Methods for treating CD20-positive proliferative disorder with mosunetuzumab and polatuzumab vedotin

Abstract

To provide methods for treating subjects having a CD20-positive cell proliferative disorder.SOLUTION: The invention pertains to the treatment of subjects having a CD20-positive cell proliferative disorder by administering a combination of mosunetuzumab and polatuzumab vedotin.SELECTED DRAWING: Figure 2A

Description

[Technical field]

[0001] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format and is incorporated by reference in its entirety. Said ASCII copy, created on May 4, 2022, is named 50474-269WO2_Sequence_Listing_5_4_2022_ST25.txt and is 35,336 bytes in size.

[0002] FIELD OF THEINVENTION The present invention relates to the treatment of subjects with CD20-positive cell proliferative disorders (e.g., B-cell proliferative disorders). More specifically, the present invention relates to the combined treatment of subjects with CD20-positive cell proliferative disorders (e.g., B-cell proliferative disorders; e.g., non-Hodgkin's lymphoma (NHL); e.g., aggressive NHL) with subcutaneous administration of mosunetuzumab and intravenous administration of polatuzumab vedotin, who may have received at least one prior line of therapy. [Background technology]

[0003] background Cancer is characterized by the uncontrolled proliferation of cell subpopulations. Cancer 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. Indolent cancers can also have a profound effect on quality of life. Cancer care therefore represents a significant and ever-increasing social burden.

[0004] B-cell proliferative disorders are a major cause of cancer-related deaths. For example, non-Hodgkin's lymphoma (NHL) is rapidly progressive and fatal if untreated. In the United States, B-cell lymphomas constitute approximately 80%-85% of all cases of NHL. Aggressive NHL includes DLBCL, transformed FL, and grade 3b FL. Up to 40% of DLBCL patients treated in the first-line setting experience disease progression within 3-4 years (Friedberg JW. Hematology Am. Soc. Hematol Educ. Program. 2011, 2011:498-505), and more than half of patients treated with second-line therapy do not achieve complete remission (Gisselbrecht C et al. J. Clin. Oncol. 2010, 28:4184-4190.). Furthermore, with the introduction of the monoclonal anti-CD20 antibody rituximab, it has become more difficult to find an effective treatment for the majority of R / RDLBCL patients with previous exposure to anti-CD20 antibodies.

[0005] Approximately 3% of FLs transform annually into more aggressive NHL, most commonly DLBCL (Lossos IS and Gascoyne RD, Best Pract. Res. Clin. Haematol. 2011, 24:147-163), resulting in nearly one-third histological transformation in 10 years. These DLBCL patients have transformed from their previous FL histology and are treated with the same standard of care as aggressive lymphomas. Follicular lymphoma grade 3b is a distinct subgroup of FL that is genetically, immunophenotypically and clinically more common with DLBCL than other indolent FLs, and coexistence with DLBCL is frequent (Harris NL and Kluin P. Follicular lymphoma grade 3B: is it a real disease? Haematologica. 2011, 96:1244-1246). The clinical course of patients with FL grade 3b is similar to that of patients with DLBCL, and FL grade 3b is generally treated as DLBCL (National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. B-Cell Lymphoma and Prevention and Treatment of Cancer-Related Infections [resource on the Internet]. 2020. Available from: nccn.org).

[0006] Despite the biological and clinical heterogeneity of B-cell lymphomas, subjects with advanced stage B-cell malignancies are typically initially treated with potent cytotoxic chemotherapy in combination with monoclonal antibodies (mAbs), such as anti-CD20 mAb, rituximab (Rituxan®, MabThera®). Although durable responses can be achieved in some subjects, the majority of subjects will eventually experience progressive or recurrent disease. NHL remains an incurable disease with currently available therapies. The addition of rituximab to commonly used induction chemotherapy including cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP); cyclophosphamide, vincristine, and prednisone (CVP); fludarabine, cyclophosphamide, and mitoxantrone (FCM); bendamustine; or gemcitabine and oxaliplatin; (Zelenetz et al. J. Natl. Compr. Canc. Netw. 2014,12(6):916-946; Forstpointner et al. Blood. 2006,108(13):4003-4008; Mounier et al., Haematologica. 2013,98(11):1726-1731) followed by rituximab maintenance therapy has resulted in long-term remissions and improved subject outcomes. In particular, R-GemOx (rituximab, gemcitabine and oxaliplatin; see Mounier et al., Haematologica. 2013, 98(11):1726-1731) is the recommended regimen in the NCCN Guidelines 2021 for subjects with R / R DLBCL who are not candidates for autologous stem cell transplant (ASCT) therapy.

[0007] For such subjects, alternative or secondary therapies such as bispecific antibody-based immunotherapy may be particularly effective. Bispecific antibodies such as mosunetuzumab may simultaneously bind to 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 goal of destroying the cancer cells to which the bound cytotoxic cells are bound. Antibody drug conjugates may bind to cell surface epitopes (e.g., targeting CD79b; e.g., polatuzumab vedotin) to facilitate internalization of the bound drug conjugate for targeted delivery of cytotoxic agents. However, such antibody-based immunotherapy and antibody-drug conjugate-based immunotherapy may 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.

[0008] Thus, there is an unmet need in the art for the development of effective combination dosing methods for treating CD20 positive cell proliferative disorders, including B cell proliferative disorders, such as non-Hodgkin's lymphoma (NHL) (e.g., diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), high-grade B cell lymphoma (HGBL), mantle cell lymphoma (MCL), high-grade B cell lymphoma, primary mediastinal (thymic) large B cell lymphoma (PMLBCL), diffuse B cell lymphoma, small lymphocytic lymphoma, marginal zone lymphoma (MZL), Burkitt's lymphoma, or lymphoplasmacytic lymphoma) that achieve a more favorable benefit-risk profile. Summary of the Invention

[0009] Summary of the Invention The present invention relates to 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., diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), high-grade B-cell lymphoma (HGBL), mantle cell lymphoma (MCL), high-grade B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma (PMLBCL), diffuse B-cell lymphoma, small lymphocytic lymphoma, marginal zone lymphoma (MZL), Burkitt's lymphoma, or lymphoplasmacytic lymphoma), chronic lymphocytic leukemia (CLL), or central nervous system lymphoma (CNSL)) by administering mosunetuzumab and polatuzumab vedotin as a combination therapy. In particular, the present invention relates to methods of treating subjects with aggressive NHL (e.g., DLBCL, transformed FL, or grade 3b FL) with subcutaneous administration of mosunetuzumab and intravenous administration of polatuzumab vedotin as combination therapy.

[0010] In one aspect, the invention provides a method of treating a subject having a CD20-positive cell proliferative disorder, comprising administering mosunetuzumab subcutaneously to the subject and administering polatuzumab vedotin intravenously to the subject 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 (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, a third dose (C1D3) of mosunetuzumab, and a first dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of mosunetuzumab is about 5 mg (e.g., 5 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg; e.g., 5 mg) and C1D2 of mosunetuzumab is about 15 mg (e.g., 15 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg; e.g., 5 mg). or ±3 mg; e.g., 15 mg) or about 45 mg (e.g., 45 mg ±0.01 mg, ±0.025 mg, ±0.05 mg, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg; e.g., 45 mg), and the C1D3 of mosunetuzumab is about 45 mg (e.g., 45 mg ±0.01 mg, ±0.025 mg, ±0.05 mg, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ± (b) the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab and a single dose (C2D1) of polatuzumab vedotin, and the C2D1 of mosunetuzumab is about 45 mg (e.g., 45 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg; e.g., 45 mg), and the C1D1 of polatuzumab vedotin is about 1.8 mg / kg;and the C2D1 of polatuzumab vedotin is about 1.8 mg / kg (e.g., 1.8 mg / kg ±0.01 mg / kg, ±0.025 mg / kg, ±0.05 mg / kg, ±0.075 mg / kg, ±0.1 mg / kg, ±0.2 mg / kg, ±0.3 mg / kg, ±0.4 mg / kg, ±0.5 mg / kg, ±0.75 mg / kg, or ±1 mg / kg; e.g., 1.8 mg / kg).

[0011] In some embodiments, C1D2 is about 45 mg (e.g., 45 mg ±0.01 mg, ±0.025 mg, ±0.05 mg, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg; e.g., 45 mg).

[0012] In some embodiments, C1D2 is about 15 mg (e.g., 15 mg ±0.01 mg, ±0.025 mg, ±0.05 mg, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg; e.g., 15 mg).

[0013] In some embodiments, the first dosing cycle is a 21 day (± 1 day) dosing cycle. In some embodiments, C1D1, C1D2, and C1D3 of mosunetuzumab are administered on, or about, days 1, 8 (± 1 day), and 15 (± 1 day) of the first dosing cycle. In some embodiments, C1D1 of polatuzumab vedotin is administered on day 1 of the first dosing cycle.

[0014] In some embodiments, the second dosing cycle is a 21 day (± 1 day) dosing cycle. In some embodiments, C2D1 of mosunetuzumab is administered on day 1 of the second dosing cycle.

[0015] In some embodiments, polatuzumab vedotin C2D1 is administered on day 1 of the second dosing cycle. In some embodiments, the method further comprises one or more additional dosing cycles. In some embodiments, the method comprises 4 to 6 additional dosing cycles. In some embodiments, the method comprises 6 additional dosing cycles. In some embodiments, each additional dosing cycle is a 21 day (± 1 day) dosing cycle.

[0016] In some embodiments, one or more of the additional administration cycles comprises an additional single dose of mosunetuzumab and an additional single dose of polatuzumab vedotin. In some embodiments, the additional single dose of polatuzumab vedotin is about 1.8 mg / kg (e.g., 1.8 mg / kg ± 0.01 mg / kg, ± 0.025 mg / kg, ± 0.05 mg / kg, ± 0.075 mg / kg, ± 0.1 mg / kg, ± 0.2 mg / kg, ± 0.3 mg / kg, ± 0.4 mg / kg, ± 0.5 mg / kg, ± 0.75 mg / kg, or ± 1 mg / kg; e.g., 1.8 mg / kg). In some embodiments, each 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. In some embodiments, one or more of the additional dosing cycles comprises an additional single dose of mosunetuzumab and does not include administration of polatuzumab vedotin.

[0017] In some embodiments, the additional single dose of mosunetuzumab is about 45 mg (e.g., 45 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg; e.g., 45 mg). In some embodiments, each additional single dose of mosunetuzumab is administered to the subject on day 1 of each additional dosing cycle comprising the additional dose of mosunetuzumab.

[0018] In some embodiments, the dosing regimen includes six additional dosing cycles, each of the six additional dosing cycles comprising a single dose of mosunetuzumab, and no more than four of the six additional dosing cycles include administration of polatuzumab vedotin.

[0019] In one aspect, the invention provides a method of treating a subject having a CD20-positive cell proliferative disorder, comprising administering mosunetuzumab subcutaneously to the subject and administering polatuzumab vedotin intravenously to the subject, in a dosing regimen comprising eight dosing cycles, wherein: (a) a first dosing cycle comprises (i) a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, and a third dose (C1D3) of mosunetuzumab, wherein the C1D1 of mosunetuzumab is about 5 mg (e.g., For example, 5 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg; e.g., 5 mg) and C1D2 of mosunetuzumab is about 45 mg (e.g., 45 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg , ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg; e.g., 45 mg), and C1D3 of mosunetuzumab is about 45 mg (e.g., 45 mg ±0.01 mg, ±0.025 mg, ±0.05 mg, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg; e.g., 45 mg). , and C1D3 of mosunetuzumab, and (ii) a single dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of polatuzumab vedotin is about 1.8 mg / kg (e.g., 1.8 mg / kg ± 0.01 mg / kg, ± 0.025 mg / kg, ± 0.05 mg / kg, ± 0.075 mg / kg, ± 0.1 mg / kg, ± 0.2 mg / kg, ± 0.3 mg / kg, ± 0.4 mg / kg, ± 0.5 mg / kg, ± 0.75 mg / kg, or ± 1 mg / kg; e.g., 1.(b) the second through sixth administration cycles each comprise a single dose (C2D1-C6D1) of mosunetuzumab and a single dose (C2D1-C6D1) of polatuzumab vedotin, wherein each single dose C2D1-C6D1 of mosunetuzumab is about 45 mg (e.g., 45 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg). g, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg; e.g., 45 mg), and each single dose of polatuzumab vedotin C2D1-C6D1 is about 1.8 mg / kg (e.g., 1.8 mg / kg ±0.01 mg / kg, ±0.025 mg / kg, ±0.05 mg / kg, ±0.06 mg / kg, ±0.08 mg / kg, ±0.09 mg / kg, ±0.10 mg / kg, ±0.15 mg / kg, ±0.25 mg / kg, ±0.3 mg / kg, ±0.4 mg / kg, ±0.5 mg / kg, ±0.75 mg / kg, ±1 mg / kg, ±1.5 mg / kg, ±2 mg, or ±3 mg; e.g., 45 mg). (c) the seventh and eighth dosing cycles each comprise a single dose, C7D1 and C8D1 of mosunetuzumab, respectively, and polatuzumab The method does not include administration of vedotin, and each single dose of C7D1 and C8D1 is about 45 mg (e.g., 45 mg ±0.01 mg, ±0.025 mg, ±0.05 mg, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg; e.g., 45 mg).

[0020] In one aspect, the invention provides a method of treating a subject having a CD20-positive cell proliferative disorder, comprising administering mosunetuzumab subcutaneously to the subject and administering polatuzumab vedotin intravenously to the subject, in a dosing regimen comprising eight dosing cycles, wherein: (a) a first dosing cycle comprises (i) a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, and a third dose (C1D3) of mosunetuzumab, wherein the C1D1 of mosunetuzumab is about 5 mg (e.g., For example, 5 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg; e.g., 5 mg) and C1D2 of mosunetuzumab is about 15 mg (e.g., 15 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg , ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg; e.g., 15 mg), and C1D3 of mosunetuzumab is about 45 mg (e.g., 45 mg ±0.01 mg, ±0.025 mg, ±0.05 mg, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg; e.g., 45 mg). , and C1D3 of mosunetuzumab, and (ii) a single dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of polatuzumab vedotin is about 1.8 mg / kg (e.g., 1.8 mg / kg ± 0.01 mg / kg, ± 0.025 mg / kg, ± 0.05 mg / kg, ± 0.075 mg / kg, ± 0.1 mg / kg, ± 0.2 mg / kg, ± 0.3 mg / kg, ± 0.4 mg / kg, ± 0.5 mg / kg, ± 0.75 mg / kg, or ± 1 mg / kg; e.g., 1.(b) the second through sixth administration cycles each comprise a single dose (C2D1-C6D1) of mosunetuzumab and a single dose (C2D1-C6D1) of polatuzumab vedotin, wherein each single dose C2D1-C6D1 of mosunetuzumab is about 45 mg (e.g., 45 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg). g, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg; e.g., 45 mg), and each single dose of polatuzumab vedotin C2D1-C6D1 is about 1.8 mg / kg (e.g., 1.8 mg / kg ±0.01 mg / kg, ±0.025 mg / kg, ±0.05 mg / kg, ±0.06 mg / kg, ±0.08 mg / kg, ±0.09 mg / kg, ±0.10 mg / kg, ±0.15 mg / kg, ±0.25 mg / kg, ±0.3 mg / kg, ±0.4 mg / kg, ±0.5 mg / kg, ±0.75 mg / kg, ±1 mg / kg, ±1.5 mg / kg, ±2 mg, or ±3 mg; e.g., 45 mg). (c) the seventh and eighth dosing cycles each comprise a single dose, C7D1 and C8D1 of mosunetuzumab, respectively, and polatuzumab The method does not include administration of vedotin, and each single dose of C7D1 and C8D1 is about 45 mg (e.g., 45 mg ±0.01 mg, ±0.025 mg, ±0.05 mg, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg; e.g., 45 mg).

[0021] In some embodiments, each dosing cycle is a 21 day (± 1 day) dosing cycle. In some embodiments, C1D1, C1D2, and C1D3 of mosunetuzumab are administered on days 1, 8 (± 1 day), and 15 (± 1 day), or about days 1, about 8 (± 1 day), and about 15 (± 1 day), of the first dosing cycle, respectively. In some embodiments, each single dose of C2D1-C8D1 of mosunetuzumab is administered on day 1 of the respective dosing cycle.

[0022] In some embodiments, each single dose of polatuzumab vedotin C1D1-C6D1 is administered on day 1 of each administration cycle.

[0023] In some embodiments, C1D1 of polatuzumab vedotin is administered prior to administration of C1D1 of mosunetuzumab, and C2D1 of polatuzumab vedotin is administered prior to administration of C2D1 of mosunetuzumab. In some embodiments, each single dose C3D1-C6D1 of polatuzumab vedotin is administered prior to administration of each single dose C3D1-C6D1 of mosunetuzumab, respectively. In some embodiments, polatuzumab vedotin is administered at least about 60 minutes prior to administration of mosunetuzumab.

[0024] In some embodiments, the method further comprises administering to the subject one or more additional therapeutic agents.

[0025] In some embodiments, the one or more additional therapeutic agents are corticosteroids or IL-6R antagonists. In some embodiments, the one or more additional therapeutic agents are IL-6R antagonists. In some embodiments, the IL-6R antagonist is tocilizumab. In some embodiments, tocilizumab is administered to the subject as a single dose of about 8 mg / kg (e.g., 8 mg / kg ± 0.01 mg / kg, ± 0.025 mg / kg, ± 0.05 mg / kg, ± 0.075 mg / kg, ± 0.1 mg / kg, ± 0.2 mg / kg, ± 0.3 mg / kg, ± 0.4 mg / kg, ± 0.5 mg / kg, ± 0.75 mg / kg, ± 1 mg / kg, ± 1.5 mg / kg, or ± 2 mg / kg; e.g., 8 mg / kg), and the single dose does not exceed 800 mg. In some embodiments, tocilizumab is administered to the subject as a single dose of about 12 mg / kg (e.g., 12 mg / kg ±0.01 mg / kg, ±0.025 mg / kg, ±0.05 mg / kg, ±0.075 mg / kg, ±0.1 mg / kg, ±0.2 mg / kg, ±0.3 mg / kg, ±0.4 mg / kg, ±0.5 mg / kg, ±0.75 mg / kg, ±1 mg / kg, ±1.5 mg / kg, or ±2 mg / kg; e.g., 12 mg / kg), wherein the single dose does not exceed 800 mg. In some embodiments, tocilizumab is administered intravenously.

[0026] In some embodiments, the one or more additional therapeutic agents are corticosteroids. In some embodiments, the corticosteroid is dexamethasone, prednisone, or methylprednisolone.

[0027] In some embodiments, the corticosteroid is dexamethasone. In some aspects, dexamethasone is administered as a single dose of about 10 mg (e.g., 10 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg; e.g., 10 mg) every 6 hours. In some embodiments, dexamethasone is administered intravenously. In some embodiments, dexamethasone is administered as a single dose of about 20 mg (e.g., 20 mg ±0.01 mg, ±0.025 mg, ±0.05 mg, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg; e.g., 20 mg) prior to administration of any dose of mosunetuzumab. In some embodiments, dexamethasone is administered orally.

[0028] In some embodiments, the corticosteroid is methylprednisolone. In some embodiments, the methylprednisolone is administered at a dose of about 1000 mg / day (e.g., 1000 mg / day ±1 mg / day, ±2.5 mg / day, ±5 mg / day, ±7.5 mg / day, ±10 mg / day, ±20 mg / day, ±30 mg / day, ±40 mg / day, ±50 mg / day, ±75 mg / day, ±100 mg / day, ±150 mg / day, ±200 mg / day, or ±300 mg / day; e.g., 1000 mg / day). In some embodiments, the methylprednisolone is administered intravenously.

[0029] In some embodiments, the corticosteroid is prednisone. In some aspects, prednisone is administered at a dose of about 10-30 mg / day (e.g., about 10 mg / day, about 11 mg / day, about 12 mg / day, about 13 mg / day, about 14 mg / day, about 15 mg / day, about 16 mg / day, about 17 mg / day, about 18 mg / day, about 19 mg / day, about 20 mg / day, about 21 mg / day, about 22 mg / day, about 23 mg / day, about 24 mg / day, about 25 mg / day, about 26 mg / day, about 27 mg / day, about 28 mg / day) , about 29 mg / day, or about 30 mg / day; e.g., 10 mg / day, 11 mg / day, 12 mg / day, 13 mg / day, 14 mg / day, 15 mg / day, 16 mg / day, 17 mg / day, 18 mg / day, 19 mg / day, 20 mg / day, 21 mg / day, 22 mg / day, 23 mg / day, 24 mg / day, 25 mg / day, 26 mg / day, 27 mg / day, 28 mg / day, 29 mg / day, or 30 mg / day). In some embodiments, prednisone is administered orally.

[0030] In some embodiments, the one or more additional therapeutic agents are acetaminophen or paracetamol. In some embodiments, the acetaminophen or paracetamol is administered as a single dose of about 500 to 1000 mg (e.g., about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg; e.g., 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg) prior to administration of any dose of polatuzumab vedotin. In some embodiments, the acetaminophen or paracetamol is administered orally.

[0031] In some embodiments, the one or more additional therapeutic agents is diphenhydramine. In some embodiments, diphenhydramine is administered as a single dose of about 50-100 mg (e.g., about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg; e.g., 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg) prior to administration of any dose of polatuzumab vedotin. In some embodiments, diphenhydramine is administered orally.

[0032] 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).

[0033] In some embodiments, the NHL is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), high-grade B-cell lymphoma (HGBL), mantle cell lymphoma (MCL), high-grade B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma (PMLBCL), diffuse B-cell lymphoma, small lymphocytic lymphoma, marginal zone lymphoma (MZL), Burkitt's lymphoma, or lymphoplasmacytic lymphoma. In some embodiments, the NHL is relapsed and / or refractory (R / R) NHL.

[0034] In some embodiments, the NHL is DLBCL. In some embodiments, the DLBCL is R / R DLBCL. In some embodiments, the DLBCL is Richter's transformed.

[0035] In some embodiments, the NHL is FL (e.g., grade 1, 2, 3a, or 3b FL). In some embodiments, the FL is R / R FL. In some embodiments, the FL is transformed FL. In some embodiments, the FL is grade 3b FL.

[0036] In some embodiments, the NHL is HGBL. In some embodiments, the HGBL is R / R HGBL.

[0037] In some embodiments, the NHL is aggressive NHL. In some embodiments, the aggressive NHL is DLBCL, transformed FL, or grade 3b FL. In some embodiments, the NHL is R / R NHL.

[0038] In some embodiments, the subject is ineligible for autologous stem cell transplantation (ASCT).

[0039] In some embodiments, the subject has relapsed after two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) prior lines of therapy or is refractory to two or more prior lines of therapy.

[0040] In some embodiments, the subject is a human.

[0041] In one aspect, the invention provides a method of treating a population of subjects having a CD20-positive cell proliferative disorder, comprising subcutaneously administering mosunetuzumab to the subjects of the population and intravenously administering polatuzumab vedotin to the subjects of the population for at least a first administration cycle and a second administration cycle, wherein: (a) the first administration cycle comprises a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, a third dose (C1D3) of mosunetuzumab, and a first dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of mosunetuzumab is about 5 mg (5 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg; e.g., 5 mg) and C1D2 of mosunetuzumab is about 15 mg (e.g., 15 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg; e.g., 5 mg). g; e.g., 15 mg) or about 45 mg (e.g., 45 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg; e.g., 45 mg), and C1D3 of mosunetuzumab is about 45 mg (e.g., 45 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg , ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg; e.g., 45 mg), mosunetuzumab at C1D1, mosunetuzumab at C1D2, and mosunetuzumab at C1D3, and polatuzumab vedotin at C1D1 is about 1.8 mg / kg (e.g., 1.8 mg / kg ±0.01 mg / kg, ±0.025 mg / kg, ±0.05 mg / kg, ±0.075 mg / kg, ±0.1 mg / kg, ±0.2 mg / kg, ±0.3 mg / kg, ±0.4 mg / kg, ±0.5 mg / kg, ±0.75 mg / kg, or ±1 mg / kg; e.g., 1.(b) a 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 45 mg (e.g., 45 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ±3 mg; e.g., 45 mg) and the C2D1 of polatuzumab vedotin is about 1.8 mg / kg (e.g., 1.8 mg / kg ±0.01 mg / kg, ±0.025 mg / kg, ±0.05 mg / kg, ±0.075 mg / kg, ±0.1 mg / kg, ±0.2 mg / kg, ±0.3 mg / kg, ±0.4 mg / kg, ±0.5 mg / kg, ±0.75 mg / kg, or ±1 mg / kg; e.g., 1.8 mg / kg).

[0042] In one aspect, the invention provides a method of treating a population of subjects having a CD20-positive cell proliferative disorder, comprising administering mosunetuzumab subcutaneously to the subjects of the population and administering polatuzumab vedotin intravenously to the subjects of the population, in a dosing regimen comprising eight dosing cycles, wherein (a) a first dosing cycle comprises: (i) a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, and a third dose (C1D3) of mosunetuzumab, wherein C1D1 of mosunetuzumab is about 5 mg (e.g., 5 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg; e.g., 5 mg) and C1D2 of mosunetuzumab is about 45 mg (e.g., 45 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg; e.g., 5 mg). and C1D3 of mosunetuzumab is about 45 mg (e.g., 45 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg; e.g., 45 mg). mab, and mosunetuzumab at C1D3, and (ii) a single dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of polatuzumab vedotin is about 1.8 mg / kg (e.g., 1.8 mg / kg ± 0.01 mg / kg, ± 0.025 mg / kg, ± 0.05 mg / kg, ± 0.075 mg / kg, ± 0.1 mg / kg, ± 0.2 mg / kg, ± 0.3 mg / kg, ± 0.4 mg / kg, ± 0.5 mg / kg, ± 0.75 mg / kg, or ± 1 mg / kg; e.g., 1.(b) the second through sixth administration cycles each comprise a single dose (C2D1-C6D1) of mosunetuzumab and a single dose (C2D1-C6D1) of polatuzumab vedotin, wherein each single dose C2D1-C6D1 of mosunetuzumab is about 45 mg (e.g., 45 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg). g, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg; e.g., 45 mg), and each single dose of polatuzumab vedotin C2D1-C6D1 is about 1.8 mg / kg (e.g., 1.8 mg / kg ±0.01 mg / kg, ±0.025 mg / kg, ±0.05 mg / kg, ±0.06 mg / kg, ±0.08 mg / kg, ±0.09 mg / kg, ±0.10 mg / kg, ±0.15 mg / kg, ±0.25 mg / kg, ±0.3 mg / kg, ±0.4 mg / kg, ±0.5 mg / kg, ±0.75 mg / kg, ±1 mg / kg, ±1.5 mg / kg, ±2 mg, or ±3 mg; e.g., 45 mg). (c) the seventh and eighth dosing cycles each comprise a single dose, C7D1 and C8D1 of mosunetuzumab, respectively, and polatuzumab The method does not include administration of vedotin, and each single dose of C7D1 and C8D1 is about 45 mg (e.g., 45 mg ±0.01 mg, ±0.025 mg, ±0.05 mg, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg; e.g., 45 mg).

[0043] In some embodiments, the mean duration of progression-free survival for the subject population is longer than the reference mean duration of progression-free survival for a reference subject population.

[0044] In some embodiments, the complete response rate in the subject population is higher than the reference complete response rate in the reference subject population.

[0045] In some embodiments, the objective response rate in the subject population is higher than the reference objective response rate in the reference subject population.

[0046] In some embodiments, the mean duration of response of the subject population is longer than the reference mean duration of response of a reference subject population.

[0047] In some embodiments, the mean duration of complete response in a subject population is longer than the reference mean duration of complete response in a reference subject population.

[0048] In some embodiments, the reference population is administered a combination therapy comprising rituximab, gemcitabine and oxaliplatin. In some embodiments, the combination therapy is administered to the reference population in dosing cycles comprising 8 dosing cycles. In some embodiments, each dosing cycle is a 14 day (± 1 day) dosing cycle. The combination therapy is administered to the reference population about every 2 weeks (Q2W). In some aspects, the rituximab is administered at about 375 mg / m 2 (For example, 375 mg / m 2 ±1mg / m 2 , ±2.5mg / m 2 , ±5mg / m 2 , ±7.5mg / m 2 , ±10mg / m 2 , ±20mg / m 2 , ±30mg / m 2 , ±40mg / m 2 , or ±50 mg / m 2 For example, 375 mg / m 2 ) given intravenously every 2 weeks, with gemcitabine at a dose of approximately 1000 mg / m 2 (For example, 1000 mg / m 2 ±1mg / m 2 , ±2.5mg / m 2 , ±5mg / m 2 , ±7.5mg / m 2 , ±10mg / m 2 , ±20mg / m 2 , ±30mg / m 2 , ±40mg / m 2 , ±50mg / m 2 ;±100mg / m 2 ;±150mg / m 2 ;±200mg / m 2 ;±250mg / m 2 ;±300mg / m2 For example, 1000 mg / m 2 ) administered intravenously every 2 weeks, with oxaliplatin at a dose of approximately 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 , ±2.5mg / m 2 , ±5mg / m 2 , ±7.5mg / m 2 , ±10mg / m 2 , ±20mg / m 2 , or ±30 mg / m 2 For example, 100 mg / m 2 ) given intravenously every two weeks.

[0049] In some embodiments, the CD20-positive cell proliferative disorder is a B-cell proliferative disorder. In some aspects, the B-cell proliferative disorder is non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), or central nervous system lymphoma (CNSL).

[0050] In some embodiments, the NHL is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), high-grade B-cell lymphoma (HGBL), mantle cell lymphoma (MCL), high-grade B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma (PMLBCL), diffuse B-cell lymphoma, small lymphocytic lymphoma, marginal zone lymphoma (MZL), Burkitt's lymphoma, or lymphoplasmacytic lymphoma. In some embodiments, the NHL is relapsed and / or refractory (R / R) NHL.

[0051] In some embodiments, the NHL is DLBCL. In some embodiments, the DLBCL is R / R DLBCL. In some embodiments, the DLBCL is Richter's transformed.

[0052] In some embodiments, the NHL is FL (e.g., grade 1, 2, 3a, or 3b FL). In some embodiments, the FL is R / R FL. In some embodiments, the FL is transformed FL. In some embodiments, the FL is grade 3b FL.

[0053] In some embodiments, the NHL is HGBL. In some embodiments, the HGBL is R / R HGBL.

[0054] In some embodiments, the NHL is aggressive NHL. In some embodiments, the aggressive NHL is DLBCL, transformed FL, or grade 3b FL. In some embodiments, the NHL is R / R NHL.

[0055] In some embodiments, each subject in the subject population is ineligible for autologous stem cell transplantation (ASCT).In some embodiments, each subject in the subject population has relapsed after two or more prior lines of therapy or is refractory to two or more prior lines of therapy.In some embodiments, each subject in the subject population is human.

[0056] In some embodiments, each subject in the reference subject population is ineligible for autologous stem cell transplantation (ASCT).In some embodiments, each subject in the reference subject population has relapsed after two or more prior lines of therapy or is refractory to two or more prior lines of therapy.In some embodiments, each subject in the reference subject population is human. [Brief description of the drawings]

[0057] [Figure 1]Figure 1 is a schematic diagram of the study design described in Example 1. 2L = second line; DLBCL = diffuse large B-cell lymphoma; CRR = complete response rate; FL = follicular lymphoma; M = mosunetuzumab; NOS = not otherwise specified; OS = overall survival; ORR = objective response rate; P = polatuzumab vedotin; PFS = progression-free survival; Q2W = every 2 weeks (i.e., 14-day dosing cycle); Q3W = every 3 weeks (i.e., 21-day dosing cycle); RGemOx = rituximab, gemcitabine and oxaliplatin; R / R = relapsed and / or refractory. [Figure 2A] FIG. 2A is a schematic diagram of the dosing regimen for Group A (mosunetuzumab + polatuzumab vedotin arm) described in Example 1. Treatment includes 8 total dosing cycles (cycles 1-8). Mosunetuzumab is administered subcutaneously at the following doses and timings: 5 mg on day 1 of cycle 1, 45 mg on day 8 of cycle 1, day 15 of cycle 1, and day 1 of cycles 2-8. Polatuzumab vedotin is administered intravenously at the following doses and timings: 1.8 mg / kg on day 1 of cycles 1-6. Each cycle is 21 days long. [Figure 2B] FIG. 2B is a schematic diagram of the dosing regimen for Group B (R-GemOx group) described in Example 1. Treatment includes 8 total dosing cycles (Cycles 1-8). 375 mg / m2 of rituximab is administered IV on day 1 of cycles 1-8. 1000 mg / m2 of gemcitabine is administered IV on day 1 of cycles 1-8. 100 mg / m2 of oxaliplatin is administered IV on day 1 of cycles 1-8. Each cycle is 14 days long. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0058] Detailed Description The present invention relates to methods of treating a subject or population of subjects having a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder; e.g., non-Hodgkin's lymphoma (NHL) (e.g., diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), high-grade B-cell lymphoma (HGBL), mantle cell lymphoma (MCL), high-grade B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma (PMLBCL), diffuse B-cell lymphoma, small lymphocytic lymphoma, marginal zone lymphoma (MZL), Burkitt's lymphoma, or lymphoplasmacytic lymphoma), chronic lymphocytic leukemia (CLL), or central nervous system lymphoma (CNSL)) by administering mosunetuzumab and polatuzumab vedotin as a combination therapy. In particular, the present invention relates to methods of treating a subject or population of subjects with aggressive NHL (e.g., DLBCL, transformed FL or grade 3b FL) with subcutaneous administration of mosunetuzumab and intravenous administration of polatuzumab vedotin as combination therapy.

[0059] The invention relates, in part, to a combination therapy comprising subcutaneous administration of mosunetuzumab and intravenous administration of polatuzumab vedotin over multiple dosing cycles (e.g., a first dosing cycle is a boosted fraction dosing cycle), which provides a method for treating patients with CD20-positive cell proliferative disorders (e.g., B-cell proliferative disorders; e.g., non-Hodgkin's lymphoma (NHL) (e.g., diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), high-grade B-cell lymphoma (HGBL), myeloma, myeloma, leukemia, and ovarian cancer) while maintaining an acceptable safety profile (e.g., with respect to frequency and severity of adverse events, such as cytokine release syndrome (CRS)) by administering mosunetuzumab and polatuzumab vedotin as a combination therapy. The present invention is based on the discovery that the present invention can effectively treat subjects or subject populations with MCL, high-grade B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma (PMLBCL), diffuse B-cell lymphoma, small lymphocytic lymphoma, marginal zone lymphoma (MZL), Burkitt's lymphoma, or lymphoplasmacytic lymphoma), chronic lymphocytic leukemia (CLL), or central nervous system lymphoma (CNSL), particularly subjects or subject populations with aggressive NHL (e.g., DLBCL, transformed FL, or grade 3b FL), and / or subjects or subject populations who are relapsed and / or refractory (R / R) to at least one prior therapy. In some examples, the subject or subject population may have received two or more lines of prior therapy. In some examples, the subject or subject population may be ineligible for autologous stem cell transplantation (ASCT).

[0060] I. General techniques The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodology by those of skill in the art, and are described, for example, in Sambrook et al., Molecular Cloning: A Laboratory Manual 3rd ed. (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Current Protocols in Molecular Biology (FMAusubel et al., eds., (2003)); the series Methods in Enzymology (Academic Press, Inc.): PCR2: A Practical Approach (MJ MacPherson, BD Hames, and GR Taylor, eds. (1995)), Antibodies, A Laboratory Manual, Harlow and Lane, eds. (1988), and Animal Cell Culture (RI Freshney, ed. (1987)); Oligonucleotide Synthesis (MJ Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Manual, vol. Notebook (ed. J. E. Elis, 1998) Academic Press; Animal Cell Culture (ed. R. I. Freshney, 1987); Introduction to Cell and Tissue Culture (J. P. Mather and P. E. Oberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (eds. A. Doyle, J. B. Griffiths, and D. G. Newell, 1993-8) J. Wiley and Sons; Handbook of Experimental Immunology (eds. D. M. Weir and C. C. Blackwell); Gene Transfer Vectors for Mammalian Cells (J. M. Miller and M. P.Calos, ed., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., ed., 1994); Current Protocols in Immunology (JE Coligan et al., ed., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (C.A. Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: A Practical Approach (D. Catty, ed., IRL Press, 1988-1989); Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and JD Capra, eds., Harwood Academic Press, Publishers, 1995); and Cancer: Principles and Practice of Oncology (V.T. DeVita et al., eds., J.B. Lippincott Company, 1993). Examples of widely used methodologies include those described in

[0061] II. Definition It is understood that aspects and embodiments of the invention described herein include "comprising," "consisting," and "consisting essentially of" aspects and embodiments.

[0062] As used herein, the singular forms "a," "an," and "the" include plural referents unless otherwise indicated.

[0063] As used herein, the term "about" refers to the normal range of error for the respective value, which is 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.

[0064] The terms "cancer" and "cancerous" refer to or describe a physiological condition in a mammal that is typically characterized by uncontrolled cell growth. Examples of cancer include, but are not limited to, hematological cancers, such as Hodgkin's lymphoma, but not limited to non-Hodgkin's lymphoma (NHL), such as diffuse large B-cell lymphoma (DLBCL), which may be relapsed and / or refractory DLBCL or Richter's transformation. Other specific examples of cancer include germinal center B-cell-like (GCB) diffuse large B-cell lymphoma (DLBCL), activated B-cell-like (ABC) DLBCL, follicular lymphoma (FL), transformed FL, mantle cell lymphoma (MCL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), marginal zone lymphoma (MZL), transformed MZL, high-grade B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma (PMLBCL), Small lymphocytic leukemia (SLL), lymphoplasmacytic lymphoma (LL), transformed LL, Waldenstrom's macroglobulinemia (WM), central nervous system lymphoma (CNSL), Burkitt's lymphoma (BL), B-cell prolymphocytic leukemia, splenic marginal zone lymphoma, hairy cell leukemia, splenic lymphoma / leukemia, unclassified, splenic diffuse red pulp small B-cell lymphoma, hairy cell leukemia variant, heavy chain leukemia, alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease Heavy chain disease, plasma cell myeloma, isolated plasmacytoma of bone, 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 DLBCL of the CNS, primary cutaneous DLBCL, leg type, EBV-positive DLBCL of the elderly, DLBCL associated with chronic inflammation, lymphoma These include: myelomatous granulomatosis, intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, plasmablastic lymphoma, large B-cell lymphoma due to HV8-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.In addition, 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 cancer 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; large mass lesion NHL; AIDS-related lymphoma; and acute lymphocytic leukemia (ALL); chronic myeloblastic leukemia; and post-transplant lymphoproliferative disorder (PTLD).

[0065] "Tumor," as used herein, refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. The terms "cancer," "cancerous," "cell proliferative disorder," "proliferative disorder," and "tumor" are not mutually exclusive as referred to herein.

[0066] 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.

[0067] 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.

[0068] The term "B cell proliferative disease" or "B cell malignancy" refers to diseases that are associated with some degree of abnormal B cell proliferation, including, for example, lymphoma, leukemia, myeloma, and myelodysplastic syndrome. In some examples, the B cell proliferative disorder is a lymphoma, such as non-Hodgkin's lymphoma (NHL), including, for example, follicular lymphoma (FL) (e.g., relapsed and / or refractory FL or transformed FL (trFL)), diffuse large B cell lymphoma (DLBCL) (e.g., relapsed and / or refractory DLBCL or Richter's transformation), mantle cell lymphoma (MCL), high-grade B cell lymphoma (HGBL), primary mediastinal (thymic) large B cell lymphoma (PMLBCL), diffuse B cell lymphoma, small lymphocytic lymphoma, marginal zone lymphoma (MZL), Burkitt's lymphoma, or lymphoplasmacytic lymphoma. In other embodiments, the B cell proliferative disorder is leukemia, such as chronic lymphocytic leukemia (CLL). In one embodiment, the B cell proliferative disorder is relapsed and / or refractory. In some embodiments, the NHL can be aggressive NHL (aNHL). "Aggressive" NHL grows and spreads quickly, usually with severe symptoms, in contrast to "indolent" NHL, which grows and spreads slowly and tends to show few symptoms. Examples of NHL include, for example, HGBL, DLBCL, trFL, and grade 3b FL (see Swerdlow SH, et al. Blood 2016;127:2375-90).

[0069] "Refractory disease" is defined as lack of complete remission to at least first-line therapy. In one embodiment, refractory disease is defined as lack of response to prior therapy or relapse within 6 months of prior therapy. In one embodiment, refractory disease is characterized by one or more of stable disease (SD) as best response after at least one prior therapy, or partial response (PR) as best response, and residual disease or disease progression by biopsy evidence after partial response. "Relapsed disease" is defined as complete remission to first-line therapy. In one embodiment, disease recurrence is biopsy-proven. In one embodiment, the subject has relapsed after or failed to respond to at least one prior systemic treatment regimen.

[0070] As used herein, "treatment" (and grammatical variations thereof, such as "treat" or "treating") refers to clinical intervention in an attempt to alter the natural course of the subject being treated, and may be performed for prophylaxis or during the course of clinical pathology. The desired effects of treatment include, but are not limited to, preventing the onset or recurrence of disease, alleviating symptoms, attenuating any direct or indirect pathological consequences of the disease, preventing metastasis, slowing the rate of disease progression, remission or palliation of the disease, and improving recovery or prognosis. In some embodiments, the antibodies and antibody drug conjugates of the invention are used to delay the onset of disease or to slow the progression of the disease.

[0071] As used herein, "delaying the progression" of a disorder or disease means postponing, preventing, delaying, stabilizing, and / or postponing the onset of a disease or disorder (e.g., CD20-positive cell proliferative disorder). This delay can be of various durations depending on the history of the disease and / or the individual being treated. As will be apparent to those skilled 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 onset of metastasis, can be delayed.

[0072] "Reduce" or "inhibit" refers to the ability to cause an overall reduction, for example, of 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95% or more. For clarity, the term also includes reduction to zero (or below the detection limit of the analytical method), i.e., complete disappearance or elimination. In certain embodiments, reduction or inhibition may refer to a reduction or inhibition of undesirable events, such as cytokine-driven toxicity (e.g., cytokine release syndrome (CRS)), infusion-related reactions (IRR), macrophage activation syndrome (MAS), neurotoxicity, severe tumor lysis syndrome (TLS), neutropenia, thrombocytopenia, elevated liver enzymes, and / or central nervous system (CNS) toxicity, following treatment with mostuzumab using the step-up dosing regimen of the present invention, compared to a preset administration of the unaltered target dose of mostutuzumab. In other embodiments, reducing or inhibiting can refer to antibody effector functions mediated by the antibody Fc region, including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP). In other embodiments, reducing or inhibiting can refer to symptoms of the CD20-positive cell proliferative disorder (e.g., B-cell proliferative disorder) being treated, the presence or size of metastases, or the size of the primary tumor. In yet other embodiments, reducing or inhibiting cancer recurrence means reducing or inhibiting tumor or cancer recurrence, or tumor or cancer progression.

[0073] As used herein, "administering" refers to a method of providing a dosage of a compound (e.g., a bispecific antibody (e.g., mosunetuzumab) and / or an antibody drug conjugate (e.g., polatuzumab vedotin)) or composition (e.g., a pharmaceutical composition, e.g., a pharmaceutical composition including a bispecific antibody (e.g., mosunetuzumab) and / or an antibody drug conjugate (e.g., polatuzumab vedotin)) to a subject. The compounds and / or compositions utilized in the methods described herein may be administered subcutaneously (e.g., by subcutaneous injection) or intravenously (e.g., by intravenous infusion).

[0074] A "fixed" or "constant" dose of a therapeutic agent (e.g., a bispecific antibody (e.g., mosunetuzumab) or an antibody drug conjugate (e.g., polatuzumab vedotin)) herein refers to a dose administered to a patient regardless of the patient's weight or body surface area (BSA). The fixed or constant dose may therefore be expressed as a mg / kg dose or a mg / m 2 It is not provided as a dose, but rather as an absolute amount (eg, mg) of therapeutic agent.

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

[0076] As used herein, a "reference population," e.g., a "reference subject population," refers to a population (e.g., a subject population) used for comparison purposes. In some embodiments, a reference subject population refers to a population (e.g., a subject population) that is a patient suffering from a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder; e.g., a non-Hodgkin's lymphoma (NHL) (e.g., diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), high-grade B-cell lymphoma (HGBL), mantle cell lymphoma (MCL), high-grade B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma (PMLBCL), diffuse B-cell lymphoma, small lymphocytic lymphoma, marginal lymphoma, peripheral leukemia, and / or myeloma). The reference subject population includes subjects with myeloma, myeloma zone lymphoma (MZL), Burkitt's lymphoma, or lymphoplasmacytic lymphoma), chronic lymphocytic leukemia (CLL), or central nervous system lymphoma (CNSL), for example, subjects with aggressive NHL (e.g., DLBCL, transformed FL, or grade 3b FL), or subjects who have relapsed after at least one prior line of therapy or are refractory (R / R) to two or more prior lines of therapy. In some embodiments, the reference subject population is ineligible for autologous stem cell transplant (ASCT) therapy or is R / R to at least two prior therapies. In some embodiments, the reference subject population is treated with R-GemOx. In some embodiments, the reference subject population has been treated with R-GemOx. In some embodiments, the reference subject population does not include subjects who are treated with or have been treated with mosunetuzumab and / or polatuzumab vedotin. In some embodiments, the reference subject population is not treated with mosunetuzumab and / or polatuzumab vedotin and is not receiving treatment.Furthermore, those skilled in the art will understand "reference population" in the context of the purpose of the comparison to be made.For example, in some embodiments, the reference population is an untreated population with CD20-positive cell proliferative disorder, and in other embodiments, the reference population is a population with CD20-positive cell proliferative disorder that has been previously treated with at least two preceding therapies.

[0077] An "individual response" or "response" can be assessed using any endpoint that indicates a subject's benefit, including, but not limited to, (1) some inhibition (including principle and complete halt) of disease progression (e.g., progression of a CD20 positive cell proliferative disorder (e.g., a B cell proliferative disorder)); (2) reduction in tumor size; (3) inhibition (i.e., reduction, slowing or complete halt) of cancer cell invasion into adjacent peripheral organs and / or tissues; (4) inhibition (i.e., reduction, slowing or complete halt) of metastasis; (5) some alleviation of one or more symptoms associated with a CD20 positive cell proliferative disorder (e.g., a B cell proliferative disorder); (6) prolongation or increase in survival, including overall survival and progression-free survival; and / or (9) reduction in mortality at some time point following treatment.

[0078] As used herein, "complete response" or "CR" refers to the disappearance of all target lesions (ie, all evidence of disease).

[0079] 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 sum of the product of diameters (SPD) of target lesions referenced to a baseline SPD.

[0080] As used herein, "objective response" (ORR) means the sum of the complete response (CR) rate and the partial response (PR) rate.

[0081] 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.

[0082] As used herein, "tumor burden" refers to the total amount of tumor (e.g., tumor cells or tumor mass) in a subject (e.g., a human subject) with cancer, such as a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder). In some embodiments, tumor burden is defined as the sum of the diameters of target lesions or the sum of the products of target lesions. In certain embodiments, tumor burden is defined as the sum of the products of the diameters of (SPD) target lesions. In some embodiments, the diameters of target lesions are quantified by computed tomography (CT).

[0083] "Sustained response" refers to the sustained effect of reducing tumor growth after the cessation of treatment.For example, tumor size can remain the same or become smaller compared to the size at the beginning of the administration period.In some embodiments, the sustained response has a duration of at least the same as the treatment period, or at least 1.5 times, 2.0 times, 2.5 times or 3.0 times the treatment period.

[0084] A subject's "effective response" or subject's "responsiveness" to treatment with a pharmaceutical agent and similar words refer 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 complete or partial response), or ameliorating signs or symptoms of cancer.

[0085] A subject who "does not respond effectively" to a treatment refers to a subject who does not have any of the following: an extension of survival (including overall survival and progression-free survival), an objective response (including a complete or partial response), or an improvement in the signs or symptoms of cancer.

[0086] As used herein, "survival" refers to a subject remaining alive, and includes overall survival as well as progression-free survival.

[0087] As used herein, "overall survival" (OS) refers to the proportion of subjects in a group who are surviving a particular period of time, such as one year or five years from the time of diagnosis or treatment.

[0088] As used herein, "progression-free survival" (PFS) refers to the length of time during and after treatment during which the disease being treated (e.g., a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder)) 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.

[0089] 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.

[0090] As used herein, "progressive disease" or "PD" refers to an increase in the SLD of a target lesion by at least 20% relative to the smallest SLD, or an increase in the SPD of a target lesion by at least 50% relative to the smallest SPD recorded after the start of treatment or the presence of one or more new lesions.

[0091] As used herein, "delaying progression" of a disorder or disease means postponing, preventing, delaying, stabilizing, and / or postponing the onset of a disease or disorder (e.g., a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder)). This delay may be of varying duration depending on the history of the disease and / or the subject being treated. As will be apparent to one of skill in the art, a sufficient or significant delay may in effect encompass prevention, in that the subject does not develop the disease. For example, in late-stage cancer, the development of central nervous system (CNS) metastases may be delayed.

[0092] "Extending survival" refers to extending the overall survival or progression-free survival of a treated subject compared to an untreated subject (e.g., a subject not treated with a pharmaceutical agent), or compared to a subject that does not express a specified level of a biomarker, and / or compared to a subject treated with an approved anti-tumor agent. Objective response refers to a measurable response, including complete response (CR) or partial response (PR).

[0093] 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.

[0094] "Antibody fragment" refers to a molecule other than an intact antibody that binds to an antigen bound by the intact antibody and is composed of a portion of the intact antibody. 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.

[0095] The terms "full length antibody," "intact antibody," and "whole antibody" are used interchangeably herein to refer to an antibody having a heavy chain having a structure substantially similar to a native antibody structure or containing an Fc region as defined herein.

[0096] "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 VH and / or VL domains of antibodies), receptors, ligands, aptamers, and other molecules with identified binding partners.

[0097] The term "Fc region" is used herein to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. This term includes native sequence Fc regions and variant Fc regions. In one embodiment, 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 specified herein, the numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system (also referred to as the EU index), as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0098] The "class" of an antibody refers to the type of constant domain or constant region carried by its heavy chain. There are five major classes of antibodies, namely IgA, IgD, IgE, IgG, and IgM, some of which can be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0099] 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.

[0100] "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 typically appear in the following order in a VH (or VL): FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0101] 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 as in Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed., NIH Publication 91-3242, Bethesda MD (1991), vols. 1-3. In one embodiment, for VL, the subgroup is subgroup kappa I in Kabat et al. (see above). In one embodiment, for VH, the subgroup is subgroup III in Kabat et al. (see above).

[0102] 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.

[0103] A "humanized" antibody refers to a chimeric antibody that comprises amino acid residues from non-human HVRs and amino acid residues from human FRs. In certain embodiments, a humanized antibody comprises substantially all of at least one, and typically two, variable domains, in which all or substantially all of the HVRs (e.g., CDRs) correspond to a non-human antibody and all or substantially all of the FRs correspond to 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 been subjected to humanization.

[0104] A "human antibody" is an antibody having an amino acid sequence that corresponds to the amino acid sequence of an antibody produced by a human or human cell, or of an antibody derived from a non-human source utilizing a human antibody repertoire, or to a sequence encoding another human antibody. This definition of a human antibody specifically excludes humanized antibodies that contain non-human antigen-binding residues. Human antibodies can be produced using a variety of techniques known in the art, such as phage display libraries. The methods described in Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991). The methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p.77 (1985); Boerner et al., J. Immunol., 147(1):86-95 (1991) can also be 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, that have been engineered to produce such antibodies in response to antigen challenge, but whose endogenous loci have been disabled (see, e.g., U.S. Patent Nos. 6,075,181 and 6,150,584, regarding XENOMOUSE™ technology). See also, e.g., Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006), regarding human antibodies generated by human B-cell hybridoma technology.

[0105] The term "variable region" or "variable domain" refers to the domain of an antibody heavy or light chain that is involved in binding the antibody (i.e., mosunetuzumab) to an antigen. The heavy and light chain variable domains (VH and VL, respectively) of natural antibodies generally have a similar structure, with each domain containing four conserved framework regions (FR) and three hypervariable regions (HVR). See, for example, Kindt et al., Kuby Immunology, 6 th , WH Freeman and Co., page 91 (2007). A single VH or VL domain may be sufficient to confer antigen-binding specificity. Moreover, antibodies that bind to a specific antigen may be isolated by using the VH or VL domain of an 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).

[0106] 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 that structurally form defined loops ("hypervariable loops") and / or contain residues that contact the antigen ("antigen contacts"). Generally, antibodies contain six HVRs, three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3). Exemplary HVRs of the invention include the following: (a) hypervariable loops occurring at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)); (b) CDRs 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) (MacCallum et al. J. Mol. Biol. 262:732-745 (1996)); and (d) combinations 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).

[0107] Unless otherwise indicated, HVR residues and other residues in the variable domain (eg, FR residues) are numbered herein according to Kabat et al., supra.

[0108] An "immunoconjugate" is an antibody conjugated to one or more heterologous molecules, including, but not limited to, a cytotoxic agent.

[0109] The term "isolated antibody", as used to describe the various antibodies disclosed herein, refers to an antibody that has been identified, separated and / or recovered from the cell or cell culture in which it was expressed. Contaminant components of its natural environment are materials that would typically interfere with diagnostic or therapeutic uses of the polypeptide and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In some embodiments, the antibody is purified to greater than 95% or greater than 99% purity, as determined, for example, by electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse-phase HPLC). For a review of methods for assessing antibody purity, see, for example, Flatman et al., J. Chromatogr. B 848:79-87 (2007). In a preferred embodiment, the antibody (i.e., mosunetuzumab) is purified (1) to a sufficient extent to obtain at least 15 residues of N-terminal or internal amino acid sequence by using a spinning cup sequencer, or (2) to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or, preferably, silver staining. An isolated antibody includes an antibody in situ in a recombinant cell, since at least one component of the polypeptide's natural environment is not present. However, an isolated polypeptide is usually prepared by at least one purification step.

[0110] The term "monoclonal antibody" as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies constituting the population are identical and / or bind to the same epitope, except for possible variant antibodies, e.g., variants that are usually present in minor amounts, including naturally occurring mutations or that arise during the production of a monoclonal antibody preparation. 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 (i.e., mosunetuzumab) as being obtained from a substantially homogeneous antibody population, and should not be construed as requiring production of the antibody by a particular method. For example, the monoclonal antibodies used in accordance with the present invention (i.e., mosunetuzumab) may be made 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 a portion of the human immunoglobulin loci; such methods and other exemplary methods for making monoclonal antibodies are described herein.

[0111] "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 and exemplary embodiments for measuring binding affinity are described below.

[0112] An "affinity matured" antibody refers to an antibody that has one or more modifications in one or more hypervariable regions (HVRs) compared to a parent antibody that does not possess such modifications, which improve the affinity of the antibody for antigen.

[0113] The terms "anti-CD3 antibody" and "antibody that binds CD3" refer to an antibody that can bind CD3 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent targeting CD3. In one embodiment, the extent of binding of an anti-CD3 antibody to unrelated non-CD3 proteins 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 CD3 has an affinity of 1 μM or less, 100 nM or less, 10 nM or less, 1 nM or less, 0.1 nM or less, 0.01 nM or less, or 0.001 nM or less (e.g., 10 -8 M or less, e.g. 10 -8 M~10 -13 M, for example 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.

[0114] 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, 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).

[0115] The terms "anti-CD20 antibody" and "antibody that binds to CD20" refer to an antibody that can bind to CD20 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting CD20. In one embodiment, the extent of 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 or less, 100 nM or less, 10 nM or less, 1 nM or less, 0.1 nM or less, 0.01 nM or less, or 0.001 nM or less (e.g., 10 -8 M or less, e.g. 10 -8 M~10 -13 M, 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 various species. In some embodiments, the anti-CD20 antibody is a monoclonal antibody. In some embodiments, the anti-CD20 antibody or anti-CD20 monoclonal antibody is rituximab. In some embodiments, the anti-CD20 antibody or anti-CD20 monoclonal antibody is obinutuzumab.

[0116] As used herein, the term "rituximab" or "RITUXAN®" refers to an anti-CD20 antibody (e.g., an anti-CD20 monoclonal antibody) having Proposed International Nonproprietary Names for Pharmaceutical Substances (Proposed INN) List 77 (WHO Drug Information, Vol. 11, No. 2, 1997, p. 99) or CAS Registry Number 174722-31-7.

[0117] As used herein, the term "obinutuzumab" or "GAZYVA®" refers to an anti-CD20 antibody (e.g., an anti-CD20 monoclonal antibody) having the Proposed International Nonproprietary Name for Pharmaceutical Substances (Proposed INN) List 99 (WHO Drug Information, Vol. 22, No. 2, 2008, p. 396), Proposed International Nonproprietary Name for Pharmaceutical Substances (Proposed INN) List 108 (WHO Drug Information, Vol. 26, No. 4, 2012, p. 453), or CAS Registry Number 949142-50-1.

[0118] The term "cluster of differentiation 20" or "CD20" as used herein refers to any native CD20 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. The term encompasses "full-length" unprocessed CD20, as well as any form of CD20 that results from processing within a cell. 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 sequence numbers NP_068769.2 and NP_690605.1), which is, for example, 297 amino acids in length and can be produced from a mutant mRNA transcript lacking, for example, a portion of the 5' UTR (see, e.g., NCBI reference sequence number NM_021950.3), or a longer mutant mRNA transcript (see, e.g., NCBI reference sequence number NM_152866.2).

[0119] 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 mosunetuzumab.

[0120] As used herein, the term "mosunetuzumab" refers to an anti-CD20 / anti-CD3 bispecific antibody having the International Nonproprietary Names for Pharmaceutical Substances (INN) list 117 (WHO Drug Information, Vol. 31, No. 2, 2017, p. 303) or CAS Registry Number 1905409-39-3.

[0121] The terms "anti-CD79b antibody" and "antibody that binds CD79b" refer to an antibody that can bind CD79b with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic in targeting CD79b. In one embodiment, the extent of 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, e.g., as measured by radioimmunoassay (RIA). In certain embodiments, an antibody that binds CD79b has an affinity of 1 μM or less, 100 nM or less, 10 nM or less, 1 nM or less, 0.1 nM or less, 0.01 nM or less, or 0.001 nM or less (e.g., 10 -8 M or less, e.g. 10 -8 M~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 various species. As used herein, the anti-CD79b antibody is polatuzumab.

[0122] As used herein, the term "polatuzumab vedotin" refers to an antibody drug conjugate comprising an anti-CD79b antibody conjugated to monomethyl auristatin E (MMAE, i.e., vedotin). Polatuzumab vedotin is also referred to as IUPHAR / BPS number 8404, KEGG number D10761, or CAS Registry Number 1313206-42-6. Polatuzumab vedotin-piiq is also referred to interchangeably as "polatuzumab vedotin-piiq", "huMA79bv28-MC-vc-PAB-MMAE", or "DCDS4501A".

[0123] 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 a 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 an antibody that binds to this target with higher affinity, avidity, more readily, and / or with 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 or less, 100 nM or less, 10 nM or less, 1 nM or less, or 0.1 nM or less. 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 does not require, exclusive binding. As used herein, the term refers to, for example, binding to a target that is more than 10 -4 M or less, or 10 -5 M or less, or 10 -6 M or less, or 10 -7 M or less, or 10 -8 M or less, or 10 -9 M or less, or 10 -10 M or less, or 10 -11 M or less, or 10 -12 K below 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 of skill 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.

[0124] "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 the amino acid residues in the reference polypeptide, after aligning the sequences and introducing gaps, if necessary, to obtain the maximum percent sequence identity, without considering any conservative substitutions as part of the sequence identity. Alignment to determine percent amino acid sequence identity can be accomplished in a variety of ways that are within the skill of those skilled in 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 required 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 may be compiled from its source code. The ALIGN-2 program must 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.

[0125] In situations where ALIGN-2 is used for amino acid sequence comparisons, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (alternatively, it may be written as a given amino acid sequence A having or containing a certain % amino acid sequence identity to, or against, 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 its 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 be equal to the % amino acid sequence identity of B to A. Unless specifically indicated otherwise, all % amino acid sequence identity values ​​used herein are obtained using the ALIGN-2 computer program as described in the immediately preceding paragraph.

[0126] The term "pharmaceutical formulation" refers to a preparation in which the biological activity of the active ingredients 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.

[0127] "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.

[0128] As used herein, the term "chemotherapeutic agent" refers to a compound useful for the treatment of a CD20-positive cell proliferative disorder (e.g., a B cell proliferative disorder) B cell proliferative disorder; e.g., non-Hodgkin's lymphoma (NHL) (e.g., diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), high-grade B cell lymphoma (HGBL), mantle cell lymphoma (MCL), high-grade B cell lymphoma, primary mediastinal (thymic) large B cell lymphoma (PMLBCL), diffuse B cell lymphoma, small lymphocytic lymphoma, marginal zone lymphoma (MZL), Burkitt's lymphoma, or lymphoplasmacytic lymphoma), chronic lymphocytic leukemia (CLL), or central nervous system lymphoma (CNSL)). Examples of chemotherapeutic agents include EGFR inhibitors (small molecule inhibitors (e.g., erlotinib (TARCEVA®, Genentech / OSI Pharm.); PD183805 (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]-phenol;(R)-6-(4-hydroxyphenyl)-4[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine;CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butyramide);EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide) (Wyeth);AG1478 (Pfizer); AG1571 (SU5271; Pfizer); and lapatinib (a dual EGFR / HER2 tyrosine kinase inhibitor such as TYKERB®, GSK572016 or N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6[5[[2-methylsulfonyl])ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine)); tyrosine kinase inhibitors (e.g., EGFR inhibitors; small molecule HER2 kinase inhibitors such as TAK165 (Takeda) HER2 kinase inhibitors; CP-724,714 (Pfizer and OSI), an oral selective inhibitor of the ErbB2 receptor tyrosine kinase; 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 Pharmaceuticals), which inhibits Raf-1 signaling; non-HER-targeted tyrosine kinase inhibitors such as imatinib mesylate (GLEEVEC®, Glaxo SmithKline); multi-targeted tyrosine kinase inhibitors such as sunitinib (SUTENT®, Pfizer); vatalanib (PTK787 / ZK222584, Novartis / Schering) VEGF receptor tyrosine kinase inhibitors such as PD-AG; MAPK extracellular regulated kinase I inhibitor CI-1040 (Pharmacia); quinazolines, e.g., PD153035, 4-(3-chloroanilino)quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines, such as CGP59326, CGP60261 and CGP62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidines; curcumin (diferuloylmethane, 4,5-bis(4-fluoroanilino)phthalimide); tyrophosphines containing a nitrothiophene moiety; PD-0183805 (Warner-Lamber); antisense molecules (e.g., those that bind to HER-encoding nucleic acids); quinoxalines (U.S. Pat. No. 5,804,396);Triphostin (U.S. Pat. No. 5,804,396); ZD6474 (AstraZeneca); PTK-787 (Novartis / Schering AG); pan-HER inhibitors such as CI-1033 (Pfizer); Affinitac (ISIS3521; Isis / Lilly); PKI166 (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®)); e.g. bortezomib (VELCADE®, Millennium Proteasome inhibitors such as cyclosporin, ... Labs; alkylating agents such as AG1478, thiotepa, and CYTOXAN® cyclophosphamide; alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, metoledopa, and uredopa; ethylenimines and methylamelanamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylomelanamine; acetogenins (especially bullatacin and bullatacinone); camptothecins (including topotecan, irinotecan); bryostatin; kallistatin; CC-1065 (including its adozelesin, carzelesin, and bizelesin synthetic analogs);Cryptophycins (especially cryptophycin 1 and cryptophycin 8);corticosteroids (including prednisone and prednisolone);cyproterone acetate;5α-reductases (including finasteride and dutasteride);vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat dolastatins;aldesleukin, talc duocarmycins (including synthetic analogs, KW-2189 and CB1-TM1);eleutherobin;pancratistatin;sarcodictin;spongiostatins;chlorambucil, clo Nitrogen mustards such as mafazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembitine, phenesterine, prednimustine, trophosfamide, 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); dynemicin (dynemicin A bisphosphonates, such as clodronate; esperamicin; also neocarzinostatin chromophores and related enediyne antibiotic chromophores), aclacinomycin, actinomycin, ausramycin, azaserine, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycin, dactinomycin, detrevicin, 6-diazo-5-oxo-L-norleucine, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxo rubicin), mitomycins such as epirubicin, esorubicin, idarubicin, marcelomycin, and mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, queramycin, rodorubicin, 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;Purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmoful, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; antiadrenergics such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as floric acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid. Acid; Eniluracil; Amsacrine; Bestravcil; Bisantrene; Edatraxate; Defofamine; Demecolcine; Diazicon; Elfomitin; Elliptinium acetate; Epothilone; Etoglucide; Gallium nitrate; Hydroxyurea; Lentinan; Lonidynin; Maytansinoids such as maytansine and ansamitocin; Mitoguazone; Mitoxantrone; Mopidamunol; Nitrelin; Pentostatin; Fenamet; Pirarubicin; Rosoxantrone; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; PSK® Polysaccharide Complex (JHS Natural Products); Razoxane; Rhizoxin; Schizofuran; Spirogermanium; Tenuazonic acid; Triazicon; 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-Thioguam; amine; mercaptopurine; 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.

[0129] 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), including tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxyfene, ketoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as 4(5)-imidazole, aminoglutethimide, MEGASE® (megestrol 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, pan-translatal acid, fenretinide and troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those that inhibit the expression of genes in signal transduction pathways involved in abnormal cell proliferation, such as PKC-alpha, Ralf and H-Ras; (vii) ribozymes, such as VEGF expression inhibitors (e.g. ANGIOZYME®) and HER2 expression inhibitors; (viii) vaccines, such as gene therapy vaccines, such as ALLOVECTIN®, LEUVECTIN® and VAXID®;(ix) proliferation inhibitors, including the 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;

[0130] The term "chemoimmunotherapy" refers to a combination therapy that includes both chemotherapy and immunotherapy. In some embodiments, chemoimmunotherapy is used to treat cancer, such as CD20 positive cancer, such as NHL, such as diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), high-grade B-cell lymphoma (HGBL), mantle cell lymphoma (MCL), high-grade B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma (PMLBCL), diffuse B-cell lymphoma, small lymphocytic lymphoma, marginal zone lymphoma (MZL), Burkitt's lymphoma, or lymphoplasmacytic lymphoma. In some embodiments, the immunotherapy includes an antibody, such as an anti-CD20 antibody (e.g., an anti-CD20 monoclonal antibody). In some embodiments, the anti-CD20 antibody or anti-CD20 monoclonal antibody is rituximab. In some embodiments, the chemoimmunotherapy comprises R-GemOx.

[0131] As used herein, the term "R-GemOx" refers to a treatment including rituximab (RITUXAN®; CAS Number: 174722-31-7) plus gemcitabine (CAS Number: 95058-81-4) and oxaliplatin (CAS Number: 61825-94-3). In some embodiments, R-GemOx is a chemotherapy treatment or regimen used to treat cancer, optionally a B-cell proliferative disorder (e.g., non-Hodgkin's lymphoma; e.g., diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), high-grade B-cell lymphoma (HGBL), mantle cell lymphoma (MCL), high-grade B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma (PMLBCL), diffuse B-cell lymphoma, small lymphocytic lymphoma, marginal zone lymphoma (MZL), Burkitt's lymphoma, or lymphoplasmacytic lymphoma). In some embodiments, R-GemOx is the standard of care (SOC) or standard of care administered to a subject to treat cancer, optionally a B-cell proliferative disorder (e.g., non-Hodgkin's lymphoma; e.g., diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), high-grade B-cell lymphoma (HGBL), mantle cell lymphoma (MCL), high-grade B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma (PMLBCL), diffuse B-cell lymphoma, small lymphocytic lymphoma, marginal zone lymphoma (MZL), Burkitt's lymphoma, or lymphoplasmacytic lymphoma). In some embodiments, R-GemOx is the standard of care to be administered to subjects who have relapsed and / or are refractory to a prior therapy and / or are ineligible for autologous stem cell therapy (ASCT). In some embodiments, R-GemOx is administered every two weeks (14-day administration cycles) for eight administration cycles. In some embodiments, the administration regimen for R-GemOx therapy includes eight 14-day administration cycles, during each administration cycle, the subject receives at least 375 mg / m 2 of rituximab was administered intravenously (IV) at 1000 mg / m 2 of gemcitabine was administered IV at 1000 mg / m 2 of oxaliplatin is given IV.

[0132] The term "cytotoxic agent," as used herein, refers to any agent that is detrimental to cells (e.g., causes cell death, inhibits growth, or otherwise interferes with cell function). Cytotoxic agents include radioisotopes (e.g., 211 At, 131 I, 125 I, 90 Y, 186 Re, 188 Re, 153 Sm, 212 Bi, 32 P, 212 Pb, and radioisotopes of Lu); chemotherapeutic agents; enzymes such as nucleases and fragments thereof; and toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and / or variants thereof. Exemplary cytotoxic agents can be selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, LDH-A inhibitors, fatty acid biosynthesis inhibitors, cell cycle signal transduction inhibitors, HDAC inhibitors, proteasome inhibitors, and cancer metabolism inhibitors. In one example, the cytotoxic agent is a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin). In one example, the cytotoxic agent is an antagonist of EGFR, such as N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (e.g., erlotinib).In one example, the cytotoxic agent is a RAF inhibitor, such as a BRAF and / or CRAF inhibitor.In one example, the RAF inhibitor is vemurafenib.In one example, the cytotoxic agent is a PI3K inhibitor.

[0133] The term "package insert" is used to refer to instructions customarily included in the commercial packaging of a therapeutic product that contain information regarding the indications, uses, dosage, administration, concomitant therapy, contraindications and / or warnings regarding the use of such therapeutic product.

[0134] III. Treatment method Provided herein are methods of treating a subject or population of subjects having a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder; e.g., non-Hodgkin's lymphoma (NHL) (e.g., diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), high-grade B-cell lymphoma (HGBL), mantle cell lymphoma (MCL), high-grade B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma (PMLBCL), diffuse B-cell lymphoma, small lymphocytic lymphoma, marginal zone lymphoma (MZL), Burkitt's lymphoma, or lymphoplasmacytic lymphoma), chronic lymphocytic leukemia (CLL), or central nervous system lymphoma (CNSL)) by administering mosunetuzumab and polatuzumab vedotin as a combination therapy. In particular, methods are provided herein for treating a subject or subject population with aggressive NHL (e.g., DLBCL, transformed FL, or grade 3b FL) by subcutaneous administration of mosunetuzumab and intravenous administration of polatuzumab vedotin as combination therapy. In some examples, the subject or subject population is relapsed and / or refractory (R / R) to at least one prior therapy while maintaining an acceptable safety profile (e.g., in terms of frequency and severity of adverse events such as cytokine release syndrome (CRS)). In some examples, the subject or subject population may have received two or more lines of prior therapy. In some examples, the subject may be ineligible for autologous stem cell transplantation (ASCT).

[0135] A. Therapeutic Methods for Administration of Mosunetuzumab In one aspect, the invention provides a method of treating a subject having a CD20-positive cell proliferative disorder, comprising administering mosunetuzumab subcutaneously to the subject and administering polatuzumab vedotin intravenously to the subject 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 (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, a third dose (C1D3) of mosunetuzumab, and a first dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of mosunetuzumab is about 5 mg (e.g., 5 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg; e.g., 5 mg) and C1D2 of mosunetuzumab is about 15 mg (e.g., 15 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg; e.g., 5 mg). or ±3 mg; e.g., 15 mg) or about 45 mg (e.g., 45 mg ±0.01 mg, ±0.025 mg, ±0.05 mg, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg; e.g., 45 mg), and the C1D3 of mosunetuzumab is about 45 mg (e.g., 45 mg ±0.01 mg, ±0.025 mg, ±0.05 mg, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ± (b) the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab and a single dose (C2D1) of polatuzumab vedotin, and the C2D1 of mosunetuzumab is about 45 mg (e.g., 45 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg; e.g., 45 mg), and the C1D1 of polatuzumab vedotin is about 1.8 mg / kg;and the C2D1 of polatuzumab vedotin is about 1.8 mg / kg (e.g., 1.8 mg / kg ±0.01 mg / kg, ±0.025 mg / kg, ±0.05 mg / kg, ±0.075 mg / kg, ±0.1 mg / kg, ±0.2 mg / kg, ±0.3 mg / kg, ±0.4 mg / kg, ±0.5 mg / kg, ±0.75 mg / kg, or ±1 mg / kg; e.g., 1.8 mg / kg).

[0136] In some embodiments, C1D2 is about 45 mg (e.g., 45 mg ±0.01 mg, ±0.025 mg, ±0.05 mg, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg; e.g., 45 mg).

[0137] In some embodiments, C1D2 is about 15 mg (e.g., 15 mg ±0.01 mg, ±0.025 mg, ±0.05 mg, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg; e.g., 15 mg).

[0138] In some embodiments, the first dosing cycle is a 21 day (± 1 day) dosing cycle. In some embodiments, C1D1, C1D2, and C1D3 of mosunetuzumab are administered on, or about, days 1, 8 (± 1 day), and 15 (± 1 day) of the first dosing cycle. In some embodiments, C1D1 of polatuzumab vedotin is administered on day 1 of the first dosing cycle.

[0139] In some embodiments, the second dosing cycle is a 21 day (± 1 day) dosing cycle. In some embodiments, C2D1 of mosunetuzumab is administered on day 1 of the second dosing cycle. In some embodiments, C2D1 of polatuzumab vedotin is administered on day 1 of the second dosing cycle.

[0140] In some embodiments, the method further comprises one or more additional dosing cycles. In some embodiments, the method comprises 4 to 6 additional dosing cycles. In some embodiments, the method comprises 6 additional dosing cycles. In some embodiments, each additional dosing cycle is a 21 day (± 1 day) dosing cycle.

[0141] In some embodiments, one or more of the additional administration cycles comprises an additional single dose of mosunetuzumab and an additional single dose of polatuzumab vedotin. In some embodiments, the additional single dose of polatuzumab vedotin is about 1.8 mg / kg (e.g., 1.8 mg / kg ± 0.01 mg / kg, ± 0.025 mg / kg, ± 0.05 mg / kg, ± 0.075 mg / kg, ± 0.1 mg / kg, ± 0.2 mg / kg, ± 0.3 mg / kg, ± 0.4 mg / kg, ± 0.5 mg / kg, ± 0.75 mg / kg, or ± 1 mg / kg; e.g., 1.8 mg / kg). In some embodiments, each 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. In some embodiments, one or more of the additional dosing cycles comprises an additional single dose of mosunetuzumab and does not include administration of polatuzumab vedotin.

[0142] In some embodiments, the additional single dose of mosunetuzumab is about 45 mg (e.g., 45 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg; e.g., 45 mg). In some embodiments, each additional single dose of mosunetuzumab is administered to the subject on day 1 of each additional dosing cycle comprising the additional dose of mosunetuzumab.

[0143] In some embodiments, the dosing regimen includes six additional dosing cycles, each of the six additional dosing cycles comprising a single dose of mosunetuzumab, and no more than four of the six additional dosing cycles include administration of polatuzumab vedotin.

[0144] In one aspect, the invention provides a method of treating a subject having a CD20-positive cell proliferative disorder, comprising administering mosunetuzumab subcutaneously to the subject and administering polatuzumab vedotin intravenously to the subject, in a dosing regimen comprising eight dosing cycles, wherein (a) a first dosing cycle comprises (i) a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, and a third dose (C1D3) of mosunetuzumab, wherein the C1D1 of mosunetuzumab is about 5 mg (e.g., For example, 5 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg; e.g., 5 mg) and C1D2 of mosunetuzumab is about 45 mg (e.g., 45 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg , ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg; e.g., 45 mg), and C1D3 of mosunetuzumab is about 45 mg (e.g., 45 mg ±0.01 mg, ±0.025 mg, ±0.05 mg, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg; e.g., 45 mg). , and C1D3 of mosunetuzumab, and (ii) a single dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of polatuzumab vedotin is about 1.8 mg / kg (e.g., 1.8 mg / kg ± 0.01 mg / kg, ± 0.025 mg / kg, ± 0.05 mg / kg, ± 0.075 mg / kg, ± 0.1 mg / kg, ± 0.2 mg / kg, ± 0.3 mg / kg, ± 0.4 mg / kg, ± 0.5 mg / kg, ± 0.75 mg / kg, or ± 1 mg / kg; e.g., 1.(b) the second through sixth administration cycles each comprise a single dose (C2D1-C6D1) of mosunetuzumab and a single dose (C2D1-C6D1) of polatuzumab vedotin, wherein each single dose C2D1-C6D1 of mosunetuzumab is about 45 mg (e.g., 45 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg). g, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg; e.g., 45 mg), and each single dose of polatuzumab vedotin C2D1-C6D1 is about 1.8 mg / kg (e.g., 1.8 mg / kg ±0.01 mg / kg, ±0.025 mg / kg, ±0.05 mg / kg, ±0.06 mg / kg, ±0.08 mg / kg, ±0.09 mg / kg, ±0.10 mg / kg, ±0.15 mg / kg, ±0.25 mg / kg, ±0.3 mg / kg, ±0.4 mg / kg, ±0.5 mg / kg, ±0.75 mg / kg, ±1 mg / kg, ±1.5 mg / kg, ±2 mg, or ±3 mg; e.g., 45 mg). (c) the seventh and eighth dosing cycles each comprise a single dose, C7D1 and C8D1 of mosunetuzumab, respectively, and polatuzumab The method does not include administration of vedotin, and each single dose of C7D1 and C8D1 is about 45 mg (e.g., 45 mg ±0.01 mg, ±0.025 mg, ±0.05 mg, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg; e.g., 45 mg).

[0145] In one aspect, the invention provides a method of treating a subject having a CD20-positive cell proliferative disorder, comprising administering mosunetuzumab subcutaneously to the subject and administering polatuzumab vedotin intravenously to the subject, in a dosing regimen comprising eight dosing cycles, wherein (a) a first dosing cycle comprises (i) a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, and a third dose (C1D3) of mosunetuzumab, wherein the C1D1 of mosunetuzumab is about 5 mg (e.g., For example, 5 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg; e.g., 5 mg) and C1D2 of mosunetuzumab is about 15 mg (e.g., 15 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg , ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg; e.g., 15 mg), and C1D3 of mosunetuzumab is about 45 mg (e.g., 45 mg ±0.01 mg, ±0.025 mg, ±0.05 mg, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg; e.g., 45 mg). , and C1D3 of mosunetuzumab, and (ii) a single dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of polatuzumab vedotin is about 1.8 mg / kg (e.g., 1.8 mg / kg ± 0.01 mg / kg, ± 0.025 mg / kg, ± 0.05 mg / kg, ± 0.075 mg / kg, ± 0.1 mg / kg, ± 0.2 mg / kg, ± 0.3 mg / kg, ± 0.4 mg / kg, ± 0.5 mg / kg, ± 0.75 mg / kg, or ± 1 mg / kg; e.g., 1.(b) the second through sixth administration cycles each comprise a single dose (C2D1-C6D1) of mosunetuzumab and a single dose (C2D1-C6D1) of polatuzumab vedotin, wherein each single dose C2D1-C6D1 of mosunetuzumab is about 45 mg (e.g., 45 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg). g, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg; e.g., 45 mg), and each single dose of polatuzumab vedotin C2D1-C6D1 is about 1.8 mg / kg (e.g., 1.8 mg / kg ±0.01 mg / kg, ±0.025 mg / kg, ±0.05 mg / kg, ±0.06 mg / kg, ±0.08 mg / kg, ±0.09 mg / kg, ±0.10 mg / kg, ±0.15 mg / kg, ±0.25 mg / kg, ±0.3 mg / kg, ±0.4 mg / kg, ±0.5 mg / kg, ±0.75 mg / kg, ±1 mg / kg, ±1.5 mg / kg, ±2 mg, or ±3 mg; e.g., 45 mg). (c) the seventh and eighth dosing cycles each comprise a single dose, C7D1 and C8D1 of mosunetuzumab, respectively, and polatuzumab The method does not include administration of vedotin, and each single dose of C7D1 and C8D1 is about 45 mg (e.g., 45 mg ±0.01 mg, ±0.025 mg, ±0.05 mg, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg; e.g., 45 mg).

[0146] In some embodiments, each dosing cycle is a 21 day (± 1 day) dosing cycle. In some embodiments, C1D1, C1D2, and C1D3 of mosunetuzumab are administered on days 1, 8 (± 1 day), and 15 (± 1 day), or about days 1, about 8 (± 1 day), and about 15 (± 1 day), of the first dosing cycle, respectively. In some embodiments, each single dose of C2D1-C8D1 of mosunetuzumab is administered on day 1 of the respective dosing cycle.

[0147] In some embodiments, each single dose of polatuzumab vedotin C1D1-C6D1 is administered on day 1 of each administration cycle.

[0148] In some embodiments, C1D1 of polatuzumab vedotin is administered prior to administration of C1D1 of mosunetuzumab, and C2D1 of polatuzumab vedotin is administered prior to administration of C2D1 of mosunetuzumab. In some embodiments, each single dose C3D1-C6D1 of polatuzumab vedotin is administered prior to administration of each single dose C3D1-C6D1 of mosunetuzumab, respectively. In some embodiments, when mosunetuzumab and polatuzumab vedotin are administered on the same day, mosunetuzumab may be administered prior to, concurrently with, or after administration of polatuzumab vedotin. In some examples, mosunetuzumab is administered after administration of polatuzumab vedotin. In certain examples, mosunetuzumab is administered at least 60 minutes (e.g., 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours) after administration of polatuzumab vedotin. In some embodiments, polatuzumab vedotin is administered at least about 60 minutes (e.g., 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours) before administration of mosunetuzumab.

[0149] In some embodiments, the CD20-positive cell proliferative disorder is a B-cell proliferative disorder. In some aspects, the B-cell proliferative disorder is non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), or central nervous system lymphoma (CNSL).

[0150] In some embodiments, the NHL is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), high-grade B-cell lymphoma (HGBL), mantle cell lymphoma (MCL), high-grade B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma (PMLBCL), diffuse B-cell lymphoma, small lymphocytic lymphoma, marginal zone lymphoma (MZL), Burkitt's lymphoma, or lymphoplasmacytic lymphoma. In some embodiments, the NHL is relapsed and / or refractory (R / R) NHL.

[0151] In some embodiments, the NHL is DLBCL. In some embodiments, the DLBCL is R / R DLBCL. In some embodiments, the DLBCL is Richter's transformed.

[0152] In some embodiments, the NHL is FL (e.g., grade 1, 2, 3a, or 3b FL). In some embodiments, the FL is R / R FL. In some embodiments, the FL is transformed FL.

[0153] In some embodiments, the NHL is HGBL. In some embodiments, the HGBL is R / R HGBL.

[0154] In some embodiments, the NHL is aggressive NHL. In some embodiments, the aggressive NHL is DLBCL, transformed FL, or grade 3b FL. In some embodiments, the NHL is R / R NHL.

[0155] In some embodiments, the subject is ineligible for autologous stem cell transplant (ASCT).

[0156] In some embodiments, the subject has relapsed after two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) prior lines of treatment or is refractory to two or more prior lines of treatment.

[0157] In some embodiments, the subject is a human.

[0158] In one aspect, the invention provides a method of treating a population of subjects having a CD20-positive cell proliferative disorder, comprising subcutaneously administering mosunetuzumab to the subjects of the population and intravenously administering polatuzumab vedotin to the subjects of the population for at least a first administration cycle and a second administration cycle, wherein: (a) the first administration cycle comprises a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, a third dose (C1D3) of mosunetuzumab, and a first dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of mosunetuzumab is about 5 mg (5 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg; e.g., 5 mg) and C1D2 of mosunetuzumab is about 15 mg (e.g., 15 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg; e.g., 5 mg). g; e.g., 15 mg) or about 45 mg (e.g., 45 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg; e.g., 45 mg), and C1D3 of mosunetuzumab is about 45 mg (e.g., 45 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg , ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg; e.g., 45 mg), mosunetuzumab at C1D1, mosunetuzumab at C1D2, and mosunetuzumab at C1D3, and polatuzumab vedotin at C1D1 is about 1.8 mg / kg (e.g., 1.8 mg / kg ±0.01 mg / kg, ±0.025 mg / kg, ±0.05 mg / kg, ±0.075 mg / kg, ±0.1 mg / kg, ±0.2 mg / kg, ±0.3 mg / kg, ±0.4 mg / kg, ±0.5 mg / kg, ±0.75 mg / kg, or ±1 mg / kg; e.g., 1.(b) a 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 45 mg (e.g., 45 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ±3 mg; e.g., 45 mg) and the C2D1 of polatuzumab vedotin is about 1.8 mg / kg (e.g., 1.8 mg / kg ±0.01 mg / kg, ±0.025 mg / kg, ±0.05 mg / kg, ±0.075 mg / kg, ±0.1 mg / kg, ±0.2 mg / kg, ±0.3 mg / kg, ±0.4 mg / kg, ±0.5 mg / kg, ±0.75 mg / kg, or ±1 mg / kg; e.g., 1.8 mg / kg).

[0159] In one aspect, the invention provides a method of treating a population of subjects having a CD20-positive cell proliferative disorder, comprising administering mosunetuzumab subcutaneously to the subjects of the population and administering polatuzumab vedotin intravenously to the subjects of the population, in a dosing regimen comprising eight dosing cycles, wherein (a) a first dosing cycle comprises: (i) a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, and a third dose (C1D3) of mosunetuzumab, wherein C1D1 of mosunetuzumab is about 5 mg (e.g., 5 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg; e.g., 5 mg) and C1D2 of mosunetuzumab is about 45 mg (e.g., 45 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg; e.g., 5 mg). and C1D3 of mosunetuzumab is about 45 mg (e.g., 45 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg; e.g., 45 mg). mab, and mosunetuzumab at C1D3, and (ii) a single dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of polatuzumab vedotin is about 1.8 mg / kg (e.g., 1.8 mg / kg ± 0.01 mg / kg, ± 0.025 mg / kg, ± 0.05 mg / kg, ± 0.075 mg / kg, ± 0.1 mg / kg, ± 0.2 mg / kg, ± 0.3 mg / kg, ± 0.4 mg / kg, ± 0.5 mg / kg, ± 0.75 mg / kg, or ± 1 mg / kg; e.g., 1.(b) the second through sixth administration cycles each comprise a single dose (C2D1-C6D1) of mosunetuzumab and a single dose (C2D1-C6D1) of polatuzumab vedotin, wherein each single dose C2D1-C6D1 of mosunetuzumab is about 45 mg (e.g., 45 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg). g, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg; e.g., 45 mg), and each single dose of polatuzumab vedotin C2D1-C6D1 is about 1.8 mg / kg (e.g., 1.8 mg / kg ±0.01 mg / kg, ±0.025 mg / kg, ±0.05 mg / kg, ±0.06 mg / kg, ±0.08 mg / kg, ±0.09 mg / kg, ±0.10 mg / kg, ±0.15 mg / kg, ±0.25 mg / kg, ±0.3 mg / kg, ±0.4 mg / kg, ±0.5 mg / kg, ±0.75 mg / kg, ±1 mg / kg, ±1.5 mg / kg, ±2 mg, or ±3 mg; e.g., 45 mg). (c) the seventh and eighth dosing cycles each comprise a single dose, C7D1 and C8D1 of mosunetuzumab, respectively, and polatuzumab The method does not include administration of vedotin, and each single dose of C7D1 and C8D1 is about 45 mg (e.g., 45 mg ±0.01 mg, ±0.025 mg, ±0.05 mg, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg; e.g., 45 mg).

[0160] In some embodiments, the mean duration of progression-free survival for the subject population is longer than the reference mean duration of progression-free survival for a reference subject population.

[0161] In some embodiments, the complete response rate in the subject population is higher than the reference complete response rate in the reference subject population.

[0162] In some embodiments, the objective response rate in the subject population is higher than the reference objective response rate in the reference subject population.

[0163] In some embodiments, the mean duration of response of the subject population is longer than the reference mean duration of response of a reference subject population.

[0164] In some embodiments, the mean duration of complete response in a subject population is longer than the reference mean duration of complete response in a reference subject population.

[0165] In some embodiments, the reference population is administered a combination therapy comprising rituximab, gemcitabine and oxaliplatin. In some embodiments, the combination therapy is administered to the reference population in dosing cycles comprising 8 dosing cycles. In some embodiments, each dosing cycle is a 14 day (± 1 day) dosing cycle. In some embodiments, the combination therapy is administered to the reference population of subjects about every 2 weeks (Q2W). In some aspects, rituximab is administered at about 375 mg / m 2 (For example, 375 mg / m 2 ±1mg / m 2 , ±2.5mg / m 2 , ±5mg / m 2 , ±7.5mg / m 2 , ±10mg / m 2 , ±20mg / m 2 , ±30mg / m 2 , ±40mg / m 2 , or ±50 mg / m 2 For example, 375 mg / m 2 ) given intravenously every 2 weeks, with gemcitabine at a dose of approximately 1000 mg / m 2 (For example, 1000 mg / m 2 ±1mg / m 2 , ±2.5mg / m 2 , ±5mg / m 2 , ±7.5mg / m 2 , ±10mg / m 2 , ±20mg / m 2 , ±30mg / m 2 , ±40mg / m 2 , ±50mg / m 2 ;±100mg / m 2 ;±150mg / m 2 ;±200mg / m 2 ;±250mg / m 2;±300mg / m 2 For example, 1000 mg / m 2 ) administered intravenously every 2 weeks, with oxaliplatin at a dose of approximately 100 mg / m 2 (e.g., 100 mg / m 2 ±1mg / m 2 , ±2.5mg / m 2 , ±5mg / m 2 , ±7.5mg / m 2 , ±10mg / m 2 , ±20mg / m 2 , or ±30 mg / m 2 For example, 100 mg / m 2 ) given intravenously every two weeks.

[0166] In some embodiments, the CD20-positive cell proliferative disorder is a B-cell proliferative disorder. In some aspects, the B-cell proliferative disorder is non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), or central nervous system lymphoma (CNSL).

[0167] In some embodiments, the NHL is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), high-grade B-cell lymphoma (HGBL), mantle cell lymphoma (MCL), high-grade B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma (PMLBCL), diffuse B-cell lymphoma, small lymphocytic lymphoma, marginal zone lymphoma (MZL), Burkitt's lymphoma, or lymphoplasmacytic lymphoma. In some embodiments, the NHL is relapsed and / or refractory (R / R) NHL.

[0168] In some embodiments, the NHL is DLBCL. In some embodiments, the DLBCL is R / R DLBCL. In some embodiments, the DLBCL is Richter's transformed.

[0169] In some embodiments, the NHL is FL (e.g., grade 1, 2, 3a, or 3b FL). In some embodiments, the FL is R / R FL. In some embodiments, the FL is transformed FL.

[0170] In some embodiments, the NHL is HGBL. In some embodiments, the HGBL is R / R HGBL.

[0171] In some embodiments, the NHL is aggressive NHL. In some embodiments, the aggressive NHL is DLBCL, transformed FL, or grade 3b FL. In some embodiments, the NHL is R / R NHL.

[0172] In some embodiments, each subject in the subject population is ineligible for autologous stem cell transplantation (ASCT).In some embodiments, each subject in the subject population has relapsed after two or more prior lines of therapy or is refractory to two or more prior lines of therapy.In some embodiments, each subject in the subject population is human.

[0173] In some embodiments, each subject in the reference subject population is ineligible for autologous stem cell transplantation (ASCT).In some embodiments, each subject in the reference subject population has relapsed after two or more prior lines of therapy, or is refractory to two or more prior lines of therapy.In some embodiments, each subject in the reference subject population is human.

[0174] B. Dosing Strategies to Reduce Adverse Events The present invention relates to methods of treating a subject or population of subjects having a CD20-positive cell proliferative disorder (e.g., a B-cell proliferative disorder; e.g., non-Hodgkin's lymphoma (NHL) (e.g., diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), high-grade B-cell lymphoma (HGBL), mantle cell lymphoma (MCL), high-grade B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma (PMLBCL), diffuse B-cell lymphoma, small lymphocytic lymphoma, marginal zone lymphoma (MZL), Burkitt's lymphoma, or lymphoplasmacytic lymphoma), chronic lymphocytic leukemia (CLL), or central nervous system lymphoma (CNSL)) by administering mosunetuzumab and polatuzumab vedotin as a combination therapy. In particular, the present invention relates to a method of treating a subject or a population of subjects with aggressive NHL (e.g., DLBCL, transformed FL, or grade 3b FL) by subcutaneous administration of mosunetuzumab and intravenous administration of polatuzumab vedotin as a combination therapy. In some examples, the subject or population of subjects has relapsed after and / or is refractory (R / R) to at least one prior therapy while maintaining an acceptable safety profile (e.g., in terms of frequency and severity of adverse events such as cytokine release syndrome (CRS)). In some examples, the subject or population of subjects may have received two or more lines of prior therapy. In some examples, the subject may be ineligible for autologous stem cell transplantation (ASCT). The treatments and dosing regimens described herein provide an acceptable safety profile in subjects or populations of subjects with R / R NHL treated with the dosing regimens described.

[0175] 1. CRS Symptoms and Grading Any of the methods described herein may involve monitoring the subject for cytokine release syndrome (CRS) (e.g., a CRS event following initiation of any of the above methods). Current clinical responses are focused on treating individual signs and symptoms, providing supportive care, and attempting to dampen 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 to allow for rapid recognition, treatment of CRS (Lee et al. Biol Blood Marrow Transplantation. 25(4):625-638, 2019). The ASTCT criteria are objective, easy to apply, and are intended to more accurately classify the severity of CRS. This CRS grading system is shown in Table 1 below.

[0176] [Table 1] ASTCT = American Society for Transplant and Cellular Therapy; BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; CRS = cytokine release syndrome; CTCAE = Common Terminology Criteria for Adverse Events.

[0177] Fever is defined as a temperature of 38°C or higher not attributable to other causes. In subjects with CRS, fever is then no longer required to grade the severity of subsequent CRS once they have received antipyretic or anticytokine therapy such as tocilizumab or steroids. In this case, the grading of CRS is determined by hypotension and / or hypoxia.

[0178] CRS grade is determined by the more severe events, hypotension or hypoxia that are not attributable to other causes. For example, a subject with a temperature of 39.5°C, hypotension requiring a vasopressor, and hypoxia requiring a low-flow nasal cannula is classified as grade 3 CRS.

[0179] Low-flow nasal cannulas are defined as oxygen delivered at 6 L / min or less. Low-flow also includes blow-by oxygen delivery, which is sometimes used in pediatrics. High-flow nasal cannulas are defined as oxygen delivered at greater than 6 L / min.

[0180] CRS is associated with an increase in a variety of cytokines, with marked increases in IFNγ, IL-6, and TNF-α levels. Emerging evidence specifically implicates CRS and IL-6 as a central mediator. IL-6 is a proinflammatory, multifunctional cytokine produced by a variety of cell types that has been shown to be involved in a wide variety of physiological processes, including T cell activation. Regardless of the inducer, CRS is correlated with higher levels of IL-6 (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 having significantly higher IL-6 levels than subjects experiencing no CRS or mild CRS (grades 0-3) (Chen et al. J. Immunol. Methods. 434:1-8, 2016).

[0181] Therefore, blocking the inflammatory effects of IL-6 using an agent that inhibits IL-6-mediated signaling to manage CRS observed in subjects during a two-fractionated dose-escalating dosing regimen is considered an alternative to steroid treatment that is not expected to adversely affect T cell function or reduce the efficacy or clinical benefit of mosunetuzumab therapy in the treatment of CD20 positive cell proliferative disorders (e.g., B cell proliferative disorders).

[0182] If the subject has a CRS event that does not resolve or worsens within 24 hours after administering an IL-6R antagonist to treat the symptoms of the CRS event, the method may further include administering one or more additional doses of an IL-6R antagonist to the subject to manage the CRS event.If the CRS event is not managed through administration of an IL-6R antagonist, the subject may be administered a corticosteroid such as methylprednisolone or dexamethasone.

[0183] 2. Other Adverse Events and Grading Any of the methods described herein can include monitoring the subject for additional non-CRS adverse events.The incidence, nature and severity of physical findings and adverse events, with severity determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events, 5th Edition (NCI CTCAE v5.0).Other than CRS, one of the most common adverse events reported in subjects receiving treatment with mosunetuzumab is neutropenia (e.g., febrile neutropenia).

[0184] Neutropenia is characterized by abnormally low blood levels of neutrophils, a type of white blood cell. Neutropenia may result in an increased risk of infection. The generally accepted reference range for absolute neutrophil count (ANC) in adults is 1,500 to 8,000 cells / μL blood. Mild neutropenia is characterized by an ANC of 1,000 to 1,500 cells / μL (grade 1 to 2); moderate neutropenia is characterized by an ANC of 500 to 1,000 cells / μL (grade 3), and severe neutropenia is characterized by an ANC of less than 500 cells / μL (grade 4). Febrile neutropenia (grade 3+ neutropenia) is characterized by an ANC of less than 1,000 cells / μL in addition to either a single temperature measurement above 38.3°C or a sustained temperature measurement above 38°C.

[0185] 3. A dosing regimen with an acceptable safety profile In one aspect, the invention provides a method of treating a population of subjects having a CD20-positive cell proliferative disorder, comprising administering mosunetuzumab subcutaneously to the subjects of the population and administering polatuzumab vedotin intravenously to the subjects of the population for at least a first administration cycle and a second administration cycle, wherein: (a) the first administration cycle comprises a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, a third dose (C1D3) of mosunetuzumab, and a first dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of mosunetuzumab is about 5 mg (5 mg / kg); mg ±0.01 mg, ±0.025 mg, ±0.05 mg, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg; e.g., 5 mg) and C1D2 of mosunetuzumab is about 15 mg (e.g., 15 mg ±0.01 mg, ±0.025 mg, ±0.05 mg, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg; and C1D3 of mosunetuzumab is about 45 mg (e.g., 45 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg; e.g., 45 mg). ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg; e.g., 45 mg), mosunetuzumab at C1D1, mosunetuzumab at C1D2, and mosunetuzumab at C1D3, and polatuzumab vedotin at C1D1 about 1.8 mg / kg (e.g., 1.8 mg / kg ±0.01 mg / kg, ±0.025 mg / kg, ±0.05 mg / kg, ±0.075 mg / kg, ±0.1 mg / kg, ±0.2 mg / kg, ±0.3 mg / kg, ±0.4 mg / kg, ±0.5 mg / kg, ±0.75 mg / kg, or ±1 mg / kg; e.g., 1.(b) a 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 45 mg (e.g., 45 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ±3 mg; e.g., 45 mg) and the C2D1 of polatuzumab vedotin is about 1.8 mg / kg (e.g., 1.8 mg / kg ±0.01 mg / kg, ±0.025 mg / kg, ±0.05 mg / kg, ±0.075 mg / kg, ±0.1 mg / kg, ±0.2 mg / kg, ±0.3 mg / kg, ±0.4 mg / kg, ±0.5 mg / kg, ±0.75 mg / kg, or ±1 mg / kg; e.g., 1.8 mg / kg).

[0186] In one aspect, the invention provides a method of treating a population of subjects having a CD20-positive cell proliferative disorder, comprising administering mosunetuzumab subcutaneously to the subjects of the population and administering polatuzumab vedotin intravenously to the subjects of the population, in a dosing regimen comprising eight dosing cycles, wherein (a) a first dosing cycle comprises: (i) a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, and a third dose (C1D3) of mosunetuzumab, wherein C1D1 of mosunetuzumab is about 5 mg (e.g., 5 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg; e.g., 5 mg) and C1D2 of mosunetuzumab is about 45 mg (e.g., 45 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg; e.g., 5 mg). and C1D3 of mosunetuzumab is about 45 mg (e.g., 45 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg; e.g., 45 mg). mab, and mosunetuzumab at C1D3, and (ii) a single dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of polatuzumab vedotin is about 1.8 mg / kg (e.g., 1.8 mg / kg ± 0.01 mg / kg, ± 0.025 mg / kg, ± 0.05 mg / kg, ± 0.075 mg / kg, ± 0.1 mg / kg, ± 0.2 mg / kg, ± 0.3 mg / kg, ± 0.4 mg / kg, ± 0.5 mg / kg, ± 0.75 mg / kg, or ± 1 mg / kg; e.g., 1.(b) the second through sixth administration cycles each comprise a single dose (C2D1-C6D1) of mosunetuzumab and a single dose (C2D1-C6D1) of polatuzumab vedotin, wherein each single dose C2D1-C6D1 of mosunetuzumab is about 45 mg (e.g., 45 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg). g, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg; e.g., 45 mg), and each single dose of polatuzumab vedotin C2D1-C6D1 is about 1.8 mg / kg (e.g., 1.8 mg / kg ±0.01 mg / kg, ±0.025 mg / kg, ±0.05 mg / kg, ±0.06 mg / kg, ±0.08 mg / kg, ±0.09 mg / kg, ±0.10 mg / kg, ±0.15 mg / kg, ±0.25 mg / kg, ±0.3 mg / kg, ±0.4 mg / kg, ±0.5 mg / kg, ±0.75 mg / kg, ±1 mg / kg, ±1.5 mg / kg, ±2 mg, or ±3 mg; e.g., 45 mg). (c) the seventh and eighth dosing cycles each comprise a single dose, C7D1 and C8D1 of mosunetuzumab, respectively, and polatuzumab The method does not include administration of vedotin, and each single dose of C7D1 and C8D1 is about 45 mg (e.g., 45 mg ±0.01 mg, ±0.025 mg, ±0.05 mg, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg; e.g., 45 mg).

[0187] In one aspect, the methods of the invention feature administering to a subject one or more additional therapeutic agents to mitigate adverse effects of administration of mosunetuzumab and / or polatuzumab vedotin. In some embodiments, premedication with a corticosteroid reduces the rate of cytokine release syndrome (CRS) in subjects treated with mosunetuzumab (e.g., in subjects administered a combination of mosunetuzumab and polatuzumab vedotin).

[0188] In some embodiments, the one or more additional therapeutic agents are corticosteroids or IL-6R antagonists. In some embodiments, the one or more additional therapeutic agents are IL-6R antagonists. In some embodiments, the IL-6R antagonist is tocilizumab. In some embodiments, tocilizumab is administered to the subject as a single dose of about 8 mg / kg (e.g., 8 mg / kg ± 0.01 mg / kg, ± 0.025 mg / kg, ± 0.05 mg / kg, ± 0.075 mg / kg, ± 0.1 mg / kg, ± 0.2 mg / kg, ± 0.3 mg / kg, ± 0.4 mg / kg, ± 0.5 mg / kg, ± 0.75 mg / kg, ± 1 mg / kg, ± 1.5 mg / kg, or ± 2 mg / kg; e.g., 8 mg / kg), and the single dose does not exceed 800 mg. In some embodiments, tocilizumab is administered to the subject as a single dose of about 12 mg / kg (e.g., 12 mg / kg ±0.01 mg / kg, ±0.025 mg / kg, ±0.05 mg / kg, ±0.075 mg / kg, ±0.1 mg / kg, ±0.2 mg / kg, ±0.3 mg / kg, ±0.4 mg / kg, ±0.5 mg / kg, ±0.75 mg / kg, ±1 mg / kg, ±1.5 mg / kg, or ±2 mg / kg; e.g., 12 mg / kg), wherein the single dose does not exceed 800 mg. In some embodiments, tocilizumab is administered intravenously.

[0189] In some embodiments, the one or more additional therapeutic agents are corticosteroids. In some embodiments, the corticosteroid is dexamethasone, prednisone, or methylprednisolone.

[0190] In some embodiments, the corticosteroid is dexamethasone. In some embodiments, dexamethasone is administered as a single dose of about 10 mg (e.g., 10 mg ± 0.01 mg, ± 0.025 mg, ± 0.05 mg, ± 0.075 mg, ± 0.1 mg, ± 0.2 mg, ± 0.3 mg, ± 0.4 mg, ± 0.5 mg, ± 0.75 mg, ± 1 mg, ± 1.5 mg, ± 2 mg, or ± 3 mg; e.g., 10 mg) every 6 hours. In some embodiments, dexamethasone is administered intravenously. In some embodiments, dexamethasone is administered as a single dose of about 20 mg (e.g., 20 mg ±0.01 mg, ±0.025 mg, ±0.05 mg, ±0.075 mg, ±0.1 mg, ±0.2 mg, ±0.3 mg, ±0.4 mg, ±0.5 mg, ±0.75 mg, ±1 mg, ±1.5 mg, ±2 mg, or ±3 mg; e.g., 20 mg) prior to administration of any dose of mosunetuzumab. In some embodiments, dexamethasone is administered orally.

[0191] In some embodiments, the corticosteroid is methylprednisolone. In some embodiments, the methylprednisolone is administered at a dose of about 1000 mg / day (e.g., 1000 mg / day ±1 mg / day, ±2.5 mg / day, ±5 mg / day, ±7.5 mg / day, ±10 mg / day, ±20 mg / day, ±30 mg / day, ±40 mg / day, ±50 mg / day, ±75 mg / day, ±100 mg / day, ±150 mg / day, ±200 mg / day, or ±300 mg / day; e.g., 1000 mg / day). In some embodiments, the methylprednisolone is administered intravenously.

[0192] In some embodiments, the corticosteroid is prednisone. In some aspects, prednisone is administered at a dose of about 10-30 mg / day (e.g., about 10 mg / day, about 11 mg / day, about 12 mg / day, about 13 mg / day, about 14 mg / day, about 15 mg / day, about 16 mg / day, about 17 mg / day, about 18 mg / day, about 19 mg / day, about 20 mg / day, about 21 mg / day, about 22 mg / day, about 23 mg / day, about 24 mg / day, about 25 mg / day, about 26 mg / day, about 27 mg / day, about 28 mg / day) , about 29 mg / day, or about 30 mg / day; e.g., 10 mg / day, 11 mg / day, 12 mg / day, 13 mg / day, 14 mg / day, 15 mg / day, 16 mg / day, 17 mg / day, 18 mg / day, 19 mg / day, 20 mg / day, 21 mg / day, 22 mg / day, 23 mg / day, 24 mg / day, 25 mg / day, 26 mg / day, 27 mg / day, 28 mg / day, 29 mg / day, or 30 mg / day). In some embodiments, prednisone is administered orally.

[0193] In some embodiments, the one or more additional therapeutic agents are acetaminophen or paracetamol. In some embodiments, the acetaminophen or paracetamol is administered as a single dose of about 500 to 1000 mg (e.g., about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg; e.g., 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg) prior to administration of any dose of polatuzumab vedotin. In some embodiments, the acetaminophen or paracetamol is administered orally.

[0194] In some embodiments, the one or more additional therapeutic agents is diphenhydramine. In some embodiments, diphenhydramine is administered as a single dose of about 50-100 mg (e.g., about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg; e.g., 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg) prior to administration of any dose of polatuzumab vedotin. In some embodiments, diphenhydramine is administered orally.

[0195] The methods described herein may provide an acceptable safety profile for subjects with a CD20-positive cell proliferative disorder (e.g., a B-cell disorder, e.g., a non-Hodgkin's lymphoma, e.g., an aggressive NHL, e.g., an R / R aggressive NHL) being treated with a combination therapy of mosunetuzumab and polatuzumab vedotin. In a particular example, the combination therapy comprising mosunetuzumab and polatuzumab vedotin comprises mosunetuzumab administered subcutaneously and polatuzumab vedotin administered intravenously.

[0196] IV. Therapeutic Drugs A. Mosunetuzumab The present invention provides mosunetuzumab, a bispecific antibody that binds to CD20 and CD3, and is useful for treating CD20-positive cell proliferative disorders. In some examples, the CD20-positive cell proliferative disorder is relapsed and / or refractory (R / R) non-Hodgkin's lymphoma (NHL) (e.g., aggressive NHL (aNHL)), including, for example, R / R diffuse large cell DLBCL, R / R HGBL, R / R trFL, and R / R grade 3bFL.

[0197] In some examples, mosunetuzumab comprises an anti-CD20 arm having a first binding domain comprising at least one, two, three, four, five or six hypervariable regions (HVRs) selected from: (a) an HVR-H1 comprising the amino acid sequence of GYTFTSYNMH (SEQ ID NO: 1); (b) an HVR-H2 comprising the amino acid sequence of AIYPGNGDTSYNQKFKG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of VVYYSNSYWYFDV (SEQ ID NO: 3); (d) an HVR-L1 comprising the amino acid sequence of RASSSVSYMH (SEQ ID NO: 4); (e) an HVR-L2 comprising the amino acid sequence of APSNLAS (SEQ ID NO: 5); and (f) an HVR-L3 comprising the amino acid sequence of QQWSFNPPT (SEQ ID NO: 6). In some examples, mosunetuzumab comprises an anti-CD20 arm that comprises a first binding domain that 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: 17-20, 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: 21-24, respectively. In some examples, mosunetuzumab 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) thereto; (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) thereto; or (c) an anti-CD20 arm comprising a first binding domain comprising a VH domain as in (a) and a VL domain as in (b). Thus, in some examples, the first binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO:7, and a VL domain comprising the amino acid sequence of SEQ ID NO:8.

[0198] In some examples, mosunetuzumab comprises an anti-CD3 arm having a second binding domain comprising at least one, two, three, four, five or six HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of NYYIH (SEQ ID NO: 9); (b) HVR-H2 comprising the amino acid sequence of WIYPGDGNTKYNEKFKG (SEQ ID NO: 10); (c) HVR-H3 comprising the amino acid sequence of DSYSNYYFDY (SEQ ID NO: 11); (d) HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 13); and (f) HVR-L3 comprising the amino acid sequence of TQSFILRT (SEQ ID NO: 14). In some examples, mosunetuzumab comprises an anti-CD3 arm that comprises a second binding domain that 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:25-28, 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:29-32, respectively. In some examples, mosunetuzumab comprises an anti-CD3 arm comprising: (a) a VH domain comprising an amino acid sequence of SEQ ID NO: 15, or at least 90% sequence identity thereto (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto); (b) a VL domain comprising an amino acid sequence of SEQ ID NO: 16, or at least 90% sequence identity thereto (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto); or (c) a second binding domain comprising a VH domain as in (a) and a VL domain as in (b). Thus, in some examples, the second binding domain comprises a VH domain comprising an amino acid sequence of SEQ ID NO: 15 and a VL domain comprising an amino acid sequence of SEQ ID NO: 16.

[0199] In some examples, mosunetuzumab is an anti-CD20 antibody having a first binding domain comprising at least one, two, three, four, five, or six HVRs selected from: (1) an HVR-H1 comprising the amino acid sequence of GYTFTSYNMH (SEQ ID NO: 1); (b) an HVR-H2 comprising the amino acid sequence of AIYPGNGDTSYNQKFKG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of VVYYSNSYWYFDV (SEQ ID NO: 3); (d) an HVR-L1 comprising the amino acid sequence of RASSSVSYMH (SEQ ID NO: 4); (e) an HVR-L2 comprising the amino acid sequence of APSNLAS (SEQ ID NO: 5); (f) an HVR-L3 comprising the amino acid sequence of QQWSFNPPT (SEQ ID NO: 6). and (2) an anti-CD3 arm having a second binding domain comprising at least one, two, three, four, five or six HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of NYYIH (sequence number 9); (b) HVR-H2 comprising the amino acid sequence of WIYPGDGNTKYNEKFKG (sequence number 10); (c) HVR-H3 comprising the amino acid sequence of DSYSNYYFDY (sequence number 11); (d) HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (sequence number 12); (e) HVR-L2 comprising the amino acid sequence of WASTRES (sequence number 13); and (f) HVR-L3 comprising the amino acid sequence of TQSFILRT (sequence number 14).In some examples, mosunetuzumab is an anti-C-cell antibody that comprises: (1) a first binding domain that 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 that comprise the sequences of SEQ ID NOs: 17-20, 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 that comprise the sequences of SEQ ID NOs: 21-24, respectively. and (2) an anti-CD3 arm comprising a second binding domain comprising at least one (e.g., one, two, three, or four) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4, each comprising the sequences of SEQ ID NOs: 25-28, and / or at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4, each comprising the sequences of SEQ ID NOs: 29-32. In some examples, mosunetuzumab is an anti-CD2 antibody that comprises: (1) an anti-CD2 antibody that comprises a first binding domain that comprises: (a) a VH domain comprising an amino acid sequence having SEQ ID NO:7, or 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 that sequence; (b) a VL domain comprising an amino acid sequence having SEQ ID NO:8, or 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 that sequence; or (c) a first binding domain that comprises a VH domain such as (a) and a VL domain such as (b). 0 arm, and (2) an anti-CD3 arm comprising (a) a VH domain comprising SEQ ID NO:15, or an amino acid sequence having at least 90% sequence identity thereto (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity); (b) a VL domain comprising SEQ ID NO:16, or an amino acid sequence having at least 90% sequence identity thereto (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity); or (c) a second binding domain comprising a VH domain such as (a) and a VL domain such as (b).In some examples, mosunetuzumab comprises (1) an anti-CD20 arm comprising a first binding domain comprising a VH domain comprising the amino acid sequence of SEQ ID NO:7 and a VL domain comprising the amino acid sequence of SEQ ID NO:8, and (2) an anti-CD3 arm comprising a second binding domain comprising a VH domain comprising the amino acid sequence of SEQ ID NO:15 and a VL domain comprising the amino acid sequence of SEQ ID NO:16.

[0200] In some examples, mosunetuzumab has International Nonproprietary Name (INN) List 117 (WHO Drug Information, Vol. 31, No. 2, 2017, p. 303), or CAS Registry Number 1905409-39-3, and has (1) an anti-CD20 arm comprising the heavy chain and light chain sequences of SEQ ID NOs: 33 and 34, respectively, and (2) an anti-CD3 arm comprising the heavy chain and light chain sequences of SEQ ID NOs: 35 and 36, respectively. In some examples, mosunetuzumab comprises: (1) (a) a heavy chain comprising an amino acid sequence set forth in SEQ ID NO: 33, or a sequence having at least 90% sequence identity thereto (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity); (b) a light chain comprising an amino acid sequence set forth in SEQ ID NO: 34, or a sequence having at least 90% sequence identity thereto (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity); (c) an anti-CD20 arm comprising a first binding domain comprising a heavy chain as in (a) and a light chain as in (b); and (2) (a ) an anti-CD3 arm comprising a second binding domain comprising a heavy chain comprising SEQ ID NO:35, or 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 that sequence; (b) a light chain comprising SEQ ID NO:36, or 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 that sequence; or (c) an anti-CD3 arm comprising a second binding domain comprising a heavy chain as in (a) and a light chain as in (b). In some examples, mosunetuzumab comprises (1) an anti-CD20 arm comprising a first binding domain comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO: 34, and (2) an anti-CD3 arm comprising a second binding domain comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 35 and a light chain comprising the amino acid sequence of SEQ ID NO: 36.

[0201] The amino acid sequence of mosunetuzumab is summarized in Table 2 below. [Table 2]

[0202] Mosunetuzumab can be produced using recombinant methods and compositions, for example, as described in US Pat. No. 4,816,567.

[0203] B. Polatuzumab vedotin The present invention provides polatuzumab vedotin, an anti-CD79b antibody-drug conjugate, useful for treating CD20-positive cell proliferative disorders. In some examples, the CD20-positive cell proliferative disorder is relapsed and / or refractory (R / R) non-Hodgkin's lymphoma (NHL) (e.g., aggressive NHL (aNHL)), including, for example, R / R diffuse large cell DLBCL, R / R HGBL, R / R trFL, and R / R grade 3bFL.

[0204] In some examples, the anti-CD79b antibody of polatuzumab vedotin (i.e., polatuzumab) comprises an anti-CD79b binding domain that comprises 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: 37; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42. 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 (sequence number 37); (b) HVR-H2 comprising the amino acid sequence of GEILPGGGDTNYNEIFKG (sequence number 38); (c) HVR-H3 comprising the amino acid sequence of TRRVPIRLDY (sequence number 39); (d) HVR-L1 comprising the amino acid sequence of KASQSVDYEGDSFLN (sequence number 40); (e) HVR-L2 comprising the amino acid sequence of AASNLES (sequence number 41); (f) HVR-L3 comprising the amino acid sequence of QQSNEDPLT (sequence number 42).

[0205] In some examples, the anti-CD79b antibody of polatuzumab vedotin (i.e., polatuzumab) 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: 45-48, 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: 49-52, respectively. In some examples, the anti-CD79b antibody drug conjugate comprises: (a) a heavy chain variable (VH) domain comprising an amino acid sequence of SEQ ID NO:43, or at least 90% sequence identity thereto (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto); (b) a light chain variable (VL) domain comprising an amino acid sequence of SEQ ID NO:44, or at least 90% sequence identity thereto (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto); or (c) a VH domain as in (a) and a VL domain as in (b). Thus, in some examples, the anti-CD79b antibody of polatuzumab vedotin (i.e., polatuzumab) comprises a VH domain comprising the amino acid sequence of SEQ ID NO:43, and a VL domain comprising the amino acid sequence of SEQ ID NO:44.

[0206] In some examples, the anti-CD79b antibody of polatuzumab vedotin (i.e., polatuzumab) comprises: (a) a heavy chain comprising an amino acid sequence of SEQ ID NO:53, or having at least 90% sequence identity thereto (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto); (b) a light chain comprising an amino acid sequence of SEQ ID NO:54, or having at least 90% sequence identity thereto (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto); or (c) a heavy chain as in (a) and a light chain as in (b). Thus, in some examples, the anti-CD79b antibody of polatuzumab vedotin (i.e., polatuzumab) comprises a heavy chain comprising an amino acid sequence of SEQ ID NO:53, and a light chain comprising an amino acid sequence of SEQ ID NO:54.

[0207] The sequence of the anti-CD79b antibody (i.e., polatuzumab) of polatuzumab vedotin (i.e., polatuzumab) is summarized in Table 3 below.

[0208] [Table 3]

[0209] In some examples, the anti-CD79b antibody of polatuzumab vedotin (i.e., polatuzumab) is linked to monomethyl auristatin E (MMAE, i.e., vedotin). In some examples, polatuzumab vedotin (Immunoglobulin G1-kappa auristatin E conjugate, anti-[Homo sapiens CD79b (Immunoglobulin-associated CD79 beta)] is a humanized monoclonal antibody conjugated to auristatin E; gamma 1 heavy chain (1-447) [humanized VH (Homo sapiens IGHV3-23*04 (76.50%) -(IGHD)-IGHJ4*01)[8.8.10](1-117)-Homo sapiens IGHG1*03(CH1R120>K(214)(118-215), hinge(216-230), CH2(231-340), CH3(341-445), CHS(446-447))(118-447)], with kappa light chain(220-218')-disulfide(1'-218')[humanized V-KAPPA(Homo sapiens IGKV1-39*01( 85.90%)-IGKJ1*01)[10.3.9](1'-111')-Homo sapiens IGKC*01(112'-218')]; dimeric (226-226':229-229'')-bisdisulfide; an average of 3-4 cysteinyls are conjugated to monomethylauristatin E (MMAE) via a cleavable maleimidocaproyl-valyl-citrullinyl-p-aminobenzyloxycarbonyl (mc-val-cit-PABC) type linker. Polatuzumab vedotin is a nucleotide analog of polatuzumab vedotin (also known as RG-7596, or RO5541077-000). Polatuzumab vedotin is also known as IUPHAR / BPS number 8404, KEGG number D10761, or CAS#:1313206-42-6. Polatuzumab vedotin is also referred to interchangeably as "polatuzumab vedotin-piiq", "huMA79bv28-MC-vc-PAB-MMAE", or "DCDS4501A".

[0210] In some examples, polatuzumab vedotin has the formula: [ka] wherein Ab is polatuzumab as described herein and p is 1 to 8.

[0211] In some embodiments, polatuzumab vedotin comprises an anti-CD79b antibody (i.e., polatuzumab) comprising a VH as in any of the embodiments provided herein, and a VL as in any of the embodiments provided herein. In some embodiments, polatuzumab vedotin comprises an anti-CD79b antibody (i.e., polatuzumab) comprising a VH and VL sequence having the amino acid sequence of SEQ ID NO: 43 and SEQ ID NO: 44, respectively. In some embodiments, polatuzumab vedotin comprises an anti-CD79b antibody (i.e., polatuzumab) comprising a heavy chain having the amino acid sequence of SEQ ID NO: 53, and a light chain having the amino acid sequence of SEQ ID NO: 54.

[0212] In some embodiments, polatuzumab vedotin comprises a substantially full-length anti-CD79b antibody, such as an IgG1 antibody or other antibody class or isotype described elsewhere herein. Polatuzumab vedotin can be produced using recombinant methods and compositions, for example, as described in U.S. Patent No. 4,816,567. In some examples, polatuzumab vedotin is described in U.S. Patent No. 8,088,378, the entirety of which is incorporated herein by reference.

[0213] C. Additional Therapeutic Agents In some examples, the methods described herein include administering mosunetuzumab and polatuzumab vedotin in combination with one or more additional therapeutic agents.

[0214] In some examples, the one or more additional therapeutic agents may reduce the rate or severity of cytokine release syndrome (CRS). In some examples, the one or more additional therapeutic agents may prevent symptoms associated with CRS. In certain instances, the additional therapeutic agent used to reduce the rate or severity of CRS or to prevent symptoms associated with CRS is a corticosteroid (e.g., dexamethasone (CAS No.: 50-02-2), prednisone (CAS No.: 53-03-2), prednisolone (CAS No.: 50-42-8) or methylprednisolone (CAS No.: 83-43-2) or an IL-6R antagonist (e.g., tocilizumab (CAS No.: 375823-41-9), sarilumab (CAS No.: 1189541-98-7), bovalilizumab (ALX-0061; CAS No.: 1628814-88-9), satralizumab (SA-237; CAS No.: 1535963-91-7), and variants thereof).

[0215] In some examples, the additional therapeutic agent is tocilizumab. In some examples, the additional therapeutic agent is a corticosteroid. In some examples, the corticosteroid is dexamethasone. In some examples, the corticosteroid is prednisone. In some examples, the corticosteroid is methylprednisolone.

[0216] In some examples, the one or more additional therapeutic agents is acetaminophen or paracetamol. Acetaminophen or paracetamol has the CAS number: 103-90-2.

[0217] In some examples, the one or more additional therapeutic agents is diphenhydramine. Diphenhydramine has the CAS number: 58-73-1.

[0218] V. Pharmaceutical Compositions and Formulations Mosunetuzumab and / or polatuzumab vedotin described herein may be used in pharmaceutical compositions and formulations. Pharmaceutical compositions and formulations of mosunetuzumab, polatuzumab vedotin, and / or other therapeutic agents (e.g., dexamethasone, methylprednisolone, prednisone, acetaminophen, paracetamol, and diphenhydramine) described herein may be prepared by mixing one, two, or all three agents with the desired purity in the form of a lyophilized formulation or aqueous solution with one or more optional pharma- ceutically acceptable carriers (Remington's Pharmaceutical Sciences, 16th ed., Osol, A. ed. (1980)). Polatuzumab vedotin may also be formulated according to standard formulation and / or manufacturing practices. Dexamethasone, methylprednisolone, prednisone, acetaminophen, paracetamol, and diphenhydramine may also be formulated according to standard formulation and / or manufacturing practices. Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed and include, for example, buffers such as phosphate, citric acid, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzylammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride; phenol, butyl, or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides. proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as polyethylene glycol (PEG).Exemplary pharma- ceutically acceptable carriers herein further include intermediate drug dispersing agents, such as soluble neutral active hyaluronidase glycoproteins (sHASEGPs), e.g., human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20 (HYLENEX®, Baxter International, Inc.). Several exemplary sHASEGPs, including rHuPH20, and methods of use are described in U.S. Patent Application Publication Nos. 2005 / 0260186 and 2006 / 0104968. In one embodiment, the sHASEGP is combined with one or more additional glycosaminoglycanases (e.g., chondroitinases).

[0219] Exemplary lyophilized antibody formulations are described in U.S. Patent No. 6,267,958. Aqueous antibody formulations include those described in U.S. Patent No. 6,171,586 and WO 2006 / 044908, the latter formulations including histidine acetate buffers.

[0220] The formulations herein may also contain two or more active ingredients as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other.For example, it may be desirable to further provide additional therapeutic agents (e.g., corticosteroids, chemotherapeutic agents, cytotoxic agents, growth inhibitors and / or antihormonal agents, such as those listed hereinabove).Such active ingredients are suitably present in combination in amounts effective for the intended purpose.

[0221] The active ingredient may be encapsulated in microcapsules, such as hydroxymethylcellulose or gelatin-microcapsules and poly-(methyl methacrylate) microcapsules, respectively, prepared, for example, by coacervation techniques or by interfacial polymerization, in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences, 16th Edition, Osol, A. Ed. (1980).

[0222] Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, or microcapsules.

[0223] Formulations to be used for in vivo administration are generally sterile. Sterilization may be readily accomplished, for example, by filtration through sterile filtration membranes.

[0224] In some embodiments, mosunetuzumab is formulated for subcutaneous administration. In some embodiments, polatuzumab vedotin is formulated for intravenous administration. In some embodiments, dexamethasone is formulated for intravenous administration. In some embodiments, dexamethasone is formulated for oral administration. In some embodiments, methylprednisolone is formulated for intravenous administration. In some embodiments, prednisone is formulated for oral administration. In some embodiments, acetaminophen or paracetamol is formulated for oral administration. In some embodiments, diphenhydramine is formulated for oral administration.

[0225] VI. Kits and Products In another aspect of the present invention, a kit or article of manufacture is provided that includes materials useful for treating, preventing, and / or diagnosing disorders. The kit or article of manufacture includes a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, and the like. The container may be formed from a variety of materials, such as glass or plastic. The container holds a composition, alone or in combination with another composition, that is effective for treating, preventing, and / or diagnosing a condition, and may have a sterile access port (e.g., the container may be a vial with a stopper that can be pierced by a hypodermic needle). At least one active agent in the composition is mosunetuzumab or polatuzumab vedotin as described herein. The label or package insert indicates that the composition is used to treat relapsed and / or refractory (R / R) follicular lymphoma (FL) and further includes information related to at least one of the dosing regimens described herein. In some embodiments, the label or package insert indicates that the composition is used to treat a CD20-positive cell proliferative disorder in a subject who is relapsed and / or refractory (R / R) to at least one prior therapy and autologous stem cell transplant (ASCT), or who is R / R to at least two prior therapies. Additionally, the kit or article of manufacture may include (a) a first container having a composition contained therein, the composition comprising mosunetuzumab, polatotuzumab vedotin, or both mosunetuzumab and polatotuzumab vedotin; and (b) a second container having a composition contained therein, the composition comprising an additional therapeutic agent. Examples of additional therapeutic agents include dexamethasone, methylprednisolone, prednisone, acetaminophen, paracetamol, and diphenhydramine. Alternatively, or additionally, the kit or article of manufacture may further comprise a second (or third) container comprising a pharma- ceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution.The article of manufacture may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes. EXAMPLES

[0226] Working Example The following are examples of the methods and compositions of the present invention. Given the general description above, it will be understood that various other embodiments may be practiced.

[0227] Example 1. A Randomized, Open-Label, Multicenter Phase III Study Evaluating the Efficacy and Safety of Mosunetuzumab in Combination with Polatuzumab Vedotin Compared to Rituximab in Combination with Gemcitabine Plus Oxaliplatin (R-GemOx) in Subjects with Relapsed and / or Refractory Aggressive B-Cell Non-Hodgkin's Lymphoma C. Study Design This is a Phase III, open-label, multicenter, randomized controlled trial in subjects with R / R DLBCL, trFL or FL grade 3b who are not candidates for ASCT. Approximately 222 eligible subjects will be randomized in a 2:1 ratio to receive either mosunetuzumab (M) + polatuzumab vedotin (P) (arm A) or R-GemOx (rituximab, gemcitabine, oxaliplatin) (arm B). The trial will evaluate the efficacy and safety of mosunetuzumab compared to R-GemOx in subjects with R / R high-grade non-Hodgkin lymphoma (aNHL), including DLBCL, trFL and FL grade 3b, who have received at least one prior systemic therapy and are not candidates for ASCT. The trial schema is shown in Figure 1.

[0228] Randomization Subjects in this trial will be stratified at randomization for two factors: Number of prior lines of systemic therapy for aggressive lymphoma (1 vs. ≥2) Outcome after last systemic therapy (relapsed vs. refractory)

[0229] Recurrent disease in this study is defined as disease that recurs ≧6 months after completion of the last treatment.

[0230] Refractory disease is defined as disease that has progressed during treatment or within 6 months (<6 months) of last treatment.

[0231] Treatment group A (mosunetuzumab + polatuzumab vedotin) The A treatment group consists of mosunetuzumab administered subcutaneously (SC) and polatuzumab vedotin administered intravenously (IV) (see Figure 2A). One cycle of treatment is 21 days (e.g., a 21-day dosing cycle). Mosunetuzumab is administered at 5 mg SC on cycle 1, day 1 (cycle 1 dose 1; i.e., C1D1); on cycle 1, day 8 (cycle 1 dose 2; i.e., C1D2); on cycle 1, day 15 (cycle 1 dose 3; i.e., C1D3); and on cycles 2-8, days 1 (cycle 2-8 dose 1; i.e., C2D1-C8D1). Polatuzumab vedotin is administered IV at 1.8 mg / kg on day 1 of cycles 1-6 (C1D1-C6D1). Prophylactic (preemptive) or therapeutic use of granulocyte colony-stimulating factor (G-CSF) is permitted. Peripheral neuropathy grade ≤ 1, 1000 / mm 3 ANC of 75,000 / mm 3 If the subject's clinical evaluation and laboratory values ​​are acceptable, including platelet counts ≥ 100%, dosing will occur. Details of each drug administration are provided in the Study Treatment section below.

[0232] Treatment group B (rituximab, gemcitabine, oxaliplatin) The B treatment group consisted of R-GemOx (see FIG. 2B). One cycle of treatment was 14 days (e.g., a 14-day dosing cycle). Rituximab 375 mg / m 2 is given IV on day 1. Gemcitabine 1000 mg / m 2 is given IV on day 1. Oxaliplatin 100 mg / m 2is administered IV on day 1. Prophylactic (preventative) or therapeutic use of G-CSF is permitted at the discretion of the treating physician. 3 ANC of 75,000 / mm 3 If the subject's clinical evaluation and laboratory values, such as a platelet count of 100 mg or more, are acceptable, administration will be performed. If these required hematological parameters are not met within 2 weeks after the last treatment, treatment will be delayed. If such a delay occurs despite prophylactic (preventive) use of GCSF, it is acceptable to change the treatment cycle to every 21 days (e.g., a 21-day administration cycle) instead of 14 days for subsequent treatments. Treatment will be administered for up to 8 cycles. Details of each drug administration are described in the Study Treatment section below. In some examples, the reference population of subjects includes subjects assigned to group B and / or subjects receiving treatment in group B.

[0233] Evaluation during the test All subjects will be monitored for adverse events, clinical laboratory results, and vital signs throughout the study and for at least 90 days after the final dose of study treatment. Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0, except for cytokine release syndrome (CRS) severity, which will be determined according to the American Society for Transplantation and Cellular Therapy (ASTCT) CRS grading criteria CRS (Lee et al. Biol Blood Marrow Transplantation. 25(4):625-638, 2019). Response assessments will be performed according to the 2014 Lugano response criteria (Cheson BD, et al. J Clin Oncol 2014;32:1-9), as assessed by positron emission tomography (PET) / computed tomography. Blood samples will be taken at various time points before and after dosing to characterize the pharmacokinetic (PK) profile and immune response in response to study treatment.

[0234] Inclusion criteria Subjects in this study meet the following inclusion criteria: Subjects who are ≥ 18 years of age at the time they sign the informed consent form Subjects with Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 - Subjects with a life expectancy of at least 12 weeks Subjects with CD20-positive aggressive lymphoma (e.g., aggressive non-Hodgkin lymphoma [aNHL]) as determined by a local hematopathology laboratory from the following diagnoses according to the 2016 World Health Organization Classification of Lymphoid Neoplasms: -Diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) -High-grade B-cell lymphoma (HGBL; NOS or double / triple hit) -Transformed follicular lymphoma (trFL):-Disease must be R / R to standard treatment for trFL - Grade 3b follicular lymphoma (FL) Patients who have received at least one prior systemic therapy for NHL Subjects who have relapsed or become refractory to a prior regimen must meet the following criteria: - Relapse to a prior regimen after a documented history of response (CR or PR) ≥ 6 months from completion of the regimen - Refractory to any preceding regimen, defined as no response to prior therapy or progression within 6 months of completion of the last dose of treatment. Subjects who have received only one prior line of therapy must be ineligible for ASCT. Subjects with measurable disease, defined as at least one bidimensionally measurable nodular lesion defined as >1.5 cm in its longest dimension, or at least one extra bidimensionally measurable nodular lesion defined as >1.0 cm in its longest dimension. Subjects who have pathology reports for the initial histopathology diagnosis and the most recent histopathology diagnosis prior to study entry - Subjects with trFL must also have a completed pathology report at the time of disease transformation Representative tumor specimens and corresponding pathology reports are available for confirmation of diagnosis and biomarker analysis - Requires excision, incision, forceps, or at least one core needle tumor biopsy pre-treatment sample. Cytology or fine needle aspiration samples are not acceptable. - Fresh biopsy is preferred. However, subjects unable to undergo a biopsy procedure may be eligible for study enrollment if they can send to the sponsor an archived sample of tumor tissue obtained after the most recent systemic procedure as a paraffin block or at least 10 unstained slides (preferably 15). - Receipt of tumor samples or central review of diagnoses is not required prior to study enrollment. Subjects with adequate liver, hematology and renal function as defined by the following laboratory values: Liver function: AST and ALT ≤ 2.5 x upper limit of normal (ULN); total bilirubin ≤ 1.5 x ULN; subjects with a documented history of Gilbert's syndrome and elevated total bilirubin accompanied by elevated indirect bilirubin are eligible. Hematological function: Platelet count ≥ 75,000 / mm without transfusion within 14 days prior to first dose of study treatment 3 ;ANC≧1000 / mm 3 total hemoglobin ≥ 9 g / dL without transfusion within 14 days prior to the first dose of study treatment. Subjects with extensive bone marrow involvement of lymphoma and / or disease-related cytopenia (e.g., immune thrombocytopenia) may be enrolled if the following is met: platelet count ≥ 50,000 / mm without transfusion within 14 days of study treatment. 3 ;ANC≧500 / mm 3 have not had a blood transfusion but have hemoglobin within 7 days prior to the first dose of study treatment; Renal function: Creatinine clearance (CrCl) estimated at ≥ 40 mL / min by the Cockroft-Gault method (see Gault MH, Longerich LL, Harnett JD, et al., Nephron 1992, 62:249) or other institutional standard method. · For women of childbearing potential: subjects who agree to abstinence (refraining from sexual intercourse with the opposite sex) or contraception and agree to refrain from donating eggs. For men: Subjects who agree to abstinence (refraining from heterosexual intercourse) or to use condoms and agree to refrain from donating sperm.

[0235] Exclusion criteria Subjects in this study did not meet the following exclusion criteria: Subjects who are pregnant, breastfeeding, or intend to become pregnant during the study or within 3 months after the last dose of mosunetuzumab, 9 months after the last dose of polatuzumab vedotin, 12 months after the last dose of rituximab, 6 months after the last dose of gemcitabine, 9 months after the last dose of oxaliplatin, and 3 months after the last dose of tocilizumab. Women of childbearing potential must have a negative serum pregnancy test result within 7 days prior to the start of study treatment. Subjects who have received prior treatment with mosunetuzumab or other CD20-directed bispecific antibodies, prior treatment with polatuzumab vedotin, and / or prior treatment with R-GemOx or GemOx -Subjects who have a contraindication to any component of the test treatment Subjects with current grade >1 peripheral neuropathy Subjects who have received anti-lymphoma treatment with a monoclonal antibody, radioimmunoconjugate, or ADC within 4 weeks prior to the first dose of study treatment Subjects who have received treatment with any chemotherapy agent or any other anticancer agent (investigational or otherwise) within 4 weeks or 5 half-lives of the drug, whichever is shorter, prior to the first dose of study treatment Subjects who received radiation therapy within 2 weeks prior to the first dose of study treatment - Subjects who have received radiation therapy within 4 weeks prior to the first dose of study treatment must have at least one measurable lesion outside the radiation field. - Subjects with only one measurable lesion who was previously irradiated but has since progressed are eligible Subjects who have had an ASCT within 100 days prior to first study treatment administration -Subjects who received prior treatment with CAR T therapy within 30 days prior to first study treatment administration Subjects who have previously undergone allogeneic SCT -Subjects who have had a solid organ transplant Subjects with a known or suspected history of HLH Subjects with a confirmed history of progressive multifocal leukoencephalopathy Subjects with a history of severe allergic or anaphylactic reactions to monoclonal antibody therapy (or recombinant antibody-related fusion proteins) Subjects with a history of a malignancy treated with curative intent within ≥2 years prior to screening, except for the cancers under investigation in this study and malignancies with negligible risk of metastasis or death (e.g., 5-year OS rate >90%), such as adequately treated intraepithelial neoplasia of the cervix, nonmelanoma skin cancer, localized prostate cancer, ductal carcinoma in situ, or stage I uterine cancer - Subjects with prostate cancer who have no evidence of metastatic disease and have not received active therapy except for antiandrogen therapy may be permitted to participate in the study - Subjects with a history of curatively treated basal or squamous cell carcinoma of the skin or intraepithelial carcinoma of the cervix are permitted - Subjects with malignancies that have been in treatment-free remission for ≥ 2 years prior to first study treatment administration are allowed Subjects with or who have had a past medical history of CNS involvement of lymphoma Subjects with a history of CNS disease that was symptomatic or required treatment within the past year, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease Subjects with significant cardiovascular disease, such as New York Heart Association Class III or IV heart disease, myocardial infarction within the past 6 months, unstable arrhythmia, or unstable angina Subjects with significant active pulmonary disease (e.g., bronchospasm and / or obstructive pulmonary disease) Subjects with a known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of the nail bed) at the time of study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization (associated with completion of a course of antibiotics) within 2 weeks prior to the first study treatment dose Subjects with known or suspected chronic active Epstein-Barr virus (EBV) infection Subjects undergoing major surgery within 4 weeks of the first dose of study treatment. Protocol-specified procedures (e.g., tumor biopsy and bone marrow biopsy) are permitted. Subjects who test positive for chronic hepatitis B infection (defined as positive hepatitis B surface antigen [HBsAg] serology). Subjects with latent or prior hepatitis B infection (defined as positive total hepatitis B core antibody and negative HBsAg) may be included if they have undetectable hepatitis B virus (HBV) DNA at screening. These subjects should be considered for prophylactic antiviral medications (e.g., entecavir) prior to and throughout treatment and should be willing to undergo monthly DNA testing. Subjects with acute or chronic Hepatitis C virus (HCV) infection. Subjects who are HCV antibody positive must be negative for HCV by polymerase chain reaction (PCR) to be eligible for study participation. -Subjects with a history of HIV infection Subjects who have received a live attenuated vaccine within 4 weeks prior to the first dose of study treatment administration or who anticipate that such a live attenuated vaccine will be required during the study. Subjects should not receive a live attenuated vaccine (e.g., FluMist®) while receiving study treatment and after the last dose until B cells have recovered to the normal range. Killed vaccines or toxoids should be administered at least 4 weeks prior to the first dose of study treatment to allow for the development of adequate immunity. Subjects with a history of autoimmune disease, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. - Subjects with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible. - Subjects with type 1 diabetes mellitus who are receiving an insulin regimen and are under control are eligible for the study Subjects who have received systemic immunosuppressive medication (including but not limited to cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF agents) with the exception of corticosteroid treatment ≤ 10 mg / day prednisone or equivalent within 2 weeks of the first dose of study treatment - Subjects receiving acute low-dose systemic immunosuppressants (e.g., a single dose of dexamethasone for nausea or B symptoms) may be enrolled in the study. - Use of inhaled corticosteroids is tolerated - Use of mineralocorticoids for management of orthostatic hypotension is tolerated - Physiologic doses of corticosteroids for the management of adrenal insufficiency are tolerated Subjects who received any study treatment, whether intended to treat lymphoma or not, within 7 days prior to the start of study treatment Subjects with a clinically significant history of liver disease, including viral or other hepatitis, or cirrhosis Subjects with serious medical conditions or abnormalities in clinical laboratory studies that would prevent the subject's safe participation and completion of the study, or that may affect compliance with the protocol or interpretation of the results.

[0236] Study treatments and combination therapies The investigational medicinal products (IMPs) for this study are mosunetuzumab, polatuzumab vedotin, rituximab, gemcitabine, oxaliplatin, and tocilizumab. On the days when the two IMPs are administered, the order of administration in group A should be polatuzumab vedotin followed by mosunetuzumab, and the interval between the end of the polatuzumab vedotin infusion and the mosunetuzumab injection should be at least 60 minutes. In group B, gemcitabine should be administered before oxaliplatin. Administration of rituximab can be either before gemcitabine or after oxaliplatin.

[0237] A. Polatuzumab vedotin The dose of polatuzumab vedotin is 1.8 mg / kg. Polatuzumab vedotin is administered intravenously (IV) on days 1 of cycles 1 through 6 (C1D1 through C6D1). If a subject's weight within the 96 hours prior to day 1 of a given treatment cycle increases or decreases by more than 10% from the weight obtained on day 1 of cycle 1, the most recent weight is used to calculate the dose. The weight that resulted in the dose adjustment is considered the new reference weight for future dose adjustments. All subsequent doses are modified accordingly.

[0238] After reconstitution with sterile water for injection and dilution into an IV bag containing isotonic sodium chloride solution (0.9% NaCl), polatuzumab vedotin is administered by IV infusion using a dedicated standard administration set with 0.2 μM or 0.22 μM in the line filter, with final polatuzumab vedotin concentrations determined by subject-specific dosing.

[0239] The initial dose is administered over 90 (± 10) minutes to well-hydrated subjects. Premedication (e.g., 500-1000 mg oral acetaminophen or paracetamol and 50 ± 100 mg diphenhydramine (per institutional standard practice)) may be administered to individual subjects prior to administration of polatuzumab vedotin. Administration of corticosteroids is permitted at the treating physician's discretion. If infusion-related reactions (IRR) are observed with the first infusion in the absence of premedication, premedication must be administered prior to subsequent doses.

[0240] Polatuzumab vedotin infusions are discontinued or interrupted for subjects experiencing infusion-related symptoms. After the first dose, subjects are observed for 90 minutes for fever, chills, rigors, hypotension, nausea, or other infusion-related symptoms. If the prior infusion is well tolerated, subsequent doses of polatuzumab vedotin are administered over 30 (± 10) minutes, followed by a 30-minute post-infusion observation period. The time interval between the end of the polatuzumab vedotin infusion and the start of the mosunetuzumab injection is at least 60 minutes.

[0241] Mosunetuzumab Mosunetuzumab is administered subcutaneously (SC) in a step-up dosing regimen for cycle 1. The same dosage is used for mosunetuzumab regardless of body weight. In cycle 1, subjects receive mosunetuzumab on day 1 (5 mg; cycle 1 dose 1 (C1D1)), day 8 (45 mg; cycle 1 dose 2 (C1D2)), and day 15 (45 mg; cycle 1 dose 3 (C1D3)). In cycles 2 through 8, subjects receive mosunetuzumab on day 1 (45 mg; cycle 2 dose 1 through cycle 8 dose 1 (C2D1 through C8D1)).

[0242] Mosunetuzumab is delivered by standard medical syringe in a final volume not to exceed 2.0 mL.

[0243] Mosunetuzumab will be administered to well-hydrated subjects. Corticosteroid premedication with 20 mg dexamethasone will be administered prior to administration of each mosunetuzumab dose. Administration of corticosteroid premedication may be optional at the investigator's discretion from cycle 2 onwards. However, if a subject experiences CRS with a preceding dose of mosunetuzumab, steroid premedication must be administered for subsequent doses until no further CRS events are observed. Additionally, premedication with oral acetaminophen or paracetamol (e.g., 500-1000 mg) and / or 50-100 mg diphenhydramine may be administered according to standard institutional practice prior to administration of mosunetuzumab.

[0244] Mosunetuzumab is administered over 30 seconds to 2 minutes. For further details such as syringe size and preferred injection site, please refer to the pharmacy manual. During the first and second cycles, and during subsequent cycles if CRS occurs after the last mosunetuzumab, subjects are observed for at least 30 minutes after administration of mosunetuzumab for fever, chills, rigors, hypotension, nausea, or other signs and symptoms of CRS. Vital signs are recorded before injection (within 30 minutes) and then 30 (± 15) minutes after mosunetuzumab administration. From cycle 3 onwards, if CRS is not present after the last dose of mosunetuzumab, the observation time after mosunetuzumab injection is at least 15 minutes. Vital signs are assessed before mosunetuzumab injection (within 30 minutes before injection) and then at least once after injection during the observation period.

[0245] Tocilizumab Tocilizumab is administered intravenously (IV) only to subjects experiencing a CRS event for which tocilizumab is indicated. Subjects weighing 30 kg or more receive 8 mg / kg tocilizumab in a 100 mL infusion bag or bottle, and subjects weighing more than 30 kg receive 12 mg / kg tocilizumab in a 50 mL infusion bag or bottle. Doses greater than 800 mg per infusion are not recommended. Infusions are administered IV over 60 minutes. Treatment is repeated every 8 hours (up to 4 times) as needed.

[0246] Rituximab Rituximab was administered at 375 mg / m2 by intravenous (IV) infusion on day 1 of each 14-day cycle (Cycles 1 to 8). 2 Rituximab is administered at a dose of 0.1 mg / kg / day. Once the rituximab infusion is complete, the subject will be observed for 30 minutes before the start of another infusion. If the subject is at high risk for infusion-related reactions (IRR) (high tumor burden or high peripheral lymphocyte count), the rituximab infusion may be split over two days. For subjects who experience adverse events during the rituximab infusion, administration of R-GemOx may be continued the next day, if necessary. Rituximab may be administered on the same day before gemcitabine or after oxaliplatin.

[0247] Gemcitabine Gemcitabine was administered at 1000 mg / m on day 1 of each 14-day cycle. 2 Gemcitabine is given intravenously (IV) on the same day as oxaliplatin (Cycles 1-8).

[0248] Oxaliplatin Oxaliplatin was administered at 100 mg / m on day 1 of each 14-day cycle (cycles 1 to 8). 2 Oxaliplatin is given intravenously (IV) on the same day after gemcitabine.

[0249] Acceptable Concomitant Therapies In general, the investigator may manage the subject's care (including pre-existing conditions) through the use of supportive care. Subjects experiencing infusion-related symptoms may treat symptoms with acetaminophen, ibuprofen, diphenhydramine, and / or H2 receptor antagonists (e.g., famotidine, cimetidine), or equivalent agents. Prophylactic use of hematopoietic growth factors or anti-infective agents for viral, fungal, bacterial, or Pneumocystis infections is permitted. Premedication with antihistamines, antipyretics, and / or analgesics is also possible.

[0250] Careful combination therapy Considering the expected pharmacology of mosunetuzumab, the transient release of cytokines (mostly degraded within the first 24 hours of dosing on Cycle 1, Day 1) may suppress CYP450 enzymes, leading to drug-drug interactions. Subjects who may be at highest risk for drug-drug interactions are those receiving concomitant medications that are CYP450 substrates and have narrow therapeutic indices.

[0251] In vitro data suggest that unconjugated MMAE is metabolized primarily by CYP3A4 and, to a lesser extent, by CYP2D6. Based on validated physiologically based PK model simulations (Chen et al. 2015), strong CYP3A4 inhibitors can increase the exposure (e.g., AUC) of unconjugated MMAE by approximately 50%, while the PK of antibody-conjugated monomethyl auristatin E (acMMAE; e.g., polatuzumab vedotin) is unaffected. Caution should be exercised with concomitant medications that are strong CYP3A4 inhibitors, as they may cause adverse effects.

[0252] Cytochrome P450 enzymes in the liver are downregulated by infection and inflammatory stimuli, including cytokines such as IL-6. Inhibition of IL-6 signaling in subjects with rheumatoid arthritis treated with tocilizumab may restore CYP450 activity to a higher level than subjects not treated with tocilizumab, resulting in increased metabolism of drugs that are CYP450 substrates. In vitro studies have shown that tocilizumab has the potential to affect the expression of multiple CYP enzymes, such as CYP1A2, CY2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. The effect of tocilizumab on CYP2C8 or transporters is unknown. In vivo studies with omeprazole (metabolized by CYP2C19 and CYP3A4) and simvastatin (metabolized by CYP3A4) showed up to a 28% and 57% reduction in exposure, respectively, 1 week after administration of a single dose of tocilizumab. The effects of tocilizumab on CYP450 enzyme activity may persist for several weeks after cessation of treatment.

[0253] Prohibited Concomitant Therapies Herbal remedies for the treatment of lymphoma are prohibited. Concomitant therapies aimed at the treatment of cancer (including but not limited to chemotherapy, hormonal therapy, immunotherapy, radiation therapy, and herbal therapy), whether approved by health authorities or experimental, are prohibited for various periods of time, depending on the agent, before initiating study treatment and during study treatment until disease progression is documented and the subject discontinues study treatment. Intrathecal chemotherapy for CNS prophylaxis is permissible. Adjuvant endocrine therapy for non-metastatic hormone receptor positive breast cancer and anti-androgen therapy for non-metastatic prostate cancer are acceptable. · Study treatment, whether or not intended to treat lymphoma, is prohibited within 7 days before and during the start of study treatment. Systemic immunosuppressive therapy is prohibited (except for drugs indicated according to protocol, which include corticosteroids and tocilizumab). Live viral vaccines are prohibited for at least 4 weeks prior to the start of study treatment or at any time during study treatment.

[0254] Efficacy evaluation Subjects will undergo tumor evaluations according to the Lugano Criteria 2014 (Cheson BD, et al. J Clin Oncol 2014;32:1-9) at screening, every 8 weeks for the first 6 months after treatment initiation, and every 3 months until radiological disease progression, study discontinuation, or up to 2 years, whichever occurs first. All measurable and / or evaluable lesions will be assessed and recorded at screening.

[0255] Radiological evaluation Fluorodeoxyglucose (FDG) PET-CT scans, along with diagnostic-quality CT scans, are required for screening, interim response assessment, and end-of-treatment. After treatment is completed, a CT scan (preferably) or FDG PET-CT scan will be performed. A diagnosis of disease progression based on clinical examination will be confirmed radiographically by imaging (e.g., CT scan, FDG PET-CT scan) or histopathologically by biopsy as soon as possible (within 30 days) and prior to the initiation of non-protocol-specified anticancer therapy.

[0256] All measurable and / or evaluable disease will be recorded at screening and reassessed at each subsequent tumor assessment. Response will be assessed by the investigator and IRF based on physical examination, CT scan, and FDGPET-CT scan.

[0257] Bone marrow evaluation Subjects may have a screening PET / CT scan to assess bone marrow involvement. Bone marrow examination is not required unless clinically indicated (Cheson BD, et al. J Clin Oncol 2014;32:1-9).

[0258] Response evaluation Objective response will be determined at specified time points according to the Lugano Response Criteria (Cheson BD, et al. J Clin Oncol 2014;32:1-9).

[0259] Endpoints (e.g., ORR, CRR, PFS, DOR, duration of complete response [DOCR]) will be calculated in the program.

[0260] Safety assessment Adverse events An adverse event is any untoward medical occurrence in a patient or clinical trial subject temporarily associated with the use of a study treatment, whether or not it is considered related to the study treatment.

[0261] The following events meet the definition of an adverse event: Any abnormal clinical laboratory results (haematology, clinical chemistry or urinalysis) or other safety assessments (e.g., ECG, radiology scans, vital sign measurements), e.g., any deterioration from baseline or that, in the investigator's medical and scientific judgment, are considered clinically important (i.e., not related to progression of the underlying disease) · Worsening of a chronic or intermittent pre-existing condition, including an increase in the frequency and / or intensity of the condition -New conditions that may have existed before the start of the study but are detected or diagnosed after administration of the study treatment Signs, symptoms, or clinical sequelae of a suspected drug-drug interaction Signs, symptoms, or clinical sequelae suggestive of an overdose of either the study treatment or concomitant medications Overdose itself is not reported as an adverse event or serious adverse event unless it is an intentional overdose with the potential for suicide or self-harm. Such overdoses are reported regardless of sequelae. "Lack of efficacy" or "failure to achieve expected pharmacological effect" is not, in itself, reported as an adverse event or serious adverse event. Such instances are captured in the efficacy evaluation. However, signs, symptoms and / or clinical sequelae attributable to lack of efficacy are reported as adverse events or serious adverse events if they meet the definition of an adverse event or serious adverse event.

[0262] The investigator will assess the severity of each adverse event reported during the study by use of the NCI CTCAE (v5.0) grading scale.

[0263] Serious Adverse Events A serious adverse event is defined as any untoward medical event at any dose that: results in death; is life-threatening; requires hospitalization of the patient or an extension of an existing hospitalization; results in lasting disability or incapacity; results in a congenital anomaly or birth defect; or other adverse event that is considered a serious adverse event, e.g., intensive care in the emergency room or at home for invasive or malignant cancer, allergic bronchospasm, blood disorders or convulsions, or the development of drug dependence or abuse.

[0264] The terms "severe" and "serious" are not synonymous. Severity refers to the intensity of the adverse event (e.g., rated as mild, moderate, or severe, or rated according to the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] (v5.0)) and the event itself may be relatively medically insignificant (e.g., severe headache with no further findings). Severity and severity should be assessed separately for each adverse event recorded in the eCRF.

[0265] Adverse events of particular interest Adverse events of particular interest (AESIs) for this study include cases of potential drug-induced liver injury, including ALT or AST elevations combined with either elevated bilirubin or clinical jaundice, and cases of suspected transmission of infectious agents due to study treatment. Additionally, AESIs specific to mosunetuzumab or polatuzumab vedotin are as follows: Mosunetuzumab: Grade ≥2 CRS Grade ≥2 neurological adverse events Grade ≥2 injection site reaction - Suspected hepatitis B or macrophage activation syndrome TLS grade ≥ 3 Febrile neutropenia grade ≥ 3 Grade ≥2 elevation of AST, ALT, or total bilirubin Disseminated intravascular coagulation of any grade (minimum grade 2 by definition) Grade ≥2 tumor flare (e.g., development of signs / symptoms related to an increase in size of known nodal or extranodal disease by clinical or radiological assessment, new onset or worsening of pre-existing pleural effusion) Pneumonitis / interstitial lung disease of any grade (excluding pneumonia of infectious etiology) Polatuzumab vedotin: Any grade of TLS (minimum grade 3 by definition) Second malignant tumor

[0266] Pharmacokinetics Serum / plasma samples are collected for measurement of serum / plasma concentrations of mosunetuzumab and polatuzumab vedotin. Samples are used to evaluate the pharmacokinetics of mosunetuzumab and polatuzumab vedotin. Samples collected for analysis of mosunetuzumab and polatuzumab vedotin concentrations may also be used to evaluate safety or efficacy aspects related to concerns that arise during or after the study. These data are also used to understand the relationship of PK exposure to dose and to support characterization of dose / exposure-response relationships in the combination setting. Additionally, these data are used to investigate and characterize potential PK interactions between mosunetuzumab and polatuzumab vedotin.

[0267] Clinical outcome assessment A subject-reported outcome (PRO) instrument will be completed to assess the treatment benefit of mosunetuzumab and polatuzumab vedotin compared to R-GemOx. Additionally, the PRO instrument will allow for the collection of direct empirical data for each subject with mosunetuzumab and polatuzumab vedotin.

[0268] Subject-reported outcome data will be collected using the following instruments: the European Organization for Research and Treatment of Cancer Quality of Life-Core 30 Questionnaire (EORTC QLQ-C30; Aaronson et al. J. Natl Cancer Inst. 1993, 85(5):365-376; Fitzsimmons et al., Eur. J. Cancer. 1999, 35(6):939-941; Functional Assessment of Cancer Therapy-Lymphoma subscale (see FACT Lym LymS; Hlubocky et al., Leuk Lymphoma. 2013, 54(9):1942-1946); Functional Assessment of Cancer Therapy-Gynecologic Oncology Group-Neurotoxicity (FACT / GOG-Ntx; Huang et al., Int. J. Gynecol. Cancer. 2007, 17(2):387-393); and the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L; see EuroQol GroupHealth Policy. 1990, 16(3):199-208; BrooksHealth Policy 1996, 37(1):53-72; Herdman et al. Qual. Life. Res. 2011, 20(10):1727-1736; Janssen et al. Qual. Life. Res. 2013, 22(7):1717-1727).

[0269] Additional samples Additional samples can be obtained from consenting subjects. Additional sample types include tissue samples (e.g., body fluids, solid tissues, and those derived therefrom), blood samples, tumor biopsies. Samples can be used for exploratory biomarker research. Samples can be used for biomolecule extraction (e.g., DNA, RNA, and / or protein extraction).

[0270] Embodiment Some embodiments of the technology described herein may be defined according to any of the following numbered embodiments. 1. A method of treating a subject having a CD20-positive cell proliferative disorder, comprising administering mosunetuzumab subcutaneously to the subject and administering polatuzumab vedotin intravenously to the subject in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle; (a) a first dosing cycle comprises a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, a third dose (C1D3) of mosunetuzumab, and a first dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of mosunetuzumab is about 5 mg, the C1D2 of mosunetuzumab is about 15 mg or about 45 mg, the C1D3 of mosunetuzumab is about 45 mg, and the C1D1 of polatuzumab vedotin is about 1.8 mg / kg; (b) The method, wherein the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab and a single dose (C2D1) of polatuzumab vedotin, wherein the C2D1 of mosunetuzumab is about 45 mg and the C2D1 of polatuzumab vedotin is about 1.8 mg / kg. 2. Mosunetuzumab and polatuzumab vedotin for use in treating a subject having a CD20-positive cell proliferative disorder, wherein the mosunetuzumab is administered subcutaneously to the subject and the polatuzumab vedotin is administered intravenously to the subject in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle; (a) a first dosing cycle comprises a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, a third dose (C1D3) of mosunetuzumab, and a first dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of mosunetuzumab is about 5 mg, the C1D2 of mosunetuzumab is about 15 mg or about 45 mg, the C1D3 of mosunetuzumab is about 45 mg, and the C1D1 of polatuzumab vedotin is about 1.8 mg / kg; (b) Mosunetuzumab and polatuzumab vedotin, wherein the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab and a single dose (C2D1) of polatuzumab vedotin, wherein the C2D1 of mosunetuzumab is about 45 mg and the C2D1 of polatuzumab vedotin is about 1.8 mg / kg. 3. A use of mosunetuzumab and polatuzumab vedotin to treat a subject having a CD20-positive cell proliferative disorder, wherein mosunetuzumab is administered subcutaneously to the subject and polatuzumab vedotin is administered intravenously to the subject in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle; (a) a first dosing cycle comprises a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, a third dose (C1D3) of mosunetuzumab, and a first dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of mosunetuzumab is about 5 mg, the C1D2 of mosunetuzumab is about 15 mg or about 45 mg, the C1D3 of mosunetuzumab is about 45 mg, and the C1D1 of polatuzumab vedotin is about 1.8 mg / kg; (b) The use, wherein the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab and a single dose (C2D1) of polatuzumab vedotin, wherein the C2D1 of mosunetuzumab is about 45 mg and the C2D1 of polatuzumab vedotin is about 1.8 mg / kg. 4. Use of mosunetuzumab in the manufacture of a medicament for use in combination with polatuzumab vedotin to treat a subject having a CD20-positive cell proliferative disorder, wherein mosunetuzumab is administered subcutaneously to the subject and polatuzumab vedotin is administered intravenously to the subject in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle; (a) a first dosing cycle comprises a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, a third dose (C1D3) of mosunetuzumab, and a first dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of mosunetuzumab is about 5 mg, the C1D2 of mosunetuzumab is about 15 mg or about 45 mg, the C1D3 of mosunetuzumab is about 45 mg, and the C1D1 of polatuzumab vedotin is about 1.8 mg / kg; (b) The use, wherein the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab and a single dose (C2D1) of polatuzumab vedotin, wherein the C2D1 of mosunetuzumab is about 45 mg and the C2D1 of polatuzumab vedotin is about 1.8 mg / kg. 5. Use of polatuzumab vedotin in the manufacture of a medicament for use in combination with mosunetuzumab to treat a subject having a CD20-positive cell proliferative disorder, wherein mosunetuzumab is administered subcutaneously to the subject and polatuzumab vedotin is administered intravenously to the subject in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle; (a) a first dosing cycle comprises a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, a third dose (C1D3) of mosunetuzumab, and a first dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of mosunetuzumab is about 5 mg, the C1D2 of mosunetuzumab is about 15 mg or about 45 mg, the C1D3 of mosunetuzumab is about 45 mg, and the C1D1 of polatuzumab vedotin is about 1.8 mg / kg; (b) The use, wherein the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab and a single dose (C2D1) of polatuzumab vedotin, wherein the C2D1 of mosunetuzumab is about 45 mg and the C2D1 of polatuzumab vedotin is about 1.8 mg / kg. 6. Use of mosunetuzumab and polatuzumab vedotin in the manufacture of a medicament for treating a subject having a CD20-positive cell proliferative disorder, wherein mosunetuzumab is administered subcutaneously to the subject and polatuzumab vedotin is administered intravenously to the subject in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle; (a) a first dosing cycle comprises a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, a third dose (C1D3) of mosunetuzumab, and a first dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of mosunetuzumab is about 5 mg, the C1D2 of mosunetuzumab is about 15 mg or about 45 mg, the C1D3 of mosunetuzumab is about 45 mg, and the C1D1 of polatuzumab vedotin is about 1.8 mg / kg; (b) The use, wherein the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab and a single dose (C2D1) of polatuzumab vedotin, wherein the C2D1 of mosunetuzumab is about 45 mg and the C2D1 of polatuzumab vedotin is about 1.8 mg / kg. 7. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to any one of embodiments 1 to 6, wherein C1D2 is about 45 mg. 8. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to any one of embodiments 1 to 6, wherein C1D2 is about 15 mg. 9. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to any one of embodiments 1-8, wherein the first dosing cycle is a 21-day dosing cycle. 10. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 9, wherein C1D1, C1D2 and C1D3 of mosunetuzumab are administered or will be administered on, or about, days 1, 8 and 15 of the first dosing cycle, respectively. 11. The method, mosunetuzumab and polatuzumab vedotin for use, or use according to embodiment 9 or 10, wherein C1D1 of polatuzumab vedotin is or will be administered on day 1 of the first dosing cycle. 12. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to any one of embodiments 1 to 11, wherein the second dosing cycle is a 21-day dosing cycle. 13. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 12, wherein C2D1 of mosunetuzumab is or will be administered on day 1 of the second dosing cycle. 14. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to embodiment 12 or 13, wherein C2D1 of polatuzumab vedotin is or will be administered on day 1 of the second administration cycle. 15. The method, the use of mosunetuzumab and polatuzumab vedotin, or the use according to any one of embodiments 1 to 14, wherein the method further comprises one or more additional administration cycles. 16. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to embodiment 15, wherein the method comprises 4 to 6 additional administration cycles. 17. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to embodiment 16, wherein the method comprises six additional administration cycles. 18. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to embodiment 16 or 17, wherein each additional dosing cycle is a 21-day dosing cycle. 19. The method, for use, or use of mosunetuzumab and polatuzumab vedotin according to any one of embodiments 16-18, wherein one or more of the additional administration cycles comprises an additional single dose of mosunetuzumab and an additional single dose of polatuzumab vedotin. 20. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to embodiment 19, wherein the additional single dose of polatuzumab vedotin is about 1.8 mg / kg. 21. The method, use, or use of mosunetuzumab and polatuzumab vedotin of embodiment 19 or 20, wherein each additional single dose of polatuzumab vedotin is or will be administered to the subject on day 1 of each additional dosing cycle comprising each additional dose of polatuzumab vedotin. 22. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to any one of embodiments 16-21, wherein one or more of the additional administration cycles comprises an additional single dose of mosunetuzumab and does not comprise administration of polatuzumab vedotin. 23. The method, use or use of mosunetuzumab and polatuzumab vedotin according to any one of embodiments 19-22, wherein the single dose of additional mosunetuzumab is about 45 mg. 24. The method, for use, or use of mosunetuzumab and polatuzumab vedotin of any one of embodiments 19-23, wherein each additional single dose of mosunetuzumab is or will be administered to the subject on day 1 of each additional dosing cycle comprising the additional dose of mosunetuzumab. 25. The method, use, or use of mosunetuzumab and polatuzumab vedotin of any one of embodiments 15-24, wherein the dosing regimen comprises six additional dosing cycles, each of the six additional dosing cycles comprising a single dose of mosunetuzumab, and no more than four doses of polatuzumab vedotin are administered among the six additional dosing cycles. 26. A method of treating a subject having a CD20-positive cell proliferative disorder, comprising administering mosunetuzumab subcutaneously to the subject and administering polatuzumab vedotin intravenously to the subject in a dosing regimen comprising eight dosing cycles; (a) a first administration cycle (i) a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, and a third dose (C1D3) of mosunetuzumab, wherein C1D1 of mosunetuzumab is about 5 mg, C1D2 of mosunetuzumab is about 45 mg, and C1D3 of mosunetuzumab is about 45 mg; and (ii) a single dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of polatuzumab vedotin is about 1.8 mg / kg; (b) the second through sixth dosing cycles each comprise a single dose (C2D1-C6D1) of mosunetuzumab and a single dose (C2D1-C6D1) of polatuzumab vedotin, wherein each single dose C2D1-C6D1 of mosunetuzumab is about 45 mg and each single dose C2D1-C6D1 of polatuzumab vedotin is about 1.8 mg / kg; (c) The method, wherein the seventh and eighth administration cycles each comprise a single dose of mosunetuzumab, C7D1 and C8D1, respectively, and do not include administration of polatuzumab vedotin, and wherein each single dose of C7D1 and C8D1 is about 45 mg. 27. Mosunetuzumab and polatuzumab vedotin for use in treating a subject having a CD20-positive cell proliferative disorder, wherein mosunetuzumab is administered subcutaneously to the subject and polatuzumab vedotin is administered intravenously to the subject in a dosing regimen comprising eight dosing cycles; (a) a first dosing cycle comprises a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, a third dose (C1D3) of mosunetuzumab, and a first dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of mosunetuzumab is about 5 mg, the C1D2 of mosunetuzumab is about 15 mg or about 45 mg, the C1D3 of mosunetuzumab is about 45 mg, and the C1D1 of polatuzumab vedotin is about 1.8 mg / kg; (b) The use, wherein the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab and a single dose (C2D1) of polatuzumab vedotin, wherein the C2D1 of mosunetuzumab is about 45 mg and the C2D1 of polatuzumab vedotin is about 1.8 mg / kg. 28. Use of mosunetuzumab and polatuzumab vedotin to treat a subject having a CD20-positive cell proliferative disorder, wherein mosunetuzumab is administered subcutaneously to the subject and polatuzumab vedotin is administered intravenously to the subject in a dosing regimen comprising eight dosing cycles; (a) a first dosing cycle comprises a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, a third dose (C1D3) of mosunetuzumab, and a first dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of mosunetuzumab is about 5 mg, the C1D2 of mosunetuzumab is about 15 mg or about 45 mg, the C1D3 of mosunetuzumab is about 45 mg, and the C1D1 of polatuzumab vedotin is about 1.8 mg / kg; (b) The use, wherein the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab and a single dose (C2D1) of polatuzumab vedotin, wherein the C2D1 of mosunetuzumab is about 45 mg and the C2D1 of polatuzumab vedotin is about 1.8 mg / kg. 29. Use of mosunetuzumab in the manufacture of a medicament for use in combination with polatuzumab vedotin to treat a subject having a CD20-positive cell proliferative disorder, wherein mosunetuzumab is administered subcutaneously to the subject and polatuzumab vedotin is administered intravenously to the subject in a dosing regimen comprising eight dosing cycles; (a) a first dosing cycle comprises a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, a third dose (C1D3) of mosunetuzumab, and a first dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of mosunetuzumab is about 5 mg, the C1D2 of mosunetuzumab is about 15 mg or about 45 mg, the C1D3 of mosunetuzumab is about 45 mg, and the C1D1 of polatuzumab vedotin is about 1.8 mg / kg; (b) The use, wherein the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab and a single dose (C2D1) of polatuzumab vedotin, wherein the C2D1 of mosunetuzumab is about 45 mg and the C2D1 of polatuzumab vedotin is about 1.8 mg / kg. 30. Use of polatuzumab vedotin in the manufacture of a medicament for use in combination with mosunetuzumab to treat a subject having a CD20-positive cell proliferative disorder, wherein mosunetuzumab is administered subcutaneously to the subject and polatuzumab vedotin is administered intravenously to the subject in a dosing regimen comprising eight dosing cycles; (a) a first dosing cycle comprises a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, a third dose (C1D3) of mosunetuzumab, and a first dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of mosunetuzumab is about 5 mg, the C1D2 of mosunetuzumab is about 15 mg or about 45 mg, the C1D3 of mosunetuzumab is about 45 mg, and the C1D1 of polatuzumab vedotin is about 1.8 mg / kg; (b) The use, wherein the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab and a single dose (C2D1) of polatuzumab vedotin, wherein the C2D1 of mosunetuzumab is about 45 mg and the C2D1 of polatuzumab vedotin is about 1.8 mg / kg. 31. Use of mosunetuzumab and polatuzumab vedotin in the manufacture of a medicament for treating a subject having a CD20-positive cell proliferative disorder, wherein mosunetuzumab is administered subcutaneously to the subject and polatuzumab vedotin is administered intravenously to the subject in a dosing regimen comprising eight dosing cycles; (a) a first dosing cycle comprises a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, a third dose (C1D3) of mosunetuzumab, and a first dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of mosunetuzumab is about 5 mg, the C1D2 of mosunetuzumab is about 15 mg or about 45 mg, the C1D3 of mosunetuzumab is about 45 mg, and the C1D1 of polatuzumab vedotin is about 1.8 mg / kg; (b) The use, wherein the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab and a single dose (C2D1) of polatuzumab vedotin, wherein the C2D1 of mosunetuzumab is about 45 mg and the C2D1 of polatuzumab vedotin is about 1.8 mg / kg. 32. A method of treating a subject having a CD20-positive cell proliferative disorder, comprising administering mosunetuzumab subcutaneously to the subject and administering polatuzumab vedotin intravenously to the subject in a dosing regimen comprising eight dosing cycles; (a) a first administration cycle (i) a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, and a third dose (C1D3) of mosunetuzumab, wherein C1D1 of mosunetuzumab is about 5 mg, C1D2 of mosunetuzumab is about 15 mg, and C1D3 of mosunetuzumab is about 45 mg; and (ii) a single dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of polatuzumab vedotin is about 1.8 mg / kg; (b) the second through sixth dosing cycles each comprise a single dose (C2D1-C6D1) of mosunetuzumab and a single dose (C2D1-C6D1) of polatuzumab vedotin, wherein each single dose C2D1-C6D1 of mosunetuzumab is about 45 mg and each single dose C2D1-C6D1 of polatuzumab vedotin is about 1.8 mg / kg; (c) The method, wherein the seventh and eighth administration cycles each comprise a single dose of mosunetuzumab, C7D1 and C8D1, respectively, and do not include administration of polatuzumab vedotin, and wherein each single dose of C7D1 and C8D1 is about 45 mg. 33. Mosunetuzumab and polatuzumab vedotin for use in treating a subject having a CD20-positive cell proliferative disorder, wherein mosunetuzumab is administered subcutaneously to the subject and polatuzumab vedotin is administered intravenously to the subject in a dosing regimen comprising eight dosing cycles; (a) a first dosing cycle comprises a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, a third dose (C1D3) of mosunetuzumab, and a first dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of mosunetuzumab is about 5 mg, the C1D2 of mosunetuzumab is about 15 mg or about 45 mg, the C1D3 of mosunetuzumab is about 45 mg, and the C1D1 of polatuzumab vedotin is about 1.8 mg / kg; (b) The use, wherein the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab and a single dose (C2D1) of polatuzumab vedotin, wherein the C2D1 of mosunetuzumab is about 45 mg and the C2D1 of polatuzumab vedotin is about 1.8 mg / kg. 34. Use of mosunetuzumab and polatuzumab vedotin to treat a subject having a CD20-positive cell proliferative disorder, wherein mosunetuzumab is administered subcutaneously to the subject and polatuzumab vedotin is administered intravenously to the subject in a dosing regimen comprising eight dosing cycles; (a) a first dosing cycle comprises a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, a third dose (C1D3) of mosunetuzumab, and a first dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of mosunetuzumab is about 5 mg, the C1D2 of mosunetuzumab is about 15 mg or about 45 mg, the C1D3 of mosunetuzumab is about 45 mg, and the C1D1 of polatuzumab vedotin is about 1.8 mg / kg; (b) The use, wherein the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab and a single dose (C2D1) of polatuzumab vedotin, wherein the C2D1 of mosunetuzumab is about 45 mg and the C2D1 of polatuzumab vedotin is about 1.8 mg / kg. 35. Use of mosunetuzumab in the manufacture of a medicament for use in combination with polatuzumab vedotin to treat a subject having a CD20-positive cell proliferative disorder, wherein mosunetuzumab is administered subcutaneously to the subject and polatuzumab vedotin is administered intravenously to the subject in a dosing regimen comprising eight dosing cycles; (a) a first dosing cycle comprises a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, a third dose (C1D3) of mosunetuzumab, and a first dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of mosunetuzumab is about 5 mg, the C1D2 of mosunetuzumab is about 15 mg or about 45 mg, the C1D3 of mosunetuzumab is about 45 mg, and the C1D1 of polatuzumab vedotin is about 1.8 mg / kg; (b) The use, wherein the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab and a single dose (C2D1) of polatuzumab vedotin, wherein the C2D1 of mosunetuzumab is about 45 mg and the C2D1 of polatuzumab vedotin is about 1.8 mg / kg. 36. Use of polatuzumab vedotin in the manufacture of a medicament for use in combination with mosunetuzumab to treat a subject having a CD20-positive cell proliferative disorder, wherein mosunetuzumab is administered subcutaneously to the subject and polatuzumab vedotin is administered intravenously to the subject in a dosing regimen comprising eight dosing cycles; (a) a first dosing cycle comprises a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, a third dose (C1D3) of mosunetuzumab, and a first dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of mosunetuzumab is about 5 mg, the C1D2 of mosunetuzumab is about 15 mg or about 45 mg, the C1D3 of mosunetuzumab is about 45 mg, and the C1D1 of polatuzumab vedotin is about 1.8 mg / kg; (b) The use, wherein the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab and a single dose (C2D1) of polatuzumab vedotin, wherein the C2D1 of mosunetuzumab is about 45 mg and the C2D1 of polatuzumab vedotin is about 1.8 mg / kg. 37. Use of mosunetuzumab and polatuzumab vedotin in the manufacture of a medicament for treating a subject having a CD20-positive cell proliferative disorder, wherein mosunetuzumab is administered subcutaneously to the subject and polatuzumab vedotin is administered intravenously to the subject in a dosing regimen comprising eight dosing cycles; (a) a first dosing cycle comprises a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, a third dose (C1D3) of mosunetuzumab, and a first dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of mosunetuzumab is about 5 mg, the C1D2 of mosunetuzumab is about 15 mg or about 45 mg, the C1D3 of mosunetuzumab is about 45 mg, and the C1D1 of polatuzumab vedotin is about 1.8 mg / kg; (b) The use, wherein the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab and a single dose (C2D1) of polatuzumab vedotin, wherein the C2D1 of mosunetuzumab is about 45 mg and the C2D1 of polatuzumab vedotin is about 1.8 mg / kg. 38. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to any one of embodiments 26-37, wherein each dosing cycle is a 21-day dosing cycle. 39. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to embodiment 38, wherein C1D1, C1D2 and C1D3 of mosunetuzumab are administered on days 1, 8 and 15, or about days 1, about 8 and about 15, of the first administration cycle, respectively. 40. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to any one of embodiments 26-39, wherein each single dose of C2D1-C8D1 of mosunetuzumab is administered on day 1 of the respective administration cycle. 41. The method, mosunetuzumab and polatuzumab vedotin for use, or use according to any one of embodiments 26-40, wherein each single dose of C1D1 to C6D1 of polatuzumab vedotin is administered on day 1 of the respective administration cycle. 42. The method, use or use of mosunetuzumab and polatuzumab vedotin according to any one of embodiments 1 to 41, wherein C1D1 of polatuzumab vedotin is or will be administered prior to administration of C1D1 of mosunetuzumab, and C2D1 of polatuzumab vedotin is or will be administered prior to administration of C2D1 of mosunetuzumab. 43. The method, use or use of mosunetuzumab and polatuzumab vedotin according to any one of embodiments 26-42, wherein each single dose C3D1 to C6D1 of polatuzumab vedotin is or will be administered prior to administration of each single dose C3D1 to C6D1 of mosunetuzumab, respectively. 44. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to embodiment 42 or 43, wherein polatuzumab vedotin is administered, or will be administered, at least about 60 minutes prior to administration of mosunetuzumab. 45. The method of any one of embodiments 1, 7-26, 32, and 38-44, further comprising administering one or more additional therapeutic agents to the subject. 46. ​​Mosunetuzumab and polatuzumab vedotin for use according to any one of embodiments 2-25, 27-31, and 33-44, which is for use in combination with one or more additional therapeutic agents. 47. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to embodiment 45 or 46, wherein the one or more additional therapeutic agents are corticosteroids or IL-6R antagonists. 48. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 47, wherein the IL-6R antagonist is tocilizumab. 49. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 48, wherein tocilizumab is or will be administered to the subject as a single dose of about 8 mg / kg, and wherein the single dose does not exceed 800 mg. 50. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 48, wherein tocilizumab is or will be administered to the subject as a single dose of about 12 mg / kg, and wherein the single dose does not exceed 800 mg. 51. The method, use or use of mosunetuzumab and polatuzumab vedotin according to any one of embodiments 48 to 50, wherein tocilizumab is or will be administered intravenously. 52. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to embodiment 47, wherein the one or more additional therapeutic agents are corticosteroids. 53. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to embodiment 52, wherein the corticosteroid is dexamethasone, prednisone, or methylprednisolone. 54. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 53, wherein the corticosteroid is dexamethasone. 55. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to embodiment 54, wherein dexamethasone is or will be administered as a single dose of about 10 mg every 6 hours. 56. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 54 or 55, wherein dexamethasone is or will be administered intravenously. 57. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to embodiment 54, wherein dexamethasone is or will be administered as a single dose of about 20 mg prior to administration of any dose of mosunetuzumab. 58. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 54 or 57, wherein dexamethasone is or will be administered orally. 59. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to embodiment 53, wherein the corticosteroid is methylprednisolone. 60. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to embodiment 59, wherein methylprednisolone is or will be administered in a dose of about 1000 mg / day. 61. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 59 or 60, wherein methylprednisolone is or will be administered intravenously. 62. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to embodiment 53, wherein the corticosteroid is prednisone. 63. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 62, wherein prednisone is or will be administered in a dose of about 10 to 30 mg / day. 64. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 62 or 63, wherein prednisone is administered orally. 65. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to embodiment 45 or 46, wherein the one or more additional therapeutic agents is acetaminophen or paracetamol. 66. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to embodiment 65, wherein acetaminophen or paracetamol is or will be administered as a single dose of about 500 to 1000 mg prior to administration of any dose of polatuzumab vedotin. 67. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 65 or 66, wherein acetaminophen or paracetamol is or will be administered orally. 68. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to embodiment 45 or 46, wherein the one or more additional therapeutic agents is diphenhydramine. 69. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to embodiment 68, wherein diphenhydramine is or will be administered as a single dose of about 50 to 100 mg prior to administration of any dose of polatuzumab vedotin. 70. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 68 or 69, wherein diphenhydramine is or will be administered orally. 71. The method, use or use of mosunetuzumab and polatuzumab vedotin according to any one of embodiments 1 to 70, wherein the CD20-positive cell proliferative disorder is a B-cell proliferative disorder. 72. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 71, wherein the B-cell proliferative disorder is non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), or central nervous system lymphoma (CNSL). 73. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 72, wherein the NHL is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), high-grade B-cell lymphoma (HGBL), mantle cell lymphoma (MCL), high-grade B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma (PMLBCL), diffuse B-cell lymphoma, small lymphocytic lymphoma, marginal zone lymphoma (MZL), Burkitt's lymphoma, or lymphoplasmacytic lymphoma. 74. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 72, wherein the NHL is relapsed and / or refractory (R / R) NHL. 75. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 73, wherein the NHL is DLBCL. 76. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 75, wherein the DLBCL is R / R DLBCL. 77. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 75, wherein the DLBCL is Richter's transformed. 78. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 73, wherein the NHL is FL. 79. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 78, wherein FL is R / R FL. 80. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 78, wherein the FL is transformed FL. 81. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 73, wherein the NHL is HGBL. 82. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 81, wherein HGBL is R / R HGBL. 83. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 72 or 74, wherein the NHL is aggressive NHL. 84. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 83, wherein the aggressive NHL is DLBCL, transformed FL, or grade 3b FL. 85. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to any one of embodiments 1 to 84, wherein the subject is ineligible for autologous stem cell transplantation (ASCT). 86. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to any one of embodiments 1 to 85, wherein the subject has relapsed after two or more prior lines of therapy or is refractory to two or more prior lines of therapy. 87. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to any one of embodiments 1 to 86, wherein the subject is a human. 88. A method of treating a population of subjects having a CD20-positive cell proliferative disorder, comprising administering mosunetuzumab subcutaneously to the subjects of the population and administering polatuzumab vedotin intravenously to the subjects of the population in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle; (a) a first dosing cycle comprises a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, a third dose (C1D3) of mosunetuzumab, and a first dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of mosunetuzumab is about 5 mg, the C1D2 of mosunetuzumab is about 15 mg or about 45 mg, the C1D3 of mosunetuzumab is about 45 mg, and the C1D1 of polatuzumab vedotin is about 1.8 mg / kg; (b) The use, wherein the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab and a single dose (C2D1) of polatuzumab vedotin, wherein the C2D1 of mosunetuzumab is about 45 mg and the C2D1 of polatuzumab vedotin is about 1.8 mg / kg. 89. Mosunetuzumab and polatuzumab vedotin for use in treating a population of subjects having a CD20-positive cell proliferative disorder, wherein the mosunetuzumab is administered subcutaneously to the subjects of the population and the polatuzumab vedotin is administered intravenously to the subjects of the population in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle; (a) a first dosing cycle comprises a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, a third dose (C1D3) of mosunetuzumab, and a first dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of mosunetuzumab is about 5 mg, the C1D2 of mosunetuzumab is about 15 mg or about 45 mg, the C1D3 of mosunetuzumab is about 45 mg, and the C1D1 of polatuzumab vedotin is about 1.8 mg / kg; (b) The use, wherein the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab and a single dose (C2D1) of polatuzumab vedotin, wherein the C2D1 of mosunetuzumab is about 45 mg and the C2D1 of polatuzumab vedotin is about 1.8 mg / kg. 90. Use of mosunetuzumab and polatuzumab vedotin to treat a population of subjects having a CD20-positive cell proliferative disorder, wherein mosunetuzumab is administered subcutaneously to the subjects of the population and polatuzumab vedotin is administered intravenously to the subjects of the population in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle; (a) a first dosing cycle comprises a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, a third dose (C1D3) of mosunetuzumab, and a first dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of mosunetuzumab is about 5 mg, the C1D2 of mosunetuzumab is about 15 mg or about 45 mg, the C1D3 of mosunetuzumab is about 45 mg, and the C1D1 of polatuzumab vedotin is about 1.8 mg / kg; (b) The use, wherein the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab and a single dose (C2D1) of polatuzumab vedotin, wherein the C2D1 of mosunetuzumab is about 45 mg and the C2D1 of polatuzumab vedotin is about 1.8 mg / kg. 91. Use of mosunetuzumab in the manufacture of a medicament for use in combination with polatuzumab vedotin to treat a population of subjects having a CD20-positive cell proliferative disorder, wherein mosunetuzumab is administered subcutaneously to the subjects of the population and polatuzumab vedotin is administered intravenously to the subjects of the population in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle; (a) a first dosing cycle comprises a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, a third dose (C1D3) of mosunetuzumab, and a first dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of mosunetuzumab is about 5 mg, the C1D2 of mosunetuzumab is about 15 mg or about 45 mg, the C1D3 of mosunetuzumab is about 45 mg, and the C1D1 of polatuzumab vedotin is about 1.8 mg / kg; (b) The use, wherein the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab and a single dose (C2D1) of polatuzumab vedotin, wherein the C2D1 of mosunetuzumab is about 45 mg and the C2D1 of polatuzumab vedotin is about 1.8 mg / kg. 92. Use of polatuzumab vedotin in the manufacture of a medicament for use in combination with mosunetuzumab to treat a population of subjects having a CD20-positive cell proliferative disorder, wherein mosunetuzumab is administered subcutaneously to the subjects of the population and polatuzumab vedotin is administered intravenously to the subjects of the population in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle; (a) a first dosing cycle comprises a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, a third dose (C1D3) of mosunetuzumab, and a first dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of mosunetuzumab is about 5 mg, the C1D2 of mosunetuzumab is about 15 mg or about 45 mg, the C1D3 of mosunetuzumab is about 45 mg, and the C1D1 of polatuzumab vedotin is about 1.8 mg / kg; (b) The use, wherein the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab and a single dose (C2D1) of polatuzumab vedotin, wherein the C2D1 of mosunetuzumab is about 45 mg and the C2D1 of polatuzumab vedotin is about 1.8 mg / kg. 93. Use of mosunetuzumab and polatuzumab vedotin in the manufacture of a medicament for treating a population of subjects having a CD20-positive cell proliferative disorder, wherein mosunetuzumab is administered subcutaneously to the subjects of the population and polatuzumab vedotin is administered intravenously to the subjects of the population in a dosing regimen comprising at least a first dosing cycle and a second dosing cycle; (a) a first dosing cycle comprises a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, a third dose (C1D3) of mosunetuzumab, and a first dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of mosunetuzumab is about 5 mg, the C1D2 of mosunetuzumab is about 15 mg or about 45 mg, the C1D3 of mosunetuzumab is about 45 mg, and the C1D1 of polatuzumab vedotin is about 1.8 mg / kg; (b) The use, wherein the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab and a single dose (C2D1) of polatuzumab vedotin, wherein the C2D1 of mosunetuzumab is about 45 mg and the C2D1 of polatuzumab vedotin is about 1.8 mg / kg. 94. A method of treating a population of subjects having a CD20-positive cell proliferative disorder, comprising administering mosunetuzumab subcutaneously to the subjects of the population and administering polatuzumab vedotin intravenously to the subjects of the population in a dosing regimen comprising eight dosing cycles; (a) a first administration cycle (i) a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, and a third dose (C1D3) of mosunetuzumab, wherein C1D1 of mosunetuzumab is about 5 mg, C1D2 of mosunetuzumab is about 45 mg, and C1D3 of mosunetuzumab is about 45 mg; and (ii) a single dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of polatuzumab vedotin is about 1.8 mg / kg; (b) the second through sixth dosing cycles each comprise a single dose (C2D1-C6D1) of mosunetuzumab and a single dose (C2D1-C6D1) of polatuzumab vedotin, wherein each single dose C2D1-C6D1 of mosunetuzumab is about 45 mg and each single dose C2D1-C6D1 of polatuzumab vedotin is about 1.8 mg / kg; (c) The method, wherein the seventh and eighth administration cycles each comprise a single dose of mosunetuzumab, C7D1 and C8D1, respectively, and do not include administration of polatuzumab vedotin, and wherein each single dose of C7D1 and C8D1 is about 45 mg. 95. Mosunetuzumab and polatuzumab vedotin for use in treating a population of subjects having a CD20-positive cell proliferative disorder, wherein mosunetuzumab is administered subcutaneously to the subjects of the population and polatuzumab vedotin is administered intravenously to the subjects of the population in a dosing regimen comprising eight dosing cycles; (a) a first dosing cycle comprises a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, a third dose (C1D3) of mosunetuzumab, and a first dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of mosunetuzumab is about 5 mg, the C1D2 of mosunetuzumab is about 15 mg or about 45 mg, the C1D3 of mosunetuzumab is about 45 mg, and the C1D1 of polatuzumab vedotin is about 1.8 mg / kg; (b) The use, wherein the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab and a single dose (C2D1) of polatuzumab vedotin, wherein the C2D1 of mosunetuzumab is about 45 mg and the C2D1 of polatuzumab vedotin is about 1.8 mg / kg. 96. Use of mosunetuzumab and polatuzumab vedotin to treat a population of subjects having a CD20-positive cell proliferative disorder, wherein mosunetuzumab is administered subcutaneously to the subjects of the population and polatuzumab vedotin is administered intravenously to the subjects of the population in a dosing regimen comprising eight dosing cycles; (a) a first dosing cycle comprises a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, a third dose (C1D3) of mosunetuzumab, and a first dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of mosunetuzumab is about 5 mg, the C1D2 of mosunetuzumab is about 15 mg or about 45 mg, the C1D3 of mosunetuzumab is about 45 mg, and the C1D1 of polatuzumab vedotin is about 1.8 mg / kg; (b) The use, wherein the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab and a single dose (C2D1) of polatuzumab vedotin, wherein the C2D1 of mosunetuzumab is about 45 mg and the C2D1 of polatuzumab vedotin is about 1.8 mg / kg. 97. Use of mosunetuzumab in the manufacture of a medicament for use in combination with polatuzumab vedotin to treat a population of subjects having a CD20-positive cell proliferative disorder, wherein mosunetuzumab is administered subcutaneously to the subjects of the population and polatuzumab vedotin is administered intravenously to the subjects of the population in a dosing regimen comprising eight dosing cycles; (a) a first dosing cycle comprises a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, a third dose (C1D3) of mosunetuzumab, and a first dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of mosunetuzumab is about 5 mg, the C1D2 of mosunetuzumab is about 15 mg or about 45 mg, the C1D3 of mosunetuzumab is about 45 mg, and the C1D1 of polatuzumab vedotin is about 1.8 mg / kg; (b) The use, wherein the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab and a single dose (C2D1) of polatuzumab vedotin, wherein the C2D1 of mosunetuzumab is about 45 mg and the C2D1 of polatuzumab vedotin is about 1.8 mg / kg. 98. Use of polatuzumab vedotin in the manufacture of a medicament for use in combination with mosunetuzumab to treat a population of subjects having a CD20-positive cell proliferative disorder, wherein mosunetuzumab is administered subcutaneously to the subjects of the population and polatuzumab vedotin is administered intravenously to the subjects of the population in a dosing regimen comprising eight dosing cycles; (a) a first dosing cycle comprises a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, a third dose (C1D3) of mosunetuzumab, and a first dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of mosunetuzumab is about 5 mg, the C1D2 of mosunetuzumab is about 15 mg or about 45 mg, the C1D3 of mosunetuzumab is about 45 mg, and the C1D1 of polatuzumab vedotin is about 1.8 mg / kg; (b) The use, wherein the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab and a single dose (C2D1) of polatuzumab vedotin, wherein the C2D1 of mosunetuzumab is about 45 mg and the C2D1 of polatuzumab vedotin is about 1.8 mg / kg. 99. Use of mosunetuzumab and polatuzumab vedotin in the manufacture of a medicament for treating a population of subjects having a CD20-positive cell proliferative disorder, wherein mosunetuzumab is administered subcutaneously to the subjects of the population and polatuzumab vedotin is administered intravenously to the subjects of the population in a dosing regimen comprising eight dosing cycles; (a) a first dosing cycle comprises a first dose (C1D1) of mosunetuzumab, a second dose (C1D2) of mosunetuzumab, a third dose (C1D3) of mosunetuzumab, and a first dose (C1D1) of polatuzumab vedotin, wherein the C1D1 of mosunetuzumab is about 5 mg, the C1D2 of mosunetuzumab is about 15 mg or about 45 mg, the C1D3 of mosunetuzumab is about 45 mg, and the C1D1 of polatuzumab vedotin is about 1.8 mg / kg; (b) The use, wherein the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab and a single dose (C2D1) of polatuzumab vedotin, wherein the C2D1 of mosunetuzumab is about 45 mg and the C2D1 of polatuzumab vedotin is about 1.8 mg / kg. 100. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to any one of embodiments 88 to 99, wherein the mean duration of progression-free survival of the subject population is longer than a reference mean duration of progression-free survival of a reference subject population. 101. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to any one of embodiments 88-99, wherein the complete response rate in the subject population is higher than the reference complete response rate in a reference subject population. 102. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to any one of embodiments 88-99, wherein the objective response rate in the subject population is higher than the reference objective response rate in the reference subject population. 103. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to any one of embodiments 88-99, wherein the mean duration of response of the subject population is longer than the reference mean duration of response of a reference subject population. 104. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to any one of embodiments 88-99, wherein the mean duration of complete response in the subject population is longer than the reference mean duration of complete response in a reference subject population. 105. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to any one of embodiments 100 to 104, wherein the reference population of subjects is or will be administered a combination therapy comprising rituximab, gemcitabine and oxaliplatin. 106. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to embodiment 105, wherein the combination therapy is administered or will be administered to a reference population of subjects in an administration cycle comprising eight administration cycles. 107. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to embodiment 106, wherein each administration cycle is a 14-day administration cycle. 108. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to any one of embodiments 105-107, wherein the combination therapy is or will be administered to a reference population of subjects approximately every two weeks (Q2W). 109. Rituximab is approximately 375 mg / m 2 Gemcitabine is administered intravenously at a dose of approximately 1000 mg / m Q2W every 2 weeks. 2 Administered intravenously Q2W at a dose of approximately 100 mg / m 2 The method, use, or use of any one of embodiments 105-108, wherein the mosunetuzumab and polatuzumab vedotin are administered intravenously every two weeks at a dose of Q2W. 110. The method, mosunetuzumab and polatuzumab vedotin for use, or use according to any one of embodiments 100 to 109, wherein each subject in the reference subject population has a CD20-positive cell proliferative disorder. 111. The method, use or use of mosunetuzumab and polatuzumab vedotin according to any one of embodiments 88 to 110, wherein the CD20-positive cell proliferative disorder is a B-cell proliferative disorder. 112. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 111, wherein the B-cell proliferative disorder is non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), or central nervous system lymphoma (CNSL). 113. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 112, wherein the NHL is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), high-grade B-cell lymphoma (HGBL), mantle cell lymphoma (MCL), high-grade B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma (PMLBCL), diffuse B-cell lymphoma, small lymphocytic lymphoma, marginal zone lymphoma (MZL), Burkitt's lymphoma, or lymphoplasmacytic lymphoma. 114. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 112, wherein the NHL is relapsed and / or refractory (R / R) NHL. 115. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 113, wherein the NHL is DLBCL. 116. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 115, wherein the DLBCL is R / R DLBCL. 117. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 115, wherein the DLBCL is Richter's transformed. 118. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 113, wherein the NHL is FL. 119. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 118, wherein FL is R / R FL. 120. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 118, wherein the FL is transformed FL. 121. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 113, wherein the NHL is HGBL. 122. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 121, wherein HGBL is R / R HGBL. 123. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 112 or 113, wherein the NHL is aggressive NHL. 124. The method, use or use of mosunetuzumab and polatuzumab vedotin according to embodiment 123, wherein the aggressive NHL is DLBCL, transformed FL, or grade 3b FL. 125. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to any one of embodiments 88 to 124, wherein each subject in the subject population is ineligible for autologous stem cell transplantation (ASCT). 126. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to any one of embodiments 88-124, wherein each subject in the subject population has relapsed after two or more prior lines of therapy or is refractory to two or more prior lines of therapy. 127. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to any one of embodiments 88 to 124, wherein each subject in the subject population is a human. 128. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to any one of embodiments 100-124, wherein each subject in the reference subject population is ineligible for autologous stem cell transplantation (ASCT). 129. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to any one of embodiments 100-124, wherein each subject in the reference subject population has relapsed after two or more prior lines of therapy or is refractory to two or more prior lines of therapy. 130. The method, use, or use of mosunetuzumab and polatuzumab vedotin according to any one of embodiments 100 to 124, wherein each subject in the reference subject population is a human.

[0271] Other embodiments The foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, but these descriptions and examples should not be construed as limiting the scope of the invention. The disclosures of all patent and scientific literature cited herein are expressly incorporated by reference in their entirety.

Claims

[Claim 1] An invention as described in the specification.

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