunetuzumab in a dosing regimen comprising eight or more dosing cycles, wherein (a) the first dosing cycle comprises: (i) a first dose of mosunetuzumab (C1D1), a second dose of mosunetuzumab (C1D2), and a third dose of mosunetuzumab (C1D3), wherein C1D1 of mosunetuzumab is about 1 mg; (b) a first dose of mosunetuzumab (C1D1), a second dose of mosunetuzumab (C1D2), and a third dose of mosunetuzumab (C1D3), wherein C1D2 of mosunetuzumab is about 2 mg and C1D3 of mosunetuzumab is about 9 mg, about 13.5 mg, about 20 mg, about 40 mg, about 45 mg, or about 60 mg; and (ii) a single dose of polatuzumab vedotin (C1D1); (b) a second administration cycle comprising a single dose of mosunetuzumab (C2D1) and a single dose of polatuzumab vedotin (C2D3). (c) the third administration cycle comprises a single dose of mosunetuzumab (C3D1) and a single dose of polatuzumab vedotin (C3D1); (d) the fourth administration cycle comprises a single dose of mosunetuzumab (C4D1) and a single dose of polatuzumab vedotin (C4D1); (e) the fifth administration cycle comprises a single dose of mosunetuzumab (C5D1) and a single dose of polatuzumab vedotin (C5D1); (f) the sixth administration cycle comprises a single dose of mosunetuzumab (C6D1) and (g) the seventh administration cycle includes a single dose of mosunetuzumab (C7D1) and does not include administration of polatuzumab vedotin; and (h) the eighth administration cycle includes a single dose of mosunetuzumab (C8D1) and does not include administration of polatuzumab vedotin, wherein each single dose of mosunetuzumab C2D1 to C8D1 is approximately equal to or less than C1D3, and each single dose of polatuzumab vedotin C1D1 to C6D1 is approximately 1.8 mg / kg.

[0052] In yet another aspect, the invention provides a method of treating a subject with NHL (e.g., relapsed and / or refractory NHL), comprising administering to the subject polatuzumab vedotin and mosunetuzumab in a dosing regimen comprising eight or more dosing cycles, wherein: (a) the first dosing cycle comprises a first dose of mosunetuzumab (C1D1), a second dose of mosunetuzumab (C1D2), and a third dose of mosunetuzumab, wherein C1D1 of mosunetuzumab is about 0.02 mg to Between about 5.0 mg (e.g., about 0.05 mg to about 5 mg, about 0.1 mg to about 5.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 2 mg to about 5.0 mg, about 3 mg to about 5.0 mg, about 0.05 mg to about 4.0 mg, about 0.05 mg to about 3.0 mg, about 0.05 mg to about 2.0 mg, about 0.1 mg to about 2.0 mg, about 0.5 mg to about 2.0 mg, about 2 mg to about 4.0 mg, about 1 mg to about 3.0 mg, about 1 mg, about 2 mg, or about 5 mg) and C1D2 is between about 0.05 mg and about 10.0 mg (e.g., about 0.1 mg to about 10.0 mg, about 0.5 mg to about 10.0 mg, 1 mg to about 10.0 mg, about 2 mg to about 3.0 mg, about 5 mg to about 10.0 mg, about 8 mg to about 10.0 mg, about 0.5 mg to about 7.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 1 mg to about 3.0 mg, about 3 mg to about 8.0 mg, about 1 mg, about 2 mg, or about 5 mg) or about 10 mg to about 60 mg (e.g., about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 20 mg to about 50 mg, about 30 mg to about 50 mg, about 40 mg to about 50 mg, about 45 mg to about 50 mg, about 13 mg to about 17 mg, about 43 mg to about 48 mg, about 15 mg to about 35 mg, about 25 mg to about 45 mg, about 15 mg, about 30 mg, or about 45 mg), and C1D3 is about 9 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 23 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, or about 45 mg).(b) the first dose of mosunetuzumab (C1D1), the second dose of mosunetuzumab (C1D2), and the third dose of mosunetuzumab are about 5 mg, about 20 mg, about 40 mg, about 45 mg, or about 60 mg; (b) the second administration cycle comprises a single dose of mosunetuzumab (C2D1) and a single dose of polatuzumab vedotin (C2D1); (c) the third administration cycle comprises a single dose of mosunetuzumab (C3D1) and a single dose of polatuzumab vedotin (C3D1); (d) the fourth administration cycle comprises a single dose of mosunetuzumab (C4D1) and a single dose of polatuzumab vedotin (C4D1); (e) the fifth administration cycle comprises a single dose of mosunetuzumab (f) the sixth administration cycle comprises a single dose of mosunetuzumab (C6D1) and a single dose of polatuzumab vedotin (C6D1); (g) the seventh administration cycle comprises a single dose of mosunetuzumab (C7D1) but does not include administration of polatuzumab vedotin; and (h) the eighth administration cycle comprises a single dose of mosunetuzumab (C8D1) but does not include administration of polatuzumab vedotin, wherein each single dose of mosunetuzumab C2D1 to C8D1 is approximately equal to or less than C1D3, and each single dose of polatuzumab vedotin C2D1 to C6D1 is approximately 1.8 mg / kg.

[0053] In a further aspect, the invention provides a method of treating a subject with NHL, comprising administering to the subject polatuzumab vedotin and mosunetuzumab in a dosing regimen comprising eight or more dosing cycles, wherein (a) the first dosing cycle comprises (i) a first dose (C1D1) and a second dose (C1D2) of mosunetuzumab, wherein C1D1 of mosunetuzumab is between about 0.02 mg and about 5.0 mg (e.g., about 0.05 mg to about 5 mg, about 0.1 mg to about 5.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 5.0 mg, about 2 mg to about 5.0 mg, about 3 mg to about 5.0 mg, about 0.05 mg to about 4.0 mg, about 0.05 mg to about 3.0 mg, about 0.05 mg to about 2.0 mg, about 0.1 mg to about 2.0 mg, about 0.5 mg to about 2.0 mg, about 2 mg to about 4.0 mg, about 1 mg to about 3.0 mg, about 1 mg, about 2 mg, or about 5 mg), and C1D2 is between about 0.05 mg and about 10.0 mg (for example, about 0.1 mg to about 10.0 mg, about 0.5 mg to about 10.0 mg, 1 mg to about 10.0 mg, about 2 mg g to about 3.0 mg, about 5 mg to about 10.0 mg, about 8 mg to about 10.0 mg, about 0.5 mg to about 7.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 1 mg to about 3.0 mg, about 3 mg to about 8.0 mg, about 1 mg, about 2 mg, or about 5 mg) or between about 10 mg and about 60 mg (e.g., about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 20 mg to about 50 mg, about 30 mg to about 50 mg, about 4 (b) a second administration cycle comprising (i) a first dose (C1D1) and a second dose (C1D2) of mosunetuzumab, wherein the C2D1 dose of mosunetuzumab is about 9 mg to about 50 mg, about 45 mg to about 50 mg, about 13 mg to about 17 mg, about 43 mg to about 48 mg, about 15 mg to about 35 mg, about 25 mg to about 45 mg, about 15 mg, about 30 mg, or about 45 mg; and (ii) a single dose (C1D1) of polatuzumab vedotin; (b) a second administration cycle comprising (i) a single dose (C2D1) of mosunetuzumab, wherein the C2D1 dose of mosunetuzumab is about 9 mg, about 13 mg, about 15 mg, about 30 mg, or about 45 mg.(c) a third administration cycle comprising a single dose of mosunetuzumab (C3D1) and a single dose of polatuzumab vedotin (C3D1); (d) a fourth administration cycle comprising a single dose of mosunetuzumab (C4D1) and a single dose of polatuzumab vedotin (C4D1); (e) a fifth administration cycle comprising a single dose of mosunetuzumab (C5D1) and a single dose of polatuzumab vedotin (C5D1). (f) the sixth administration cycle comprises a single dose of mosunetuzumab (C6D1) and a single dose of polatuzumab vedotin (C6D1); (g) the seventh administration cycle comprises a single dose of mosunetuzumab (C7D1) and does not comprise administration of polatuzumab vedotin; and (h) the eighth administration cycle comprises a single dose of mosunetuzumab (C8D1) and does not comprise administration of polatuzumab vedotin, wherein each of the single doses of mosunetuzumab C2D1 to C8D1 is approximately equal to or less than C1D3, and each of the single doses of polatuzumab vedotin C1D1 to C6D1 is approximately 1.8 mg / kg.

[0054] In some embodiments, the NHL is aggressive NHL (e.g., de novo DLBCL, transformed FL, or grade 3b FL). In some embodiments, the NHL is DLBCL. In some embodiments, the NHL is R / RMCL.

[0055] In one aspect, the invention provides a method of treating a population of subjects having a CD20-positive cell proliferative disorder, comprising administering to the subject an anti-CD79b antibody drug conjugate and 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: (i) a first dose of the bispecific antibody (C1D1), a second dose of the bispecific antibody (C1D2), and a third dose of the bispecific antibody (C1D3), wherein C1D1 of the bispecific antibody is between about 0.02 mg and about 2.0 mg (e.g., For example, between about 0.05 mg and about 2 mg, between about 0.1 mg and about 2 mg, between about 0.5 mg and about 2 mg, between about 0.5 mg and about 1.5 mg, between about 0.8 mg and about 1.2 mg, between about 0.5 mg and about 1 mg, or between about 1 mg and about 2 mg, for example, about 0.5 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.5 mg, or about 2 mg), and C1D2 of the bispecific antibody is between about 0.05 mg and about 5 mg (for example, between about 0.1 mg and about 5 mg, between about 0.1 mg and about 4 mg, between about 0.1 mg and about 3 mg, about 0.5 mg a first dose (C1D1) of the bispecific antibody, a second dose (C1D2) of the bispecific antibody, and a third dose (C1D3) of the bispecific antibody, wherein the first dose (C1D1) of the bispecific antibody is about 9 mg, about 13.5 mg, about 20 mg, or about 40 mg, between about 1 mg and about 3 mg, between about 1.5 mg and about 2.5 mg, between about 1.8 mg and about 2.2 mg, between about 3 mg and about 5 mg, between about 2 mg and about 4 mg, or between about 1 mg and about 5 mg; for example, about 0.5 mg, about 1 mg, about 1.5 mg, about 1.8 mg, about 1.9 mg, about 2 mg, about 2.1 mg, about 2.2 mg, about 2.5 mg, about 3 mg, about 4 mg, or about 5 mg), and the C1D3 of the bispecific antibody is about 9 mg, about 13.5 mg, about 20 mg, or about 40 mg. (b) a second administration cycle comprising (i) a single dose of the bispecific antibody (C2D1), wherein the C2D1 of the bispecific antibody is approximately equal to the C1D3 dose; and (ii) a single dose of the anti-CD79b antibody drug conjugate (C2D1), wherein the C1D1 of the anti-CD79b antibody drug conjugate and the C2D1 of the anti-CD79b antibody drug conjugate are each approximately 1.It contains a single dose of anti-CD79b antibody drug conjugate (C2D1) at 8 mg / kg.

[0056] In another aspect, the invention provides a method of treating a population of subjects having a CD20-positive cell proliferative disorder, comprising administering to the subjects an anti-CD79b antibody drug conjugate and 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: (i) a first dose of the bispecific antibody (C1D1), a second dose of the bispecific antibody (C1D2), and a third dose of the bispecific antibody (C1D3), wherein C1D1 of the bispecific antibody is about 1 mg, C1D2 of the bispecific antibody is about 2 mg, and C1D3 of the bispecific antibody is about 9 mg, about 13.5 mg, about 20 mg, or about 40 mg. (b) a second administration cycle comprising: (i) a single dose of the bispecific antibody (C2D1), wherein the C2D1 of the bispecific antibody is approximately equivalent to the C1D3 dose; and (ii) a single dose of the anti-CD79b antibody drug conjugate (C1D1), wherein the C1D1 of the anti-CD79b antibody drug conjugate and the C2D1 of the anti-CD79b antibody drug conjugate are each approximately 1.8 mg / kg.

[0057] In another aspect, the invention provides a method of treating a population of subjects having a CD20-positive cell proliferative disorder, comprising administering to the subjects an anti-CD79b antibody drug conjugate and a bispecific antibody that binds CD20 and CD3 in a dosing regimen comprising eight or more administration cycles, wherein (a) the first administration cycle comprises (i) a first dose of the bispecific antibody (C1D1), a second dose of the bispecific antibody (C1D2), and a third dose of the bispecific antibody (C1D3), wherein C1D1 of the bispecific antibody is between about 0.02 mg and about 2.0 mg (e.g., between about 0.05 mg and about 2 mg, between about 0.1 mg and about 2 mg, between about 0.5 mg and about 2 mg, between about 0.5 mg and about 1.5 mg, between about 0.8 mg and about 1.2 mg, between about 0.5 mg and about 1 mg, or about 1 mg). and the C1D2 of the bispecific antibody is between about 0.05 mg and about 5 mg (for example, between about 0.1 mg and about 5 mg, between about 0.1 mg and about 4 mg, between about 0.1 mg and about 3 mg, between about 0.5 mg and about 3 mg, between about 1 mg and about The bispecific antibody C1D3 is about 9 mg, about 13 mg, about 15 mg, about 20 mg, about 3 mg, about 1.5 mg to about 2.5 mg, about 3 mg to about 5 mg, about 2 mg to about 4 mg, or about 1 mg to about 5 mg; for example, about 0.5 mg, about 1 mg, about 1.5 mg, about 1.8 mg, about 1.9 mg, about 2 mg, about 2.1 mg, about 2.2 mg, about 2.5 mg, about 3 mg, about 4 mg, or about 5 mg).(b) a first dose of the bispecific antibody (C1D1), a second dose of the bispecific antibody (C1D2), and a third dose of the bispecific antibody (C1D3), each dose being about 5 mg, about 20 mg, or about 40 mg; and (ii) a single dose of an anti-CD79b antibody drug conjugate (C1D1); (b) a second administration cycle comprising a single dose of the bispecific antibody (C2D1) and a single dose of the anti-CD79b antibody drug conjugate (C2D1); (c) a third administration cycle comprising a single dose of the bispecific antibody (C3D1) and a single dose of the anti-CD79b antibody drug conjugate (C3D1); (d) a fourth administration cycle comprising a single dose of the bispecific antibody (C4D1) and a single dose of the anti-CD79b antibody drug conjugate (C4D1); (e) a fifth administration cycle comprising a single dose of the bispecific antibody (C4D1) and a single dose of the anti-CD79b antibody drug conjugate (C4D1); (f) the sixth administration cycle comprises a single dose of the bispecific antibody (C5D1) and a single dose of the anti-CD79b antibody drug conjugate (C5D1); (f) the sixth administration cycle comprises a single dose of the bispecific antibody (C6D1) and a single dose of the anti-CD79b antibody drug conjugate (C6D1); (g) the seventh administration cycle comprises a single dose of the bispecific antibody (C7D1) but does not include administration of the anti-CD79b antibody drug conjugate; and (h) the eighth administration cycle comprises a single dose of the bispecific antibody (C8D1) but does not include administration of the anti-CD79b antibody drug conjugate, wherein each single dose of the bispecific antibody, C2D1 to C8D1, is approximately equivalent to C1D3, and each single dose of the anti-CD79b antibody drug conjugate, C1D1 to C6D1, is approximately 1.8 mg / kg.

[0058] In another aspect, the invention provides a method of treating a population of subjects having a CD20-positive cell proliferative disorder, comprising administering to the subject an anti-CD79b antibody drug conjugate and a bispecific antibody that binds CD20 and CD3 in a dosing regimen comprising eight or more dosing cycles, wherein: (a) the first dosing cycle comprises a first dose of the bispecific antibody (C1D1), a second dose of the bispecific antibody (C1D2), and a third dose of the bispecific antibody, wherein the bispecific antibody C1D1 is administered in a dose range of about 0.02 mg to about 5.0 mg; (b) a first administration cycle comprising a first dose of the bispecific antibody (C1D1), a second dose of the bispecific antibody (C1D2), and a third dose of the bispecific antibody, wherein C1D2 is between about 0.05 mg and about 60 mg, C1D3 is about 9 mg, about 13.5 mg, about 20 mg, or about 40 mg; (b) a second administration cycle comprising a single dose of the bispecific antibody (C2D1) and a single dose of the anti-CD79b antibody drug conjugate (C2D1); (c) a third administration cycle comprising a single dose of the bispecific antibody (C3D (d) a fourth administration cycle comprising a single dose of the bispecific antibody (C4D1) and a single dose of the anti-CD79b antibody drug conjugate (C4D1); (e) a fifth administration cycle comprising a single dose of the bispecific antibody (C5D1) and a single dose of the anti-CD79b antibody drug conjugate (C5D1); (f) a sixth administration cycle comprising a single dose of the bispecific antibody (C6D1) and a single dose of the anti-CD79b antibody drug conjugate. (g) a seventh administration cycle comprises a single dose of the bispecific antibody (C7D1) and does not comprise administration of an anti-CD79b antibody drug conjugate; and (h) an eighth administration cycle comprises a single dose of the bispecific antibody (C8D1) and does not comprise administration of an anti-CD79b antibody drug conjugate, wherein each single dose C2D1-C8D1 of the bispecific antibody is approximately equivalent to C1D3, and each single dose C1D1-C6D1 of the anti-CD79b antibody drug conjugate is approximately 1.8 mg / kg.

[0059] In some embodiments, the CD20-positive cell proliferative disorder is NHL. In some embodiments, the overall response rate is at least 55% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%; e.g., between 55% and 100%, between 55% and 90%, between 55% and 80%, between 55% and 70%, between 55% and 65%, between 55% and 60%, between 60% and 65%, between 60% and 70%, between 60% and 90%, or between 70% and 90%; e.g., about 55%, about 60%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%). In some embodiments, the overall response rate is at least 65%. In some embodiments, the complete response rate is at least 45% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 80%, at least 85%, at least 90%, or at least 95%; e.g., between 45% and 100%, between 45% and 80%, between 45% and 60%, between 45% and 55%, between 45% and 50%, between 50% and 55%, between 50% and 65%, between 50% and 70%, between 60% and 70%, or between 70% and 90%; e.g., about 45%, about 50%, about 53%, about 54%, about 55%, about 56%, about 57%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%). In some embodiments, the complete response rate is at least 55%.

[0060] In some embodiments, the CD20-positive cell proliferative disorder is aggressive NHL (eg, de novo DLBCL, transformed FL, or grade 3b FL). In some embodiments, the overall response rate is at least 50% (e.g., at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%; e.g., between 50% and 100%, between 50% and 80%, between 50% and 60%, between 50% and 55%, between 55% and 60%, between 55% and 65%, between 50% and 70%, between 60% and 70%, or between 70% and 90%; e.g., about 50%, about 55%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%). In some embodiments, the overall response rate is at least 60%. In some embodiments, the complete response rate is at least 35% (e.g., at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 70%, at least 80%, or at least 90%; e.g., between 35% and 100%, between 35% and 80%, between 35% and 60%, between 35% and 55%, between 35% and 50%, between 35% and 45%, between 40% and 60%, between 45% and 50%, between 45% and 55%, between 45% and 60%, or 50% and 70%; e.g., about 35%, about 40%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 55%, about 60%, about 70%, about 80%, about 90%, or about 95%). In some embodiments, the complete response rate is at least 45%.

[0061] In some embodiments, the CD20-positive cell proliferative disorder is NHL, and the subjects in the population are post-CAR-T subjects (e.g., patients who were treated with CAR-T therapy at least 30 days prior to administration of the first study treatment (e.g., an anti-CD20 / anti-CD3 bispecific antibody and / or an anti-CD79b antibody drug conjugate; e.g., mosunetuzumab and / or polatuzumab vedotin)). In some embodiments, the overall response rate is at least 50% (e.g., at least 55%, at least 60%, at least 65%, at least 70%, at least 80%, at least 85%, at least 90%, or at least 95%; e.g., between 50% and 100%, between 50% and 80%, between 50% and 60%, between 50% and 55%, between 55% and 60%, between 55% and 65%, between 50% and 70%, between 60% and 70%, or between 70% and 90%; e.g., about 50%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%). In some embodiments, the overall response rate is at least 55%. In some embodiments, the complete response rate is at least 20% (e.g., at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 90%; e.g., between 20% and 100%, between 20% and 80%, between 20% and 60%, between 20% and 40%, between 20% and 30%, between 20% and 25%, between 25% and 30%, between 25% and 35%, between 25% and 50%, between 30% and 60%, or between 50% and 70%; e.g., about 20%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 35%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%). In some embodiments, the complete response rate is at least 25%.

[0062] In some embodiments, the CD20-positive cell proliferative disorder is FL. In some embodiments, the overall response rate is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99%; e.g., between 80% and 100%, between 80% and 95%, between 80% and 90%, between 80% and 85%, between 85% and 95%, between 90% and 100%, or between 95% and 100%; e.g., about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%). In some embodiments, the overall response rate is at least 90%. In some embodiments, the complete response rate is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99%; e.g., between 80% and 100%, between 80% and 95%, between 80% and 90%, between 80% and 85%, between 85% and 95%, between 90% and 100%, or between 95% and 100%; e.g., about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%). In some embodiments, the complete response rate is at least 90%.

[0063] In some embodiments, the bispecific antibody is mosunetuzumab. In some embodiments, the anti-CD79b antibody drug conjugate is polatuzumab vedotin.

[0064] In some embodiments of any of the above aspects, the subject is a human. [Brief explanation of the drawings]

[0065] The 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 graph showing the combination efficacy of anti-CD20 / anti-CD3 T cell-dependent bispecific (TDB) antibody (CD20 TDB) + / - anti-CD79b(SN8v28)-MC-vc-PAB-MMAE (anti-CD79b-MC-v-PAB-MMAE) against WSU-DLCL2 B cell lymphoma cells in NSG mice supplemented with human peripheral blood mononuclear cells (PBMCs). From top left to bottom right, the order of the lines is: 5 mg / kg CD20 TDB + no PBMC, vehicle + PBMC, 1 mg / kg CD20 TDB + PBMC, 0.5 mg / kg CD20 TDB + PBMC, 5 mg / kg CD20 TDB + PBMC, anti-CD79b-MC-v-PAB-MMAE + PBMC, anti-CD79b-MC-v-PAB-MMAE + no PBMC, anti-CD79b-MC-v-PAB-MMAE + 0.5 mg / kg CD20 TDB + PBMC, and anti-CD79b-MC-v-PAB-MMAE + 1 mg / kg CD20 TDB + PBMC. [Figure 2] 2 is a series of graphs showing the change in tumor volume over time for individual mice treated as described in Example 1. In particular, panel 1 corresponds to vehicle + PBMC; panel 2 corresponds to 5 mg / kg CD20 TDB + no PBMC; panel 3 corresponds to 0.5 mg / kg CD20 TDB + PBMC; panel 4 corresponds to 1 mg / kg CD20 TDB + PBMC; panel 5 corresponds to 5 mg / kg CD20 TDB + PBMC; panel 6 corresponds to anti-CD79b-MC-v-PAB-MMAE + no PBMC; panel 7 corresponds to anti-CD79b-MC-v-PAB-MMAE + PBMC; panel 8 corresponds to anti-CD79b-MC-v-PAB-MMAE + 0.5 mg / kg CD20 TDB + PBMC; and panel 9 corresponds to anti-CD79b-MC-v-PAB-MMAE + 1 mg / kg CD20 TDB + PBMC. The dashed lines in panels 2-9 indicate the reference fit (vehicle + PBMC in panel 1). The solid black lines in panels 2-9 indicate the fit of the data to each panel. [Figure 3]Figure 3 is an image outlining the study design as described in Example 2. 2L+ = second line or later; approx. = approximately; BR = bendamustine + rituximab; DLBCL = diffuse large B-cell lymphoma; FL = follicular lymphoma; Pola = polatuzumab vedotin; R = randomized; R / R = relapsed or refractory. [Figure 4] Figure 4 is an image outlining the response assessment schedule as described in Example 2. BR = bendamustine + rituximab; CT = computed tomography (scan); PET-CT = positron emission tomography-computed tomography (scan); Pola = polatuzumab vedotin. [Figure 5] Figure 5 is an image showing the administration of mosunetuzumab and polatuzumab vedotin during the dose escalation phase for Groups A, B, and C, as described in Example 2. DL1-DL3 indicate bifractionated dose levels 1-3 of mosunetuzumab. C = cycle (except for Group / Cohort "C"); D = day; DL = dose level; DLT = dose-limiting toxicity; PV = polatuzumab vedotin; MAD = maximum assessed dose. [Figure 6] FIG. 6 is a flow chart showing the schedule of dose-limiting toxicity (DLT) administration and evaluation periods for Group A, as described in Example 2. [Figure 7] FIG. 7 is a flow chart showing the schedule of DLT administration and evaluation periods for Group B, as described in Example 2. [Figure 8] FIG. 7 is a flow chart showing the schedule of DLT administration and evaluation periods for Group C, as described in Example 2. [Figure 9] FIG. 9 is a flow chart outlining the duration of initial study treatment and options for retreatment or extension of study treatment beyond the initial 8 cycles with either mosunetuzumab alone or mosunetuzumab plus polatuzumab vedotin, as described in Example 2. [Figure 10]Figure 10 is a table reporting the frequency of all adverse events associated with mosunetuzumab in 22 safety-evaluable patients in a study of combination treatment with mosunetuzumab and polatuzumab vedotin. The doses reported at the top of the table reflect the C1D1, C1D2, and C1D3 doses of mosunetuzumab. [Figure 11] Figure 11 is a table reporting the frequency of all adverse events associated with polatuzumab vedotin in 22 safety-evaluable patients in a study of combination treatment with mosunetuzumab and polatuzumab vedotin. The doses reported at the top of the table reflect the C1D1, C1D2, and C1D3 doses of mosunetuzumab. [Figure 12] Figures 12A and 12B are a series of graphs showing representative cytokine levels after anti-CD20 / CD3 combination treatment. Figure 12A shows the level of IFNγ in the culture supernatant, and Figure 12B shows the level of TNFα in the culture supernatant. Purified PBMCs from two healthy donors (HD-1 and HD-2) were treated with 100 ng / mL of anti-CD20 / CD3 bispecific antibody and another test article, as indicated. Polatuzumab vedotin, polatuzumab antibody, or gD-vcMMAE was at μg / mL concentrations, while free MMAE was at nM concentrations as labeled. Assays were performed in duplicate. Mean cytokine levels are shown. [Figure 13] Figure 13 is a series of graphs showing T cell activation after anti-CD20 / CD3 combination treatment. Purified PBMCs from two healthy donors (HD-1 and HD-2) were treated with 100 ng / mL of anti-CD20 / CD3 bispecific antibody and another test article, as indicated. Polatuzumab vedotin, polatuzumab antibody, or gD-vcMMAE were at μg / mL concentrations, while free MMAE was at nM concentrations. T cell activation was quantified as the percentage of CD69+ / CD25+ cells among total CD8+ T cells. Assays were performed in duplicate. Mean values ​​are shown. DETAILED DESCRIPTION OF THE INVENTION

[0066] Detailed Description of the Invention I. General TechniquesThe techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodology by those of skill in the art, for example, widely used methodologies such as those described 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); DG Newell, 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 M.P.Calos, eds.,1987);PCR: The Polymerase Chain Reaction,(Mullis et al.,eds.,1994);Current Protocols in Immunology(JEColigan et al.,eds.,1991);Short Protocols inMolecular Biology(Wiley and Sons, 1999); Immunobiology (CA Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Press,2000);Using Antibodies:A Laboratory Manual(E.Harlow and D.Lane(Cold Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and JDCapra, eds., Harwood Academic Publishers, 1995); and Cancer: Principles and Practice of Oncology (VTDeVita et al., eds., JBLippincott Company, 1993). .

[0067] II. Definition It is understood that aspects and embodiments of the invention described herein include aspects and embodiments "comprising," "consisting of," and "consisting essentially of." As used herein, the singular forms "a," "an," and "the" include plural unless otherwise indicated.

[0068] The term "about," as used herein, refers to a normal range of error for the respective value, which would be readily understood by one of ordinary skill in the art. Reference herein to "about" a value or parameter includes (and describes) embodiments that are directed to the value or parameter itself.

[0069] As used interchangeably herein, the "amount," "level," or "expression level" of a biomarker refers to a detectable level in a biological sample. "Expression" generally refers to the process by which information (e.g., genetic coding information and / or epigenetic information) is converted into structures present and functioning in a cell. Thus, as used herein, "expression" can refer to transcription into a polynucleotide, translation into a polypeptide, or even polynucleotide and / or polypeptide modification (e.g., post-translational modification of a polypeptide). Fragments of a transcribed polynucleotide, a translated polypeptide, or a polynucleotide and / or polypeptide modification (e.g., post-translational modification of a polypeptide) should also be considered expressed, regardless of whether they are derived from a transcript generated by alternative splicing or a degraded transcript, or from post-translational processing of a polypeptide, for example, by proteolysis. "Expressed genes" include those that are transcribed into a polynucleotide as mRNA and then translated into a polypeptide, and also those that are transcribed into RNA but not translated into a polypeptide (e.g., transfer and ribosomal RNA). The expression level can be measured by methods known to those skilled in the art and also disclosed herein.

[0070] The presence and / or expression levels / amounts of the various biomarkers described herein in a sample can be analyzed by several methodologies, many of which are known in the art and understood by those of skill in the art, including immunohistochemistry ("IHC"), Western blot analysis, immunoprecipitation, molecular binding assays, ELISA, ELIFA, fluorescence activated cell sorting ("FACS"), MassARRAY, proteomics, quantitative blood-based assays (e.g., serum ELISA), biochemical enzyme activity assays, in situ hybridization, fluorescence in situ hybridization (FISH), and smearing. The assays include, but are not limited to, any one of a wide variety of assays that can be performed by Northern analysis, whole genome sequencing, massively parallel DNA sequencing (e.g., next-generation sequencing), NANOSTRING®, polymerase chain reaction (PCR) including quantitative real-time PCR (qRT-PCR) and other amplification-based detection methods such as branched DNA, SISBA, TMA, RNA-Seq, microarray analysis, gene expression profiling, and / or serial analysis of gene expression ("SAGE"), and protein, gene, and / or tissue array analysis. Multiplexed immunoassays, such as those available from Rules Based Medicine or Meso Scale Discovery ("MSD"), can also be used.

[0071] The terms "cancer" and "cancerous" refer to or describe a physiological condition in mammals that is typically characterized by uncontrolled cell growth. Examples of cancer include, but are not limited to, hematological cancers, such as mature B-cell cancers, e.g., non-Hodgkin's lymphoma (NHL) (which may be relapsed and / or refractory NHL), diffuse large B-cell lymphoma (DLBCL) (which may be relapsed and / or refractory DLBCL), follicular lymphoma (FL) (which may be relapsed and / or refractory FL and / or transformed FL), and mantle cell lymphoma (MCL) (which may be relapsed and / or refractory MCL). DLBCL includes Richter's transformed, germinal center B-cell-like (GCB) DLBCL, and activated B-cell-like DLBCL. Other specific examples of cancer include acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), marginal zone lymphoma (MZL), small lymphocytic leukemia (SLL), lymphoplasmacytic lymphoma (LL), Waldenstrom's hypergammaglobulinemia (WM), central nervous system lymphoma (CNSL), Burkitt's lymphoma (BL), B-cell prolymphocytic leukemia, splenic marginal zone lymphoma, hairy cell leukemia, splenic lymphoma / leukemia, and classification. Impossible, 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, plasma cell myeloma, isolated bone plasmacytoma, extraosseous 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-associated DLBCL, lymphomatoid granulomatosis, primary mediastinal (thymic) large B-cell lymphoma (PMLBCL), intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, plasmablastic lymphoma, large B-cell lymphoma due to HHV8-associated multicentric Castleman disease, primary effusion lymphoma; unclassifiable B-cell lymphoma with features intermediate between DLBCL and Burkitt lymphoma; and unclassifiable B-cell lymphoma with features 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). In some embodiments, NHL may include aggressive NHL, including de novo DLBCL, transformed FL, and grade 3b FL.

[0072] "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," as referred to herein, are not mutually exclusive.

[0073] A "disorder" is any condition that would benefit from treatment, including, but not limited to, chronic and acute disorders or diseases, including pathological conditions that predispose a mammal to the disorder in question.

[0074] 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.

[0075] The terms "B-cell proliferative disorder" or "B-cell malignancy" refer to diseases associated with some degree of abnormal B-cell proliferation and include, for example, lymphoma, leukemia, myeloma, and myelodysplastic syndrome. In one embodiment, the B-cell proliferative disorder is a lymphoma, such as non-Hodgkin's lymphoma (NHL), including, for example, relapsed and / or refractory NHL, DLBCL (e.g., relapsed or refractory DLBCL), FL (e.g., relapsed or refractory FL or transformed FL), or MCL (e.g., relapsed or refractory MCL). In another embodiment, the B-cell proliferative disorder is a leukemia, such as chronic lymphocytic leukemia (CLL). In yet another embodiment, the B-cell proliferative disorder is central nervous system lymphoma (CNSL).

[0076] As used herein, "treatment" (and grammatical variations thereof, such as "treat" or "treating") refers to a clinical intervention aimed at altering the natural history of the individual being treated, and may be performed for prophylaxis or during the clinical pathology process. Desired effects of treatment include preventing the onset or recurrence of disease, alleviating symptoms, attenuating any direct or indirect pathological consequences of the disease, preventing metastasis, reducing the rate of disease progression, remission or palliation of the condition, and improving or improving prognosis. In some embodiments, the present invention can delay the onset of disease or slow the progression of the disease.

[0077] As used herein, "administering" refers to a method of providing a dose of a compound (e.g., an anti-CD79b antibody drug conjugate and / or an anti-CD20 / anti-CD3 bispecific antibody) or composition (e.g., a pharmaceutical composition, e.g., a pharmaceutical composition comprising an anti-CD79b antibody drug conjugate and / or an anti-CD20 / anti-CD3 bispecific antibody) to a subject. The compounds and / or compositions utilized in the methods described herein can be administered, for example, intravenously (e.g., by intravenous infusion), subcutaneously, intramuscularly, intradermally, transcutaneously, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, intraperitoneally, subconjunctivally, intravesicularly, transmucosally, intrapericardially, intraumbilically, intraocularly, orally, topically, or locally, or by inhalation, injection, infusion, continuous infusion, local perfusion directly into target cells, catheter, or irrigation, or in a cream, or lipid composition. The method of administration can vary depending on various factors (e.g., the compound or composition being administered and the severity of the condition, disease, or disorder being treated).

[0078] A "fixed" or "flat" dose of a therapeutic agent (e.g., an anti-CD79b antibody drug conjugate and / or an anti-CD20 / anti-CD3 bispecific antibody) herein refers to a dose administered to a subject without regard to the subject's body 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.

[0079] A "subject," "patient," or "individual" is a mammal. Mammals include, but are not limited to, primates (e.g., humans and non-human primates such as monkeys), livestock animals (e.g., cows, sheep, cats, dogs, and horses), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the subject, patient, or individual is human.

[0080] A "post-CAR-T subject" or "post-CAR-T patient" is a subject or patient previously treated with CAR-T (chimeric antigen receptor T-cell) therapy. Typically, the subject or patient also undergoes a minimum waiting period before administration of a subsequent non-CAR-T treatment. In some embodiments, a post-CAR-T subject or patient is one who received CAR-T therapy at least 30 days prior to the first administration of the non-CAR-T treatment. In some embodiments, the non-CAR-T treatment is an anti-CD20 / anti-CD3 bispecific antibody (e.g., mosunetuzumab), an anti-CD79b antibody drug conjugate (e.g., polatuzumab vedotin), or a combination thereof.

[0081] As used herein, "complete response" or "CR" refers to the disappearance of all target lesions (ie, all evidence of disease).

[0082] 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.

[0083] As used herein, "objective response" (ORR) means the sum of the complete response (CR) rate and the partial response (PR) rate.

[0084] 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 within 30 days of the last dose of treatment or death from any cause, whichever occurs first.

[0085] A "durable response" refers to a sustained effect on reducing tumor growth after cessation of treatment. For example, the tumor size may remain the same or may be smaller compared to the size at the beginning of the administration period. 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.

[0086] 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 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.

[0087] A subject who "does not respond effectively" to treatment is one 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.

[0088] As used herein, the term "survival" refers to the subject being alive, and includes overall survival and progression-free survival.

[0089] 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.

[0090] As used herein, "progression-free survival" (PFS) refers to the length of time during and after treatment during which the disease being treated does not worsen. Progression-free survival can include the amount of time a subject experiences a complete or partial response, as well as the amount of time a subject experiences stable disease.

[0091] 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.

[0092] 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.

[0093] As used herein, "delaying the progression" of a disorder or disease means postponing, preventing, slowing, retarding, stabilizing, and / or delaying the development of the disease or disorder (e.g., a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder, e.g., NHL (e.g., DLBCL, FL, or MCL)). The delay can be of varying duration depending on the history of the disease and / or the individual being treated. As will be apparent to one of skill in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease. For example, late-stage cancer, such as the development of metastases, can be delayed.

[0094] "Reducing" or "inhibiting" refers to the ability to produce an overall decrease, e.g., of 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 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, liver enzyme elevation, and / or central nervous system (CNS) toxicity following treatment with an anti-CD20 / anti-CD3 bispecific antibody using a fractionated dose-escalation regimen of the invention compared to treatment with an anti-CD20 / anti-CD3 bispecific antibody using a non-fractionated regimen. In other embodiments, reducing or inhibiting can refer to antibody effector functions mediated by the antibody Fc region, specifically including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP).

[0095] 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.

[0096] By "prolonged survival" is meant an increase in overall survival or progression-free survival in a treated subject relative to an untreated subject (e.g., relative to a subject not treated with a pharmaceutical agent), or relative to a subject that does not express a biomarker at a specified level, and / or relative to a subject treated with an approved anti-tumor agent. "Objective response rate" refers to a measurable response, including a complete or partial response.

[0097] Unless otherwise indicated, the term "protein" as used herein refers to any naturally occurring protein from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice, rats), unless otherwise specified. The term also includes "full-length," unprocessed proteins and any forms of proteins that result from processing within a cell. The term also encompasses naturally occurring variants of the protein, such as splice variants or allelic variants.

[0098] The term "antibody" is used herein in the broadest sense and encompasses a variety of antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired antigen-binding activity.

[0099] "Antibody fragment" refers to a molecule other than an intact antibody that contains a portion of the intact antibody that binds 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.

[0100] 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.

[0101] "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.

[0102] The term "Fc region" is used herein to define the C-terminal region of an immunoglobulin heavy chain containing at least a portion of the constant region. This term includes native-sequence Fc regions and variant Fc regions. In one embodiment, a 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 indicated herein, numbering of amino acid residues in an Fc region or constant region is according to the EU numbering system, also known as the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0103] 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: IgA, IgD, IgE, IgG, and IgM, and some of these can be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy-chain constant domains that correspond to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0104] The term IgG "isotype" or "subclass" as used herein means any of the subclasses of immunoglobulins defined by the chemical and antigenic properties of their constant regions.

[0105] "Framework" or "FR" refers to variable domain residues other than hypervariable region (HVR) residues. The FR of a variable domain generally consists of four FR domains: FR1, FR2, FR3, and FR4. Thus, the HVR and FR sequences generally appear in VH (or VL) in the following order: FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0106] A "human consensus framework" is a framework that represents the most commonly occurring amino acid residues in a 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 described 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 as described in Kabat et al. (supra). In one embodiment, for VH, the subgroup is subgroup III as described in Kabat et al. (supra).

[0107] 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.

[0108] 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 may comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the HVRs (e.g., CDRs) correspond to those of a non-human antibody and all or substantially all of the FRs correspond to those of a human antibody. 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.

[0109] A "human antibody" is an antibody having an amino acid sequence corresponding to an antibody produced by a human or human cell, or an antibody of non-human origin using human antibody-encoding sequences, such as the human antibody repertoire. This definition of a human antibody specifically excludes humanized antibodies, which contain non-human antigen-binding residues. Human antibodies can be generated using various techniques known in the art, including phage display libraries. Hoogenboom, Mand Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991). 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 used to prepare human monoclonal antibodies. See also van Dijk and van de Winkel, Curr. Opin. Pharmacol., 5:368-74 (2001). Human antibodies can be prepared by administering antigen to transgenic animals, e.g., immunized xenomouse, which have been engineered to produce such antibodies in response to antigen challenge but have their endogenous gene locus disabled (e.g., XENOMOUSE TM (See U.S. Patent Nos. 6,075,181 and 6,150,584 for related technology.) Also, see, e.g., Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006) for human antibodies produced by human B cell hybridoma technology.

[0110] The term "chimeric" antibody refers to an antibody in which a portion of the heavy and / or light chain is derived from a particular source or species, while the remainder of the heavy and / or light chain is derived from a different source or species.

[0111] The term "variable region" or "variable domain" refers to the domain of an antibody heavy chain or light chain that is involved in binding the antibody to an antigen. The variable domains of the heavy and light chains (VH and VL, respectively) of natural antibodies generally have similar structures, with each domain containing four conserved framework regions (FR) and three hypervariable regions (HVR). (See, e.g., Kindt et al., Kuby Immunology, 6 th ed., W.H. Freeman and Co., p. 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 antibody that binds the antigen 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).

[0112] The term "hypervariable region" or "HVR" as used herein refers to each of the regions of an antibody variable domain that are hypervariable in sequence ("complementarity determining regions" or "CDRs") and / or form structurally distinct loops ("hypervariable loops") and / or contain antigen contact residues ("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 located 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) antigen 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) (MacCallu 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).

[0113] 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.

[0114] An "immunoconjugate" is an antibody conjugated to one or more heterologous molecules, including, but not limited to, a cytotoxic agent. In certain embodiments, the immunoconjugate is an antibody-drug conjugate. In certain embodiments, the antibody-drug conjugate is an anti-CD79b antibody-drug conjugate, such as polatuzumab vedotin, anti-CD79b-MC-vc-PAB-MMAE, or an anti-CD79b antibody-drug conjugate described in any one of U.S. Pat. No. 8,088,378 and / or U.S. Patent Application Publication No. 2014 / 0030280.

[0115] An "isolated" antibody is one that is separated from components of its natural environment. In some embodiments, the antibody is purified to greater than 95% or greater than 99% purity, for example, as determined by electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse-phase HPLC). For a review of testing methods for antibody purification, see, e.g., Flatman et al., J. Chromatogr. B 848:79-87 (2007).

[0116] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and / or bind the same epitope, except for variant antibodies that contain, for example, naturally occurring mutations or that may arise during production of the monoclonal antibody preparation, in which such variants are generally present in minor amounts. 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.

[0117] A "naked antibody" refers to an antibody that is not conjugated to a heterologous moiety (e.g., a cytotoxic moiety) or radiolabel. Naked antibodies may be present in a pharmaceutical formulation.

[0118] "Native antibodies" refer to naturally occurring immunoglobulin molecules with various structures. For example, native IgG antibodies are heterotetrameric glycoproteins of approximately 150,000 daltons composed of two identical light chains and two identical heavy chains that are disulfide-bonded. From the N-terminus to the C-terminus, each heavy chain has a variable region (VH), also called a variable heavy domain or heavy chain variable domain, followed by three constant domains (CH1, CH2, and CH3). Similarly, from the N-terminus to the C-terminus, each light chain has a variable region (VL), also called a variable light domain or light chain variable domain, followed by a constant light (CL) domain. The light chain of an antibody can be assigned to one of two types, called kappa (κ) or lambda (λ), based on the amino acid sequence of its constant domain.

[0119] "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 is generally determined by the dissociation constant (K D ) Affinity can be measured by common methods known in the art, including those described herein. Specific illustrative examples and exemplary embodiments for measuring binding affinity are described below.

[0120] An "affinity matured" antibody refers to an antibody that has one or more alterations in one or more hypervariable regions (HVRs) compared to a parent antibody that does not have such alterations, which improve the affinity of the antibody for its antigen.

[0121] The terms "anti-CD3 antibody" and "antibody that binds to CD3" refer to an antibody that can bind to CD3 with sufficient affinity so as to be useful as a CD3-targeted diagnostic and / or therapeutic agent. 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.

[0122] The terms "anti-CD20 antibody" and "antibody that binds to CD20" refer to an antibody that can bind to CD20 with sufficient affinity so as to be useful as a CD20-targeted diagnostic and / or therapeutic agent. In one embodiment, the binding of an anti-CD20 antibody to an unrelated, non-CD20 protein is less than about 10% of the binding of the antibody to CD20 as measured, for example, by radioimmunoassay (RIA). In certain embodiments, an antibody that binds to CD20 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 M~10 -13 M, or for example 10 -9 M~10 -13 Dissociation constant (K D In certain embodiments, the anti-CD20 antibody binds to an epitope of CD20 that is conserved among CD20 from different species.

[0123] 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 a multispecific antibody (e.g., a bispecific antibody) that is 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 extent of binding of an anti-CD20 / anti-CD3 bispecific antibody to an unrelated non-CD3 protein and / or a non-CD20 protein 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, an antibody that binds to CD20 and 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 M~10 -13 M, or for example 10 -9 M~10 -13 Dissociation constant (K D ). In certain embodiments, the anti-CD20 / anti-CD3 bispecific antibody binds to an epitope of CD3 that is conserved among CD3 from different species and / or an epitope of CD20 that is conserved among CD20 from different species. In some examples, the anti-CD20 / anti-CD3 bispecific antibody is mosunetuzumab (also known as BTCT4465A or RG 7828), as defined by the International Nonproprietary Names for Pharmaceutical Substances (INN) List 117 (WHO Drug Information, Vol. 31, No. 2, 2017, pp. 304-305).

[0124] As used herein, the terms "bind," "specifically bind to," or "specific for" refer to a measurable and reproducible interaction, such as binding between a target and an antibody, that is determinative of 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 may be an epitope) is one that binds to this target with higher affinity, avidity, more readily, and / or with a longer duration than it binds to other targets. In one embodiment, the extent to which an antibody binds to an unrelated 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) of ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, or ≦0.1 nM. D In certain embodiments, the antibody specifically binds to an epitope on a protein that is conserved among proteins from different species. In another embodiment, specific binding can include, but is not required to include, exclusive binding. As used herein, the term "specific binding" refers to, for example, binding to an epitope on a protein that is conserved among proteins from different species. -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 K against targets less than or equal to M D , or 10 -4 M~10 -6 M or 10 -6 M~10 -10 M or 10 -7 M~10 -9 K in the M range D As will be appreciated by those skilled in the art, affinity and K D The values ​​are inversely correlated: a high affinity for the antigen corresponds to a 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.

[0125] "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 sequence, 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 purposes of determining percent amino acid sequence identity can be accomplished in a variety of ways within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for sequence alignment, including any algorithms necessary to achieve maximum alignment over the entire 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.

[0126] In situations where ALIGN-2 is used for amino acid sequence comparison, the % amino acid sequence identity of a given amino acid sequence A to, with, or relative to a given amino acid sequence B (alternatively, it may be written as a given amino acid sequence A having or comprising a certain % amino acid sequence identity to, with, or relative to a given amino acid sequence B) is calculated as follows: 100 x fraction X / Y where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in that program's alignment of A and B, 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 is not equal to the length of amino acid sequence B, then the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A. Unless otherwise specified, all % amino acid sequence identity values ​​used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.

[0127] The term "pharmaceutical formulation" refers to a preparation in which the biological activity of the active ingredient contained in the preparation is in a form such that it is effective, and which does not contain additional components that are unacceptably toxic to the subject to which the formulation is administered.

[0128] A "pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, that is non-toxic to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0129] As used herein, the term "chemotherapeutic agent" refers to a compound useful in the treatment of cancer, such as a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder (e.g., a relapsed or refractory B-cell proliferative disorder), e.g., non-Hodgkin's lymphoma (NHL; e.g., diffuse large B-cell lymphoma (DLBCL; e.g., Richter's transformed), 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 such as 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; ZM105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-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]-phenyl); (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);EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide) (also known as N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-6-quinolizyl (Wyeth); AG1478 (Pfizer); AG1571 (SU 5271; Pfizer); and dual EGFR / HER2 tyrosine kinase inhibitors, such as lapatinib (TYKERB®, GSK572016 or N-[3-chloro-4-[(3fluorophenyl)methoxy]phenyl]-6[5[[(2methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine)); tyrosine kinase inhibitors (e.g., EGFR inhibitors; small molecule HER2 tyrosine kinase inhibitors, such as TAK165 (Takeda); CP-724, 714, oral selective inhibitors of ErbB2 receptor tyrosine kinase (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 (ISIS), which inhibits Raf-1 signaling. Pharmaceuticals; non-HER-targeted tyrosine kinase inhibitors, such as imatinib mesylate (GLEEVEC®, GlaxoSmithKline); multi-targeted tyrosine kinase inhibitors, such as sunitinib (SUTENT®, Pfizer); VEGF receptor tyrosine kinase inhibitors, such as vatalanib (PTK787 / ZK222584, Novartis / Schering AG); MAPK extracellular regulated kinase I inhibitor CI-1040 (Pharmacia); quinazolines, such as PD 153035, 4-(3-chloroanilino)quinazoline; pyridopyrimidines; pyrimidopyrimidines; 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); tyrphostins containing a nitrothiophene moiety; PD-0183805 (Warner-Lambert); antisense molecules (e.g., those that bind to HER-encoding nucleic acids); quinoxalines (U.S. Pat. No. 5,804,396); tryphostin (U.S. Pat. No. 5,804,396); ZD6474 (Astra Zeneca); PTK-787 (Novartis / Schering AG); pan-HER inhibitors, e.g., CI-1033 (Pfizer); 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®); proteasome inhibitors such as bortezomib (VELCADE®, Millennium Pharmaceuticals); disulfiram; epigallocatechin gallate; salinosporamide A; carfilzomib; 17-AAG (geldanamycin); radicicol; lactate dehydrogenase A (LDH-A); fulvestrant (FASLODEX®, AstraZeneca); letrozole (FEMARA®, Novartis), finasunate (VATALANIB®, Novartis); oxaliplatin (ELOXATIN®, Sanofi); 5-FU (5-fluorouracil); leucovorin; lonafamib (SCH 66336); sorafenib (NEXAVAR®, Bayer Labs); AG1478, alkylating agents such as thiotepa and CYTOXAN®, cyclophosphamide; alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridine compounds such as benzodopa, carboquone, metsudopa, and uredopa;Ethylenimines and methylamines such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylmelamine; acetogenins (especially bullatacin and bullatacinone); camptothecins (including topotecan and irinotecan); bryostatin; kallistatin; CC-1065 (including its adozelesin, carzelesin, and bizelesin synthetic analogs); cryptophycins (especially cryptophycin 1 and cryptophycin 8); corticosteroids (such as prednisone and prednisolone); cyproterone acetate; 5α-reductase inhibitors including finasteride and dutasteride; vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat, dolastatins; aldesleukin, talc, ducarmycin ( synthetic analogs, including KW-2189, CB1-TM1); eleutherobin; pancratistatin; sarcodictine; spongistatin; nitrogen mustards such as chlorambucil, chromafazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembitine, fenesterone, prednimustine, trofosfamide, and uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics such as enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gamma 1 and calicheamicin omega 1); dynemicins, including dynemicin A; bisphosphonates such as clodronate; esperamicin;and neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomycin, actinomycin, autramycin, azaserine, cactinomycin, carabicin, caminomycin, cardinophilin, chromomycin, dactinomycin, detorubicin, 6-diazo-5-oxo-L-norleucine, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolinodoxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mycobacterium erythropoietin ... Mitomycins such as tocopherol C, mycophenolic acid, nogamicin, olivomycin, peplomycin, porfiromycin, puromycin, chelamycin, rhodrubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimetrexate; and purine analogs such as fludarabine, 6-mercaptopurine, thiamine, and thioguanine. Pyrimidines such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enokitabine, and floxuridine; androgens such as calucelone, dromostanolone propionate, epiostanol, mepitiostane, and testolactone; antiadrenergic agents such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as floric acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; enyllatil; amsacrine; and bestrabsi le; bisantrene, edatraxate, defofamine, demecolcine, diaziconazole, elfumitin, elliptinium acetate, epothilone, etoglucide, gallium nitrate, hydroxyurea, lentinan; lonidynin; maytansinoids (maytansine, ansamitocin, etc.); mitoguazone; mitoxantrone; mopidamol; nitraelin; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazide; procarbazine; PSK (registered trademark) polysaccharide complex (JHS Natural Products); razoxane; rhizoxin; schizofuran;Spirogermanium; Tenuazonic acid; Triazicone; 2,2',2''-Trichlorotriethylamine; Trichothecenes (especially T-2 toxin, veracrine A, roridin A, and anguidin); Urethane; Vindesine, Dacarbazine, Mannomustine, Mitobronitol, Mitolactol, Pipobroman, Gacytosine, Arabinoside ("Ara-C"), Thiotepa; Chlorambucil; GEMZAR® (Gemcitabine); 6-Thioguanine; Mercaptopuril methotrexate; etoposide (VP-16); ifosfamide; mitoxantrone; novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; the topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids, prodrugs, and derivatives of any of the above.

[0130] Chemotherapeutic agents also include: (i) antihormonal agents that act to regulate or inhibit hormone action on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), e.g., tamoxifen (including NOLVADEX®, tamoxifen citrate), raloxifene, droxifene, iodoxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit aromatase, an enzyme that regulates estrogen production in the adrenal glands, e.g., 4(5)-imidazole, aminoglutethimide, MEGASE® (megstrol acetate), AROMASIN® (exemestane; Pfizer), formestany, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMI®. DEX® (anastrozole; AstraZeneca); (iii) antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all-trans retionic acid, fenretinide, and troxacitabine (1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly agents that inhibit the expression of genes in signal transduction pathways involved in abnormal cell proliferation, e.g., PKC-alpha, Ralf, and H-Ras; (vii) ribozymes, such as VEGF expression inhibitors (e.g., ANGIOZYME®), HER2 expression inhibitors; (viii) vaccines, such as gene therapy vaccines, e.g., ALLOVECTIN®, LEUVECTIN®, VAXID®;(ix) growth inhibitors, including vincas (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., tamoxigen, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, and ara-C); and (x) pharmaceutically acceptable salts, acids, prodrugs, and derivatives of any of the above.

[0131] The term "PD-1 axis binding antagonist" refers to a molecule that inhibits the interaction of a PD-1 axis binding partner with one or more of its binding partners in order to eliminate T cell dysfunction resulting from signaling on the PD-1 signaling axis, thereby restoring or enhancing T cell function (e.g., proliferation, cytokine production, and / or 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.

[0132] The term "PD-1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, abrogates, or prevents signaling resulting from the interaction of PD-1 with one or more of its binding partners, e.g., PD-L1, PD-L2. 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 particular aspects, 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, abrogate, or prevent signaling resulting from the interaction of PD-1 with PD-L1 and / or PD-L2. In one embodiment, the PD-1 binding antagonist reduces negative costimulatory signals mediated by or through cell surface proteins expressed on T lymphocytes that mediate PD-1-mediated signaling, rendering dysfunctional T cells less dysfunctional (e.g., enhancing the effector response to antigen recognition). In some embodiments, the PD-1 binding antagonist is an anti-PD-1 antibody. In a particular embodiment, the PD-1 binding antagonist is MDX-1106 (nivolumab). In another particular embodiment, the PD-1 binding antagonist is MK-3475 (pembrolizumab, formerly known as lambrolizumab). In another particular embodiment, the PD-1 binding antagonist is AMP-224. In another embodiment, the PD-1 antagonist antibody is MEDI-0680 (AMP-514), PDR001 (spartalizumab), REGN2810 (cemiplimab), BGB-108, prololimab, canrelizumab, sintilimab, tislelizumab, or toripalimab.

[0133] The term "PD-L1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, abrogates, or prevents signaling resulting from the interaction of PD-L1 with any one or more of its binding partners (e.g., 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 partners. In particular aspects, PD-L1 binding antagonists inhibit the binding of PD-L1 to PD-1 and / or B7-1. In some embodiments, PD-L1 binding antagonists include anti-PD-L1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, abrogate, or prevent signaling resulting from the interaction of PD-L1 with one or more of its binding partners (e.g., PD-1 or B7-1). In one embodiment, the PD-L1 binding antagonist reduces the negative costimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes that mediate PD-L1-mediated signaling, thereby alleviating the dysfunctional state of dysfunctional T cells (e.g., enhancing the effector response to antigen recognition). In some embodiments, the PD-L1 binding antagonist is an anti-PD-L1 antibody. In a specific embodiment, the anti-PD-L1 antibody is atezolizumab (CAS Registry Number: 1422185-06-5), also known as MPDL3280A. In another specific embodiment, the anti-PD-L1 antibody is MDX-1105. In yet another specific aspect, the anti-PD-L1 antibody is MEDI4736.

[0134] As used herein, the term "atezolizumab" refers to the anti-PD-L1 antagonist antibody having International Nonproprietary Name (INN) List 112 (WHO Drug Information, Vol. 28. No. 4, 2014, p. 488) or CAS Registry Number 1380723-44-3.

[0135] The term "PD-L2 binding antagonist" refers to a molecule that reduces, blocks, inhibits, abrogates, or prevents signaling resulting from the interaction of PD-L2 with any one or more of its binding partners, e.g., PD-1. In some embodiments, a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to one or more of its binding partners. In particular aspects, PD-L2 binding antagonists inhibit the binding of PD-L2 to PD-1. In some embodiments, PD-L2 antagonists include anti-PD-L2 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, abrogate, or prevent signaling resulting from the interaction of PD-L2 with any one or more of its binding partners, e.g., PD-1. In one embodiment, the PD-L2 binding antagonist reduces the negative costimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes that mediate signaling through PD-L2, reducing the dysfunction of dysfunctional T cells (e.g., enhancing the effector response to antigen recognition). In some examples, the PD-L2 binding antagonist is an immunoadhesin.

[0136] 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).

[0137] As used herein, the term "cluster of differentiation 20" or "CD20," unless otherwise indicated, refers to any native CD20 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). The term encompasses "full-length," unprocessed CD20 and any form of CD20 resulting from intracellular processing. The term also encompasses naturally occurring variants of CD20, including, for example, splice variants or allelic variants. CD20 includes, for example, the human CD20 protein (see, e.g., NCBI Reference SEQ ID NOs: NP_068769.2 and NP_690605.1), which is, for example, 297 amino acids in length and can be produced from, for example, a variant mRNA transcript lacking a portion of the 5'UTR (see, e.g., NCBI Reference SEQ ID NO: NM_021950.3), or a longer variant mRNA transcript (see, e.g., NCBI Reference SEQ ID NO: NM_152866.2).

[0138] As used herein, the term "cluster of differentiation 79b" or "CD79b," unless otherwise indicated, refers to any native CD79b from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). The term encompasses "full-length," unprocessed CD79b, as well as any form of CD79b resulting from intracellular processing. The term also encompasses naturally occurring variants of CD79b, including, for example, splice variants or allelic variants. CD79b includes, for example, the human CD79b protein, which is 229 amino acids in length (NCBI RefSeq No. NP_000617).

[0139] The terms "anti-CD79b antibody" and "antibody that binds to CD79b" refer to an antibody that is capable of binding to CD79b with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting CD79b. In one embodiment, the binding of an anti-CD79b antibody to an unrelated, non-CD79b protein is less than about 10% of the binding of the antibody to CD79b as measured, for example, by radioimmunoassay (RIA). In certain embodiments, an antibody that binds to CD79b 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 M~10 -13 M, or for example 10 -9 M~10 -13 Dissociation constant (K D In certain embodiments, the anti-CD79b antibody binds to an epitope of CD79b that is conserved among CD79b from different species.

[0140] The term "cytotoxic agent," as used herein, refers to a substance that inhibits or prevents the function of cells and / or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioisotopes (e.g., 211 At, 131 I, 125 I, 90 Y, 186 Re, 188 Re, 153 Sm, 212 Bi, 32 P, 212 Pb, and radioactive isotopes of Lu); chemotherapeutic agents or drugs (e.g., methotrexate, adriamycin, or vinca alkaloids (vincristine, vinblastine, or etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin, or other intercalating agents); growth inhibitory agents; enzymes and fragments thereof, e.g., nucleases; antibiotics; toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant, or animal origin, including fragments and / or variants thereof; and various anti-tumor or anti-cancer agents as disclosed below.

[0141] "Effector function" refers to a biological activity attributable to the Fc region of an antibody, which varies depending on the antibody isotype. Examples of antibody effector functions include C1q binding and complement-dependent cytotoxicity (CDC), Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), phagocytosis, down-regulation of cell surface receptors (e.g., B cell receptors), and B cell activation.

[0142] An "effective amount" of a compound, e.g., an anti-CD79b antibody-drug conjugate and / or an anti-CD20 / anti-CD3 bispecific antibody, or composition thereof (e.g., pharmaceutical composition), is at least the minimum amount necessary to achieve a desired therapeutic result, such as a measurable improvement in a particular disorder (e.g., a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder, e.g., NHL (e.g., DLBCL, FL, or MCL))). The effective amount herein may vary depending on factors such as the disease state, age, sex, and weight of the subject, and the ability of the antibody to elicit a desired response in the individual. An effective amount is also one in which any toxic or adverse effects of the treatment are outweighed by the therapeutically beneficial effects. In the case of prophylactic use, beneficial or desired results include results such as eliminating or reducing the risk of disease, reducing the severity of disease, or delaying the onset of disease, including biochemical, histological, and / or behavioral symptoms of disease, its complications, and intermediate pathological phenotypes manifest during the development of disease. For therapeutic use, beneficial or desired results include clinical results such as alleviation of one or more symptoms caused by the disease, improvement in the quality of life of those suffering from the disease, reduction in the dose of other drugs required to treat the disease, enhancement of the effect of another drug (e.g., by targeting), delay in disease progression, and / or prolonged survival. In the case of cancer or tumors, an effective amount of a drug may have the effect of reducing the number of cancer cells, reducing tumor size, inhibiting (i.e., slowing to some extent or desirably stopping) the invasion of cancer cells into peripheral organs, inhibiting (i.e., slowing to some extent or desirably stopping) tumor metastasis, inhibiting tumor growth to some extent, and / or alleviating to some extent one or more symptoms associated with the disorder. An effective amount may be administered in one or more doses. In the present invention, an effective amount of a drug, compound, or pharmaceutical composition is an amount sufficient to achieve therapeutic treatment directly or indirectly. As understood in the clinical field, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an "effective amount" can be considered in the context of administration of one or more therapeutic agents, and a single agent can be considered to be given in an effective amount if, in conjunction with one or more other agents, a desired result can be or is achieved.

[0143] As used herein, the term "cytokine release syndrome" (abbreviated as "CRS") refers to elevated levels of cytokines, particularly tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin-2 (IL-2), and / or interleukin-8 (IL-8), in a subject's blood during or shortly after administration of a therapeutic agent, resulting in adverse symptoms. In some instances, for example, after administration of CAR-T cells, CRS may occur only several days after administration during expansion of the CAR-T cells. The incidence and severity typically decrease with subsequent infusions. Symptoms may range from symptomatic discomfort to fatal events and may include fever, chills, dizziness, high blood pressure, low blood pressure, dyspnea, restlessness, sweating, flushing, skin rash, tachycardia, tachypnea, headache, tumor pain, nausea, vomiting, and / or organ failure. Those skilled in the art should recognize that CRS can be graded by several different published CRS grading systems, including but not limited to those outlined in the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading criteria (Lee et al., Biology of Blood and Marrow Transplantation. 25(4):625-638, 2019), the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03, NCI CTCAE v5.0, and the Lee criteria (Lee et al., Blood. 2014. 124:188-195). Unless otherwise specified, CRS grading herein follows the ASTCT consensus grading criteria.

[0144] The term "package insert" is used to refer to instructions typically included in commercial packaging for therapeutic products, including information regarding the indications, uses, dosages, administration, concomitant therapy, contraindications and / or warnings regarding such therapeutic products.

[0145] As used herein, a "week" is 7 days ± 2 days.

[0146] III. Treatment Methods The methods provided herein benefit patients by providing a way to treat CD20-positive disorders while achieving a more favorable benefit-risk profile. Thus, provided herein are methods for treating a subject with a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder (e.g., non-Hodgkin's lymphoma (NHL) (e.g., relapsed and / or refractory NHL, diffuse large B-cell lymphoma (DLBCL) (e.g., relapsed and / or refractory DLBCL), follicular lymphoma (FL) (e.g., relapsed and / or refractory FL or transformed FL), or mantle cell lymphoma (MCL) (e.g., relapsed and / or refractory MCL)), chronic lymphocytic leukemia (CLL), or central nervous system lymphoma (CNSL)) by administering a combination of an anti-CD79b antibody drug conjugate and a bispecific antibody that binds CD20 and CD3 in a multi-cycle dosing regimen comprising fractionated escalating doses of the bispecific antibody in the first dosing cycle. In particular, the two-step fractionation provided by the methods described herein can be an effective safety mitigation strategy for dose-escalation regimens of anti-CD20 / anti-CD3 bispecific antibodies. Furthermore, T cell-mobilizing anti-CD20 / anti-CD3 bispecific antibodies can promote tumor cell recognition by T cells, while anti-CD79b ADCs can induce tumor cell killing, which can result in the release of tumor-specific neoantigens that can elicit further anti-tumor adaptive immune responses. Each agent targets a different cell surface antigen (CD20, CD79b), which can mitigate antigen loss escape mechanisms of resistance to a single agent. The methods provided herein can reduce or inhibit undesired treatment effects, including 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 hepatotoxicity. In particular, the methods provided herein can mitigate potentially exacerbating overlapping toxicities of two antibodies, including combination-related toxicities not previously identified with single-agent treatment and / or toxicities that are more severe or more frequent than those observed with the individual agents.

[0147] A. Therapeutic Methods for Administration of Anti-CD20 / Anti-CD3 Bispecific Antibody and Anti-CD79b ADC The present invention provides methods of treating a subject having a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder (e.g., non-Hodgkin's lymphoma (NHL) (e.g., relapsed and / or refractory NHL, diffuse large B-cell lymphoma (DLBCL) (e.g., relapsed and / or refractory DLBCL), follicular lymphoma (FL) (e.g., relapsed and / or refractory FL or transformed FL), or mantle cell lymphoma (MCL) (e.g., relapsed or refractory MCL)), chronic lymphocytic leukemia (CLL), or central nervous system lymphoma (CNSL))), comprising administering to the subject an anti-CD79b antibody drug conjugate and / or an anti-CD20 / anti-CD3 bispecific antibody, e.g., in a fractionated dose-escalation regimen. In some examples, the method is used to treat a subject with relapsed and / or refractory NHL (e.g., an aggressive NHL (e.g., relapsed and / or refractory DLBCL, relapsed and / or refractory FL, or relapsed and / or refractory MCL)). In some examples, the subject has relapsed to one or more (e.g., one, two, three, or more) previous therapies (e.g., one or more previous systemic therapies, e.g., one or more previous systemic chemotherapies (e.g., one or more previous systemic therapies comprising administration of an anthracycline), one or more previous stem cell therapies, or one or more previous CAR-T cell therapies) after having a documented history of response (e.g., complete or partial response) for at least six months in the period since completion of the treatment. In some examples, the subject is refractory to any previous therapy (e.g., has not had a response to the previous therapy or has progressed within six months of completing the last dose of therapy). Thus, in some embodiments, the dosing regimen is a second-line therapy. In some embodiments, the dosing regimen is a third-line therapy. In some embodiments, the subject has transformed FL that is refractory to standard treatment for transformed FL. In some embodiments, the FL is graded FL (e.g., grade 1, 2, 3a, or 3b FL).

[0148] In some examples, the present invention provides a method for treating a subject with a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL, DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), or MCL (e.g., relapsed or refractory MCL)), CLL, or CNSL)) by administering to the subject a bispecific antibody that binds to CD20 and CD3 in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle. (a) a first administration cycle includes treating an elephant with a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of the bispecific antibody, wherein C1D1 is between about 0.02 mg and about 5.0 mg (e.g., about 0.05 mg to about 5 mg, about 0.1 mg to about 5.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 2 mg to about 5.0 mg, about 3 mg to about 5.0 mg, about 0.05 mg to about 4.0 mg, about 0.05 mg to about 3.0 mg, about 0.05 mg to about 2.0 mg, about 0.1 mg to about 2.0 mg, 0.0 mg, about 0.5 mg to about 2.0 mg, about 2 mg to about 4.0 mg, about 1 mg to about 3.0 mg, about 1 mg, about 2 mg, or about 5 mg), and C1D2 is between about 0.05 mg to about 10.0 mg (e.g., about 0.1 mg to about 10.0 mg, about 0.5 mg to about 10.0 mg, 1 mg to about 10.0 mg, about 2 mg to about 3.0 mg, about 5 mg to about 10.0 mg, about 8 mg to about 10.0 mg, about 0.5 mg to about 7.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 1 mg to about 3.0 mg, about 3 mg to about 8.0 mg). g, about 1 mg, about 2 mg, or about 5 mg) or between about 10 mg and about 60 mg (e.g., about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 20 mg to about 50 mg, about 30 mg to about 50 mg, about 40 mg to about 50 mg, about 45 mg to about 50 mg, about 13 mg to about 17 mg, about 43 mg to about 48 mg, about 15 mg to about 35 mg, about 25 mg to about 45 mg, about 15 mg, about 30 mg, or about 45 mg), and C1D3 is about 9 mg, about 13 mg, about 15 ...(b) a second administration cycle comprising a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of the bispecific antibody, each dose being about 5 mg, about 20 mg, about 40 mg, about 45 mg, or about 60 mg; and (b) a second administration cycle comprising a single dose (C2D1) of the bispecific antibody, wherein C2D1 is equal to or greater than C1D3.

[0149] A method of treating a subject with a CD20-positive cell proliferative disorder, e.g., a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL, DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), or MCL (e.g., relapsed or refractory MCL)), CLL, or CNSL) comprises 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 The dosage form includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of a bispecific antibody, wherein C1D3 is equal to or greater than C1D2 and C1D1, C1D2 is equal to or greater than C1D1, and C1D1 is between about 0.02 mg and about 5.0 mg (e.g., about 0.05 mg to about 5 mg, about 0.1 mg to about 5.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 2 mg to about 5.0 mg, about 3 mg to about 5.0 mg, about 0.05 mg to about 4.0 mg, about 0.05 mg to about 3.0 mg, about 0.05 mg to about 2.0 mg, about 0.1 mg to about 2.0 mg, about 0.5 mg to about 2.0 mg, about 2 mg to about 4.0 mg, about 1 mg to about 3.0 mg, about 1 mg, about 2 mg, or about 5 mg), and C1D2 is between about 0.05 mg to about 10.0 mg (for example, about 0.1 mg to about 10.0 mg, about 0.5 mg to about 10.0 mg, 1 mg to about 10.0 mg, about 2 mg to about 3.0 mg, about 5 mg to about 10.0 mg, about 8 mg to about 10.0 mg, about 0.5 mg to about 7.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 1 mg to about 3.0 mg, about 3 mg to about 8.0 mg, about 1 mg, about 2 mg, or about 5 mg) or between about 10 mg and about 60 mg (e.g., about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 20 mg to about 50 mg, about 30 mg to about 50 mg, about 40 mg to about 50 mg, about 45 mg to about 50 mg, about 13 mg to about 17 mg, about 43 mg to about 48 mg, about 15 mg to about 35 mg, about 25 mg to about 45 mg, about 15 mg, about 30 mg, or about 45 mg), and C1D3 is about 9 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, or about 45 mg).(b) a second administration cycle comprising a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of the bispecific antibody, each dose being about 5 mg, about 20 mg, about 40 mg, about 45 mg, or about 60 mg; and (b) a second administration cycle comprising a single dose (C2D1) of the bispecific antibody, wherein C2D1 is equal to or greater than C1D3 and is about 9 mg, about 13.5 mg, about 20 mg, about 40 mg, about 45 mg, or about 60 mg.

[0150] In some examples, (a) C1D1 is between about 0.02 mg and about 5 mg, and C1D2 is between about 0.05 mg and about 10.0 mg (e.g., about 0.1 mg to about 10.0 mg, about 0.5 mg to about 10.0 mg, 1 mg to about 10.0 mg, about 2 mg to about 3.0 mg, about 5 mg to about 10.0 mg, about 8 mg to about 10.0 mg, about 0.5 mg to about 7.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 1 mg to about 3.0 mg, about 3 mg to about 8.0 mg, about 1 mg, about 2 mg, about 5 mg) or between about 10 mg and about 60 mg (e.g., about 1 (b) C1D1 is about 9 mg, about 13.5 mg, about 20 mg, about 40 mg, about 45 mg, or about 60 mg; (c) C2D1 is greater than or equal to C1D3; (d) C2D1 is greater than or equal to C1D3; and (e) C2D1 is greater than or equal to C1D3. In some examples, (a) C1D1 is about 1 mg, C1D2 is about 2 mg, and C1D3 is about 9 mg, and (b) C2D1 is greater than or equal to C1D3. In some examples, (a) C1D1 is about 1 mg, C1D2 is about 2 mg, and C1D3 is about 9 mg, and (b) C2D1 is about 9 mg. In some examples, (a) C1D1 is about 1 mg, C1D2 is about 2 mg, and C1D3 is about 13.5 mg, and (b) C2D1 is greater than or equal to C1D3. In some examples, (a) C1D1 is about 1 mg, C1D2 is about 2 mg, and C1D3 is about 13.5 mg, and (b) C2D1 is about 13.5 mg. In some examples, (a) C1D1 is about 1 mg, C1D2 is about 2 mg, and C1D3 is about 20 mg, and (b) C2D1 is greater than or equal to C1D3. In some examples, (a) C1D1 is about 1 mg, C1D2 is about 2 mg, and C1D3 is about 20 mg, and (b) C2D1 is about 20 mg. In other examples, (a) C1D1 is about 1 mg, C1D2 is about 2 mg, and C1D3 is about 40 mg, and (b) C2D1 is equal to or greater than C1D3.In some examples, (a) C1D1 is about 1 mg, C1D2 is about 2 mg, and C1D3 is about 40 mg, and (b) C2D1 is about 40 mg. In other examples, (a) C1D1 is about 1 mg, C1D2 is about 2 mg, and C1D3 is about 60 mg, and (b) C2D1 is greater than or equal to C1D3. In some examples, (a) C1D1 is about 1 mg, C1D2 is about 2 mg, and C1D3 is about 60 mg, and (b) C2D1 is about 60 mg. In other examples, (a) C1D1 is about 5 mg, C1D2 is about 15 mg, and C1D3 is about 45 mg, and (b) C2D1 is about 45 mg. In some examples, (a) C1D1 is about 5 mg, C1D2 is about 45 mg, and C1D3 is about 45 mg, and (b) C2D1 is about 45 mg.

[0151] In some examples of the above methods, the first administration cycle comprises administering a single dose C1D1 of the anti-CD79b ADC to the subject. In some examples, the single dose C1D1 of the anti-CD79b ADC is between about 0.5 mg / kg and about 10 mg / kg (e.g., between about 0.5 mg / kg and about 9 mg / kg, between about 0.5 mg / kg and about 8 mg / kg, between about 0.5 mg / kg and about 7 mg / kg, between about 0.5 mg / kg and about 6 mg / kg, between about 0.5 mg / kg and about 5 mg / kg, between about 0.5 mg / kg and about 4 mg / kg, between about 0.5 mg / kg and about 3 mg / kg). In some examples, the single dose C1D1 of the anti-CD79b ADC is about 1.8 mg / kg. In some examples, the second administration cycle may include administering a single dose C2D1 of the anti-CD79b ADC to the subject. In some examples, the single dose C2D1 of the anti-CD79b ADC may be about 1.8 mg / kg. In some examples, the second administration cycle may include administering a single dose C2D1 of the anti-CD79b ADC to the subject. In some examples, the single dose C2D1 of the anti-CD79b ADC may be about 1.8 mg / kg. A single dose C2D1 of the ADC may be between about 0.5 mg / kg and about 10 mg / kg (e.g., between about 0.5 mg / kg and about 9 mg / kg, between about 0.5 mg / kg and about 8 mg / kg, between about 0.5 mg / kg and about 7 mg / kg, between about 0.5 mg / kg and about 6 mg / kg, between about 0.5 mg / kg and about 5 mg / kg, between about 0.5 mg / kg and about 4 mg / kg, between about 0.5 mg / kg and about 3 mg / kg). In some examples, a single dose of anti-CD79b ADC C2D1 is about 1.8 mg / kg.

[0152] In some examples, the methods herein may include a first administration cycle of 14 to 28 days (e.g., 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, or 28 days). In some examples, the length of the first administration cycle is about 3 weeks or 21 days. In some examples, the methods may include administering bispecific antibody C1D1, bispecific antibody C1D2, and bispecific antibody C1D3 to a subject on days 1, 8, and 15, or about days 1, 8, and 15, respectively, of the first administration cycle (e.g., days 1±3, 8±3, and 15±3, respectively).

[0153] In some examples, the methods herein may include a second administration cycle of 14 to 28 days (e.g., 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, or 28 days). In some examples, the length of the second administration cycle is about 3 weeks or 21 days. In some examples, the methods may include administering the bispecific antibody C2D1 to the subject on day 1 or about day 1 (e.g., day 1 ± day 3) of the second administration cycle.

[0154] In some examples, the methods described above may include one or more additional administration cycles (e.g., in addition to the first and second administration cycles). In some examples, the administration regimen has 1 to 15 additional administration cycles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 additional administration cycles (i.e., the administration regimen includes one or more of the additional administration cycle(s) C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, and C17)). In some examples, the administration regimen includes 6 to 15 additional administration cycles (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 additional cycles). In some examples, the length of each of the one or more additional administration cycles is 7 days, 14 days, 21 days, or 28 days (e.g., 7±3 days, 14±3 days, 21±3 days, or 28±3 days, respectively). In some examples, the length of each of the one or more additional administration cycles is 3 weeks or 21 days. In some examples, each of the one or more additional administration cycles comprises an additional single dose of the bispecific antibody and an additional single dose of the anti-CD79b ADC. In some examples, each additional single dose of the anti-CD79b ADC is equivalent to the amount of the bispecific antibody C2D1. In some examples, the provided methods comprise administering to the subject an additional single dose of the anti-CD79b ADC on or about day 1 of each of the one or more additional administration cycles. In some examples, each of the additional administration cycles comprises only an additional single dose of the bispecific antibody and no additional dose of the anti-CD79b ADC. In some examples, each additional single dose of the bispecific antibody is an amount equivalent to C2D1 of the bispecific antibody. In some examples, provided methods include administering to the subject an additional single dose of the bispecific antibody on or about day 1 of each of one or more additional administration cycles. In some examples, the above administration regimen may include six or more additional administration cycles, each of the six or more additional administration cycles comprising an additional single dose of the bispecific antibody, and no more than four of the six or more additional administration cycles comprising an additional single dose of the anti-CD79b ADC.

[0155] The invention further provides methods for treating a CD20-positive cell proliferative disorder, e.g., a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL, DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), or MCL (e.g., relapsed and / or refractory MCL)), CLL, or CNSL), by administering to a subject an anti-CD79b ADC and 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)(i) the first dosing cycle comprises administering an anti-CD79b ADC and a bispecific antibody that binds CD20 and CD3 to a subject; (a)(ii) the first administration cycle comprises a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody, wherein C1D1 of the bispecific antibody is between about 0.02 mg and about 5.0 mg (e.g., about 0.05 mg to about 5 mg, about 0.1 mg to about 5.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 2 mg to about 5.0 mg, about 3 mg to about 5.0 mg, about 0.05 mg to about 4.0 mg, about 0.05 mg to about 3.0 mg, about 0.05 mg to about 2.0 mg, about 0.1 mg to about 2.0 mg, 0.0 mg, about 0.5 mg to about 2.0 mg, about 2 mg to about 4.0 mg, about 1 mg to about 3.0 mg, about 1 mg, about 2 mg, or about 5 mg), and C1D2 of the bispecific antibody is between about 0.05 mg to about 10.0 mg (for example, about 0.1 mg to about 10.0 mg, about 0.5 mg to about 10.0 mg, 1 mg to about 10.0 mg, about 2 mg to about 3.0 mg, about 5 mg to about 10.0 mg, about 8 mg to about 10.0 mg, about 0.5 mg to about 7.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 1 mg to about 3.0 mg, about 3 mg to about 8.(b) (i) the second administration cycle comprises a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody that are between about 10 mg, about 1 mg, about 2 mg, or about 5 mg) or between about 10 mg and about 60 mg (e.g., about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 20 mg to about 50 mg, about 30 mg to about 50 mg, about 40 mg to about 50 mg, about 45 mg to about 50 mg, about 13 mg to about 17 mg, about 43 mg to about 48 mg, about 15 mg to about 35 mg, about 25 mg to about 45 mg, about 15 mg, about 30 mg, or about 45 mg); (b) (i) the second administration cycle comprises a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody that are between about 10 mg, about 50 mg, about 10 mg, about 40 mg, about 50 mg, about 10 mg, about 20 mg, about 30 mg, or about 45 mg); (b)(ii) the second administration cycle comprises a single dose of a bispecific antibody (C2D1), wherein the C2D1 of the bispecific antibody is greater than or equal to the C1D2 of the bispecific antibody.

[0156] The present invention also provides methods for treating a subject with a CD20-positive cell proliferative disorder, e.g., a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL, DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), or MCL (e.g., relapsed and / or refractory MCL)), CLL, or CNSL), comprising administering to the subject an anti-CD79b ADC and 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)(i) the first dosing cycle comprises administering to the subject an anti-CD79b ADC and a bispecific antibody that binds CD20 and CD3; (a)(ii) a first administration cycle comprising a first dose of the ADC (C1D1), a second dose of the bispecific antibody (C1D2), wherein C1D2 of the bispecific antibody is equal to or greater than C1D1 of the bispecific antibody, and C1D1 is between about 0.02 mg and about 5.0 mg (e.g., about 0.05 mg to about 5 mg, about 0.1 mg to about 5.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 2 mg to about 5.0 mg, about 3 mg to about 5.0 mg, about 0.05 mg to about 4.0 mg, about 0.05 mg to about 3.0 mg, about 0.0 5 mg to about 2.0 mg, about 0.1 mg to about 2.0 mg, about 0.5 mg to about 2.0 mg, about 2 mg to about 4.0 mg, about 1 mg to about 3.0 mg, about 1 mg, about 2 mg, or about 5 mg), and C1D2 is between about 0.05 mg to about 10.0 mg (e.g., about 0.1 mg to about 10.0 mg, about 0.5 mg to about 10.0 mg, 1 mg to about 10.0 mg, about 2 mg to about 3.0 mg, about 5 mg to about 10.0 mg, about 8 mg to about 10.0 mg, about 0.5 mg to about 7.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 1 mg to about 3.0 mg, or about 3 mg to about 8.(b) (i) a first dose (C1D1) of the bispecific antibody, a second dose (C1D2) of the bispecific antibody, and a second dose (C1D3) of the bispecific antibody, each dose being between about 10 mg, about 1 mg, about 2 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 45 mg, about 50 mg, about 13 mg, about 17 mg, about 43 mg, about 48 mg, about 15 mg, about 35 mg, about 25 mg, about 45 mg, about 15 mg, about 30 mg, or about 45 mg; (b) (i) a second administration cycle comprising an anti-CD79b (b)(ii) the second administration cycle comprises a single dose of the bispecific antibody (C2D1), wherein the C2D1 of the bispecific antibody is greater than or equal to the C1D2 of the bispecific antibody and is about 9 mg, about 13.5 mg, about 20 mg, about 45 mg, or about 60 mg.

[0157] In some examples, for example, (a) C1D1 of the bispecific antibody is between about 0.02 mg and about 5 mg, and C1D2 of the bispecific antibody is between about 0.05 mg and about 10.0 mg (e.g., about 0.1 mg to about 10.0 mg, about 0.5 mg to about 10.0 mg, 1 mg to about 10.0 mg, about 2 mg to about 3.0 mg, about 5 mg to about 10.0 mg, about 8 mg to about 10.0 mg, about 0.5 mg to about 7.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 1 mg to about 3.0 mg, about 3 mg to about 8.0 mg, about 1 mg, about 2 mg, or about 5 mg) or between about 10 mg and about 60 mg (e.g., about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 20 mg to about 50 mg, about 30 mg to about 50 mg, about 40 mg to about 50 mg, about 45 mg to about 50 mg, about 13 mg to about 17 mg, about 43 mg to about 48 mg, about 15 mg to about 35 mg, about 25 mg to about 45 mg, about 15 mg, about 30 mg, or about 45 mg), and (b) C2D1 of the bispecific antibody is equal to or greater than C1D2 of the bispecific antibody. In some examples, (a) C1D1 of the bispecific antibody is about 1 mg and C1D2 of the bispecific antibody is about 2 mg, and (b) C2D1 of the bispecific antibody is equal to or greater than C1D2 of the bispecific antibody. In some examples, (a) C1D1 of the bispecific antibody is about 1 mg, C1D2 of the bispecific antibody is about 2 mg, and (b) C2D1 of the bispecific antibody is about 9 mg. In some examples, (a) C1D1 of the bispecific antibody is about 1 mg, C1D2 of the bispecific antibody is about 2 mg, and (b) C2D1 of the bispecific antibody is about 13.5 mg. In some examples, (a) C1D1 of the bispecific antibody is about 1 mg, C1D2 of the bispecific antibody is about 2 mg, and (b) C2D1 of the bispecific antibody is about 20 mg. In some examples, (a) C1D1 of the bispecific antibody is about 1 mg, C1D2 of the bispecific antibody is about 2 mg, and (b) C2D1 of the bispecific antibody is about 40 mg. In other examples, (a) C1D1 is about 1 mg, C1D2 is about 2 mg, and (b) C2D1 is greater than or equal to C1D3. In some examples, (a) C1D1 is about 1 mg, C1D2 is about 2 mg, and (b) C2D1 is about 60 mg.In other examples, (a) C1D1 is about 5 mg, C1D2 is about 15 mg, and (b) C2D1 is about 45 mg. In some examples, (a) C1D1 is about 5 mg, C1D2 is about 45 mg, and (b) C2D1 is about 45 mg.

[0158] In any of the above examples, the dosing regimen may include a first dosing cycle and a second dosing cycle, where (a) the first dosing cycle includes the bispecific antibodies C1D1 and C1D2, and (b) the second dosing cycle includes the bispecific antibody C2D1. In any of the above examples, the dosing regimen may include at least a first dosing cycle and a second dosing cycle, where (a) the first dosing cycle includes the bispecific antibodies C1D1 and C1D2, and (b) the second dosing cycle includes the bispecific antibody C2D1.

[0159] In some examples of the above methods, the first administration cycle may include administering a single dose C1D1 of the anti-CD79b ADC to the subject. In some examples, the single dose C1D1 of the anti-CD79b ADC is between about 0.5 mg / kg and about 10 mg / kg (e.g., between about 0.5 mg / kg and about 9 mg / kg, between about 0.5 mg / kg and about 8 mg / kg, between about 0.5 mg / kg and about 7 mg / kg, between about 0.5 mg / kg and about 6 mg / kg, between about 0.5 mg / kg and about 5 mg / kg, between about 0.5 mg / kg and about 4 mg / kg, between about 0.5 mg / kg and about 3 mg / kg). In some examples, the single dose C1D1 of the anti-CD79b ADC is about 1.8 mg / kg. In some examples, the second administration cycle may include administering a single dose C2D1 of the anti-CD79b ADC to the subject. In some examples, the single dose C2D1 of the anti-CD79b ADC may be about 1.8 mg / kg. In some examples, the second administration cycle may include administering a single dose C2D1 of the anti-CD79b ADC to the subject. In some examples, the single dose C2D1 of the anti-CD79b ADC may be about 1.8 mg / kg. A single dose C2D1 of the ADC may be between about 0.5 mg / kg and about 10 mg / kg (e.g., between about 0.5 mg / kg and about 9 mg / kg, between about 0.5 mg / kg and about 8 mg / kg, between about 0.5 mg / kg and about 7 mg / kg, between about 0.5 mg / kg and about 6 mg / kg, between about 0.5 mg / kg and about 5 mg / kg, between about 0.5 mg / kg and about 4 mg / kg, between about 0.5 mg / kg and about 3 mg / kg). In some examples, a single dose of anti-CD79b ADC C2D1 is about 1.8 mg / kg.

[0160] In some examples, the methods may include a first administration cycle of 14 to 28 days (e.g., 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 days). In some examples, the length of the first administration cycle is about 3 weeks or 21 days. In some examples, the methods may include administering bispecific antibody C1D1 and bispecific antibody C1D2 to the subject on days 8 and 15, or about days 8 and 15, respectively, of the first administration cycle (e.g., days 8±3 and 15±3, respectively).

[0161] In some examples, the methods may include a second administration cycle of 14 to 28 days (e.g., 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, or 28 days). In some examples, the length of the second administration cycle is about 3 weeks or 21 days. In some examples, the methods may include administering the bispecific antibody C2D1 to the subject on day 1 or about day 1 (e.g., day 1 ± day 3) of the second administration cycle.

[0162] In some examples, the methods described above can include one or more additional administration cycles. In some examples, the administration regimen includes 1 to 15 additional administration cycles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 additional administration cycles (i.e., the administration regimen includes one or more of the additional administration cycle(s) C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, and C17)). In some examples, the administration regimen includes 6 to 15 additional administration cycles (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 additional cycles). In some examples, the length of each of the one or more additional administration cycles is 7 days, 14 days, 21 days, or 28 days (e.g., 7±3 days, 14±3 days, 21±3 days, or 28±3 days, respectively). In some examples, the length of each of the one or more additional administration cycles is 3 weeks or 21 days. In some examples, each of the one or more additional administration cycles comprises an additional single dose of the bispecific antibody and an additional single dose of the anti-CD79b ADC. In some examples, each additional single dose of the anti-CD79b ADC is equivalent to the amount of the bispecific antibody C2D1. In some examples, the provided methods comprise administering to the subject an additional single dose of the anti-CD79b ADC on or about day 1 of each of the one or more additional administration cycles. In some examples, each of the additional administration cycles comprises only an additional single dose of the bispecific antibody and no additional dose of the anti-CD79b ADC. In some examples, each additional single dose of the bispecific antibody is an amount equivalent to C2D1 of the bispecific antibody. In some examples, provided methods include administering to the subject an additional single dose of the bispecific antibody on or about day 1 of each of one or more additional administration cycles. In some examples, the above administration regimen may include six or more additional administration cycles, each of the six or more additional administration cycles comprising an additional single dose of the bispecific antibody, and no more than four of the six or more additional administration cycles comprising an additional single dose of the anti-CD79b ADC.

[0163] The invention further provides methods for treating a subject with a CD20-positive cell proliferative disorder, e.g., a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL, DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), or MCL (e.g., relapsed or refractory MCL)), CLL, or CNSL), comprising administering to the subject an anti-CD79b ADC and a bispecific antibody that binds CD20 and CD3 in a dosing regimen comprising eight or more dosing cycles, wherein: (a)(i) a first dosing cycle comprises two The first dose (C1D1), second dose (C1D2), and third dose (C1D3) of the bispecific antibody, wherein C1D1 is between about 0.02 mg and about 5.0 mg (e.g., about 0.05 mg to about 5 mg, about 0.1 mg to about 5.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 2 mg to about 5.0 mg, about 3 mg to about 5.0 mg, about 0.05 mg to about 4.0 mg, about 0.05 mg to about 3.0 mg, about 0.05 mg to about 2.0 mg, about 0.1 mg to about 2.0 mg, about 0.5 mg to about 2.0 mg, about 2 mg to about 4.0 mg, about 1 mg to about 3.0 mg, about 1 mg, about 2 mg, or about 5 mg), and C1D2 is between about 0.05 mg to about 10.0 mg (for example, about 0.1 mg to about 10.0 mg, about 0.5 mg to about 10.0 mg, 1 mg to about 10.0 mg, about 2 mg to about 3.0 mg, about 5 mg to about 10.0 mg, about 8 mg to about 10.0 mg, about 0.5 mg to about 7.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 1 mg to about 3.0 mg, about 3 mg to about 8.0 mg, about 1 mg, about 2 mg, or about 5 mg) or between about 10 mg and about 60 mg (e.g., about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 20 mg to about 50 mg, about 30 mg to about 50 mg, about 40 mg to about 50 mg, about 45 mg to about 50 mg, about 13 mg to about 17 mg, about 43 mg to about 48 mg, about 15 mg to about 35 mg, about 25 mg to about 45 mg, about 15 mg, about 30 mg, or about 45 mg), and C1D3 is about 9 mg, about 13 mg, or about 5 mg.(b) the second administration cycle comprises a single dose of the anti-CD79b ADC (C2D1) and a single dose of the bispecific antibody (C2D1); (c) the third administration cycle comprises a single dose of the anti-CD79b ADC (C3D1) and a single dose of the bispecific antibody (C3D1); (d) the fourth administration cycle comprises a single dose of the anti-CD79b ADC (C4D1) and a single dose of the bispecific antibody (C4D1); (e) the fifth administration cycle comprises a single dose of the anti-CD79b ADC (C4D1) and a single dose of the bispecific antibody (C4D1); (f) a sixth administration cycle comprises a single dose of an anti-CD79b ADC (C6D1) and a single dose of a bispecific antibody (C6D1); (g) a seventh administration cycle comprises a single dose of an anti-CD79b ADC (C7D1) and a single dose of a bispecific antibody (C7D1); and (h) an eighth administration cycle comprises a single dose of an anti-CD79b ADC (C8D1) and a single dose of a bispecific antibody (C8D1), wherein C2D1, C3D1, C4D1, C5D1, C6D1, C7D1, and C8D1 of the bispecific antibody are each equal to or greater than C1D3 of the bispecific antibody.

[0164] The present invention also provides methods for treating a subject with a CD20-positive cell proliferative disorder, e.g., a B-cell proliferative disorder (e.g., NHL (e.g., DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL) or MCL (e.g., relapsed or refractory MCL)), CLL or CNSL), comprising administering to the subject a bispecific antibody that binds to CD20 and CD3 in a dosing regimen comprising at least eight or more dosing cycles, wherein: (a)(i) a first dosing cycle comprises a first dose of the bispecific antibody; a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3), wherein C1D3 of the bispecific antibody is equal to or greater than C1D2 and C1D1 of the bispecific antibody, C1D2 of the bispecific antibody is equal to or greater than C1D1 of the bispecific antibody, and C1D1 is between about 0.02 mg and about 5.0 mg (e.g., about 0.05 mg to about 5 mg, about 0.1 mg to about 5.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 2 mg to about 5.0 mg, about 3 mg to about 5.0 mg, about 0.05 mg to about 4.0 mg, about 0.05 mg to about 3.0 mg, about 0.05 mg and C1D2 is between about 0.05 mg and about 10.0 mg (for example, about 0.1 mg to about 10.0 mg, about 0.5 mg to about 10.0 mg, 1 mg to about 10.0 mg, about 2 mg to about 3.0 mg, about 5 mg to about 10.0 mg, about 8 mg to about 10.0 mg, about 0.5 mg to about 7.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 1 mg to about 3.0 mg, about 3 mg to about 5.0 mg). about 8.0 mg, about 1 mg, about 2 mg, or about 5 mg) or between about 10 mg and about 60 mg (for example, about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 20 mg to about 50 mg, about 30 mg to about 50 mg, about 40 mg to about 50 mg, about 45 mg to about 50 mg, about 13 mg to about 17 mg, about 43 mg to about 48 mg, about 15 mg to about 35 mg, about 25 mg to about 45 mg, about 15 mg, about 30 mg, or about 45 mg), and the C1D3 of the bispecific antibody is about 9 mg, about 13 mg, about 17 mg, about 43 mg, about 48 mg, about 15 mg, about 35 mg, about 25 mg, about 45 mg, about 15 mg, about 30 mg, or about 45 mg).(b) the second administration cycle comprises a single dose of the anti-CD79b ADC (C2D1) and a single dose of the bispecific antibody (C2D1); (c) the third administration cycle comprises a single dose of the anti-CD79b ADC (C3D1) and a single dose of the bispecific antibody (C3D1); (d) the fourth administration cycle comprises a single dose of the anti-CD79b ADC (C4D1) and a single dose of the bispecific antibody (C4D1); (e) the fifth administration cycle comprises a single dose of the anti-CD79b ADC (C4D1) and a single dose of the bispecific antibody (C4D1); (f) a sixth administration cycle comprises a single dose of the anti-CD79b ADC (C6D1) and a single dose of the bispecific antibody (C6D1); (g) a seventh administration cycle comprises a single dose of the anti-CD79b ADC (C7D1) and a single dose of the bispecific antibody (C7D1); and (h) an eighth administration cycle comprises a single dose of the anti-CD79b ADC (C8D1) and a single dose of the bispecific antibody (C8D1), wherein C2D1, C3D1, C4D1, C5D1, C6D1, C7D1, and C8D1 of the bispecific antibodies are each equal to or greater than C1D3 of the bispecific antibody and are about 9 mg, about 13.5 mg, about 20 mg, about 40 mg, about 45 mg, or about 60 mg, respectively. .

[0165] In some examples, C1D3 and C2D1 to C8D1 of the bispecific antibody are present in approximately equal amounts. In some examples, C1D1 to C6D1 of the anti-CD79b ADC are present in approximately equal amounts.

[0166] The invention further provides methods for treating a subject with a CD20-positive cell proliferative disorder, e.g., a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL, DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), or MCL (e.g., relapsed or refractory MCL)), CLL, or CNSL), comprising administering to the subject an anti-CD79b ADC and a bispecific antibody that binds CD20 and CD3 in a dosing regimen comprising eight or more dosing cycles, wherein: (a)(i) a first dosing cycle comprises two The first dose (C1D1), second dose (C1D2), and third dose (C1D3) of the bispecific antibody, wherein C1D1 is between about 0.02 mg and about 5.0 mg (e.g., about 0.05 mg to about 5 mg, about 0.1 mg to about 5.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 2 mg to about 5.0 mg, about 3 mg to about 5.0 mg, about 0.05 mg to about 4.0 mg, about 0.05 mg to about 3.0 mg, about 0.05 mg to about 2.0 mg, about 0.1 mg to about 2.0 mg, about 0.5 mg to about 2.0 mg , about 2 mg to about 4.0 mg, about 1 mg to about 3.0 mg, about 1 mg, about 2 mg, or about 5 mg), and C1D2 is between about 0.05 mg to about 10.0 mg (for example, about 0.1 mg to about 10.0 mg, about 0.5 mg to about 10.0 mg, 1 mg to about 10.0 mg, about 2 mg to about 3.0 mg, about 5 mg to about 10.0 mg, about 8 mg to about 10.0 mg, about 0.5 mg to about 7.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 1 mg to about 3.0 mg, about 3 mg to about 8.0 mg, about 1 mg, about 2 mg, or about 5 mg) or between about 10 mg and about 60 mg (e.g., about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 20 mg to about 50 mg, about 30 mg to about 50 mg, about 40 mg to about 50 mg, about 45 mg to about 50 mg, about 13 mg to about 17 mg, about 43 mg to about 48 mg, about 15 mg to about 35 mg, about 25 mg to about 45 mg, about 15 mg, about 30 mg, or about 45 mg), and C1D3 is about 9 mg, about 13 mg, or about 5 mg.(b) the second administration cycle comprises a single dose of the anti-CD79b ADC (C2D1) and a single dose of the bispecific antibody (C2D1); (c) the third administration cycle comprises a single dose of the anti-CD79b ADC (C3D1) and a single dose of the bispecific antibody (C3D1); (d) the fourth administration cycle comprises a single dose of the anti-CD79b ADC (C4D1) and a single dose of the bispecific antibody (C4D1); (e) the fifth administration cycle comprises a single dose of the anti-CD79b ADC (C4D1) and a single dose of the bispecific antibody (C4D1); (f) a sixth administration cycle comprises a single dose of an anti-CD79b ADC (C6D1) and a single dose of a bispecific antibody (C6D1); (g) a seventh administration cycle comprises a single dose of an anti-CD79b ADC (C7D1) and a single dose of a bispecific antibody (C7D1); (h) an eighth administration cycle comprises a single dose of an anti-CD79b ADC (C8D1) and a single dose of a bispecific antibody (C8D1), wherein C1D3 and C2D1 are approximately equal, and C3D1, C4D1, C5D1, C6D1, C7D1, and C8D1 of the bispecific antibody are each less than C1D3 of the bispecific antibody.

[0167] The present invention also provides methods for treating a subject with a CD20-positive cell proliferative disorder, e.g., a B-cell proliferative disorder (e.g., NHL (e.g., DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL) or MCL (e.g., relapsed or refractory MCL)), CLL or CNSL), comprising administering to the subject a bispecific antibody that binds to CD20 and CD3 in a dosing regimen comprising at least eight or more dosing cycles, wherein: (a)(i) a first dosing cycle comprises a first dose of the bispecific antibody; a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3), wherein C1D3 of the bispecific antibody is equal to or greater than C1D2 and C1D1 of the bispecific antibody, C1D2 of the bispecific antibody is equal to or greater than C1D1 of the bispecific antibody, and C1D1 is between about 0.02 mg and about 5.0 mg (e.g., about 0.05 mg to about 5 mg, about 0.1 mg to about 5.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 2 mg to about 5.0 mg, about 3 mg to about 5.0 mg, about 0.05 mg to about 4.0 mg, about 0.05 mg to about 3.0 mg, about 0.05 mg and C1D2 is between about 0.05 mg and about 10.0 mg (for example, about 0.1 mg to about 10.0 mg, about 0.5 mg to about 10.0 mg, 1 mg to about 10.0 mg, about 2 mg to about 3.0 mg, about 5 mg to about 10.0 mg, about 8 mg to about 10.0 mg, about 0.5 mg to about 7.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 1 mg to about 3.0 mg, about 3 mg to about 5.0 mg). about 8.0 mg, about 1 mg, about 2 mg, or about 5 mg) or between about 10 mg and about 60 mg (for example, about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 20 mg to about 50 mg, about 30 mg to about 50 mg, about 40 mg to about 50 mg, about 45 mg to about 50 mg, about 13 mg to about 17 mg, about 43 mg to about 48 mg, about 15 mg to about 35 mg, about 25 mg to about 45 mg, about 15 mg, about 30 mg, or about 45 mg), and the C1D3 of the bispecific antibody is about 9 mg, about 13 mg, about 17 mg, about 43 mg, about 48 mg, about 15 mg, about 35 mg, about 25 mg, about 45 mg, about 15 mg, about 30 mg, or about 45 mg).(b) the second administration cycle comprises a single dose of the anti-CD79b ADC (C2D1) and a single dose of the bispecific antibody (C2D1); (c) the third administration cycle comprises a single dose of the anti-CD79b ADC (C3D1) and a single dose of the bispecific antibody (C3D1); (d) the fourth administration cycle comprises a single dose of the anti-CD79b ADC (C4D1) and a single dose of the bispecific antibody (C4D1); (e) the fifth administration cycle comprises a single dose of the anti-CD79b ADC (C4D1) and a single dose of the bispecific antibody (C4D1); (f) a sixth administration cycle comprising a single dose of the anti-CD79b ADC (C6D1) and a single dose of the bispecific antibody (C6D1); (g) a seventh administration cycle comprising a single dose of the anti-CD79b ADC (C7D1) and a single dose of the bispecific antibody (C7D1); (h) an eighth administration cycle comprising a single dose of the anti-CD79b ADC (C7D1) and a single dose of the bispecific antibody (C7D1); The dosage comprises a single dose of the ADC (C8D1) and a single dose of the bispecific antibody (C8D1), in which C3D1 and C2D1 are approximately equal, and C3D1, C4D1, C5D1, C6D1, C7D1, and C8D1 of the bispecific antibodies are each less than C1D3 of the bispecific antibody, and each is about 10 mg to about 45 mg (e.g., about 10 mg to about 40 mg, about 10 mg to about 35 mg, about 15 mg to about 45 mg, about 20 mg to about 45 mg, or about 25 mg to about 45 mg; for example, about 30 mg). In some examples, each of C3D1 to C8D1 is about 30 mg.

[0168] In some examples, in the above methods, each single dose of anti-CD79b ADC C1D1-C6D1 is between about 0.5 mg / kg and about 10 mg / kg (e.g., between about 0.5 mg / kg and about 9 mg / kg, between about 0.5 mg / kg and about 8 mg / kg, between about 0.5 mg / kg and about 7 mg / kg, between about 0.5 mg / kg and about 6 mg / kg, between about 0.5 mg / kg and about 5 mg / kg, between about 0.5 mg / kg and about 4 mg / kg, between about 0.5 mg / kg and about 3 mg / kg). g, between about 0.5 mg / kg and about 2 mg / kg, between about 0.75 mg / kg and about 10 mg / kg, between about 1 mg / kg and about 10 mg / kg, between about 1.5 mg / kg and about 10 mg / kg, between about 1 mg / kg and about 5 mg / kg, between about 1 mg / kg and about 3 mg / kg, between about 1.5 mg / kg and about 2.5 mg / kg, between about 1.5 mg / kg and about 2 mg / kg, or about 1.8 mg / kg). In some examples, each single dose of anti-CD79b ADC C1D1-C6D1 is about 1.8 mg / kg.

[0169] In some examples, the methods described above may include a first administration cycle of 14 to 28 days (e.g., 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, or 28 days). In some examples, the length of the first administration cycle is about 3 weeks or 21 days. In some examples, the methods may include administering to the subject bispecific antibody C1D1, bispecific antibody C1D2, and bispecific antibody C1D3 on days 1, 8, and 15, or about days 1, 8, and 15, respectively, of the first administration cycle (e.g., days 1±3, 8±3, and 15±3, respectively). In some examples, a single dose of each of the bispecific antibodies C1D1-C8D1 is administered to the subject on day 1 (e.g., day 1±3) of each administration cycle. In some examples, a single dose of each of the anti-CD79b ADCs C1D1-C6D1 is administered to a subject on day 1 of each administration cycle (e.g., day 1 ± day 3). In some examples, the length of each of the one or more additional administration cycles is 7 days, 14 days, 21 days, or 28 days (e.g., 7 ± 3 days, 14 ± 3 days, 21 ± 3 days, or 28 ± 3 days, respectively). In some examples, the length of each of the one or more additional administration cycles is 3 weeks or 21 days.

[0170] The invention further provides methods for treating a subject with a CD20-positive cell proliferative disorder, e.g., a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL, DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), or MCL (e.g., relapsed or refractory MCL)), CLL, or CNSL), comprising administering to the subject an anti-CD79b ADC and a bispecific antibody that binds CD20 and CD3 in a dosing regimen comprising eight or more dosing cycles, wherein: (a) a first dosing cycle comprises administering to the subject an anti-CD79b ADC and a bispecific antibody that binds CD20 and CD3; The first dose (C1D1), second dose (C1D2), and third dose (C1D3) of the antibody, wherein C1D1 is between about 0.02 mg and about 5.0 mg (e.g., about 0.05 mg to about 5 mg, about 0.1 mg to about 5.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 2 mg to about 5.0 mg, about 3 mg to about 5.0 mg, about 0.05 mg to about 4.0 mg, about 0.05 mg to about 3.0 mg, about 0.05 mg to about 2.0 mg, about 0.1 mg to about 2.0 mg, about 0.5 mg to about 2.0 mg, about 2 mg to about 4.0 mg, about 1 mg to about 3.0 mg, about 1 mg, about 2 mg, or about 5 mg), and C1D2 is between about 0.05 mg to about 10.0 mg (for example, about 0.1 mg to about 10.0 mg, about 0.5 mg to about 10.0 mg, 1 mg to about 10.0 mg, about 2 mg to about 3.0 mg, about 5 mg to about 10.0 mg, about 8 mg to about 10.0 mg, about 0.5 mg to about 7.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 1 mg to about 3.0 mg, about 3 mg to about 8.0 mg, about 1 mg, about 2 mg g, or about 5 mg) or between about 10 mg and about 60 mg (e.g., about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 20 mg to about 50 mg, about 30 mg to about 50 mg, about 40 mg to about 50 mg, about 45 mg to about 50 mg, about 13 mg to about 17 mg, about 43 mg to about 48 mg, about 15 mg to about 35 mg, about 25 mg to about 45 mg, about 15 mg, about 30 mg, or about 45 mg), and C1D3 is about 9 mg, about 13 mg, or about 5 mg.(b) a second administration cycle comprising a single dose of an anti-CD79b ADC (C2D1) and a single dose of the bispecific antibody (C2D1); (c) a third administration cycle comprising a single dose of an anti-CD79b ADC (C3D1) and a single dose of the bispecific antibody (C3D1); (d) a fourth administration cycle comprising a single dose of an anti-CD79b ADC (C4D1) and a single dose of the bispecific antibody (C4D1); (e) a fifth administration cycle comprising a single dose of an anti-CD79b ADC (C4D1) and a single dose of the bispecific antibody (C4D1); (f) a sixth administration cycle comprises a single dose of an anti-CD79b ADC (C6D1) and a single dose of a bispecific antibody (C6D1); (g) a seventh administration cycle comprises a single dose of an anti-CD79b ADC (C7D1) and a single dose of a bispecific antibody (C7D1); and (h) an eighth administration cycle comprises a single dose of an anti-CD79b ADC (C8D1) and a single dose of a bispecific antibody (C8D1), wherein C2D1, C3D1, C4D1, C5D1, C6D1, C7D1, and C8D1 of the bispecific antibody are each equal to or greater than C1D3 of the bispecific antibody.

[0171] The present invention also provides a method for treating a subject with a CD20-positive cell proliferative disorder, e.g., a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL, DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL) or MCL (e.g., relapsed and / or refractory MCL)), CLL or CNSL), comprising administering to the subject a bispecific antibody that binds to CD20 and CD3 in a dosing regimen comprising at least eight or more administration cycles, wherein: (a) the first administration cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of the bispecific antibody, wherein C1D3 of the bispecific antibody is equal to or greater than C1D2 and C1D1 of the bispecific antibody, and wherein C1D2 of the bispecific antibody is equal to or greater than C1D1 of the bispecific antibody, and wherein C1D1 is greater than or equal to about 0.02 mg to about 5.0 mg (e.g., about 0.05 mg to about 5 mg, about 0.1 mg to about 5.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 2 mg to about 5.0 mg, about 3 mg to about 5.0 mg, about 0.05 mg to about 4.0 mg, about 0.05 mg to about 3.0 mg, about 0.05 mg to about 2.0 mg, about 0.1 mg to about 2.0 mg, about 0.5 mg to about 2.0 mg, about 2 mg to about 4.0 mg, about 1 mg to about 3.0 mg , about 1 mg, about 2 mg, or about 5 mg), and C1D2 is about 0.05 mg to about 10.0 mg (for example, about 0.1 mg to about 10.0 mg, about 0.5 mg to about 10.0 mg, 1 mg to about 10.0 mg, about 2 mg to about 3.0 mg, about 5 mg to about 10.0 mg, about 8 mg to about 10.0 mg, about 0.5 mg to about 7.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 1 mg to about 3.0 mg, about 3 mg to about 8.0 mg, about 1 mg, about 2 mg, or about 5 mg) or between about 10 mg and about 60 mg (e.g., about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 20 mg to about 50 mg, about 30 mg to about 50 mg, about 40 mg to about 50 mg, about 45 mg to about 50 mg, about 13 mg to about 17 mg, about 43 mg to about 48 mg, (b) a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of the bispecific antibody, wherein the bispecific antibody C1D3 is about 9 mg, about 13.5 mg, about 20 mg, about 40 mg, about 45 mg, or about 60 mg; (b) a second administration cycle comprising anti-CD79b (c) a third administration cycle comprises a single dose of an anti-CD79b ADC (C2D1) and a single dose of a bispecific antibody (C2D1); (d) a fourth administration cycle comprises a single dose of an anti-CD79b ADC (C4D1) and a single dose of a bispecific antibody (C4D1); (e) a fifth administration cycle comprises a single dose of an anti-CD79b ADC (C5D1) and a single dose of a bispecific antibody (C5D1); (f) a sixth administration cycle comprises a single dose of an anti-CD79b ADC (C6D1) and a single dose of a bispecific antibody (C6D1); (g) a seventh administration cycle comprises a single dose of an anti-CD79b ADC (C6D1) and a single dose of a bispecific antibody (C6D1). (h) an eighth administration cycle comprising a single dose of the anti-CD79b ADC (C7D1) and a single dose of the bispecific antibody (C7D1); (h) an eighth administration cycle comprising a single dose of the anti-CD79b ADC (C8D1) and a single dose of the bispecific antibody (C8D1), wherein the bispecific antibodies C2D1, C3D1, C4D1, C5D1, C6D1, C7D1, and C8D1 are each equal to or greater than the bispecific antibody C1D3 and are about 9 mg, about 13.5 mg, about 20 mg, about 40 mg, about 45 mg, or about 60 mg, respectively.

[0172] In some examples, C1D3 and C2D1 to C8D1 of the bispecific antibody are present in approximately equal amounts. In some examples, C2D1 to C6D1 of the anti-CD79b ADC are present in approximately equal amounts.

[0173] In some examples, in the above methods, each single dose of anti-CD79b ADC C2D1-C6D1 is between about 0.5 mg / kg and about 10 mg / kg (e.g., between about 0.5 mg / kg and about 9 mg / kg, between about 0.5 mg / kg and about 8 mg / kg, between about 0.5 mg / kg and about 7 mg / kg, between about 0.5 mg / kg and about 6 mg / kg, between about 0.5 mg / kg and about 5 mg / kg, between about 0.5 mg / kg and about 4 mg / kg, between about 0.5 mg / kg and about 3 mg / kg). g, between about 0.5 mg / kg and about 2 mg / kg, between about 0.75 mg / kg and about 10 mg / kg, between about 1 mg / kg and about 10 mg / kg, between about 1.5 mg / kg and about 10 mg / kg, between about 1 mg / kg and about 5 mg / kg, between about 1 mg / kg and about 3 mg / kg, between about 1.5 mg / kg and about 2.5 mg / kg, between about 1.5 mg / kg and about 2 mg / kg, or about 1.8 mg / kg). In some examples, each single dose of anti-CD79b ADC C2D1-C6D1 is about 1.8 mg / kg.

[0174] In some examples, the methods described above can have a first administration cycle of 3 weeks or 21 days. In some examples, the method may include administering bispecific antibody C1D1, bispecific antibody C1D2, and bispecific antibody C1D3 to the subject on, or about, days 1, 8, and 15, respectively, of the first administration cycle. In some examples, a single dose of each of the bispecific antibodies C1D1-C8D1 is administered to the subject on day 1 of each administration cycle. In some examples, a single dose of each of the anti-CD79b ADCs C2D1-C6D1 is administered to the subject on day 1 of each administration cycle. In some examples, the length of each of the one or more additional administration cycles is 7 days, 14 days, 21 days, or 28 days (e.g., 7±3 days, 14±3 days, 21±3 days, or 28±3 days, respectively). In some examples, each of the one or more additional administration cycles is 3 weeks or 21 days in length.

[0175] The present invention further provides a method for treating a subject with a CD20-positive cell proliferative disorder, for example, a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL, DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), or MCL (e.g., relapsed and / or refractory MCL)), CLL, or CNSL), comprising administering to the subject an anti-CD79b ADC and a bispecific antibody that binds to CD20 and CD3 in a dosing regimen comprising eight or more administration cycles, wherein: (a)(i) the first administration cycle comprises a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody, wherein C1D1 of the bispecific antibody is between about 0.02 mg and about 5.0 mg (e.g., about 0.05 mg to about 5 mg, about 0.1 mg to about 5.0 mg, about 0.5 mg to about 5 0.0 mg, about 1 mg to about 5.0 mg, about 2 mg to about 5.0 mg, about 3 mg to about 5.0 mg, about 0.05 mg to about 4.0 mg, about 0.05 mg to about 3.0 mg, about 0.05 mg to about 2.0 mg, about 0.1 mg to about 2.0 mg, about 0.5 mg to about 2.0 mg, about 2 mg to about 4.0 mg, about 1 mg to about 3.0 mg, about 1 mg, about 2 mg, or about 5 mg of the bispecific antibody C1D2 is between about 0.05 mg and about 10.0 mg (e.g., about 0.1 mg to about 10.0 mg, about 0.5 mg to about 10.0 mg, 1 mg to about 10.0 mg, about 2 mg to about 3.0 mg, about 5 mg to about 10.0 mg, about 8 mg to about 10.0 mg, about 0.5 mg to about 7.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 1 mg to about 3.0 mg, about 3 mg to about 8.and (a)(ii) a first administration cycle comprising a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody that are between about 10 mg, about 1 mg, about 2 mg, or about 5 mg) or between about 10 mg and about 60 mg (e.g., about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 20 mg to about 50 mg, about 30 mg to about 50 mg, about 40 mg to about 50 mg, about 45 mg to about 50 mg, about 13 mg to about 17 mg, about 43 mg to about 48 mg, about 15 mg to about 35 mg, about 25 mg to about 45 mg, about 15 mg, about 30 mg, or about 45 mg); and (a)(ii) a first administration cycle comprising a first dose (C1D1) and a second dose (C1D2) of the bispecific antibody that are between about 10 mg, about 50 mg, about 10 mg, about 40 mg, about 50 mg, about 10 mg, about 20 mg, about 30 mg, or about 45 mg); and (b)(i) the second administration cycle comprises a single dose of the anti-CD79b ADC (C2D1); (b)(ii) the second administration cycle comprises a single dose of the bispecific antibody (C2D1), where C2D1 of the bispecific antibody is equal to or greater than C1D3; (c) the third administration cycle comprises a single dose of the anti-CD79b ADC (C3D1) and a single dose of the bispecific antibody (C3D1); (d) the fourth administration cycle comprises a single dose of the anti-CD79b ADC (C4D1) and a single dose of the bispecific antibody (C4D1); (e) the fifth administration cycle comprises a single dose of the anti-CD79b ADC (C5D1) and a single dose of the bispecific antibody (C5D1); (f) the sixth administration cycle comprises a single dose of the anti-CD79b ADC (C5D1) and a single dose of the bispecific antibody (C5D1); (g) a seventh administration cycle comprises a single dose of the anti-CD79b ADC (C7D1) and a single dose of the bispecific antibody (C7D1); (h) an eighth administration cycle comprises a single dose of the anti-CD79b ADC (C8D1) and a single dose of the bispecific antibody (C8D1). In some examples, C2D1, C3D1, C4D1, C5D1, C6D1, C7D1, and C8D1 of the bispecific antibody are each greater than C1D2 of the bispecific antibody.

[0176] The present invention also provides methods for treating a subject with a CD20-positive cell proliferative disorder, e.g., a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL, DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), or MCL (e.g., relapsed or refractory MCL)), CLL, or CNSL), comprising administering to the subject an anti-CD79b ADC and a bispecific antibody that binds to CD20 and CD3 in a dosing regimen comprising at least a first administration cycle and a second administration cycle, wherein: (a)(i) the first administration cycle comprises a first dose (C1D1) of the bispecific antibody, a second dose (C1D2) of the bispecific antibody, wherein C1D2 of the bispecific antibody is equal to or greater than C1D1 of the bispecific antibody, and C1D1 is between about 0.02 mg and about 5.0 mg (e.g., about 0.05 mg to about 5 mg, about 0.1 mg g to about 5.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 2 mg to about 5.0 mg, about 3 mg to about 5.0 mg, about 0.05 mg to about 4.0 mg, about 0.05 mg to about 3.0 mg, about 0.05 mg to about 2.0 mg, about 0.1 mg to about 2.0 mg, about 0.5 mg to about 2.0 mg, about 2 mg to about 4.0 mg, about 1 mg to about 3.0 mg, about 1 mg, about 2 mg, or about 5 mg ), and C1D2 is between about 0.05 mg and about 10.0 mg (e.g., between about 0.1 mg and about 10.0 mg, between about 0.5 mg and about 10.0 mg, between 1 mg and about 10.0 mg, between about 2 mg and about 3.0 mg, between about 5 mg and about 10.0 mg, between about 8 mg and about 10.0 mg, between about 0.5 mg and about 7.0 mg, between about 0.5 mg and about 5.0 mg, between about 1 mg and about 5.0 mg, between about 1 mg and about 3.0 mg, between about 3 mg and about 8.and (a)(ii) a first administration cycle of the bispecific antibody (C1D1), a second administration cycle of the bispecific antibody (C1D2), and a third administration cycle of the bispecific antibody (C1D3), each of which is administered in a single dose of anti-CD79b antibody (C1D4), and the third administration cycle of the bispecific antibody (C1D4) is administered in a single dose of anti-CD79b antibody (C1D5), and the fourth administration cycle of the bispecific antibody (C1D6), and the fourth administration cycle of the bispecific antibody (C1D7), and the fourth administration cycle of the bispecific antibody (C1D8), and the fourth administration cycle of the bispecific antibody (C1D9), and the fourth administration cycle of the bispecific antibody (C1D1), and the fourth administration cycle of the bispecific antibody (C1D2), and the fourth administration cycle of the bispecific antibody (C1D3) is administered in a single dose of anti-CD79b antibody (C1D4), and the fourth administration cycle of the bispecific antibody (C1D5) is administered in a single dose of anti-CD79b antibody (C1D6), and the fourth administration cycle of the bispecific antibody (C1D7) is administered in a single dose of anti-CD79b antibody (C1D8), and the fourth administration cycle of the bispecific antibody (C1D9) is administered in a single dose of anti-CD79b antibody (C1D9), and the fourth administration cycle of the bispecific antibody (C1D1), and the fourth administration cycle of the bispecific antibody (C1D2) is administered in a single dose of anti-CD79b antibody (C1D1), and the fourth administration cycle of the bispecific antibody (C1D2) is administered in a single dose of anti-CD79b antibody (C1D3), and the fourth administration cycle of the bispecific antibody (C1D3) is administered in a single dose of anti-CD79b antibody (C1D4), and the fourth administration cycle of the bispecific antibody (C1D4) is administered in a single dose of anti-CD79b antibody (C1D5 (b)(i) the second administration cycle comprises a single dose of the anti-CD79b ADC (C2D1) and a single dose of the bispecific antibody (C2D1); and (b)(ii) the second administration cycle comprises a single dose of the bispecific antibody (C2D1), wherein C2D1 is about 9 mg, about 13.5 mg, about 20 mg, about 40 mg, about 45 mg, or about 60 mg; (c) the third administration cycle comprises a single dose of the anti-CD79b ADC (C3D1) and a single dose of the bispecific antibody (C3D1); (d) the fourth administration cycle comprises a single dose of the anti-CD79b ADC (C4D1) and a single dose of the bispecific antibody (C4D1); (e) the fifth administration cycle comprises a single dose of the anti-CD79b ADC (C4D1) and a single dose of the bispecific antibody (C4D1). (f) a sixth administration cycle comprises a single dose of the anti-CD79b ADC (C6D1) and a single dose of the bispecific antibody (C6D1); (g) a seventh administration cycle comprises a single dose of the anti-CD79b ADC (C7D1) and a single dose of the bispecific antibody (C7D1); and (h) an eighth administration cycle comprises an anti-CD79b ADC (C6D1) and a single dose of the bispecific antibody (C6D1). The single dose includes a single dose of the ADC (C8D1) and a single dose of the bispecific antibody (C8D1), wherein C2D1 of the bispecific antibody is greater than or equal to C1D2 of the bispecific antibody, and C3D1, C4D1, C5D1, C6D1, C7D1, and C8D1 of the bispecific antibody are each greater than C1D2 of the bispecific antibody by about 9 mg, about 13.5 mg, about 20 mg, about 45 mg, or about 60 mg, respectively.

[0177] In some examples, C2D1 to C8D1 of the bispecific antibody are present in approximately equal amounts. In some examples, C1D1 to C6D1 of the anti-CD79b ADC are present in approximately equal amounts.

[0178] In some examples, each single dose of anti-CD79b ADC C1D1-C6D1 is between about 0.5 mg / kg and about 10 mg / kg (e.g., between about 0.5 mg / kg and about 9 mg / kg, between about 0.5 mg / kg and about 8 mg / kg, between about 0.5 mg / kg and about 7 mg / kg, between about 0.5 mg / kg and about 6 mg / kg, between about 0.5 mg / kg and about 5 mg / kg, between about 0.5 mg / kg and about 4 mg / kg, between about 0.5 mg / kg and about 3 mg / kg, In some examples, a single dose of each of the anti-CD79b ADCs C1D1-C6D1 is about 1.8 mg / kg.

[0179] In some examples, C1D1 of the bispecific drug may be administered to a subject after C1D1 of the anti-CD79b ADC, hi some examples, C1D1 of the bispecific drug may be administered to a subject about 1 week or about 7 days (e.g., 7±3 days) after C1D1 of the anti-CD79b ADC.

[0180] In some examples, the method may include administering bispecific antibody C1D1 and bispecific antibody C1D2 to the subject on, or about, days 8 and 15, respectively, of a first administration cycle (e.g., days 8±3 and 15±3, respectively). In some examples, a single dose of each of the bispecific antibodies C2D1-C8D1 is administered to the subject on day 1 (e.g., day 1±3) of each administration cycle. In some examples, a single dose of each of the anti-CD79b ADCs C1D1-C6D1 is administered to the subject on day 1 (e.g., day 1±3) of each administration cycle. In some examples, the length of each of the one or more additional administration cycles is 7 days, 14 days, 21 days, or 28 days (e.g., 7±3 days, 14±3 days, 21±3 days, or 28±3 days, respectively). In some examples, the length of each of the one or more additional administration cycles is 3 weeks or 21 days.

[0181] In some examples, the methods described above may include a dosing regimen in which one or more additional dosing cycles each comprise a single dose of the bispecific antibody. In some examples, the dosing regimen may include 1 to 9 additional dosing cycles, each of which does not comprise administration of an anti-CD79b ADC to the subject. In some examples, the length of each of the one or more additional dosing cycles is 7 days, 14 days, 21 days, or 28 days (e.g., 7±3 days, 14±3 days, 21±3 days, or 28±3 days, respectively). In some examples, the length of each of the one or more additional dosing cycles is 3 weeks or 21 days.

[0182] In the methods provided above, the anti-CD79b antibody-drug conjugate includes anti-CD79b-MC-vc-PAB-MMAE, an anti-CD79b antibody-drug conjugate described in any one of U.S. Pat. No. 8,088,378 and / or U.S. Patent Application Publication No. 2014 / 0030280, or polatuzumab vedotin. In some examples, the anti-CD79b ADC is polatuzumab vedotin. In some examples, a bispecific anti-CD20 / anti-CD3 antibody and an anti-CD79b ADC show synergistic effects in a mouse NSG:human WSU-DLCL2 model system (see, e.g., WO 2013 / 059944) when compared with either the bispecific antibody or the anti-CD79b antibody-drug conjugate alone. WSU-DLCL 2 is a human DLBCL cell line (Leibnitz Institute-DSMZ, catalog number ACC 575) isolated from the pleural effusion of a 41-year-old Caucasian male. NSG mice are available from Jackson Labs (The Jackson Laboratory; stock number 005557).

[0183] In some examples, the methods described above comprise administering an anti-CD79b ADC and a bispecific anti-CD20 / anti-CD3 antibody, including an additional chemotherapeutic agent and / or antibody-drug conjugate (ADC). In some examples, the bispecific anti-CD20 / anti-CD3 antibody is administered simultaneously with one or more additional chemotherapeutic agents selected from cyclophosphamide and doxorubicin. In some examples, the bispecific anti-CD20 / anti-CD3 antibody is administered simultaneously with the ADC. In some examples, the bispecific anti-CD20 / anti-CD3 antibody is co-administered with CHOP, replacing vincristine with the ADC.

[0184] In some examples, the methods include administering the anti-CD79b ADC and bispecific anti-CD20 / anti-CD3 antibody in combination with a corticosteroid. In some examples, the corticosteroid is dexamethasone (CAS No.: 50-02-2), prednisone (CAS No.: 53-03-2), or methylprednisolone (CAS#: 83-43-2).

[0185] Any of the methods of the invention described herein may be useful for treating CD20-positive cell proliferative disorders, such as B-cell proliferative disorders / malignancies. In particular, B-cell proliferative disorders include, but are not limited to, non-Hodgkin's lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL) and other cancers that are amenable to treatment with bispecific anti-CD20 / anti-CD3 antibodies according to these methods described herein and that can be relapsed or refractory, including germinal center B-cell-like (GCB) diffuse large B-cell lymphoma (DLBCL), activated B-cell-like (ABC) DLBCL, follicular lymphoma (FL), mantle cell lymphoma (MCL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), marginal zone lymphoma (MZL), small lymphocytic leukemia (SLL), lymphoplasmacytic lymphoma (LPLA), and other cancers. Lymphoma (LL), Waldenstrom's hypergammaglobulinemia (WM), central nervous system lymphoma (CNSL), Burkitt's 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, plasma cell myeloma, isolated bone plasmacytoma, extraskeletal 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-associated DLBCL, lymphomatoid granulomatosis, primary mediastinal (thymic) large B-cell lymphoma (PMLBCL), intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, plasmablastic lymphoma, large B-cell lymphoma due to HHV8-associated multicentric Castleman disease, primary effusion lymphoma; unclassifiable B-cell lymphoma with features intermediate between DLBCL and Burkitt lymphoma; and unclassifiable B-cell lymphoma with features intermediate between DLBCL and classical Hodgkin lymphoma.Further examples of B-cell proliferative disorders 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 lymphoblastic leukemia (ALL); chronic myeloblastic leukemia; and post-transplant lymphoproliferative disorder (PTLD). In certain examples, the B-cell proliferative disorder can be NHL (e.g., relapsed and / or refractory NHL, DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), or MCL (e.g., relapsed or refractory MCL)), CLL, or CNSL). In some examples, the NHL is aggressive NHL (e.g., de novo DLBCL, transformed FL, or grade 3b FL). In some examples, the NHL is DLBCL. In some examples, the NHL is R / RMCL.

[0186] Any of the methods of the invention described herein may be useful for treating a population of subjects with a CD20-positive cell proliferative disorder. In some examples, the invention relates to a method for treating a CD20-positive cell proliferative disorder, such as a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL), DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or phenotype), comprising administering to a subject an anti-CD79b antibody drug conjugate and a bispecific antibody that binds CD20 and CD3 in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle. (e.g., transformed FL) or MCL (e.g., relapsed or refractory MCL), CLL or CNSL), (a) a first administration cycle includes (i) a first dose of a bispecific antibody (C1D1), a second dose of the bispecific antibody (C1D2), and a third dose of the bispecific antibody (C1D3), wherein C1D1 of the bispecific antibody is between about 0.02 mg and about 2.0 mg (e.g., between about 0.05 mg and about 2 mg, between about 0.1 mg and about 2 mg between about 0.5 mg and about 2 mg, between about 0.5 mg and about 1.5 mg, between about 0.8 mg and about 1.2 mg, between about 0.5 mg and about 1 mg, or between about 1 mg and about 2 mg, for example, about 0.5 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.5 mg, or about 2 mg), and C1D2 of the bispecific antibody is between about 0.05 mg and about 5 mg (for example, between about 0.1 mg and about 5 mg, between about 0.1 mg and about 4 mg, between about 0.1 mg and about 3 mg). mg, between about 0.5 mg and about 3 mg, between about 1 mg and about 3 mg, between about 1.5 mg and about 2.5 mg, between about 1.8 mg and about 2.2 mg, between about 3 mg and about 5 mg, between about 2 mg and about 4 mg, or between about 1 mg and about 5 mg; for example, about 0.5 mg, about 1 mg, about 1.5 mg, about 1.8 mg, about 1.9 mg, about 2 mg, about 2.1 mg, about 2.2 mg, about 2.5 mg, about 3 mg, about 4 mg, or about 5 mg), and the bispecific antibody C1D3 is about 9 mg, about 13 mg, or about 16 mg.(b) a first dose of the bispecific antibody (C1D1), a second dose of the bispecific antibody (C1D2), and a third dose of the bispecific antibody (C1D3) that are about 5 mg, about 20 mg, or about 40 mg; and (ii) a single dose of the anti-CD79b antibody drug conjugate (C1D1); (b) a second administration cycle that includes (i) a single dose of the bispecific antibody (C2D1), wherein the C2D1 of the bispecific antibody is approximately equal to the C1D3; and (ii) a single dose of the anti-CD79b antibody drug conjugate (C2D1), wherein the C1D1 of the anti-CD79b antibody drug conjugate and the C2D1 of the anti-CD79b antibody drug conjugate are each about 1.8 mg / kg.

[0187] The present invention also provides a method for treating a population of subjects having a CD20-positive cell proliferative disorder, e.g., a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL, DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL) or MCL (e.g., relapsed or refractory MCL)), CLL or CNSL), comprising administering to the subject an anti-CD79b antibody drug conjugate and 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: (i) a first dose (C1D1) of the bispecific antibody, a second dose (C1D2) of the bispecific antibody, and a third dose (C1D3) of the bispecific antibody, wherein C1D1 of the bispecific antibody is about 1 mg and C1D2 of the bispecific antibody is about 1 mg; (b) a second administration cycle comprising (i) a first dose of the bispecific antibody (C1D1), a second dose of the bispecific antibody (C1D2), and a third dose of the bispecific antibody (C1D3), wherein C1D2 is about 2 mg and C1D3 of the bispecific antibody is about 9 mg, about 13.5 mg, about 20 mg, or about 40 mg; and (ii) a single dose of the anti-CD79b antibody-drug conjugate (C1D1); (b) a second administration cycle comprising (i) a single dose of the bispecific antibody (C2D (i) a single dose of a bispecific antibody (C2D1), wherein C2D1 of the bispecific antibody is approximately equivalent to C1D3; and (ii) a single dose of an anti-CD79b antibody drug conjugate (C1D1), wherein C1D1 of the anti-CD79b antibody drug conjugate and C2D1 of the anti-CD79b antibody drug conjugate are each about 1.8 mg / kg.

[0188] The present invention also provides a method for the treatment of a CD20-positive cell proliferative disorder, such as a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL, DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), or MCL (e.g., MCL)), comprising administering to a subject an anti-CD79b antibody drug conjugate and a bispecific antibody that binds to CD20 and CD3 in a dosing regimen comprising eight or more dosing cycles. (e.g., relapsed or refractory MCL), CLL, or CNSL), wherein (a) a first administration cycle comprises (i) a first dose of a bispecific antibody (C1D1), a second dose of the bispecific antibody (C1D2), and a third dose of the bispecific antibody (C1D3), wherein C1D1 of the bispecific antibody is between about 0.02 mg and about 2.0 mg (e.g., between about 0.05 mg and about 2 mg, between about 0.1 mg and about 2 mg, between about between 0.5 mg and about 2 mg, between about 0.5 mg and about 1.5 mg, between about 0.8 mg and about 1.2 mg, between about 0.5 mg and about 1 mg, or between about 1 mg and about 2 mg, for example, about 0.5 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.5 mg, or about 2 mg), and C1D2 of the bispecific antibody is between about 0.05 mg and about 5 mg (for example, between about 0.1 mg and about 5 mg, between about 0.1 mg and about 4 mg, about 0 The bispecific antibody C1D3 is preferably about 9 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95(b) a first dose of the bispecific antibody (C1D1), a second dose of the bispecific antibody (C1D2), and a third dose of the bispecific antibody (C1D3), each dose being about 5 mg, about 20 mg, or about 40 mg; and (ii) a single dose of an anti-CD79b antibody drug conjugate (C1D1); (b) a second administration cycle comprising a single dose of the bispecific antibody (C2D1) and a single dose of the anti-CD79b antibody drug conjugate (C2D1); (c) a third administration cycle comprising a single dose of the bispecific antibody (C3D1) and a single dose of the anti-CD79b antibody drug conjugate (C3D1); (d) a fourth administration cycle comprising a single dose of the bispecific antibody (C4D1) and a single dose of the anti-CD79b antibody drug conjugate (C4D1); (e) a fifth administration cycle comprising a single dose of the bispecific antibody (C4D1) and a single dose of the anti-CD79b antibody drug conjugate (C4D1); (f) the sixth administration cycle comprises a single dose of the bispecific antibody (C5D1) and a single dose of the anti-CD79b antibody drug conjugate (C5D1); (f) the sixth administration cycle comprises a single dose of the bispecific antibody (C6D1) and a single dose of the anti-CD79b antibody drug conjugate (C6D1); (g) the seventh administration cycle comprises a single dose of the bispecific antibody (C7D1) but does not include administration of the anti-CD79b antibody drug conjugate; and (h) the eighth administration cycle comprises a single dose of the bispecific antibody (C8D1) but does not include administration of the anti-CD79b antibody drug conjugate, wherein each single dose of the bispecific antibody, C2D1 to C8D1, is approximately equivalent to C1D3, and each single dose of the anti-CD79b antibody drug conjugate, C1D1 to C6D1, is approximately 1.8 mg / kg.

[0189] The present invention provides a method for the treatment of a CD20-positive cell proliferative disorder, such as a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL, DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), or MCL (e.g., Further provided is a method for treating a population of subjects with relapsed or refractory MCL), CLL, or CNSL, comprising: (a) a first administration cycle comprising a first dose of a bispecific antibody (C1D1), a second dose of the bispecific antibody (C1D2), and a third dose of the bispecific antibody, wherein C1D1 of the bispecific antibody is between about 0.02 mg and about 5.0 mg, C1D2 is between about 0.05 mg and about 60 mg, and C1D3 is between about 9 mg and about 13.(b) a first dose of the bispecific antibody (C1D1), a second dose of the bispecific antibody (C1D2), and a third dose of the bispecific antibody, each dose being about 5 mg, about 20 mg, or about 40 mg; (b) a second administration cycle comprising a single dose of the bispecific antibody (C2D1) and a single dose of the anti-CD79b antibody drug conjugate (C2D1); (c) a third administration cycle comprising a single dose of the bispecific antibody (C3D1) and a single dose of the anti-CD79b antibody drug conjugate (C3D1); (d) a fourth administration cycle comprising a single dose of the bispecific antibody (C4D1) and a single dose of the anti-CD79b antibody drug conjugate (C4D1); (e) a fifth administration cycle comprising a single dose of the bispecific antibody (C5D1 (f) a sixth administration cycle comprises a single dose of the bispecific antibody (C6D1) and a single dose of the anti-CD79b antibody drug conjugate (C6D1); (g) a seventh administration cycle comprises a single dose of the bispecific antibody (C7D1) and no administration of the anti-CD79b antibody drug conjugate; and (h) an eighth administration cycle comprises a single dose of the bispecific antibody (C8D1) and no administration of the anti-CD79b antibody drug conjugate, wherein each single dose of the bispecific antibody, C2D1-C8D1, is approximately equivalent to C1D3, and each single dose of the anti-CD79b antibody drug conjugate, C1D1-C6D1, is approximately 1.8 mg / kg.

[0190] In some embodiments, the CD20-positive cell proliferative disorder is NHL. In some embodiments, the overall response rate is at least 55% (e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%; e.g., between 55% and 100%, between 55% and 90%, between 55% and 80%, between 55% and 70%, between 55% and 65%, between 55% and 60%, between 60% and 65%, between 60% and 70%, between 60% and 90%, or between 70% and 90%; e.g., about 55%, about 60%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%). In some embodiments, the overall response rate is at least 65%. In some embodiments, the complete response rate is at least 45% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 80%, at least 85%, at least 90%, or at least 95%; e.g., between 45% and 100%, between 45% and 80%, between 45% and 60%, between 45% and 55%, between 45% and 50%, between 50% and 55%, between 50% and 65%, between 50% and 70%, between 60% and 70%, or between 70% and 90%; e.g., about 45%, about 50%, about 53%, about 54%, about 55%, about 56%, about 57%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%). In some embodiments, the complete response rate is at least 55%.

[0191] In some embodiments, the CD20-positive cell proliferative disorder is aggressive NHL (eg, de novo DLBCL, transformed FL, or grade 3b FL). In some embodiments, the overall response rate is at least 50% (e.g., at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%; e.g., between 50% and 100%, between 50% and 80%, between 50% and 60%, between 50% and 55%, between 55% and 60%, between 55% and 65%, between 50% and 70%, between 60% and 70%, or between 70% and 90%; e.g., about 50%, about 55%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%). In some embodiments, the overall response rate is at least 60%. In some embodiments, the complete response rate is at least 35% (e.g., at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 70%, at least 80%, or at least 90%; e.g., between 35% and 100%, between 35% and 80%, between 35% and 60%, between 35% and 55%, between 35% and 50%, between 35% and 45%, between 40% and 60%, between 45% and 50%, between 45% and 55%, between 45% and 60%, or 50% and 70%; e.g., about 35%, about 40%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 55%, about 60%, about 70%, about 80%, about 90%, or about 95%). In some embodiments, the complete response rate is at least 45%.

[0192] In some embodiments, the CD20-positive cell proliferative disorder is NHL, and the subjects in the population are post-CAR-T subjects (e.g., patients who were treated with CAR-T therapy at least 30 days prior to administration of the first study treatment (e.g., an anti-CD20 / anti-CD3 bispecific antibody and / or an anti-CD79b antibody drug conjugate; e.g., mosunetuzumab and / or polatuzumab vedotin)). In some embodiments, the overall response rate is at least 50% (e.g., at least 55%, at least 60%, at least 65%, at least 70%, at least 80%, at least 85%, at least 90%, or at least 95%; e.g., between 50% and 100%, between 50% and 80%, between 50% and 60%, between 50% and 55%, between 55% and 60%, between 55% and 65%, between 50% and 70%, between 60% and 70%, or between 70% and 90%; e.g., about 50%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%). In some embodiments, the overall response rate is at least 55%. In some embodiments, the complete response rate is at least 20% (e.g., at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 90%; e.g., between 20% and 100%, between 20% and 80%, between 20% and 60%, between 20% and 40%, between 20% and 30%, between 20% and 25%, between 25% and 30%, between 25% and 35%, between 25% and 50%, between 30% and 60%, or between 50% and 70%; e.g., about 20%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 35%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 95%). In some embodiments, the complete response rate is at least 25%.

[0193] In some embodiments, the CD20-positive cell proliferative disorder is FL. In some embodiments, the overall response rate is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99%; e.g., between 80% and 100%, between 80% and 95%, between 80% and 90%, between 80% and 85%, between 85% and 95%, between 90% and 100%, or between 95% and 100%; e.g., about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%). In some embodiments, the overall response rate is at least 90%. In some embodiments, the complete response rate is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99%; e.g., between 80% and 100%, between 80% and 95%, between 80% and 90%, between 80% and 85%, between 85% and 95%, between 90% and 100%, or between 95% and 100%; e.g., about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%). In some embodiments, the complete response rate is at least 90%.

[0194] In some examples, the bispecific antibody is mosunetuzumab. In some examples, the anti-CD79b antibody drug conjugate is polatuzumab vedotin.

[0195] The methods described herein may result in an improved benefit-risk profile for subjects with a CD20-positive cell proliferative disorder, e.g., a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL, DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), or MCL (e.g., relapsed or refractory MCL)), CLL, or CNSL) being treated with an anti-CD20 / anti-CD3 bispecific antibody. In some examples, treatment using the methods described herein, in which an anti-CD20 / anti-CD3 bispecific antibody is administered in the context of a fractionated dose-escalation regimen, results in a reduction (e.g., 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more) in 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 fractionated dose-escalation regimen of the invention, compared to treatment with an anti-CD20 / anti-CD3 bispecific antibody using a non-fractionated regimen. or above, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more; for example, between 20% and 100%, between 20% and 90%, between 20% and 80%, between 20% and 70%, between 20% and 60%, between 20% and 50%, between 20% and 40%, between 20% and 30%, between 40% and 100%, between 60% and 100%, between 80% and 100% between 30% and 70%, between 40% and 60%, between 30% and 50%, between 50% and 80%, or between 90% and 100%; for example, 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%, about 95%, about 97%, about 99%, or about 100%) or complete inhibition (100% reduction).

[0196] B. Treatment methods to reduce the rate of CRS The methods and uses described herein can be used to reduce the rate and / or severity of cytokine release syndrome in a population of subjects with a CD20-positive cell proliferative disorder, e.g., a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL, DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), or MCL (e.g., relapsed and / or refractory MCL)), CLL, or CNSL) who are administered an anti-CD79b ADC and a bispecific anti-CD20 / anti-CD3 antibody.

[0197] The present invention provides methods for reducing the rate of cytokine release syndrome in a population of subjects with a CD20-positive cell proliferative disorder, e.g., a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL, DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), or MCL (e.g., relapsed and / or refractory MCL)), CLL, or CNSL), compared to a population of subjects not administered an anti-CD79b ADC, administering an ADC and a bispecific antibody that binds to CD20 and CD3 to one or more subjects of the population in an administration regimen including at least a first administration cycle and a second administration cycle, wherein (a) the first administration cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of the bispecific antibody, wherein C1D3 is equal to or greater than C1D2 and C1D1, C1D2 is equal to or greater than C1D1, and C1D1 is between about 0.02 mg and about 5.0 mg (e.g., about 0.05 mg to about 5 mg, about 0.1 mg to about 5.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 2 mg to about 5.0 mg, or about 3 mg to about 5.0 mg). g, about 0.05 mg to about 4.0 mg, about 0.05 mg to about 3.0 mg, about 0.05 mg to about 2.0 mg, about 0.1 mg to about 2.0 mg, about 0.5 mg to about 2.0 mg, about 2 mg to about 4.0 mg, about 1 mg to about 3.0 mg, about 1 mg, about 2 mg, or about 5 mg, and C1D2 is between about 0.05 mg and about 10.0 mg (for example, about 0.1 mg to about 10.0 mg, about 0.5 mg to about 10.0 mg, 1 mg to about 10.0 mg, about 2 mg to about 3.0 mg, about 5 mg to about 10.0 mg, about 8 mg to about 10.0 mg, about 0.5 mg to about 7.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 1 mg to about 3.0 mg, about 3 mg to about 8.0 mg, about 1 mg, about 2 mg, or about 5 mg) or between about 10 mg and about 60 mg (e.g., about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 20 mg to about 50 mg, about 30 mg to about 50 mg, about 40 mg to about 50 mg, about 45 mg to about 50 mg, about 13 mg to about 17 mg, about 43 mg to about 48 mg, about 15 mg to about 35 mg, about 25 mg to about 45 mg, about 15 mg, about 30 mg, or about 45 mg). and C1D3 is about 9 mg, about 13.5 mg, about 20 mg, about 40 mg, about 45 mg, or about 60 mg; (b) a second administration cycle comprising a single dose of bispecific antibody (C2D1), wherein C2D1 is equal to or greater than C1D3 and is about 9 mg, about 13.5 mg, about 20 mg, about 40 mg, about 45 mg, or about 60 mg.

[0198] The invention provides a method for reducing the rate of cytokine release syndrome in a population of subjects with a CD20-positive cell proliferative disorder, e.g., a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL, DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), or MCL (e.g., relapsed and / or refractory MCL)), CLL, or CNSL), compared to a population of subjects not administered an anti-CD79b ADC, comprising administering an anti-CD79b ADC and a bispecific antibody that binds CD20 and CD3 to one or more subjects of the population in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle; (a)(ii) a first administration cycle comprising a first dose of the ADC (C1D1), a second dose of the bispecific antibody (C1D2), wherein C1D2 of the bispecific antibody is equal to or greater than C1D1 of the bispecific antibody, and C1D1 is between about 0.02 mg and about 5.0 mg (e.g., about 0.05 mg to about 5 mg, about 0.1 mg to about 5.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 2 mg to about 5.0 mg, about 3 mg to about 5.0 mg, about 0.05 mg to about 4.0 mg, about 0.05 mg to about 3.0 mg, about 0.05 mg to about 5.0 mg, mg to about 2.0 mg, about 0.1 mg to about 2.0 mg, about 0.5 mg to about 2.0 mg, about 2 mg to about 4.0 mg, about 1 mg to about 3.0 mg, about 1 mg, about 2 mg, or about 5 mg), and C1D2 is between about 0.05 mg to about 10.0 mg (e.g., about 0.1 mg to about 10.0 mg, about 0.5 mg to about 10.0 mg, 1 mg to about 10.0 mg, about 2 mg to about 3.0 mg, about 5 mg to about 10.0 mg, about 8 mg to about 10.0 mg, about 0.5 mg to about 7.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 1 mg to about 3.0 mg, or about 3 mg to about 8.(b) (i) a first dose (C1D1) of the bispecific antibody, a second dose (C1D2) of the bispecific antibody, and a second dose (C1D3) of the bispecific antibody, each dose being between about 10 mg, about 1 mg, about 2 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 45 mg, about 50 mg, about 13 mg, about 17 mg, about 43 mg, about 48 mg, about 15 mg, about 35 mg, about 25 mg, about 45 mg, about 15 mg, about 30 mg, or about 45 mg; (b) (i) a second administration cycle comprising an anti-CD79b (b)(ii) the second administration cycle comprises a single dose of the bispecific antibody (C2D1), wherein the C2D1 of the bispecific antibody is about 9 mg, about 13.5 mg, about 20 mg, about 40 mg, about 45 mg, or about 60 mg.

[0199] The present invention provides methods for reducing the rate of cytokine release syndrome in a population of subjects with a CD20-positive cell proliferative disorder, e.g., a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL, DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), or MCL (e.g., relapsed and / or refractory MCL)), CLL, or CNSL), compared to a population of subjects not administered an anti-CD79b ADC, administering the ADC and a bispecific antibody that binds to CD20 and CD3 to one or more subjects of the population in a dosing regimen comprising eight or more administration cycles, wherein (a)(i) the first administration cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of the bispecific antibody, wherein C1D3 of the bispecific antibody is equal to or greater than C1D2 and C1D1 of the bispecific antibody, wherein C1D2 of the bispecific antibody is equal to or greater than C1D1 of the bispecific antibody, and wherein C1D1 is between about 0.02 mg and about 5.0 mg (e.g., about 0.05 mg to about 5 mg, about 0.1 mg to about 5.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 2 mg to about 5.0 mg, about 3 mg to about 5.0 mg, about 0.05 mg to about 4.0 mg, about 0.05 mg to about 3.0 mg, about 0.05 mg to about 2.0 mg, about 0.1 mg to about 2.0 mg, about 0.5 mg to about 2.0 mg, about 2 mg to about 4.0 mg, about 1 mg to about 3.0 mg, about 1 mg, about 2 mg, or about 5 mg), and C1D2 is about 0.05 mg to about 10.0 mg. mg (e.g., about 0.1 mg to about 10.0 mg, about 0.5 mg to about 10.0 mg, 1 mg to about 10.0 mg, about 2 mg to about 3.0 mg, about 5 mg to about 10.0 mg, about 8 mg to about 10.0 mg, about 0.5 mg to about 7.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 1 mg to about 3.0 mg, about 3 mg to about 8.0 mg, about 1 mg, about 2 mg, or about 5 mg) or between about 10 mg and about 60 mg (e.g., about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 20 mg to about 50 mg, about 30 mg to about 50 mg, about 40 mg to about 50 mg, about 45 mg to about 50 mg, about 13 mg to about 17 mg, about 43 mg to about 48 mg, and (a)(ii) the first administration cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of the bispecific antibody, wherein the first dose (C1D1), the second dose (C1D2), and the third dose (C1D3) of the bispecific antibody are about 15 mg to about 35 mg, about 25 mg to about 45 mg, about 15 mg, about 30 mg, or about 45 mg, and the bispecific antibody C1D3 is about 9 mg, about 13.5 mg, about 20 mg, about 40 mg, or about 45 mg; and (a)(ii) the first administration cycle comprises a first administration cycle comprising an anti-CD79b (b) the second administration cycle comprises a single dose of the anti-CD79b ADC (C2D1) and a single dose of the bispecific antibody (C2D1); (c) the third administration cycle comprises a single dose of the anti-CD79b ADC (C3D1) and a single dose of the bispecific antibody (C3D1); (d) the fourth administration cycle comprises a single dose of the anti-CD79b ADC (C4D1) and a single dose of the bispecific antibody (C4D1); (e) the fifth administration cycle comprises a single dose of the anti-CD79b ADC (C5D1) and a single dose of the bispecific antibody (C5D1); (f) the sixth administration cycle comprises a single dose of the anti-CD79b ADC (C6D1) and a single dose of the bispecific antibody (C6D1); (g) the seventh administration cycle comprises a single dose of the anti-CD79b ADC (C6D1) and a single dose of the bispecific antibody (C6D1). (h) an eighth administration cycle comprising a single dose of the anti-CD79b ADC (C7D1) and a single dose of the bispecific antibody (C7D1); (h) an eighth administration cycle comprising a single dose of the anti-CD79b ADC (C8D1) and a single dose of the bispecific antibody (C8D1), wherein the bispecific antibodies C2D1, C3D1, C4D1, C5D1, C6D1, C7D1, and C8D1 are each equal to or greater than the bispecific antibody C1D3 and are about 9 mg, about 13.5 mg, about 20 mg, about 45 mg, or about 60 mg, respectively.

[0200] The present invention provides methods for reducing the rate of cytokine release syndrome in a population of subjects with a CD20-positive cell proliferative disorder, e.g., a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL, DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), or MCL (e.g., relapsed and / or refractory MCL)), CLL, or CNSL), compared to a population of subjects not administered an anti-CD79b ADC, administering the ADC and a bispecific antibody that binds to CD20 and CD3 to one or more subjects of the population in a dosing regimen comprising eight or more administration cycles, wherein (a) the first administration cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of the bispecific antibody, wherein C1D3 of the bispecific antibody is equal to or greater than C1D2 and C1D1 of the bispecific antibody, wherein C1D2 of the bispecific antibody is equal to or greater than C1D1 of the bispecific antibody, and wherein C1D1 is between about 0.02 mg and about 5.0 mg (e.g., about 0.05 mg to about 5 mg, about 0.1 mg to about 5.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 2 mg to about 5.0 mg, about 3 mg to about 5.0 mg, about 0.05 mg to about 4.0 mg, about 0.05 mg to about 3.0 mg, about 0.05 mg to about 2.0 mg, about 0.1 mg to about 2.0 mg, about 0.5 mg to about 2.0 mg, about 2 mg to about 4.0 mg, about 1 mg to about 3.0 mg, about 1 mg, about 2 mg, or about 5 mg), and C1D2 is about 0.05 mg to about 10.0 mg. mg (e.g., about 0.1 mg to about 10.0 mg, about 0.5 mg to about 10.0 mg, 1 mg to about 10.0 mg, about 2 mg to about 3.0 mg, about 5 mg to about 10.0 mg, about 8 mg to about 10.0 mg, about 0.5 mg to about 7.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 1 mg to about 3.0 mg, about 3 mg to about 8.0 mg, about 1 mg, about 2 mg, or about 5 mg) or between about 10 mg and about 60 mg (e.g., about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 20 mg to about 50 mg, about 30 mg to about 50 mg, about 40 mg to about 50 mg, about 45 mg to about 50 mg, about 13 mg to about 17 mg, about 43 mg to about 48 mg (b) a first administration cycle comprising a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of the bispecific antibody, wherein the dose of the bispecific antibody is about 9 mg, about 13.5 mg, about 20 mg, about 40 mg, about 45 mg, or about 60 mg; (b) a second administration cycle comprising a first administration cycle comprising an anti-CD79b (c) a third administration cycle comprises a single dose of an anti-CD79b ADC (C2D1) and a single dose of a bispecific antibody (C2D1); (d) a fourth administration cycle comprises a single dose of an anti-CD79b ADC (C4D1) and a single dose of a bispecific antibody (C4D1); (e) a fifth administration cycle comprises a single dose of an anti-CD79b ADC (C5D1) and a single dose of a bispecific antibody (C5D1); (f) a sixth administration cycle comprises a single dose of an anti-CD79b ADC (C6D1) and a single dose of a bispecific antibody (C6D1); (g) a seventh administration cycle comprises a single dose of an anti-CD79b ADC (C6D1) and a single dose of a bispecific antibody (C6D1). (h) an eighth administration cycle comprising a single dose of the anti-CD79b ADC (C7D1) and a single dose of the bispecific antibody (C7D1); (h) an eighth administration cycle comprising a single dose of the anti-CD79b ADC (C8D1) and a single dose of the bispecific antibody (C8D1), wherein the bispecific antibodies C2D1, C3D1, C4D1, C5D1, C6D1, C7D1, and C8D1 are each equal to or greater than the bispecific antibody C1D3 and are about 9 mg, about 13.5 mg, about 20 mg, about 40 mg, about 45 mg, or about 60 mg, respectively.

[0201] The invention provides methods for reducing the rate of cytokine release syndrome in a population of subjects with a CD20-positive cell proliferative disorder, e.g., a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL, DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), or MCL (e.g., relapsed or refractory MCL)), CLL, or CNSL), compared to a population of subjects not administered an anti-CD79b ADC, administering the ADC and a bispecific antibody that binds to CD20 and CD3 to one or more subjects of the population in a dosing regimen comprising eight or more administration cycles, wherein (a)(i) the first administration cycle comprises a first dose of the bispecific antibody (C1D1), a second dose of the bispecific antibody (C1D2), wherein C1D2 of the bispecific antibody is equal to or greater than C1D1 of the bispecific antibody, and C1D1 is between about 0.02 mg and about 5.0 mg (e.g., about 0.05 mg to about 5 mg, about 0.1 mg to about 5.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 2 mg to about 5.0 mg, about 3 mg to about 5.0 mg, about 0.05 mg to about 4.0 mg, about 0.05 mg to about 3.0 mg, about 0.05 mg to about 2.0 mg, about 0.1 mg to about 2.0 mg, about 0.5 mg to about 2.0 mg, about 2 mg to about 4.0 mg, about 1 mg to about 3.0 mg, about 1 mg, about 2 mg, or about 5 mg), and C1D2 is between about 0.05 mg and about 10.0 mg (e.g., about 0.1 mg to about 10.0 mg, about 0.5 mg to about 10.0 mg, 1 mg to about 10.0 mg, about 2 mg to about 3.0 mg, about 5 mg to about 10.0 mg, about 8 mg to about 10.0 mg, about 0.5 mg to about 7.0 mg, about 0.5 mg to about 5.0 mg, about 1 mg to about 5.0 mg, about 1 mg to about 3.0 mg, about 3 mg to about 8.and (a)(ii) a first administration cycle of the bispecific antibody (C1D1), a second administration cycle of the bispecific antibody (C1D2), and a third administration cycle of the bispecific antibody (C1D3), each of which is administered in a single dose of anti-CD79b antibody (C1D4), and the third administration cycle of the bispecific antibody (C1D4) is administered in a single dose of anti-CD79b antibody (C1D5), and the fourth administration cycle of the bispecific antibody (C1D6), and the fourth administration cycle of the bispecific antibody (C1D7), and the fourth administration cycle of the bispecific antibody (C1D8), and the fourth administration cycle of the bispecific antibody (C1D9), and the fourth administration cycle of the bispecific antibody (C1D1), and the fourth administration cycle of the bispecific antibody (C1D2), and the fourth administration cycle of the bispecific antibody (C1D3) is administered in a single dose of anti-CD79b antibody (C1D4), and the fourth administration cycle of the bispecific antibody (C1D5) is administered in a single dose of anti-CD79b antibody (C1D6), and the fourth administration cycle of the bispecific antibody (C1D7) is administered in a single dose of anti-CD79b antibody (C1D8), and the fourth administration cycle of the bispecific antibody (C1D9) is administered in a single dose of anti-CD79b antibody (C1D9), and the fourth administration cycle of the bispecific antibody (C1D1), and the fourth administration cycle of the bispecific antibody (C1D2) is administered in a single dose of anti-CD79b antibody (C1D1), and the fourth administration cycle of the bispecific antibody (C1D2) is administered in a single dose of anti-CD79b antibody (C1D3), and the fourth administration cycle of the bispecific antibody (C1D3) is administered in a single dose of anti-CD79b antibody (C1D4), and the fourth administration cycle of the bispecific antibody (C1D4) is administered in a single dose of anti-CD79b antibody (C1D5 (b)(i) the second administration cycle comprises a single dose of the anti-CD79b ADC (C2D1) and a single dose of the bispecific antibody (C2D1); (b)(ii) the second administration cycle comprises a single dose of the bispecific antibody (C2D1), wherein C2D1 is about 9 mg, about 13.5 mg, about 20 mg, about 40 mg, about 45 mg, or about 60 mg; (c) the third administration cycle comprises a single dose of the anti-CD79b ADC (C3D1) and a single dose of the bispecific antibody (C3D1); (d) the fourth administration cycle comprises a single dose of the anti-CD79b ADC (C4D1) and a single dose of the bispecific antibody (C4D1); (e) the fifth administration cycle comprises a single dose of the anti-CD79b ADC (C4D1) and a single dose of the bispecific antibody (C4D1); (f) a sixth administration cycle comprising a single dose of the anti-CD79b ADC (C6D1) and a single dose of the bispecific antibody (C6D1); (g) a seventh administration cycle comprising a single dose of the anti-CD79b ADC (C7D1) and a single dose of the bispecific antibody (C7D1); (h) an eighth administration cycle comprising a single dose of the anti-CD79b ADC (C7D1) and a single dose of the bispecific antibody (C7D1); The single dose includes a single dose of the ADC (C8D1) and a single dose of the bispecific antibody (C8D1), wherein C2D1 of the bispecific antibody is greater than or equal to C1D2 of the bispecific antibody, and C3D1, C4D1, C5D1, C6D1, C7D1, and C8D1 of the bispecific antibody are each greater than C1D2 of the bispecific antibody, and are about 9 mg, about 13.5 mg, about 20 mg, about 40 mg, about 45 mg, or about 60 mg, respectively.

[0202] The methods described herein can be used to reduce the rate of cytokine release syndrome in a population of subjects with a CD20-positive cell proliferative disorder, e.g., a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL, DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), or MCL (e.g., relapsed and / or refractory MCL)), CLL or CNSL) who are administered a bispecific anti-CD20 / anti-CD3 antibody. In some examples, the rate of cytokine release syndrome in a population of subjects with a CD20-positive cell proliferative disorder, e.g., a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL, DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), or MCL (e.g., relapsed or refractory MCL)), CLL, or CNSL) who have been administered an anti-CD79b ADC and a bispecific anti-CD20 / anti-CD3 antibody is significantly higher than that in subjects who have a CD20-positive cell proliferative disorder, e.g., a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL, DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), or MCL (e.g., relapsed or refractory MCL)), CLL, or CNSL) who have been administered an anti-CD79b ADC and a bispecific anti-CD20 / anti-CD3 antibody. The rate of cytokine release syndrome may be lower than the rate in a population of subjects with a CD20-positive cell proliferative disorder, e.g., a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL, DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), or MCL (e.g., relapsed and / or refractory MCL)), CLL, or CNSL) who have not received the ADC.In some examples, the rate of cytokine release syndrome in a population of subjects with a CD20-positive cell proliferative disorder, e.g., a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL, DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), or MCL (e.g., relapsed and / or refractory MCL)), CLL, or CNSL) receiving an anti-CD79b ADC and a bispecific anti-CD20 / anti-CD3 antibody is about 20% or less (e.g., about 19% or less, about 18% or less, about 17% or less, about 16% or less, about 15% or less, about 14% or less, about 13% or less, or about 16% or less). % or less, about 12% or less, about 11% or less, about 10% or less, about 9% or less, about 8% or less, about 7% or less, about 6% or less, about 5% or less, about 4% or less, about 3% or less, about 2% or less, or about 1% or less; for example, between about 0% and about 20%, between about 1% and about 20%, between about 5% and about 20%, between about 10% and about 20%, between about 15% and about 20%, between about 0% and about 5%, between about 1% and about 5%, between about 1% and about 10%, between about 5% and about 10%, between about 10% and about 15%, or between about 5% and about 15%; for example, about 20%, about 15%, about 10%, about 7%, about 5%, about 4%, about 3%, about 2%, about 1%, or about 0%).In some other examples, the rate of cytokine release syndrome with a grade of 2 or greater as defined by ASTCT in a population of subjects with a CD20-positive cell proliferative disorder, e.g., a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL, DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), or MCL (e.g., relapsed and / or refractory MCL)), CLL, or CNSL) administered an anti-CD79b ADC and a bispecific anti-CD20 / anti-CD3 antibody is about 20% or less (e.g., about 19% or less, about 18% or less, about 17% or less, about 16% or less, about 15% or less). or less, about 14% or less, about 13% or less, about 12% or less, about 11% or less, about 10% or less, about 9% or less, about 8% or less, about 7% or less, about 6% or less, about 5% or less, about 4% or less, about 3% or less, about 2% or less, or about 1% or less; for example, between about 0% and about 20%, between about 1% and about 20%, between about 5% and about 20%, between about 10% and about 20%, between about 15% and about 20%, between about 0% and about 5%, between about 1% and about 5%, between about 1% and about 10%, between about 5% and about 10%, between about 10% and about 15%, or between about 5% and about 15%; for example, about 20%, about 15%, about 10%, about 7%, about 5%, about 4%, about 3%, about 2%, about 1%, or about 0%).

[0203] Any of the methods described herein may involve monitoring the 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 care, and attempting to attenuate the inflammatory response using high doses of corticosteroids. However, this approach is not always successful, 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 have been published by the American Society for Transplantation and Cellular Therapy (ASTCT) to harmonize reporting across clinical trials and enable rapid recognition and treatment of CRS (Lee et al., Biology of Blood and Marrow Transplantation. 25(4):625-638, 2019). 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]

[0204] Fever is defined as a temperature of 38°C or higher that is not attributable to other causes. If a subject with CRS then receives antipyretic or anticytokine therapy, such as tocilizumab or steroids, fever is no longer required to grade the severity of subsequent CRS. In this case, CRS grading is determined by hypotension and / or hypoxia.

[0205] CRS grade is determined by the more severe events, hypotension, or hypoxia not attributable to other causes. For example, a subject with a temperature of 39.5°C, hypotension requiring one vasopressor, and hypoxia requiring a low-flow nasal cannula is classified as having grade 3 CRS.

[0206] Low-flow nasal cannulae are defined as oxygen delivered at ≤6 L / min. Low-flow also includes blow-by oxygen delivery, sometimes used in pediatrics. High-flow nasal cannulae are defined as oxygen delivered at >6 L / min.

[0207] CRS is associated with elevations in a variety of cytokines, with marked increases in IFNγ, IL-6, and TNF-α levels. Emerging evidence specifically implicates IL-6 as a central mediator in CRS. IL-6 is a proinflammatory, multifunctional cytokine produced by a variety of cell types, and this cytokine has been shown to be involved in a wide variety of physiological processes, including T cell activation. Regardless of the inducer, CRS is associated with 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. Immunology. 4(7):e39, 2015), and IL-6 correlates with CRS severity, with subjects experiencing grade 4 or 5 CRS events having significantly higher IL-6 levels compared with subjects who do not experience CRS or who experience milder CRS (grades 0-3) (Chen et al., J. Immunol. Methods. 434:1-8, 2016).

[0208] Therefore, blocking the inflammatory effects of IL-6 using agents that inhibit IL-6-mediated signaling and manage CRS observed in subjects during a two-fractionated dose-escalation regimen is an alternative to steroid treatment and is not expected to negatively affect T cell function or reduce the efficacy or clinical usefulness of anti-CD20 / anti-CD3 bispecific antibody therapy in the treatment of CD20-positive cell proliferative disorders, e.g., B cell proliferative disorders.

[0209] Tocilizumab (ACTEMRA® / RoACTEMRA®) is a recombinant, humanized, anti-human monoclonal antibody directed against the 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).

[0210] If the subject experiences a cytokine release syndrome (CRS) event after administration of the bispecific antibody, the method may 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 to the subject as a single dose of about 8 mg / kg, but not more than 800 mg per unit dose. Other anti-IL-6R antibodies that may be used in place of or in combination with tocilizumab include sarilumab, bovalilizumab (ALX-0061), satralizumab (SA-237), and variants thereof. In some examples, tocilizumab may be administered to patients being treated with the bispecific antibody (e.g., TDB) as a preventative measure (i.e., before and / or in the absence of CRS symptoms).

[0211] If the subject has a CRS event that does not improve or worsen within 24 hours of administering the IL-6R antagonist to treat the symptoms of the CRS event, the method can 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 can be administered a corticosteroid, such as methylprednisolone or dexamethasone.

[0212] Management of a CRS event can be tailored based on the stage of CRS and the presence of comorbidities. For example, if, after administration of the bispecific antibody, the subject experiences a Grade 2 cytokine release syndrome (CRS) event in the absence of comorbidities or in the presence of minimal comorbidities, the method can further comprise treating the symptoms of the Grade 2 CRS event while withholding treatment with the bispecific antibody. If the Grade 2 CRS event resolves to a Grade ≦1 CRS event for at least three consecutive days, the method can further comprise resuming treatment with the bispecific antibody at the same dosage. On the other hand, if the Grade 2 CRS event does not resolve or worsen to a Grade ≧3 event within 24 hours of treating the symptoms of the Grade 2 CRS event, 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 Grade 2 or Grade ≧3 CRS event. In some examples, tocilizumab is administered intravenously to a subject as a single dose of about 8 mg / kg. Other anti-IL-6R antibodies that may be used instead of or in combination with tocilizumab include sarilumab, bovalilizumab (ALX-0061), satralizumab (SA-237), and variants thereof.

[0213] 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 can further comprise an art-recognized method for alleviating the CRS event, such as administering to the subject a first dose of an IL-6R antagonist (e.g., an anti-IL-6R antibody, e.g., tocilizumab (ACTEMRA® / RoACTEMRA®)) to manage the CRS event while pending treatment with the bispecific antibody. Other anti-IL-6R antibodies that may be used instead of or in combination with tocilizumab include sarilumab, bovalilizumab (ALX-0061), satralizumab (SA-237), and variants thereof. In some examples, the method further comprises administering to the subject an effective amount of a corticosteroid, such as methylprednisolone or dexamethasone.

[0214] In some examples, the bispecific antibody is administered subcutaneously to a subject. In this embodiment, the bispecific antibody can be administered at a dose of between about 0.5 mg and about 40 mg. Alternatively, in this embodiment, the bispecific antibody can be administered at a dose of between 40 mg and about 60 mg. In some embodiments, the bispecific antibody is administered at a dose of between about 1.0 mg and about 20 mg, between about 1.0 mg and about 10 mg, or between about 1.0 mg and about 5 mg. In other embodiments, the bispecific antibody is administered at a dose of between about 50 mg and about 60 mg, between about 40 mg and about 50 mg, between about 45 mg and about 55 mg, or between about 55 mg and about 60 mg. In one embodiment, the bispecific antibody is administered at a dose of about 1.6 mg. In another embodiment, the bispecific antibody is administered at a dose of about 5 mg. In one embodiment, the bispecific antibody is administered at a dose of about 15 mg. In another embodiment, the bispecific antibody is administered at a dose of about 45 mg. In yet another embodiment, the bispecific antibody is administered at a dose of about 60 mg. Subsequent doses may be administered in amounts equal to the initial subcutaneous dose.

[0215] IV. Therapeutic Agents for Use in the Methods of the Invention Described herein are exemplary anti-CD79b antibody drug conjugates and anti-CD20 / anti-CD3 bispecific antibodies for treating a subject with a CD20-positive cell proliferative disorder, e.g., a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL, DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), or MCL (e.g., relapsed and / or refractory MCL)), CLL, or CNSL) according to the methods of the invention.

[0216] A. Anti-CD79b Antibody Drug Conjugates Anti-CD79b antibody drug conjugates useful in the methods described herein (e.g., for treating a CD20-positive cell proliferative disorder, e.g., a B-cell proliferative disorder (e.g., NHL (e.g., relapsed and / or refractory NHL, DLBCL (e.g., relapsed and / or refractory DLBCL), FL (e.g., relapsed and / or refractory FL or transformed FL), or MCL (e.g., relapsed and / or refractory MCL)), CLL or CNSL)) include any of the anti-CD79b antibody drug conjugates described in U.S. Pat. No. 8,088,378, the entire contents of which are incorporated herein by reference. In some examples, the anti-CD79b antibody drug conjugate comprises an anti-CD79b binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 65; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 66; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 67; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 68; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 69; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 70. In some examples, the anti-CD79b antibody drug conjugate comprises an anti-CD79b binding domain that comprises all six of the following HVRs: (a) HVR-H1 comprising the amino acid sequence of GYTFSSYWIE (SEQ ID NO: 65); (b) HVR-H2 comprising the amino acid sequence of GEILPGGGDTNYNEIFKG (SEQ ID NO: 66); (c) HVR-H3 comprising the amino acid sequence of TRRVPIRLDY (SEQ ID NO: 67); (d) HVR-L1 comprising the amino acid sequence of KASQSVDYEGDSFLN (SEQ ID NO: 68); (e) HVR-L2 comprising the amino acid sequence of AASNLES (SEQ ID NO: 69); and (f) HVR-L3 comprising the amino acid sequence of QQSNEDPLT (SEQ ID NO: 70).In some examples, the anti-CD79b antibody drug conjugate comprises at least one (e.g., one, two, three, or four) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 73-76, respectively, and / or at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 77-80, respectively. In some examples, the 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: 71, or the sequence of SEQ ID NO: 71; (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: 72, or the sequence of SEQ ID NO: 72; or (c) a VH domain described in (a) and a VL domain described in (b). Thus, in some examples, the first binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 71 and a VL domain comprising the amino acid sequence of SEQ ID NO: 72.

[0217] The sequence of the anti-CD79b antibody, polatuzumab vedotin, is summarized in Table 2 below. [Table 2]

[0218] In some examples, the anti-CD79b antibody is linked 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-related CD79 beta)], a humanized monoclonal antibody conjugated to auristatin E; gamma 1 heavy chain (1-447) [humanized VH (Homo sapiens IGHV3-23)], as defined by the International Nonproprietary Names for Pharmaceutical Substances (INN) List 110 (WHO Drug Information, Vol. 27, No. 4, 2016, p. 443). * 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), CH3(341-445), CHS(446-447))(118-447)], (220-218')...

Claims

1. A pharmaceutical agent for treating a subject with a B-cell proliferative disorder in combination with mosunetuzumab, comprising polatuzumab vedotin, polatuzumab vedotin and mosunetuzumab are administered to the subject in a dosing regimen comprising at least a first dosing cycle, a second dosing cycle, and a third dosing cycle; (a) the first administration cycle comprises a first dose of mosunetuzumab (C1D1), a second dose of mosunetuzumab (C1D2), and a third dose of mosunetuzumab (C1D3), wherein the C1D1 of mosunetuzumab is about 1 mg, the C1D2 of mosunetuzumab is about 2 mg, and the C1D3 of mosunetuzumab is about 60 mg; (b) the second administration cycle comprises a single dose of mosunetuzumab (C2D1), wherein the C2D1 of mosunetuzumab is about 60 mg; and (c) the third administration cycle comprises a single dose of mosunetuzumab (C3D1), wherein the C3D1 of mosunetuzumab is about 30 mg; Mosunetuzumab is administered intravenously. the first administration cycle comprises a single dose C1D1 of polatuzumab vedotin; the second administration cycle comprises a single dose C2D1 of polatuzumab vedotin; and the third administration cycle comprises a single dose C3D1 of polatuzumab vedotin; the single dose C1D1 of polatuzumab vedotin is about 1.8 mg / kg; the single dose C2D1 of polatuzumab vedotin is about 1.8 mg / kg; and the single dose C3D1 of polatuzumab vedotin is about 1.8 mg / kg; the C1D1 of mosunetuzumab and the C1D1 of polatuzumab vedotin are administered on day 1 of the first administration cycle, and on each day comprising administration of a dose of mosunetuzumab and administration of a dose of polatuzumab vedotin, the dose of polatuzumab vedotin is administered at least 60 minutes before the administration of the dose of mosunetuzumab. Medicine.

2. A pharmaceutical agent for treating a subject having a B-cell proliferative disorder in combination with polatuzumab vedotin, comprising mosunetuzumab, polatuzumab vedotin and mosunetuzumab are administered to the subject in a dosing regimen comprising at least a first dosing cycle, a second dosing cycle, and a third dosing cycle; (a) the first administration cycle comprises a first dose of mosunetuzumab (C1D1), a second dose of mosunetuzumab (C1D2), and a third dose of mosunetuzumab (C1D3), wherein the C1D1 of mosunetuzumab is about 1 mg, the C1D2 of mosunetuzumab is about 2 mg, and the C1D3 of mosunetuzumab is about 60 mg; (b) the second administration cycle comprises a single dose of mosunetuzumab (C2D1), wherein the C2D1 of mosunetuzumab is about 60 mg; and (c) the third administration cycle comprises a single dose of mosunetuzumab (C3D1), wherein the C3D1 of mosunetuzumab is about 30 mg; Mosunetuzumab is administered intravenously. the first administration cycle comprises a single dose C1D1 of polatuzumab vedotin; the second administration cycle comprises a single dose C2D1 of polatuzumab vedotin; and the third administration cycle comprises a single dose C3D1 of polatuzumab vedotin; the single dose C1D1 of polatuzumab vedotin is about 1.8 mg / kg; the single dose C2D1 of polatuzumab vedotin is about 1.8 mg / kg; and the single dose C3D1 of polatuzumab vedotin is about 1.8 mg / kg; the C1D1 of mosunetuzumab and the C1D1 of polatuzumab vedotin are administered on day 1 of the first administration cycle, and on each day comprising administration of a dose of mosunetuzumab and administration of a dose of polatuzumab vedotin, the dose of polatuzumab vedotin is administered at least 60 minutes before the administration of the dose of mosunetuzumab. Medicine.

3. A pharmaceutical agent for treating a subject with a B-cell proliferative disorder, comprising polatuzumab vedotin and mosunetuzumab, polatuzumab vedotin and mosunetuzumab are administered to the subject in a dosing regimen comprising at least a first dosing cycle, a second dosing cycle, and a third dosing cycle; (a) the first administration cycle comprises a first dose of mosunetuzumab (C1D1), a second dose of mosunetuzumab (C1D2), and a third dose of mosunetuzumab (C1D3), wherein the C1D1 of mosunetuzumab is about 1 mg, the C1D2 of mosunetuzumab is about 2 mg, and the C1D3 of mosunetuzumab is about 60 mg; (b) the second administration cycle comprises a single dose of mosunetuzumab (C2D1), wherein the C2D1 of mosunetuzumab is about 60 mg; and (c) the third administration cycle comprises a single dose of mosunetuzumab (C3D1), wherein the C3D1 of mosunetuzumab is about 30 mg; Mosunetuzumab is administered intravenously. the first administration cycle comprises a single dose C1D1 of polatuzumab vedotin; the second administration cycle comprises a single dose C2D1 of polatuzumab vedotin; and the third administration cycle comprises a single dose C3D1 of polatuzumab vedotin; the single dose C1D1 of polatuzumab vedotin is about 1.8 mg / kg; the single dose C2D1 of polatuzumab vedotin is about 1.8 mg / kg; and the single dose C3D1 of polatuzumab vedotin is about 1.8 mg / kg; the C1D1 of mosunetuzumab and the C1D1 of polatuzumab vedotin are administered on day 1 of the first administration cycle, and on each day comprising administration of a dose of mosunetuzumab and administration of a dose of polatuzumab vedotin, the dose of polatuzumab vedotin is administered at least 60 minutes before the administration of the dose of mosunetuzumab. Medicine.

4. (a) the C1D1 of mosunetuzumab, the C1D2 of mosunetuzumab, and the C1D3 of mosunetuzumab are administered to the subject on days 1, 8, and 15, respectively, of the first administration cycle; and / or the C2D1 of mosunetuzumab is administered to the subject on day 1 of the second administration cycle; and / or (b) the C1D1 of polatuzumab vedotin is administered to the subject on day 1 of the first administration cycle; and / or the C2D1 of polatuzumab vedotin is administered to the subject on day 1 of the second administration cycle. The pharmaceutical composition according to any one of claims 1 to 3.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the first administration cycle and the second administration cycle are 21-day administration cycles.

6. The method of any one of claims 1 to 5, wherein the administration regimen comprises one or more additional administration cycles.

7. The method of claim 6, wherein the administration regimen comprises 3 to 14 additional administration cycles.

8. The pharmaceutical composition of claim 6 or 7, wherein the additional administration cycle is a 21-day administration cycle.

9. one or more of said additional administration cycles (a) an additional single dose of mosunetuzumab and an additional single dose of polatuzumab vedotin; and / or (b) an additional single dose of mosunetuzumab and no administration of polatuzumab vedotin; The pharmaceutical composition according to any one of claims 6 to 8.

10. The additional single dose of polatuzumab vedotin is equivalent to the C2D1 dose of polatuzumab vedotin; and / or 10. The method of claim 9, wherein the additional single dose of polatuzumab vedotin is administered to the subject on day 1 of each additional administration cycle comprising an additional dose of polatuzumab vedotin.

11. The pharmaceutical described in claim 9, wherein the additional single dose of mosunetuzumab is less than the C2D1 of mosunetuzumab.

12. The method of claim 11, wherein the additional single dose of mosunetuzumab is about 30 mg.

13. A pharmaceutical described in any one of claims 9, 11, and 12, wherein the additional single dose of mosunetuzumab is administered to the subject on day 1 of each additional administration cycle comprising an additional dose of mosunetuzumab.

14. 10. The pharmaceutical composition of claim 9, wherein the dosing regimen comprises five or more additional dosing cycles, each of the five or more additional dosing cycles comprising a single dose of mosunetuzumab, and no more than three of the five or more additional dosing cycles comprising administration of polatuzumab vedotin.

15. 10. The pharmaceutical composition of claim 9, wherein the dosing regimen comprises three or more additional dosing cycles, each of the three or more additional dosing cycles comprising a single dose of mosunetuzumab, and no more than three of the three or more additional dosing cycles comprising administration of polatuzumab vedotin.

16. A pharmaceutical agent for treating a subject having a B-cell proliferative disorder in combination with mosunetuzumab, comprising polatuzumab vedotin, polatuzumab vedotin and mosunetuzumab are administered to the subject in a dosing regimen comprising 8 or more dosing cycles; (a) the first administration cycle comprises: (i) a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, and a third dose (C1D3) of mosunetuzumab, wherein said C1D1 of mosunetuzumab is about 1 mg, said C1D2 of mosunetuzumab is about 2 mg, and said C1D3 of mosunetuzumab is about 60 mg; and (ii) Single dose of polatuzumab vedotin (C1D1) Including; (b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) and a single dose of polatuzumab vedotin (C2D1), wherein the C2D1 of mosunetuzumab is about 60 mg; (c) the third dosing cycle comprises a single dose of mosunetuzumab (C3D1) and a single dose of polatuzumab vedotin (C3D1); (d) the fourth dosing cycle comprises a single dose of mosunetuzumab (C4D1) and a single dose of polatuzumab vedotin (C4D1); (e) the fifth dosing cycle comprises a single dose of mosunetuzumab (C5D1) and a single dose of polatuzumab vedotin (C5D1); (f) the sixth dosing cycle comprises a single dose of mosunetuzumab (C6D1) and a single dose of polatuzumab vedotin (C6D1); (g) the seventh administration cycle comprises a single dose of mosunetuzumab (C7D1) and does not include administration of polatuzumab vedotin; and (h) the eighth administration cycle comprises a single dose of mosunetuzumab (C8D1) and does not include administration of polatuzumab vedotin; each single dose of mosunetuzumab C3D1 to C8D1 is about 30 mg; Mosunetuzumab is administered intravenously. each of C1D1 to C6D1 of polatuzumab vedotin is about 1.8 mg / kg; wherein the C1D1 of mosunetuzumab and the C1D1 of polatuzumab vedotin are administered on day 1 of the first administration cycle, and on each day comprising administration of a dose of mosunetuzumab and administration of a dose of polatuzumab vedotin, the dose of polatuzumab vedotin is administered at least 60 minutes before administration of the dose of mosunetuzumab.

17. A pharmaceutical agent for treating a subject having a B-cell proliferative disorder in combination with polatuzumab vedotin, comprising mosunetuzumab, polatuzumab vedotin and mosunetuzumab are administered to the subject in a dosing regimen comprising 8 or more dosing cycles; (a) the first administration cycle comprises: (i) a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, and a third dose (C1D3) of mosunetuzumab, wherein said C1D1 of mosunetuzumab is about 1 mg, said C1D2 of mosunetuzumab is about 2 mg, and said C1D3 of mosunetuzumab is about 60 mg; and (ii) Single dose of polatuzumab vedotin (C1D1) Including; (b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) and a single dose of polatuzumab vedotin (C2D1), wherein the C2D1 of mosunetuzumab is about 60 mg; (c) the third dosing cycle comprises a single dose of mosunetuzumab (C3D1) and a single dose of polatuzumab vedotin (C3D1); (d) the fourth dosing cycle comprises a single dose of mosunetuzumab (C4D1) and a single dose of polatuzumab vedotin (C4D1); (e) the fifth dosing cycle comprises a single dose of mosunetuzumab (C5D1) and a single dose of polatuzumab vedotin (C5D1); (f) the sixth dosing cycle comprises a single dose of mosunetuzumab (C6D1) and a single dose of polatuzumab vedotin (C6D1); (g) the seventh administration cycle comprises a single dose of mosunetuzumab (C7D1) and does not include administration of polatuzumab vedotin; and (h) the eighth administration cycle comprises a single dose of mosunetuzumab (C8D1) and does not include administration of polatuzumab vedotin; each single dose of mosunetuzumab C3D1 to C8D1 is about 30 mg; Mosunetuzumab is administered intravenously. each of C1D1 to C6D1 of polatuzumab vedotin is about 1.8 mg / kg; wherein the C1D1 of mosunetuzumab and the C1D1 of polatuzumab vedotin are administered on day 1 of the first administration cycle, and on each day comprising administration of a dose of mosunetuzumab and administration of a dose of polatuzumab vedotin, the dose of polatuzumab vedotin is administered at least 60 minutes before administration of the dose of mosunetuzumab.

18. A pharmaceutical agent for treating a subject having a B-cell proliferative disorder, comprising polatuzumab vedotin and mosunetuzumab, polatuzumab vedotin and mosunetuzumab are administered to the subject in a dosing regimen comprising 8 or more dosing cycles; (a) the first administration cycle comprises: (i) a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, and a third dose (C1D3) of mosunetuzumab, wherein said C1D1 of mosunetuzumab is about 1 mg, said C1D2 of mosunetuzumab is about 2 mg, and said C1D3 of mosunetuzumab is about 60 mg; and (ii) Single dose of polatuzumab vedotin (C1D1) Including; (b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) and a single dose of polatuzumab vedotin (C2D1), wherein the C2D1 of mosunetuzumab is about 60 mg; (c) the third dosing cycle comprises a single dose of mosunetuzumab (C3D1) and a single dose of polatuzumab vedotin (C3D1); (d) the fourth dosing cycle comprises a single dose of mosunetuzumab (C4D1) and a single dose of polatuzumab vedotin (C4D1); (e) the fifth dosing cycle comprises a single dose of mosunetuzumab (C5D1) and a single dose of polatuzumab vedotin (C5D1); (f) the sixth dosing cycle comprises a single dose of mosunetuzumab (C6D1) and a single dose of polatuzumab vedotin (C6D1); (g) the seventh administration cycle comprises a single dose of mosunetuzumab (C7D1) and does not include administration of polatuzumab vedotin; and (h) the eighth administration cycle comprises a single dose of mosunetuzumab (C8D1) and does not include administration of polatuzumab vedotin; each single dose of mosunetuzumab C3D1 to C8D1 is about 30 mg; Mosunetuzumab is administered intravenously. each of C1D1 to C6D1 of polatuzumab vedotin is about 1.8 mg / kg; wherein the C1D1 of mosunetuzumab and the C1D1 of polatuzumab vedotin are administered on day 1 of the first administration cycle, and on each day comprising administration of a dose of mosunetuzumab and administration of a dose of polatuzumab vedotin, the dose of polatuzumab vedotin is administered at least 60 minutes before administration of the dose of mosunetuzumab.

19. (a) the C1D1 of mosunetuzumab, the C1D2 of mosunetuzumab, and the C1D3 of mosunetuzumab are administered to the subject on days 1, 8, and 15, respectively, of the first administration cycle; (b) each of the C2D1 to C8D1 subunits of mosunetuzumab is administered to the subject on day 1 of each administration cycle; and / or (c) each of the C1D1 to C6D1 of polatuzumab vedotin is administered to the subject on day 1 of each administration cycle; The pharmaceutical composition according to any one of claims 16 to 18.

20. The pharmaceutical composition according to any one of claims 16 to 19, wherein each administration cycle is a 21-day administration cycle.

21. The method of any one of claims 16 to 20, wherein the dosing regimen comprises one or more additional dosing cycles comprising a single dose of mosunetuzumab.

22. the dosing regimen comprises 1 to 9 additional dosing cycles comprising a single dose of mosunetuzumab; and / or each of the additional administration cycles does not include administration of polatuzumab vedotin. The pharmaceutical composition of claim 21.

23. Each single dose of mosunetuzumab is about 30 mg. The pharmaceutical composition of claim 22.

24. The method of any one of claims 21 to 23, wherein each of the additional administration cycles is a 21-day administration cycle.

25. The method of any one of claims 1 to 24, wherein the administration regimen further comprises the administration of one or more additional therapeutic agents.

26. The pharmaceutical composition of claim 25, wherein the one or more additional therapeutic agents are a corticosteroid or an IL-6R antagonist.

27. (a) tocilizumab is administered intravenously to the subject as a single dose of about 8 mg / kg, and said single dose does not exceed 800 mg; and / or (b) the corticosteroid is dexamethasone, prednisone, or methylprednisolone; The pharmaceutical composition of claim 26.

28. 26. The medicament of claim 25, wherein the one or more additional therapeutic agents comprise one or more chemotherapeutic agents.

29. 29. The medicament of claim 28, wherein the one or more chemotherapeutic agents include cyclophosphamide or doxorubicin.

30. A pharmaceutical agent for reducing the rate of cytokine release syndrome in a population of subjects with a B-cell proliferative disorder in combination with mosunetuzumab, comprising polatuzumab vedotin, polatuzumab vedotin and mosunetuzumab are administered to one or more subjects in the population in a dosing regimen comprising eight or more dosing cycles; (a) the first administration cycle comprises: (i) a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, and a third dose (C1D3) of mosunetuzumab, wherein said C1D1 of mosunetuzumab is about 1 mg, said C1D2 of mosunetuzumab is about 2 mg, and said C1D3 of mosunetuzumab is about 60 mg; and (ii) Single dose of polatuzumab vedotin (C1D1) Including; (b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) and a single dose of polatuzumab vedotin (C2D1); (c) the third dosing cycle comprises a single dose of mosunetuzumab (C3D1) and a single dose of polatuzumab vedotin (C3D1); (d) the fourth dosing cycle comprises a single dose of mosunetuzumab (C4D1) and a single dose of polatuzumab vedotin (C4D1); (e) the fifth dosing cycle comprises a single dose of mosunetuzumab (C5D1) and a single dose of polatuzumab vedotin (C5D1); (f) the sixth dosing cycle comprises a single dose of mosunetuzumab (C6D1) and a single dose of polatuzumab vedotin (C6D1); (g) the seventh administration cycle comprises a single dose of mosunetuzumab (C7D1) and does not include administration of polatuzumab vedotin; and (h) the eighth administration cycle comprises a single dose of mosunetuzumab (C8D1) and does not include administration of polatuzumab vedotin; wherein the single dose C2D1 of mosunetuzumab is about 60 mg and each single dose C3D1-C8D1 of mosunetuzumab is about 30 mg, and the rate of cytokine release syndrome is reduced in the population of subjects compared to a reference population of subjects not receiving polatuzumab vedotin; Mosunetuzumab is administered intravenously. each of C1D1 to C6D1 of polatuzumab vedotin is about 1.8 mg / kg; the C1D1 of mosunetuzumab and the C1D1 of polatuzumab vedotin are administered on day 1 of the first administration cycle, and on each day comprising administration of a dose of mosunetuzumab and administration of a dose of polatuzumab vedotin, the dose of polatuzumab vedotin is administered at least 60 minutes before the administration of the dose of mosunetuzumab. Medicine.

31. A pharmaceutical agent for reducing the rate of cytokine release syndrome in a population of subjects with a B-cell proliferative disorder in combination with polatuzumab vedotin, comprising mosunetuzumab, polatuzumab vedotin and mosunetuzumab are administered to one or more subjects in the population in a dosing regimen comprising eight or more dosing cycles; (a) the first administration cycle comprises: (i) a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, and a third dose (C1D3) of mosunetuzumab, wherein said C1D1 of mosunetuzumab is about 1 mg, said C1D2 of mosunetuzumab is about 2 mg, and said C1D3 of mosunetuzumab is about 60 mg; and (ii) Single dose of polatuzumab vedotin (C1D1) Including; (b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) and a single dose of polatuzumab vedotin (C2D1); (c) the third dosing cycle comprises a single dose of mosunetuzumab (C3D1) and a single dose of polatuzumab vedotin (C3D1); (d) the fourth dosing cycle comprises a single dose of mosunetuzumab (C4D1) and a single dose of polatuzumab vedotin (C4D1); (e) the fifth dosing cycle comprises a single dose of mosunetuzumab (C5D1) and a single dose of polatuzumab vedotin (C5D1); (f) the sixth dosing cycle comprises a single dose of mosunetuzumab (C6D1) and a single dose of polatuzumab vedotin (C6D1); (g) the seventh administration cycle comprises a single dose of mosunetuzumab (C7D1) and does not include administration of polatuzumab vedotin; and (h) the eighth administration cycle comprises a single dose of mosunetuzumab (C8D1) and does not include administration of polatuzumab vedotin; wherein the single dose C2D1 of mosunetuzumab is about 60 mg and each single dose C3D1-C8D1 of mosunetuzumab is about 30 mg, and the rate of cytokine release syndrome is reduced in the population of subjects compared to a reference population of subjects not receiving polatuzumab vedotin; Mosunetuzumab is administered intravenously. each of C1D1 to C6D1 of polatuzumab vedotin is about 1.8 mg / kg; the C1D1 of mosunetuzumab and the C1D1 of polatuzumab vedotin are administered on day 1 of the first administration cycle, and on each day comprising administration of a dose of mosunetuzumab and administration of a dose of polatuzumab vedotin, the dose of polatuzumab vedotin is administered at least 60 minutes before the administration of the dose of mosunetuzumab. Medicine.

32. A pharmaceutical agent for reducing the rate of cytokine release syndrome in a population of subjects with a B-cell proliferative disorder, comprising polatuzumab vedotin and mosunetuzumab, polatuzumab vedotin and mosunetuzumab are administered to one or more subjects in the population in a dosing regimen comprising eight or more dosing cycles; (a) the first administration cycle comprises: (i) a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, and a third dose (C1D3) of mosunetuzumab, wherein said C1D1 of mosunetuzumab is about 1 mg, said C1D2 of mosunetuzumab is about 2 mg, and said C1D3 of mosunetuzumab is about 60 mg; and (ii) Single dose of polatuzumab vedotin (C1D1) Including; (b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) and a single dose of polatuzumab vedotin (C2D1); (c) the third dosing cycle comprises a single dose of mosunetuzumab (C3D1) and a single dose of polatuzumab vedotin (C3D1); (d) the fourth dosing cycle comprises a single dose of mosunetuzumab (C4D1) and a single dose of polatuzumab vedotin (C4D1); (e) the fifth dosing cycle comprises a single dose of mosunetuzumab (C5D1) and a single dose of polatuzumab vedotin (C5D1); (f) the sixth dosing cycle comprises a single dose of mosunetuzumab (C6D1) and a single dose of polatuzumab vedotin (C6D1); (g) the seventh administration cycle comprises a single dose of mosunetuzumab (C7D1) and does not include administration of polatuzumab vedotin; and (h) the eighth administration cycle comprises a single dose of mosunetuzumab (C8D1) and does not include administration of polatuzumab vedotin; wherein the single dose C2D1 of mosunetuzumab is about 60 mg and each single dose C3D1-C8D1 of mosunetuzumab is about 30 mg, and the rate of cytokine release syndrome is reduced in the population of subjects compared to a reference population of subjects not receiving polatuzumab vedotin; Mosunetuzumab is administered intravenously. each of C1D1 to C6D1 of polatuzumab vedotin is about 1.8 mg / kg; the C1D1 of mosunetuzumab and the C1D1 of polatuzumab vedotin are administered on day 1 of the first administration cycle, and on each day comprising administration of a dose of mosunetuzumab and administration of a dose of polatuzumab vedotin, the dose of polatuzumab vedotin is administered at least 60 minutes before the administration of the dose of mosunetuzumab. Medicine.

33. 33. The pharmaceutical of any one of claims 30 to 32, wherein the population of subjects exhibits cytokine release syndrome following administration of mosunetuzumab, and the rate of cytokine release syndrome in the population of subjects is 20% or less.

34. The method of claim 33, wherein the rate of cytokine release syndrome in the population of subjects is 10% or less.

35. The method of claim 34, wherein the rate of cytokine release syndrome in the population of subjects is 5% or less.

36. The method of claim 35, wherein the rate of cytokine release syndrome in the subject population is 3% or less.

37. The pharmaceutical agent according to any one of claims 30 to 36, wherein the rate of cytokine release syndrome of grade 2 or higher (as defined by the American Society for Transplantation and Cellular Therapy, 2019; ASTCT) is 20% or less.

38. 38. The method of claim 37, wherein the rate of cytokine release syndrome of grade 2 or higher (as defined by ASTCT) is 5% or less.

39. 39. The method of claim 38, wherein the rate of cytokine release syndrome of grade 2 or higher (as defined by ASTCT) is about 0%.

40. The pharmaceutical agent according to any one of claims 1 to 39, wherein the B-cell proliferative disorder is non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), or central nervous system lymphoma (CNSL).

41. The pharmaceutical agent of claim 40, wherein the NHL is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma (PMLBCL), diffuse B-cell lymphoma, small lymphocytic lymphoma, marginal zone lymphoma (MZL), Burkitt's lymphoma, or lymphoplasmacytic lymphoma.

42. The pharmaceutical agent according to claim 40 or 41, wherein the NHL is relapsed or refractory NHL.

43. The pharmaceutical agent according to claim 40 or 41, wherein the NHL is DLBCL.

44. The pharmaceutical agent of claim 43, wherein the DLBCL is relapsed or refractory DLBCL.

45. The method of claim 43, wherein the DLBCL is Richter's transformation.

46. The pharmaceutical agent according to claim 40 or 41, wherein the NHL is FL.

47. The method of claim 46, wherein the FL is relapsed or refractory FL.

48. The pharmaceutical agent of claim 46, wherein the FL is a transformed FL.

49. The pharmaceutical agent according to claim 40 or 41, wherein the NHL is MCL.

50. The pharmaceutical agent of claim 49, wherein the MCL is relapsed or refractory MCL.

51. The medicament according to any one of claims 1 to 39, wherein the B-cell proliferative disorder is relapsed and / or refractory.

52. Polatuzumab vedotin is administered intravenously, and / or Mosunetuzumab is administered by intravenous infusion. The pharmaceutical composition according to any one of claims 1 to 51.

53. The pharmaceutical described in claim 52, wherein polatuzumab vedotin is administered by intravenous infusion.

54. A pharmaceutical agent for treating a subject with NHL in combination with mosunetuzumab, comprising polatuzumab vedotin, polatuzumab vedotin and mosunetuzumab are administered to the subject in a dosing regimen comprising 8 or more dosing cycles; (a) the first administration cycle comprises: (i) the first dose (C1D1), the second dose (C1D2), and the third dose (C1D3) of mosunetuzumab, wherein the C1D1 of mosunetuzumab is about 1 mg, the C1D2 of mosunetuzumab is about 2 mg, and the C1D3 of mosunetuzumab is about 60 mg; and (ii) the single dose of polatuzumab vedotin (C1D1) Including; (b) a second administration cycle comprises a single dose of the mosunetuzumab (C2D1) and a single dose of the polatuzumab vedotin (C2D1), wherein the C2D1 of the mosunetuzumab is about 60 mg; (c) a third administration cycle comprises a single dose of mosunetuzumab (C3D1) and a single dose of polatuzumab vedotin (C3D1); (d) a fourth administration cycle comprises a single dose of mosunetuzumab (C4D1) and a single dose of polatuzumab vedotin (C4D1); (e) a fifth administration cycle comprises a single dose of mosunetuzumab (C5D1) and a single dose of polatuzumab vedotin (C5D1); (f) a sixth administration cycle comprises a single dose of mosunetuzumab (C6D1) and a single dose of polatuzumab vedotin (C6D1); (g) a seventh administration cycle comprises a single dose of mosunetuzumab (C7D1) and does not comprise administration of polatuzumab vedotin; and (h) an eighth administration cycle comprises a single dose of mosunetuzumab (C8D1) and does not comprise administration of polatuzumab vedotin; each single dose of the mosunetuzumab C3D1 to C8D1 is about 30 mg, and each single dose of the polatuzumab vedotin C1D1 to C6D1 is about 1.8 mg / kg, and the mosunetuzumab and polatuzumab vedotin are administered intravenously; wherein the C1D1 of mosunetuzumab and the C1D1 of polatuzumab vedotin are administered on day 1 of the first administration cycle, and on each day comprising administration of a dose of mosunetuzumab and administration of a dose of polatuzumab vedotin, the dose of polatuzumab vedotin is administered at least 60 minutes before administration of the dose of mosunetuzumab.

55. A pharmaceutical agent for treating a subject with NHL in combination with polatuzumab vedotin, comprising mosunetuzumab, polatuzumab vedotin and mosunetuzumab are administered to the subject in a dosing regimen comprising 8 or more dosing cycles; (a) the first administration cycle comprises: (i) the first dose (C1D1), the second dose (C1D2), and the third dose (C1D3) of mosunetuzumab, wherein the C1D1 of mosunetuzumab is about 1 mg, the C1D2 of mosunetuzumab is about 2 mg, and the C1D3 of mosunetuzumab is about 60 mg; and (ii) the single dose of polatuzumab vedotin (C1D1) Including; (b) a second administration cycle comprises a single dose of the mosunetuzumab (C2D1) and a single dose of the polatuzumab vedotin (C2D1), wherein the C2D1 of the mosunetuzumab is about 60 mg; (c) a third administration cycle comprises a single dose of mosunetuzumab (C3D1) and a single dose of polatuzumab vedotin (C3D1); (d) a fourth administration cycle comprises a single dose of mosunetuzumab (C4D1) and a single dose of polatuzumab vedotin (C4D1); (e) a fifth administration cycle comprises a single dose of mosunetuzumab (C5D1) and a single dose of polatuzumab vedotin (C5D1); (f) a sixth administration cycle comprises a single dose of mosunetuzumab (C6D1) and a single dose of polatuzumab vedotin (C6D1); (g) a seventh administration cycle comprises a single dose of mosunetuzumab (C7D1) and does not comprise administration of polatuzumab vedotin; and (h) an eighth administration cycle comprises a single dose of mosunetuzumab (C8D1) and does not comprise administration of polatuzumab vedotin; each single dose of the mosunetuzumab C3D1 to C8D1 is about 30 mg, and each single dose of the polatuzumab vedotin C1D1 to C6D1 is about 1.8 mg / kg, and the mosunetuzumab and polatuzumab vedotin are administered intravenously; wherein the C1D1 of mosunetuzumab and the C1D1 of polatuzumab vedotin are administered on day 1 of the first administration cycle, and on each day comprising administration of a dose of mosunetuzumab and administration of a dose of polatuzumab vedotin, the dose of polatuzumab vedotin is administered at least 60 minutes before administration of the dose of mosunetuzumab.

56. A pharmaceutical agent for treating a subject with NHL, comprising polatuzumab vedotin and mosunetuzumab, polatuzumab vedotin and mosunetuzumab are administered to the subject in a dosing regimen comprising 8 or more dosing cycles; (a) the first administration cycle comprises: (i) the first dose (C1D1), the second dose (C1D2), and the third dose (C1D3) of mosunetuzumab, wherein the C1D1 of mosunetuzumab is about 1 mg, the C1D2 of mosunetuzumab is about 2 mg, and the C1D3 of mosunetuzumab is about 60 mg; and (ii) the single dose of polatuzumab vedotin (C1D1) Including; (b) a second administration cycle comprises a single dose of the mosunetuzumab (C2D1) and a single dose of the polatuzumab vedotin (C2D1), wherein the C2D1 of the mosunetuzumab is about 60 mg; (c) a third administration cycle comprises a single dose of mosunetuzumab (C3D1) and a single dose of polatuzumab vedotin (C3D1); (d) a fourth administration cycle comprises a single dose of mosunetuzumab (C4D1) and a single dose of polatuzumab vedotin (C4D1); (e) a fifth administration cycle comprises a single dose of mosunetuzumab (C5D1) and a single dose of polatuzumab vedotin (C5D1); (f) a sixth administration cycle comprises a single dose of mosunetuzumab (C6D1) and a single dose of polatuzumab vedotin (C6D1); (g) a seventh administration cycle comprises a single dose of mosunetuzumab (C7D1) and does not comprise administration of polatuzumab vedotin; and (h) an eighth administration cycle comprises a single dose of mosunetuzumab (C8D1) and does not comprise administration of polatuzumab vedotin; each single dose of the mosunetuzumab C3D1 to C8D1 is about 30 mg, and each single dose of the polatuzumab vedotin C1D1 to C6D1 is about 1.8 mg / kg, and the mosunetuzumab and polatuzumab vedotin are administered intravenously; wherein the C1D1 of mosunetuzumab and the C1D1 of polatuzumab vedotin are administered on day 1 of the first administration cycle, and on each day comprising administration of a dose of mosunetuzumab and administration of a dose of polatuzumab vedotin, the dose of polatuzumab vedotin is administered at least 60 minutes before administration of the dose of mosunetuzumab.

57. The pharmaceutical agent according to any one of claims 54 to 56, wherein the NHL is aggressive NHL, DLBCL, and / or R / R MCL.

58. The pharmaceutical composition of any one of claims 1 to 57, wherein the subject is a human.

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