Methods for treating relapsed / refractory follicular lymphoma with mosunetuzumab and lenalidomide

Abstract

The present invention relates to the treatment of subjects with relapsed and / or refractory (R / R) follicular lymphoma (FL). More specifically, the present invention relates to the treatment of subjects with R / R FL by administering a combination of mosunetuzumab and lenalidomide.

Description

[Technical field]

[0001] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on October 29, 2021, is named 50474-262WO2_Sequence_Listing_10_28_21_ST25 and is 23,600 bytes in size.

[0002] FIELD OF THEINVENTION The present invention relates to the treatment of subjects with relapsed and / or refractory (R / R) follicular lymphoma (FL). More specifically, the present invention relates to the combination treatment of subjects with R / R FL who may have received prior treatment with an anti-CD20 antibody (e.g., an anti-CD20 monoclonal antibody, e.g., rituximab or obinutuzumab) or other treatments by administration of mosunetuzumab and lenalidomide. [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 severely impact quality of life. Thus, cancer care 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. Diffuse large B-cell lymphoma (DLBCL) is the most common type of NHL, accounting for approximately 30%-40% of all NHL diagnoses, followed by follicular lymphoma (FL; 20%-25% of all NHL diagnoses and mantle cell lymphoma (MCL; 6%-10% of all NHL diagnoses). B-cell chronic lymphocytic leukemia (CLL) is the most common leukemia in adults, with approximately 15,000 new cases each year in the United States (American Cancer Society 2015).

[0005] Lymphomas of B-cell origin constitute a diverse set of neoplasms within the larger context of non-Hodgkin's lymphoma (NHL). Follicular lymphoma (FL) is the most common subtype of indolent NHL (Al-Hamandi et al. 2015). Despite the biological and clinical heterogeneity of B-cell lymphomas, patients 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 patients, the majority of patients will eventually experience progressive or recurrent disease. FL 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; or bendamustine (Zelenetz et al. 2014, Forstpointer et al. 2006), followed by rituximab maintenance therapy, has resulted in long-term remission and improved patient outcomes. However, treatment with said therapies results in only partial responses, but not complete responses, in the majority of patients with relapsed or refractory (R / R) FL. Thus, multiple recurrent FL remains a disease with high unmet medical need for improved therapies. Summary of the Invention

[0006] The present invention relates to methods of treating subjects with relapsed and / or refractory (R / R) follicular lymphoma (FL) by administration of mosunetuzumab and lenalidomide as a combination therapy. In particular, the present invention relates to methods of treating subjects with R / R FL who are R / R to at least one prior systemic therapy, including an anti-CD20 antibody (e.g., an anti-CD20 monoclonal antibody, e.g., rituximab or obinutuzumab) or other treatment.

[0007] In one aspect, the invention features a method of treating a subject, comprising administering to the subject an effective amount of mosunetuzumab and an effective amount of lenalidomide, wherein the subject (a) has relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20, and (b) has previously been treated with at least one chemoimmunotherapy regimen (e.g., R-CHP (rituximab, cyclophosphamide, doxorubicin, and prednisone), R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone) or BR (bendamustine and rituximab)) (e.g., at least one chemoimmunotherapy comprising an anti-CD20 monoclonal antibody (e.g., rituximab or obinutuzumab)). In some embodiments, the subject has received only one prior line of systemic therapy and either (a) has a Follicular Lymphoma International Prognostic Index (FLIPI; Solal-Celigny et al.. Blood. 2004;104(5):1258-1265.) score of 2-5 (e.g., a score of 2, 3, 4, or 5), (b) is refractory to prior anti-CD20 monoclonal antibody treatment, or (c) has disease progression within 24 months after initiation of prior treatment. In some embodiments, the subject has not been treated with an anti-CD20 monoclonal antibody for at least 4 weeks (e.g., 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 60 weeks, or more) prior to administration of effective amounts of mosunetuzumab and lenalidomide. In some embodiments, mosunetuzumab and lenalidomide have a synergistic effect against R / R FL. In some embodiments, the synergy is a partial response as defined by the Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014;32:1-9). In some embodiments, the synergy is a complete response as defined by the Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014;32:1-9).

[0008] In some embodiments, administering an effective amount of mosunetuzumab comprises administering mosunetuzumab according to a dosing regimen including at least a first dosing cycle and a second dosing cycle, wherein (a) the first dosing cycle includes a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of mosunetuzumab, wherein C1D1 and C1D2 are each equal to or less than C1D3, and C1D1 is between 0.02 mg and 4.0 mg (e.g., 0.05 mg to 4.0 mg, 0.1 mg to 4.0 mg, 0.2 mg to 4.0 mg, 0.3 mg to 4.0 mg, 0.4mg~4.0mg, 0.5mg~4.0mg, 0.75mg~4.0mg, 1.0mg~4.0mg, 1.25mg~4.0mg, 1.5mg~4.0mg, 2.0mg~4.0mg, 2.5mg~4.0mg, 3.0mg~4.0mg, 3.5mg~4.0mg, 0.1 mg~3.5mg, 0.1mg~3.0mg, 0.1mg~2.5mg, 0.1mg~2.0mg, 0.1mg~1.5mg, 0.1mg~1mg, 0.1mg~0.5mg, 0.5mg~3.0mg, 0.5mg~2.0mg, 0.5mg~1.0mg, 0.75mg~1.2 5 mg, 1.0 mg to 3.0 mg, 1.5 mg to 2.0 mg, 0.7 mg to 0.9 mg, or 0.9 mg to 1.1 mg; for example, about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.75 mg, about 2.0 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3.0 mg, about 3.5 mg, or about 4.0 mg), and C1D2 is 0.05 mg ~20.0mg (e.g., 0.1mg~20.0mg, 0.2mg~20.0mg, 0.3mg~20.0mg, 0.4mg~20.0mg, 0.5mg~20.0mg, 1.0mg~20.0mg, 1.5mg~20.0mg, 2.0mg~20.0mg, 3.0mg~20.0mg, 4.0mg~20.0mg, 5.0mg~20.0mg, 6.0mg~20.0mg, 7.0mg~20.0mg, 8.0mg~20.0mg, 9.0mg~20.0mg, 10.0mg~20.0mg, 15.0mg~20.0mg, 0.5mg~15.0mg, 0.5mg-10.0mg, 0.5mg-9.0mg, 0.5mg-8.0mg, 0.5mg-7.0mg, 0.5mg-6.0mg, 0.5mg-5.0mg, 0.5mg-4.0mg, 0.5mg-3.0mg, 0.5mg-2.0mg, 0.5mg-1.0mg, 1.0mg-15.0mg, 1.0mg-10.0mg, 1.0mg-8.0mg, 1.0mg-6.0mg, 1.0mg-4.0mg, 1.0mg-3.0mg, 10.0mg-20.0mg, 15.0mg-20.0mg, 5.0mg-15.0mg, or 5.0mg-10.0mg for example, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 5.0 mg, about 6.0 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 15.0 mg, or about 20.0 mg), and C1D3 is 0.2 mg to 50.0mg (e.g., 0.3mg-50.0mg, 0.4mg-50.0mg, 0.5mg-50.0mg, 1.0mg-50.0mg, 2.0mg-50.0mg, 3.0mg-50.0mg, 4.0mg-50.0mg, 5.0mg-50.0mg, 10.0mg-50.0mg, 15.0mg-50.0mg, 20.0mg-50.0mg, 25.0mg-50.0mg, 30.0mg-50.0mg, 35.0mg-50.0mg, 40.0mg-50.0mg, 45.0mg-50.0mg, 1.0mg-45.0mg, 1.0mg-40. 0mg, 1.0mg~35.0mg, 1.0mg~30.0mg, 1.0mg~25.0mg, 1.0mg~20.0mg, 1.0mg~15.0mg, 1.0mg~10.0mg, 1.0mg~5.0mg, 10.0mg~20.0mg, 20.0mg~30.0mg, 30. 0mg~40.0mg, 5.0mg~25.0mg, 25.0mg~50.0mg, 3.0mg~45.0mg, 3.0mg~50.0mg, 4.0mg~4.5mg, 3.0mg~10.0mg, 4.0mg~5.0mg, 25.0mg~35.0mg, 28.0mg~32.0 mg, 10.0 mg to 30.0 mg, or 20.0 mg to 40.0 mg; for example, about 0.2 mg, about 0.5 mg, about 0.8 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 4.0 mg, about 4.2 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 12.0 mg, about 15.0 mg, about 20.0 mg, about 25.0 mg, about 30.0 mg, about 35.0 mg, about 40.0 mg, about 45.0 mg, or about 50.0 mg). and (b) the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab, where C2D1 is equal to or greater than C1D3 and is between 0.2 mg and 50 mg (e.g., 0.3 mg to 50.0 mg, 0.4 mg to 50.0 mg, 0.5 mg to 50.0 mg, 1.0 mg to 50.0 mg, 2.0 mg to 50.0 mg, 3.0 mg to 50.0 mg, 4.0 mg to 50.0 mg, 5.0 mg to 50.0 mg, 10.0 mg to 50.0 mg, 15.0 mg to 50.0 mg, 20.0 mg to 50.0 mg, 25.0 mg to 50.0 mg, 30.0 mg to 50.0 mg, 35.0 mg ~50.0mg, 40.0mg~50.0mg, 45.0mg~50.0mg, 1.0mg~45.0mg, 1.0mg~40.0mg, 1.0mg~35.0mg, 1.0mg~30.0mg, 1.0mg~25.0mg, 1.0mg~20.0mg, 1.0mg~15.0m g, 1.0mg~10.0mg, 1.0mg~5.0mg, 10.0mg~20.0mg, 20.0mg~30.0mg, 30.0mg~40.0mg, 5.0mg~25.0mg, 25.0mg~50.0mg, 3.0mg~45.0mg, 3.0mg~50.0mg, 4.0 mg to 4.5 mg, 3.0 mg to 10.0 mg, 4.0 mg to 5.0 mg, 25.0 mg to 35.0 mg, 28.0 mg to 32.0 mg, 10.0 mg to 30.0 mg, or 20.0 mg to 40.0 mg; for example, about 0.2 mg, about 0.5 mg, about 0.8 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 4.0 mg, about 4.2 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 12.0 mg, about 15.0 mg, about 20.0 mg, about 25.0 mg, about 30.0 mg, about 35.0 mg, about 40.0 mg, about 45.0 mg, or about 50.0 mg.

[0009] In some embodiments, (a) C1D1 is 0.4 mg to 4.0 mg (e.g., 0.5 mg to 4.0 mg, 0.75 mg to 4.0 mg, 1.0 mg to 4.0 mg, 1.25 mg to 4.0 mg, 1.5 mg to 4.0 mg, 2.0 mg to 4.0 mg, 2.5 mg to 4.0 mg, 3.0 mg to 4.0 mg, 3.5 mg to 4.0 mg, 0.5 mg to 3.5 mg, 0.5 mg to 3.0 mg, 0.5 mg to 2.0 mg, 0.5 mg to 1.0 mg, 0.75 mg to 1.25 mg, 1.0 mg to 3.0 mg, 1.5 mg to 2.0 mg, 0.7 mg to 0.9 mg, or 0 .9 mg to 1.1 mg; for example, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.75 mg, about 2.0 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3.0 mg, about 3.5 mg, or about 4.0 mg, and C1D2 is 1.0 mg to 20.0 mg (e.g., 1.1 mg to 20.0 mg, 1.2 mg to 20.0 mg, 1.3 mg to 20.0 mg, 1.4 mg to 20.0 mg, 1.5 mg to 20.0 mg, 2.0 mg to 20.0 mg, mg~20.0mg, 3.0mg~20.0mg, 4.0mg~20.0mg, 5.0mg~20.0mg, 6.0mg~20.0mg, 7.0mg~20.0mg, 8.0mg~20.0mg, 9.0mg~20.0mg, 10.0mg~20.0mg, 15.0mg~20 .0mg, 1.0mg~15.0mg, 1.0mg~10.0mg, 1.0mg~9.0mg, 1.0mg~8.0mg, 1.0mg~7.0mg, 1.0mg~6.0mg, 1.0mg~5.0mg, 1.0mg~4.0mg, 1.0mg~3.0mg, 1.0mg~2.0 mg, 10.0 mg to 20.0 mg, 15.0 mg to 20.0 mg, 5.0 mg to 15.0 mg, or 5.0 mg to 10.0 mg; for example, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 5.0 mg, about 6.0 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 15.0 mg, or about 20.0 mg) and C1D3 is 3.0 mg to 50.0mg (e.g., 4.0mg to 50.0mg, 5.0mg to 50.0mg, 10.0mg to 50.0mg, 15.0mg to 50.0mg, 20.0mg to 50.0mg, 25.0mg to 50.0mg, 30.0mg to 50.0mg, 35.0mg to 50.0mg, 40.0mg to 50.0mg, 45.0mg to 50.0mg, 3.0mg to 45.0mg, 3.0mg to 40.0mg, 3.0mg to 35.0mg, 3.0mg to 30.0mg, 3.0mg to 25.0mg, 3.0mg to 20.0mg, 3.0mg to 15.0mg, 3.0mg to 10.0mg g, 3.0 mg to 5.0 mg, 10.0 mg to 20.0 mg, 20.0 mg to 30.0 mg, 30.0 mg to 40.0 mg, 5.0 mg to 25.0 mg, 25.0 mg to 50.0 mg, 4.0 mg to 4.5 mg, 4.0 mg to 5.0 mg, 25.0 mg to 35.0 mg, 28.0 mg to 32.0 mg, 10.0 mg to 30.0 mg, or 20.0 mg to 40.0 mg; for example, about 3.0 mg, about 4.0 mg, about 4.2 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 1 and (b) C2D1 is 3.0 mg to 50.0 mg (e.g., 4.0 mg to 50.0 mg, 5.0 mg to 50.0 mg, 10.0 mg to 50.0 mg, 15.0 mg to 50.0 mg, 20.0 mg to 50.0 mg, 25.0 mg to 50.0 mg, 30.0 mg to 50.0 mg, 35.0 mg to 50.0 mg, 40.0 mg to 50.0 mg, 45.0 mg to 50.0 mg). g, 3.0mg~45.0mg, 3.0mg~40.0mg, 3.0mg~35.0mg, 3.0mg~30.0mg, 3.0mg~25.0mg, 3.0mg~20.0mg, 3.0mg~15.0mg, 3.0mg~10.0mg, 3.0mg~5.0mg, 10.0mg ~20.0mg, 20.0mg~30.0mg, 30.0mg~40.0mg, 5.0mg~25.0mg, 25.0mg~50.0mg, 4.0mg~4.5mg, 4.0mg~5.0mg, 25.0mg~35.0mg, 28.0mg~32.0mg, 10.0mg~30.0 mg, or 20.0 mg to 40.0 mg; for example, about 3.0 mg, about 4.0 mg, about 4.2 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 12.0 mg, about 15.0 mg, about 20.0 mg, about 25.0 mg, about 30.0 mg, about 35.0 mg, about 40.0 mg, about 45.0 mg, or about 50.0 mg).

[0010] In some embodiments, (a) C1D1 is in an amount of 0.8 mg to 3.0 mg (e.g., 0.9 mg to 3.0 mg, 1.0 mg to 3.0 mg, 1.25 mg to 3.0 mg, 1.5 mg to 3.0 mg, 2.0 mg to 3.0 mg, 2.5 mg to 3.0 mg, 0.8 mg to 2.5 mg, 0.8 mg to 2.0 mg, 0.5 mg to 1.5 mg, 0.8 mg to 1.0 mg, 1.0 mg to 3.0 mg, 1.5 mg to 2.0 mg, or 0.9 mg to 1.1 mg; e.g., about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, and C1D2 is 1.0 mg to 6.0 mg (e.g., 1.5 mg to 6.0 mg, 2.0 mg to 6.0 mg, 2.5 mg to 6.0 mg, 3.0 mg to 6.0 mg, 3.5 mg to 6.0 mg, 4.0 mg to 6.0 mg, 5.0 mg to 6.0 mg, 5.0 mg to 6.0 mg, 1.0 mg to 5.0 mg, 1.0 mg to 4.5 mg, 1.0 mg to 4.0 mg, 1.0 mg to 3.5 mg, 1.0 mg to 3.0 mg, 1.0 mg to 2.5 ...5.0 mg, 1.0 mg to 5.0 mg, 1.0 mg to 5.0 mg, 1.0 mg to 5.0 mg, 1.0 mg to 5.0 mg, 1.0 mg to 5.0 mg, 1.0 mg to 5.0 mg, 1.0 mg to 5.0 mg, 1.0 mg to 5.0 mg, 1.0 mg to 5.0 mg, 1.0 mg to 5.0 mg, 1.0 mg to 5 0.0mg to 2.0mg, 1.0mg to 1.5mg, 1.5mg to 2.5mg, 3.0mg to 6.0mg, 2.0mg to 4.0mg, 2.5mg to 5.0mg, or 2.5mg to 3.5mg; for example, about 1.0mg, about 1.1mg, about 1.2mg, about 1.3mg, about 1.4mg, about 1.5mg, about 1.6mg, about 1.7mg, about 1.8mg, 1.9mg, about 2.0mg, about 2.1mg, about 2.2mg, about 2.3mg, about 2.4mg, about 2.5mg, about 2.6mg, about 2.7mg, about 2.8mg, about 2.9mg, about 3.0mg, about 3.5mg, about 4.0mg , about 4.5 mg, about 5.0 mg, about 5.5 mg, or about 6.0 mg), and C1D3 is 3.0 mg to 45.0 mg (e.g., 4.0 mg to 45.0 mg, 5.0 mg to 45.0 mg, 10.0 mg to 45.0 mg, 15.0 mg to 45.0 mg, 20.0 mg to 45.0 mg, 25.0 mg to 45.0 mg, 30.0 mg to 45.0 mg, 35.0 mg to 45.0 mg, 40.0 mg to 45.0 mg, 3.0 mg to 40.0 mg, 3.0 mg to 35.0 mg, 3.0 mg to 30.0 mg, 3.0 mg to 25.0 mg, 3.0 mg to 20.0 mg, 3.0 mg to 15.0 mg, 3.0 mg to 10.0 mg, 3.0 mg to 5.0 mg, 10.0 mg to 20.0 mg, 20.0 mg to 30.0 mg, 30.0 mg to 40.0 mg, 5.0 mg to 25.0 mg, 4.0 mg to 4.5 mg, 4.0 mg to 5.0 mg, 25.0 mg to 35.0 mg, 28.0 mg to 32.0 mg, 10.0 mg to 30.0 mg, or 20.0 mg to 40.0 mg; for example, about 3.0 mg, about 4.0 mg, about 4.2 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 12.0 mg, about 15.0 mg, about 20.0 mg, about 25.0 mg, about 30.0 mg, about 35.0 mg, about 40.0 mg, or about 45.0 mg), and (b) C2D1 is 3.0 mg to 45.0 mg (for example, 4.0 mg to 45.0 mg, 5.0 mg to 45.0 mg, 10.0 mg to 45.0 mg, 15.0 mg to 45.0 mg, 20.0 mg to 45.0 mg, 25.0 mg to 45.0 mg, 30.0mg~45.0mg, 35.0mg~45.0mg, 40.0mg~45.0mg, 3.0mg~40.0mg, 3.0mg~35.0mg, 3.0mg~30.0mg, 3.0mg~25.0mg, 3.0mg~20.0mg, 3.0 mg~15.0mg, 3.0mg~10.0mg, 3.0mg~5.0mg, 10.0mg~20.0mg, 20.0mg~30.0mg, 30.0mg~40.0mg, 5.0mg~25.0mg, 4.0mg~4.5mg, 4.0mg~5.0 mg, 25.0 mg to 35.0 mg, 28.0 mg to 32.0 mg, 10.0 mg to 30.0 mg, or 20.0 mg to 40.0 mg; for example, about 3.0 mg, about 4.0 mg, about 4.2 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 12.0 mg, about 15.0 mg, about 20.0 mg, about 25.0 mg, about 30.0 mg, about 35.0 mg, about 40.0 mg, or about 45.0 mg).

[0011] In some embodiments, C1D1 and C1D2 are each smaller than C1D3. In some embodiments, C1D1 and C1D2 are approximately equal. In some embodiments, C1D2 is about 50% to about 250% larger than C1D1 (e.g., C1D2 is about 50% to about 225% larger than C1D1, C1D2 is about 50% to about 200% larger than C1D1, C1D2 is about 50% to about 175% larger than C1D1, C1D2 is about 50% to about 150% larger than C1D1, C1D2 is about 50% to about 125% larger than C1D1). greater than C1D1, C1D2 is about 50% to about 100% greater than C1D1, or C1D2 is about 50% to about 75% greater than C1D1; e.g., C1D2 is about 50% greater than C1D1, C1D2 is about 100% greater than C1D1, C1D2 is about 150% greater than C1D1, C1D2 is about 200% greater than C1D1, or C1D2 is about 250% greater than C1D1).

[0012] In some embodiments, (a) C1D1 is 0.8 mg, C1D2 is 2.0 mg, C1D3 is 4.2 mg, and C2D1 is 4.2 mg; (b) C1D1 is 1.0 mg, C1D2 is 1.0 mg, C1D3 is 3.0 mg, and C2D1 is 30.0 mg; or (c) C1D1 is 1.0 mg, C1D2 is 2.0 mg, C1D3 is 30.0 mg, and C2D1 is 30.0 mg.

[0013] In some embodiments, the length of the first dosing cycle is 21 days (± 1 day). In some embodiments, the method includes administering C1D1, C1D2, and C1D3 to the subject on days 1, 8 (± 1 day), and 15 (± 1 day), or on about days 1, about 8 (± 1 day), and about 15 (± 1 day), respectively, of the first dosing cycle. In some embodiments, the length of the second dosing cycle is 28 days (± 1 day). In some embodiments, the method includes administering C2D1 to the subject on day 1 of the second dosing cycle.

[0014] In some embodiments, the dosing regimen includes one or more additional dosing cycles (e.g., 1 dosing cycle, 2 dosing cycles, 3 dosing cycles, 4 dosing cycles, 5 dosing cycles, 6 dosing cycles, 7 dosing cycles, 8 dosing cycles, 9 dosing cycles, 10 dosing cycles, or more). In some embodiments, the dosing regimen includes 1 to 10 additional dosing cycles (e.g., 1 dosing cycle, 2 dosing cycles, 3 dosing cycles, 4 dosing cycles, 5 dosing cycles, 6 dosing cycles, 7 dosing cycles, 8 dosing cycles, 9 dosing cycles, or 10 dosing cycles). In some embodiments, the dosing regimen includes 10 additional dosing cycles. In some embodiments, the length of each of the one or more additional dosing cycles is 28 days (± 1 day). In some embodiments, each of the one or more additional dosing cycles includes an additional dose of mosunetuzumab. In some embodiments, the methods involve administering each additional dose of mosunetuzumab to the subject on day 1 of each of one or more additional dosing cycles.In some embodiments, each additional dose of mosunetuzumab is between 0.2 mg and 50.0 mg (e.g., 0.3 mg to 50.0 mg, 0.4 mg to 50.0 mg, 0.5 mg to 50.0 mg, 1.0 mg to 50.0 mg, 2.0 mg to 50.0 mg, 3.0 mg to 50.0 mg, 4.0 mg to 50.0 mg, 5.0 mg to 50.0 mg, 10.0 mg to 50.0 mg, 15.0 mg to 50.0 mg, 20.0 mg to 50.0 mg, 25 .0mg~50.0mg, 30.0mg~50.0mg, 35.0mg~50.0mg, 40.0mg~50.0mg, 45.0mg~50.0mg, 1.0mg~45.0mg, 1.0mg~40.0mg, 1. 0mg~35.0mg, 1.0mg~30.0mg, 1.0mg~25.0mg, 1.0mg~20.0mg, 1.0mg~15.0mg, 1.0mg~10.0mg, 1.0mg~5.0mg, 10.0mg~20 0.0 mg, 20.0 mg to 30.0 mg, 30.0 mg to 40.0 mg, 5.0 mg to 25.0 mg, 25.0 mg to 50.0 mg, 3.0 mg to 45.0 mg, 4.0 mg to 4.5 mg, 3.0 mg to 10.0 mg, 4.0 mg to 5.0 mg, 25.0 mg to 35.0 mg, 28.0 mg to 32.0 mg, 10.0 mg to 30.0 mg, or 20.0 mg to 40.0 mg; for example, about 0.2 mg, about 0.5 mg, about 0.8 mg , about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 4.0 mg, about 4.2 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 12.0 mg, about 15.0 mg, about 20.0 mg, about 25.0 mg, about 30.0 mg, about 35.0 mg, about 40.0 mg, about 45.0 mg, or about 50.0 mg). In some embodiments, the dosing regimen comprises 12 dosing cycles comprising mosunetuzumab and 11 dosing cycles comprising lenalidomide.

[0015] In some embodiments, administering an effective amount of mosunetuzumab comprises administering mosunetuzumab according to a dosing regimen comprising 12 dosing cycles, wherein (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of mosunetuzumab, wherein C1D1 and C1D2 are each equal to or less than C1D3, and C1D1 is between 0.02 mg and 4.0 mg (e.g., 0.05 mg and 4.0 mg, 0.1 mg and 4.0 mg, 0.2 mg and 4.0 mg, 0.3 mg and 4.0 mg, 0.4 mg and 4.0 mg, 0.5 mg and 4.0 mg). mg~4.0mg, 0.75mg~4.0mg, 1.0mg~4.0mg, 1.25mg~4.0mg, 1.5mg~4.0mg, 2.0mg~4.0mg, 2.5mg~4.0mg, 3.0mg~4.0mg, 3.5mg~4.0mg, 0.1mg~3.5mg, 0.1mg ~3.0mg, 0.1mg~2.5mg, 0.1mg~2.0mg, 0.1mg~1.5mg, 0.1mg~1mg, 0.1mg~0.5mg, 0.5mg~3.0mg, 0.5mg~2.0mg, 0.5mg~1.0mg, 0.75mg~1.25mg, 1.0mg~3.0m g, 1.5 mg to 2.0 mg, 0.7 mg to 0.9 mg, or 0.9 mg to 1.1 mg; for example, about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.75 mg, about 2.0 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3.0 mg, about 3.5 mg, or about 4.0 mg, and C1D2 is 0.05 mg to 20.0 mg (e.g., 0 .1mg~20.0mg, 0.2mg~20.0mg, 0.3mg~20.0mg, 0.4mg~20.0mg, 0.5mg~20.0mg, 1.0mg~20.0mg, 1.5mg~20.0mg, 2.0mg~20.0mg, 3.0mg~20.0mg, 4.0mg~20. 0mg, 5.0mg~20.0mg, 6.0mg~20.0mg, 7.0mg~20.0mg, 8.0mg~20.0mg, 9.0mg~20.0mg, 10.0mg~20.0mg, 15.0mg~20.0mg, 0.5mg~15.0mg, 0.5mg~10.0mg, 0.5mg to 9.0mg, 0.5mg to 8.0mg, 0.5mg to 7.0mg, 0.5mg to 6.0mg, 0.5mg to 5.0mg, 0.5mg to 4.0mg, 0.5mg to 3.0mg, 0.5mg to 2.0mg, 0.5mg to 1.0mg, 1.0mg to 15.0mg, 1.0mg to 10.0mg, 1.0mg to 8.0mg, 1.0mg to 6.0mg, 1.0mg to 4.0mg, 1.0mg to 3.0mg, 10.0mg to 20.0mg, 15.0mg to 20.0mg, 5.0mg to 15.0mg, or 5.0mg to 10.0mg; for example, about 0.1mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 5.0 mg, about 6.0 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 15.0 mg, or about 20.0 mg), and C1D3 is 0.2 mg to 50.0 mg (e.g., 0 .3mg~50.0mg, 0.4mg~50.0mg, 0.5mg~50.0mg, 1.0mg~50.0mg, 2.0mg~50.0mg, 3.0mg~50.0mg, 4.0mg~50.0mg, 5.0mg~50.0mg, 10.0mg~50.0mg, 15.0mg~ 50.0mg, 20.0mg~50.0mg, 25.0mg~50.0mg, 30.0mg~50.0mg, 35.0mg~50.0mg, 40.0mg~50.0mg, 45.0mg~50.0mg, 1.0mg~45.0mg, 1.0mg~40.0mg, 1.0mg~35 .0mg, 1.0mg-30.0mg, 1.0mg-25.0mg, 1.0mg-20.0mg, 1.0mg-15.0mg, 1.0mg-10.0mg, 1.0mg-5.0mg, 10.0mg-20.0mg, 20.0mg-30.0mg, 30.0mg-40.0mg, 5.0mg-25.0mg, 25.0mg-50.0mg, 3.0mg-45.0mg, 4.0mg-4.5mg, 3.0mg-10.0mg, 4.0mg-5.0mg, 25.0mg-35.0mg, 28.0mg-32.0mg, 10.0mg-30.0mg, or 20.0 mg to 40.0 mg; e.g., about 0.2 mg, about 0.5 mg, about 0.8 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 4.0 mg, about 4.2 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 12.0 mg, about 15.0 mg, about 20.0 mg, about 25.0 mg, about 30.0 mg, about 35.0 mg, about 40.0 mg, about 45.0 mg, or about 50.0 mg), and (b) the second through twelfth dosing cycles are Each contains a single dose (C2D1-C12D1) of mosunetuzumab, where each single dose C2D1-C12D1 is equal to or greater than C1D3 and contains 0.2 mg-50 mg (e.g., 0.3 mg-50.0 mg, 0.4 mg-50.0 mg, 0.5 mg-50.0 mg, 1.0 mg-50.0 mg, 2.0 mg-50.0 mg, 3.0 mg-50.0 mg, 4.0 mg-50.0 mg, 5.0 mg-50.0 mg, 10.0 mg-50.0 mg, 15.0 mg-50.0 mg, 20.0 mg-50.0 mg, 25.0 mg-50.0 mg, 30.0 mg-50.0 mg, 40.0 mg-50.0 mg, 50.0 mg-50.0 mg, 60.0 mg-50.0 mg, 70.0 mg-70.0 mg, 80.0 mg-80.0 mg, 90.0 mg-90.0 mg, 100.0 mg-100.0 mg, 110.0 mg-100.0 mg, 120.0 mg-100.0 mg, 130.0 mg-100.0 mg, 140.0 mg-100.0 mg, 150.0 mg-100.0 mg, 160.0 mg-100.0 mg, 170.0 mg-100.0 mg, 180.0 mg-100.0 mg, 190.0 mg-100.0 mg, 200.0 mg-100.0 mg, 210.0 mg-210.0 mg, 220.0 mg-220.0 mg, 230.0 mg-230 0mg, 35.0mg~50.0mg, 40.0mg~50.0mg, 45.0mg~50.0mg, 1.0mg~45.0mg, 1.0mg~40.0mg, 1.0mg~35.0mg, 1.0mg~30.0mg, 1.0mg~25.0mg, 1.0mg~20.0mg, 1.0mg~15.0mg, 1.0mg~10.0mg, 1.0mg~5.0mg, 10.0mg~20.0mg, 20.0mg~30.0mg, 30.0mg~40.0mg, 5.0mg~25.0mg, 25.0mg~50.0mg, 3.0mg~45.0mg, 4.0mg ~4.5mg, 3.0mg~10.0mg, 4.0mg~5.0mg, 25.0mg~35.0mg, 28.0mg~32.0mg, 10.0mg~30.0mg, or 20.0mg~40.0mg; for example, about 0.2mg, about 0.5mg, about 0.8mg, about 1.0mg, about 1.5mg, about 2.0mg, about 2.5mg, about 3.0mg, about 4.0mg, about 4.2mg, about 4.5mg, about 5.0mg, about 5.5mg, about 6.0mg, about 6.5mg, about 7.0mg, about 8.0mg, about 9.0mg, about 10.0mg, about 12.0mg, about 15.0mg, about 20.0 mg, about 25.0 mg, about 30.0 mg, about 35.0 mg, about 40.0 mg, about 45.0 mg, or about 50.0 mg.

[0016] In some embodiments, (a) C1D1 is 0.4 mg to 4.0 mg (e.g., 0.5 mg to 4.0 mg, 0.75 mg to 4.0 mg, 1.0 mg to 4.0 mg, 1.25 mg to 4.0 mg, 1.5 mg to 4.0 mg, 2.0 mg to 4.0 mg, 2.5 mg to 4.0 mg, 3.0 mg to 4.0 mg, 3.5 mg to 4.0 mg, 0.5 mg to 3.5 mg, 0.5 mg to 3.0 mg, 0.5 mg to 2.0 mg, 0.5 mg to 1.0 mg, 0.75 mg to 1.25 mg, 1.0 mg to 3.0 mg, 1.5 mg to 2.0 mg, 0.7 mg to 0.9 mg, or 0 .9 mg to 1.1 mg; for example, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.75 mg, about 2.0 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3.0 mg, about 3.5 mg, or about 4.0 mg, and C1D2 is 1.0 mg to 20.0 mg (e.g., 1.1 mg to 20.0 mg, 1.2 mg to 20.0 mg, 1.3 mg to 20.0 mg, 1.4 mg to 20.0 mg, 1.5 mg to 20.0 mg, 2.0 mg to 20.0 mg, mg~20.0mg, 3.0mg~20.0mg, 4.0mg~20.0mg, 5.0mg~20.0mg, 6.0mg~20.0mg, 7.0mg~20.0mg, 8.0mg~20.0mg, 9.0mg~20.0mg, 10.0mg~20.0mg, 15.0mg~20 .0mg, 1.0mg~15.0mg, 1.0mg~10.0mg, 1.0mg~9.0mg, 1.0mg~8.0mg, 1.0mg~7.0mg, 1.0mg~6.0mg, 1.0mg~5.0mg, 1.0mg~4.0mg, 1.0mg~3.0mg, 1.0mg~2.0 mg, 10.0 mg to 20.0 mg, 15.0 mg to 20.0 mg, 5.0 mg to 15.0 mg, or 5.0 mg to 10.0 mg; for example, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 5.0 mg, about 6.0 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 15.0 mg, or about 20.0 mg) and C1D3 is 3.0 mg to 50.0mg (e.g., 4.0mg-50.0mg, 5.0mg-50.0mg, 10.0mg-50.0mg, 15.0mg-50.0mg, 20.0mg-50.0mg, 25.0mg-50.0mg, 30.0mg-50.0mg, 35.0mg-50.0mg, 40.0mg-50.0mg, 45.0mg-50.0mg, 3.0mg-45.0mg, 3.0mg-40.0mg, 3.0mg-35.0mg, 3.0mg-30.0mg, 3.0mg-25.0mg, 3.0mg-20.0mg, 3.0mg-15.0mg, 3.0mg-10.0mg , 3.0mg to 5.0mg, 10.0mg to 20.0mg, 20.0mg to 30.0mg, 30.0mg to 40.0mg, 5.0mg to 25.0mg, 25.0mg to 50.0mg, 4.0mg to 4.5mg, 4.0mg to 5.0mg, 25.0mg to 35.0mg, 28.0mg to 32.0mg, 10.0mg to 30.0mg, or 20.0mg to 40.0mg; for example, about 3.0mg, about 4.0mg, about 4.2mg, about 4.5mg, about 5.0mg, about 5.5mg, about 6.0mg, about 6.5mg, about 7.0mg, about 8.0mg, about 9.0mg, about 10. 0 mg, about 12.0 mg, about 15.0 mg, about 20.0 mg, about 25.0 mg, about 30.0 mg, about 35.0 mg, about 40.0 mg, about 45.0 mg, or about 50.0 mg), and (b) each single dose of C2D1 to C12D1 is 3.0 mg to 50.0 mg (e.g., 4.0 mg to 50.0 mg, 5.0 mg to 50.0 mg, 10.0 mg to 50.0 mg, 15.0 mg to 50.0 mg, 20.0 mg to 50.0 mg, 25.0 mg to 50.0 mg, 30.0 mg to 50.0 mg, 35.0 mg to 50.0 mg, 40.0 mg to 50.0 mg, 45.0 mg to 50.0 mg, mg~50.0mg, 3.0mg~45.0mg, 3.0mg~40.0mg, 3.0mg~35.0mg, 3.0mg~30.0mg, 3.0mg~25.0mg, 3.0mg~20.0mg, 3.0mg~15.0mg, 3.0mg~10.0mg, 3.0mg~5.0mg , 10.0mg~20.0mg, 20.0mg~30.0mg, 30.0mg~40.0mg, 5.0mg~25.0mg, 25.0mg~50.0mg, 4.0mg~4.5mg, 4.0mg~5.0mg, 25.0mg~35.0mg, 28.0mg~32.0mg, 10.0 mg to 30.0 mg, or 20.0 mg to 40.0 mg; for example, about 3.0 mg, about 4.0 mg, about 4.2 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 12.0 mg, about 15.0 mg, about 20.0 mg, about 25.0 mg, about 30.0 mg, about 35.0 mg, about 40.0 mg, about 45.0 mg, or about 50.0 mg).

[0017] In some embodiments, (a) C1D1 is from 0.8 mg to 3.0 mg (e.g., 0.9 mg to 3.0 mg, 1.0 mg to 3.0 mg, 1.25 mg to 3.0 mg, 1.5 mg to 3.0 mg, 2.0 mg to 3.0 mg, 2.5 mg to 3.0 mg, 0.8 mg to 3.0 mg, 0.8 mg to 2.5 mg, 0.8 mg to 2.0 mg, 0.5 mg to 1.5 mg, 0.8 mg to 1.0 mg, 1.0 mg to 3.0 mg, 1.5 mg to 2.0 mg, or 0.9 mg to 1.1 mg; e.g., about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.75 mg, about 2.0 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, or about 3.0 mg), and C1D2 is 1.0 mg to 6.0 mg (e.g., 1.5 mg to 6.0 mg, 2.0 mg to 6.0 mg, 2.5 mg to 6.0 mg, 3.0 mg to 6.0 mg, 3.5 mg to 6.0 mg, 4.0 mg to 6.0 mg, 5.0 mg to 6.0 mg, 5.0 mg to 6.0 mg, 1.0 mg to 5.0 mg, 1.0 mg to 4.5 mg, 1.0 mg to 4.0 mg, 1.0 mg to 3.5 mg, 1.0 mg to 3.0 mg, 1.0 mg to 2.5 mg, 1.0 mg to 2.0 mg, 1.0 mg to 1.5 mg, 1.5 mg to 2.5 mg, 3.0 mg to 6.0 mg, 2.0 mg to 4.0 mg, 2.5 mg to 5.0 mg, or 2.5 mg to 3.5 mg; for example, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, or about 6.0 mg), and C1D3 is 3.0 mg to 45.0 mg (e.g., 4.0 mg to 45.0 mg, 5.0 mg to 45.0 mg, 10.0 mg to 45.0 mg, 15.0 mg to 45.0 mg, 20.0 mg to 45.0 mg, 25.0 mg to 45.0 mg, 30.0 mg to 45.0 mg, 35.0 mg to 45.0 mg, 40.0 mg to 45.0 mg, 3.0 mg to 40.0 mg, 3.0 mg to 35.0 mg, 3.0 mg to 30.0 mg, 3.0 mg to 25.0 mg, 3.0 mg to 20.0 mg, 3.0 mg to 15.0 mg, 3.0 mg to 10.0 mg, 3.0 mg to 5.0 mg, 10.0 mg to 20.0 mg, 20.0 mg to 30.0 mg, 30.0 mg to 40.0 mg, 5.0 mg to 25.0 mg, 4.0 mg to 4.5 mg, 4.0 mg to 5.0 mg, 25.0 mg to 35.0 mg, 28.0 mg to 32.0 mg, 10.0 mg to 30.0 mg, or 20.0 mg to 40.0 mg; for example, about 3.0 mg, about 4.0 mg, about 4.2 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 12.0 mg, about 15.0 mg, about 20.0 mg, about 25.0 mg, about 30.0 mg, about 35.0 mg, about 40.0 mg, or about 45.0 mg), and (b) each single dose of C2D1 to C12D1 is 3.0 mg to 45.0 mg (e.g., 4.0 mg to 45.0 mg, 5.0 mg to 45.0 mg, 10.0 mg to 45.0 mg, 15.0 mg to 45.0 mg, 20.0 mg to 45.0 mg, 25 .0mg~45.0mg, 30.0mg~45.0mg, 35.0mg~45.0mg, 40.0mg~45.0mg, 3.0mg~40.0mg, 3.0mg~35.0mg, 3.0mg~30.0mg, 3.0mg~25.0mg, 3.0mg~2 0.0mg, 3.0mg~15.0mg, 3.0mg~10.0mg, 3.0mg~5.0mg, 10.0mg~20.0mg, 20.0mg~30.0mg, 30.0mg~40.0mg, 5.0mg~25.0mg, 4.0mg~4.5mg, 4.0 mg to 5.0 mg, 25.0 mg to 35.0 mg, 28.0 mg to 32.0 mg, 10.0 mg to 30.0 mg, or 20.0 mg to 40.0 mg; for example, about 3.0 mg, about 4.0 mg, about 4.2 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 12.0 mg, about 15.0 mg, about 20.0 mg, about 25.0 mg, about 30.0 mg, about 35.0 mg, about 40.0 mg, or about 45.0 mg).

[0018] In some embodiments, C1D1 and C1D2 are each smaller than C1D3. In some embodiments, C1D2 is about 50% to about 250% larger than C1D1 (e.g., C1D2 is about 50% to about 225% larger than C1D1, C1D2 is about 50% to about 200% larger than C1D1, C1D2 is about 50% to about 175% larger than C1D1, C1D2 is about 50% to about 150% larger than C1D1, C1D2 is about 50% to about 125% larger than C1D1). greater than C1D1, C1D2 is about 50% to about 100% greater than C1D1, or C1D2 is about 50% to about 75% greater than C1D1; e.g., C1D2 is about 50% greater than C1D1, C1D2 is about 100% greater than C1D1, C1D2 is about 150% greater than C1D1, C1D2 is about 200% greater than C1D1, or C1D2 is about 250% greater than C1D1).

[0019] In some embodiments, (a) C1D1 is 0.8 mg, C1D2 is 2.0 mg, and C1D3 is 4.2 mg, and each single dose C2D1-C12D1 is 4.2 mg; (b) C1D1 is 1.0 mg, C1D2 is 1.0 mg, and C1D3 is 3.0 mg, and each single dose C2D1-C12D1 is 30.0 mg; or (c) C1D1 is 1.0 mg, C1D2 is 2.0 mg, and C1D3 is 30.0 mg, and each single dose C2D1-C12D1 is 30.0 mg.

[0020] In some embodiments, the first dosing cycle is 21 days (± 1 day) in length. In some embodiments, the method includes administering C1D1, C1D2, and C1D3 to the subject on days 1, 8 (± 1 day), and 15 (± 1 day), or about days 1, about 8 (± 1 day), and about 15 (± 1 day), respectively, of the first dosing cycle. In some embodiments, the second through twelfth dosing cycles are each 28 days (± 1 day) in length. In some embodiments, the method includes administering each of C2D1 through C12D1 to the subject on day 1 of each respective dosing cycle. In some embodiments, the second through twelfth dosing cycles are each 28 days (± 1 day) in length.

[0021] In some embodiments, mosunetuzumab is administered intravenously.

[0022] In some embodiments, lenalidomide is administered during the second or subsequent cycles. In some embodiments, lenalidomide is not administered during the first cycle. In some embodiments, lenalidomide is administered daily. In some embodiments, lenalidomide is administered daily for the first 21 days of each dosing cycle that includes administration of lenalidomide. In some embodiments, lenalidomide is not administered for the last 7 days of each dosing cycle that includes administration of lenalidomide. In some embodiments, lenalidomide is administered at a dose of 20 mg. In some embodiments, lenalidomide is administered orally.

[0023] In some embodiments, the subject has previously been treated with at least one anti-CD20 monoclonal antibody. In some embodiments, the subject is relapsed or refractory to treatment comprising an anti-CD20 monoclonal antibody. In some embodiments, the anti-CD20 monoclonal antibody is obinutuzumab or rituximab.

[0024] In one aspect, the invention provides a method of treating a subject comprising administering to the subject an effective amount of mosunetuzumab and an effective amount of lenalidomide, wherein the subject (i) has relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20, and (ii) has previously been treated with at least one chemoimmunotherapy regimen comprising obinutuzumab, wherein administering effective amounts of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising at least a first 21 day (± 1 day) dosing cycle and a second 28 day (± 1 day) dosing cycle, wherein (a) the first dosing cycle is administered intravenously on days 1, 8 (± 1 day), and 15 (± 1 day), respectively, of the first dosing cycle. (b) the second dosing cycle comprises a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of mosunetuzumab administered intravenously on day 1 of the second dosing cycle, where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg; (b) the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab administered intravenously on day 1 of the second dosing cycle, where C2D1 is 30 mg; and (c) the second dosing cycle further comprises orally administering 20 mg of lenalidomide daily on days 1-21 of the second dosing cycle.

[0025] In one aspect, the invention provides a method of treating a subject comprising administering to the subject an effective amount of mosunetuzumab and an effective amount of lenalidomide, wherein the subject (i) has relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20, and (ii) has previously been treated with at least one chemoimmunotherapy regimen comprising obinutuzumab, wherein administering effective amounts of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising a first 21 day (± 1 day) dosing cycle and an eleventh or subsequent 28 day (± 1 day) dosing cycle, wherein (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) administered intravenously on days 1, 8 (± 1 day), and 15 (± 1 day), respectively, of the first dosing cycle. (b) a second through a twelfth dosing cycle comprise a single dose (C2D1-C12D1) of mosunetuzumab administered intravenously on day 1 of each dosing cycle, each single dose C2D1-C12D1 being 30 mg; and (c) the second through twelfth dosing cycles further comprise orally administering 20 mg of lenalidomide daily on days 1-21 of each dosing cycle, respectively.

[0026] In one aspect, the invention provides a method of treating a subject comprising administering to the subject an effective amount of mosunetuzumab and an effective amount of lenalidomide, wherein the subject (i) has relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20, and (ii) has previously been treated with at least one chemoimmunotherapy regimen comprising rituximab, wherein administering effective amounts of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising at least a first 21 day (± 1 day) dosing cycle and a second 28 day (± 1 day) dosing cycle, wherein (a) the first dosing cycle is administered on days 1, 8 (± 1 day), and 15 (± 1 day), respectively, of the first dosing cycle. (b) the second dosing cycle comprises a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of mosunetuzumab administered on day 1 of the second dosing cycle, where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg; (b) the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab administered on day 1 of the second dosing cycle, where C2D1 is 30 mg; and (c) the second dosing cycle further comprises orally administering 20 mg of lenalidomide daily on days 1-21 of the second dosing cycle.

[0027] In one aspect, the invention provides a method of treating a subject comprising administering to the subject an effective amount of mosunetuzumab and an effective amount of lenalidomide, wherein the subject (i) has relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20, and (ii) has previously been treated with at least one chemoimmunotherapy regimen comprising rituximab, wherein administering effective amounts of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising a first 21 day (± 1 day) dosing cycle and an eleventh or subsequent 28 day (± 1 day) dosing cycle, wherein (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) administered intravenously on days 1, 8 (± 1 day), and 15 (± 1 day), respectively, of the first dosing cycle. (b) a second through a twelfth dosing cycle comprise a single dose (C2D1-C12D1) of mosunetuzumab administered intravenously on day 1 of each dosing cycle, each single dose C2D1-C12D1 being 30 mg; and (c) the second through twelfth dosing cycles further comprise orally administering 20 mg of lenalidomide daily on days 1-21 of each dosing cycle, respectively.

[0028] In some embodiments, the subject has received only one prior line of systemic therapy and either (a) has a Follicular Lymphoma International Prognostic Index (FLIPI; Solal-Celigny et al. Blood. 2004;104(5):1258-1265.) score of 2-5 (e.g., a score of 2, 3, 4, or 5), (b) is refractory to prior obinutuzumab treatment, (c) is refractory to prior rituximab treatment, or (d) has disease progression within 24 months after initiation of prior therapy. In some embodiments, the subject has not been treated with mosunetuzumab or rituximab for at least 4 weeks (e.g., 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 60 weeks, or more) prior to administration of an effective amount of mosunetuzumab and lenalidomide.

[0029] In some embodiments, mosunetuzumab and lenalidomide have a synergistic effect on R / R FL. In some embodiments, the synergy is a partial response as defined by the Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014;32:1-9). In some embodiments, the synergy is a complete response as defined by the Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014;32:1-9).

[0030] In some embodiments, the FL is histologically documented to be grade 1, 2 or 3a, but not 3b, according to the World Health Organization Classification of Lymphoid Neoplasms (referred to in Swerdlow SH, et al. Blood 2016;127:2375-90).

[0031] In one aspect, the invention provides a method of treating a population of subjects comprising administering an effective amount of mosunetuzumab and an effective amount of lenalidomide to each subject in the population, wherein each subject (a) has relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20, and (b) has been previously treated with at least one chemoimmunotherapy regimen, wherein administering effective amounts of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising at least a first 21 day (± 1 day) dosing cycle and a second 28 day (± 1 day) dosing cycle, wherein (a) the first dosing cycle comprises a first dosing cycle administered intravenously on days 1, 8 (± 1 day), and 15 (± 1 day), respectively, of the first dosing cycle. (b) the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab administered intravenously on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and (c) the second dosing cycle further comprises orally administering 20 mg of lenalidomide daily on days 1-21 of the second dosing cycle. In some embodiments, at least one chemoimmunotherapeutic regimen included an anti-CD20 monoclonal antibody (e.g., rituximab or obinutuzumab).

[0032] In one aspect, the invention provides a method of treating a population of subjects comprising administering an effective amount of mosunetuzumab and an effective amount of lenalidomide to each subject in the population, wherein each subject (a) has relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20, and (b) has been previously treated with at least one chemoimmunotherapy regimen, wherein administering effective amounts of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising a first 21 day (± 1 day) dosing cycle and an eleventh or subsequent 28 day (± 1 day) dosing cycle, wherein (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3), each administered intravenously on days 1, 8 (± 1 day), and 15 (± 1 day), respectively, of the first dosing cycle. (b) a second through a twelfth dosing cycle each comprise a single dose (C2D1-C12D1) of mosunetuzumab administered intravenously on day 1 of each dosing cycle, each single dose C2D1-C12D1 being 30 mg, and (c) a second through a twelfth dosing cycle each further comprise orally administering 20 mg of lenalidomide daily on days 1-21 of each dosing cycle, in some embodiments, at least one chemoimmunotherapeutic regimen included an anti-CD20 monoclonal antibody (e.g., rituximab or obinutuzumab).

[0033] In some embodiments, each subject has received only one prior line of systemic therapy and either (a) has a Follicular Lymphoma International Prognostic Index (FLIPI; Solal-Celigny et al. Blood. 2004;104(5):1258-1265.) score of 2-5 (e.g., a score of 2, 3, 4, or 5), (b) is refractory to prior anti-CD20 monoclonal antibody treatment, or (c) has progressive disease within 24 months after initiation of prior treatment.

[0034] In some embodiments, each subject's FL is histologically documented to be grade 1, 2, or 3a, but not 3b, according to the World Health Organization Classification of Lymphoid Neoplasms (referenced in Swerdlow SH, et al. Blood 2016;127:2375-90).

[0035] In some embodiments, each subject has not been treated with an anti-CD20 monoclonal antibody for at least 4 weeks (e.g., 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 60 weeks, or more) prior to administration of effective amounts of mosunetuzumab and lenalidomide.

[0036] In some embodiments, mosunetuzumab and lenalidomide have a synergistic effect on R / R FL. In some embodiments, the synergy is a partial response as defined by the Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014;32:1-9). In some embodiments, the synergy is a complete response as defined by the Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014;32:1-9).

[0037] In some embodiments, the incidence of adverse events is not significantly higher than when mosunetuzumab is administered alone to a population of subjects.

[0038] In some embodiments, the incidence of adverse events is not significantly higher than if lenalidomide is not administered to the subject population.

[0039] In some embodiments, the American Society for Transplant and Cellular Therapy (ASTCT) Consensus Grading for Cytokine Release Syndrome ("ASTCT CRS Grading"; Lee et al., Biol Blood Marrow Transplant The incidence of cytokine release syndrome as defined by the International Journal of Clinical Oncology (2019) is less than 45% (e.g., less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, less than 3%, or less than 1%; e.g., about 0% to about 50%, about 5% to about 40%, about 5% to about 20%, about 5% to about 10%, about 20% to about 45%, about 30% to about 40%, about 20% to about 40%, about 15% to about 35%, about 15% to about 25%, about 35% to about 45%, or about 25% to about 45%; e.g., about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, about 5%, about 1%, or about 0%). In some embodiments, the incidence of cytokine release syndrome as defined by the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading on Cytokine Release Syndrome ("ASTCT CRS Grading") is less than 35%. In some embodiments, the incidence of cytokine release syndrome as defined by the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading on Cytokine Release Syndrome ("ASTCT CRS Grading") is less than 25%.

[0040] In some embodiments, the incidence of cytokine release syndrome having a grade of 3 or greater as defined by the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading on Cytokine Release Syndrome ("ASTCT CRS Grading") is less than 10% (e.g., less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%; e.g., 0%-10%, 0%-9%, 0%-8%, 0%-7%, 0%-6%, 0%-5%, 0%-4%, 0%-3%, 0%-2%, 0%-1%, 1%-3%, 1%-5%, 1%-10%, 3%-5%, 5%-8%, 5%-10%, 8%-10%). In some embodiments, the incidence of cytokine release syndrome having a grade of 3 or greater as defined by the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading on Cytokine Release Syndrome ("ASTCT CRS Grading") is less than 5%. In some embodiments, the incidence of Grade 3 or higher cytokine release syndrome as defined by the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading on Cytokine Release Syndrome ("ASTCT CRS Grading") is less than 3%. In some embodiments, the incidence of Grade 3 or higher cytokine release syndrome as defined by the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading on Cytokine Release Syndrome ("ASTCT CRS Grading") is less than 1%.

[0041] In some embodiments, the incidence of neutropenia is less than 40% (e.g., less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, less than 3%, or less than 1%; e.g., about 0% to about 40%, about 5% to about 40%, about 5% to about 20%, about 5% to about 10%, about 20% to about 40%, about 30% to about 40%, about 15% to about 35%, about 15% to about 25%, about 35% to about 40%, or about 25% to about 40%; e.g., about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, about 5%, about 3%, about 1%, or about 0%). In some embodiments, the incidence of neutropenia is less than 30%. In some embodiments, the incidence of neutropenia is less than 20%.

[0042] In some embodiments, the overall response rate is at least 80% (e.g., at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more; e.g., at least 8 0%-100%, 85-100%, 87-100%, 90-100%, 95-100%, 80%-90%, 80-85%, 85-97%, 85-95%, 85-90%, 85-87%, 90-95%, or 93-97%; e.g., about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more). In some embodiments, the overall response rate is at least 90%. In some embodiments, the overall response rate is at least 95%. In some embodiments, the overall response rate is at least 99%.

[0043] In some embodiments, the complete response rate is at least 65% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more; e.g., 65-100%, 75-100%, 85-100%, 95-100%, 65-90%, 65-80%, 65-70%, 65-75%, or 75-85%; e.g., about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 80%, about 85%, about 90%, or more). In some embodiments, the complete response rate is at least 75%. In some embodiments, the complete response rate is at least 85%.

[0044] In some embodiments, each subject has been previously treated with at least one anti-CD20 monoclonal antibody, hi some embodiments, the anti-CD20 monoclonal antibody is obinutuzumab or rituximab.

[0045] In some embodiments, the subject is a human. In some embodiments, each subject in the population is a human.

[0046] In some embodiments, the subject shows a reduction in tumor burden after being administered an effective amount of mosunetuzumab and an effective amount of lenalidomide.In some embodiments, the reduction in tumor burden is determined by computed tomography (CT).In some embodiments, the reduction in tumor burden is a reduction in the sum of product diameters (SPD) of target lesions. In some embodiments, the reduction in SPD is at least 40% (e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more; e.g., 40-100%, 40-80%, 40-60%, 50-70%, 70-90%, 75-85%, 60-100%, 55-65%, 80-100%; e.g., about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%). In some embodiments, the reduction in SPD is at least 60%. In some embodiments, the reduction in SPD is at least 80%.

[0047] In some embodiments, at least 45% of the subjects in the population (e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more; e.g., 45-100%, 45-80%, 45-60%, 50-70%, 55-65%, 70-90%, 70-80%, 60-100%, 80-100%; e.g., about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%) exhibit a reduction in tumor burden after being administered an effective amount of mosunetuzumab and an effective amount of lenalidomide. In some embodiments, at least 60% of the subjects in the population show a reduction in tumor burden after being administered an effective amount of mosunetuzumab and an effective amount of lenalidomide. In some embodiments, at least 75% of the subjects in the population show a reduction in tumor burden after being administered an effective amount of mosunetuzumab and an effective amount of lenalidomide. In some embodiments, the reduction in tumor burden is determined by computed tomography (CT).

[0048] In some embodiments, the reduction in tumor burden is a reduction in the sum of product diameters (SPD) of target lesions. In some embodiments, the reduction in SPD is at least 40% (e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more; e.g., 40-100%, 40-80%, 40-60%, 50-70%, 70-90%, 75-85%, 60-100%, 55-65%, 80-100%; e.g., about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%). In some embodiments, the reduction in SPD is at least 60%. In some embodiments, the reduction in SPD is at least 80%.

[0049] In some embodiments, the dosing regimen further comprises administration of a corticosteroid. In some embodiments, the corticosteroid is administered to the subject during a first dosing cycle. In some embodiments, the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of a corticosteroid. In some embodiments, the corticosteroids C1D1, C1D2, and C1D3 are administered to the subject on days 1, 8 (± day 1), and 15 (± day 1), respectively, of the first dosing cycle. In some embodiments, each single dose C1D1-C1D3 of the corticosteroid is administered to the subject prior to administration of C1D1-C1D3 of mosunetuzumab, respectively. In some embodiments, each single dose of corticosteroid C1D1-C1D3 is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 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 prior to administration of each of mosunetuzumab C1D1-C1D3.

[0050] In some embodiments, a corticosteroid is administered to the subject in the first dosing cycle and not in the second dosing cycle.

[0051] In some embodiments, a corticosteroid is administered to the subject in the second dosing cycle. In some embodiments, the second dosing cycle comprises a single dose (C2D1) of a corticosteroid. In some embodiments, the C2D1 corticosteroid is administered to the subject on day 1 of the second dosing cycle. In some embodiments, the C2D1 corticosteroid is administered to the subject prior to administration of C2D1 mosunetuzumab. In some embodiments, the C2D1 corticosteroid is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 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 prior to administration of the C2D1 mosunetuzumab.

[0052] In some embodiments, the dosing regimen further comprises administration of a corticosteroid. In some embodiments, the corticosteroid is administered to the subject during a first dosing cycle. In some embodiments, the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of a corticosteroid. In some embodiments, the corticosteroids C1D1, C1D2, and C1D3 are administered to the subject on days 1, 8 (± day 1), and 15 (± day 1), respectively, of the first dosing cycle. In some embodiments, each single dose C1D1-C1D3 of the corticosteroid is administered to the subject prior to administration of C1D1-C1D3 of mosunetuzumab, respectively. In some embodiments, each single dose of corticosteroid C1D1-C1D3 is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 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 prior to administration of each of mosunetuzumab C1D1-C1D3.

[0053] In some embodiments, a corticosteroid is administered to the subject in the first dosing cycle and not in the second dosing cycle.

[0054] In some embodiments, a corticosteroid is administered to the subject in the second dosing cycle. In some embodiments, the second dosing cycle comprises a single dose (C2D1) of a corticosteroid. In some embodiments, the C2D1 corticosteroid is administered to the subject on day 1 of the second dosing cycle. In some embodiments, the C2D1 corticosteroid is administered to the subject prior to administration of C2D1 mosunetuzumab. In some embodiments, the C2D1 corticosteroid is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 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 prior to administration of the C2D1 mosunetuzumab.

[0055] In some embodiments, each additional dosing cycle comprises administering an additional dose of a corticosteroid to the subject. In some embodiments, each additional dose of a corticosteroid is administered on day 1 of each additional dosing cycle. In some embodiments, each additional dose of a corticosteroid is administered to the subject prior to administration of each additional dose of mosunetuzumab. In some embodiments, each additional dose of a corticosteroid is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 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 prior to administration of each additional dose of mosunetuzumab.

[0056] In some embodiments, the corticosteroid is administered intravenously. In some embodiments, the corticosteroid is dexamethasone. In some embodiments, each dose of dexamethasone is about 10 mg (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg). [Brief description of the drawings]

[0057] [Figure 1A] Figure 1A is a schematic diagram of the study design described in Example 1 for the dosing regimen of the combination therapy of mosunetuzumab and lenalidomide. C = cycle; D = day; FL = follicular lymphoma; IMC = internal monitoring committee; IV = intravenous; Len = lenalidomide; Mosun = mosunetuzumab; RP2D = recommended phase II dose; R / R = relapsed or refractory. Note: Cycle 1 is 21 days; cycle 2 and beyond are 28 days. [Figure 1B] 1B is a schematic diagram of the dosing regimen described in Example 1. Lenalidomide is initiated in cycle 2 to minimize risk from initiating mosunetuzumab during cycle 1 when CRS risk is highest. [Diagram 2] Figure 2 is a butterfly plot showing adverse events occurring in ≥10% of safety-evaluable patients described in Example 1, classified by MedDRA system organ class and MedDRA preferred terminology. Based on MedDRA version 23.1. Grades of adverse events are shown in the legend. Left side shows all adverse events. Right side shows adverse events attributable to treatment with mosunetuzumab (Mosun) or lenalidomide. Clinical Cut-off Date (CCOD) of April 5, 2021. [Diagram 3]Figure 3 is a butterfly plot showing adverse events occurring in ≥10% of safety-evaluable patients as described in Example 1, classified by MedDRA system organ class and MedDRA preferred terminology. Based on MedDRA version 23.1. The grade of adverse events is shown in the legend. The left side shows all adverse events. The right side shows adverse events attributable to treatment with mosunetuzumab (Mosun). CCOD as of April 5, 2021. [Figure 4] Figure 4 is a butterfly plot showing adverse events occurring in ≥10% of safety evaluable patients as described in Example 1, classified by MedDRA system organ class and MedDRA preferred terminology. Based on MedDRA version 23.1. The grade of adverse events is shown in the legend. The left side shows all adverse events. The right side shows adverse events attributable to treatment with lenalidomide. CCOD as of April 5, 2021. [Diagram 5] Figure 5 is a swim lane plot showing the onset of cytokine release syndrome (CRS) events in five patients treated with the 1 / 2 / 30 mg dosing regimen of mosunetuzumab described in Example 1. Onset of grade 1 or grade 2 CRS is indicated by light light or dark diamonds, respectively. CCOD as of April 5, 2021. [Figure 6] Figure 6 is a plot showing observed concentration-time data for mosunetuzumab (in combination with lenalidomide) from study CO41942 overlaid with a popPK model simulation based on mosunetuzumab monotherapy data from study GO29781, where the simulation was performed at 1 / 2 / 30 mg Q4W. The filled red circles and lines represent individual observed mosunetuzumab concentration measurements and mean observed values ​​from study CO41942 at 1 / 2 / 30 mg IV doses in combination with lenalidomide. The shaded area represents the simulated concentration-time profile of mosunetuzumab monotherapy based on a preliminary population PK model simulation (prediction interval of 5 to 95) developed based on clinical data from study GO29781. [Figure 7]Figure 7 is a butterfly plot showing adverse events occurring in ≥10% of safety evaluable patients as described in Example 3, classified by MedDRA system organ class and MedDRA preferred terminology. Based on MedDRA version 23.1. The grade of adverse events is shown in the legend. The left side shows all adverse events. The right side shows adverse events attributable to treatment with mosunetuzumab (Mosun) or lenalidomide. CCOD as of September 13, 2021. [Figure 8] Figure 8 is a bar graph showing cytokine release syndrome (CRS) events by dosing cycle (C) and day (D) and CRS grade (Gr). The values ​​below the graph indicate the dose of mosunetuzumab associated with each dosing cycle (C) and day (D). The C1D1 dose is administered on day 1 of the first cycle, the C1D2 dose is administered on day 8 of the first cycle, and the C1D3 dose is administered on day 15 of the first cycle. Subsequent doses are administered on day 1 of each respective dosing cycle (C2, C3+). [Figure 9] 9 is a bar graph showing neutropenia and febrile neutropenia events by dosing cycle (C) and neutropenia grade (Gr). The number of patients who received granulocyte colony-stimulating factor (G-CSF) per dosing cycle (C) is shown below the graph. [Figure 10] Figure 10 is a bar graph showing antitumor activity in patients who had one or more diagnostic computed tomography (CT) scans at the time of response evaluation. Numbers above each bar indicate % change from baseline. Change in tumor burden is quantified by comparing the sum of products of target lesion diameters (SPD) to baseline measurements. [Figure 11]Figure 11 is a bar graph showing the overall response rate (ORR), complete response rate (CR), and partial response rate (PR) in 29 patients treated with the dosing regimen of 1 / 2 / 30 mg mosunetuzumab and 20 mg oral lenalidomide described in Example 3. Response rates are shown for 29 patients as of the data cutoff date of September 13, 2021. The 95% confidence interval (CI) for each response rate value is shown in brackets below. Response rates are determined by positron emission tomography-computed tomography (PET-CT). [Figure 12] 12 is a swimlane plot showing duration of response in all 29 patients treated with the dosing regimen of 1 / 2 / 30 mg mosunetuzumab and 20 mg oral lenalidomide described in Example 3. Duration of response is shown for the 29 patients as of the data cutoff date of September 13, 2021. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0058] Detailed Description The present invention relates to a method of treating a subject with relapsed and / or refractory (R / R) follicular lymphoma (FL) by administration of mosunetuzumab and lenalidomide as a combination therapy. In particular, the present invention relates to a method of treating a subject with R / R FL who is R / R to at least one prior systemic therapy (e.g., one prior treatment with a chemoimmunotherapeutic regimen) comprising an anti-CD20 antibody (e.g., an anti-CD20 monoclonal antibody, e.g., rituximab or obinutuzumab) or other treatment. The method includes administering an effective amount of mosunetuzumab according to a dosing regimen including at least a first dosing cycle and a second dosing cycle, where (a) the first dosing cycle includes a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of mosunetuzumab, where C1D1 and C1D2 are each equal to or less than C1D3, where C1D1 is 0.02 mg to 4.0 mg, where C1D2 is 0.05 mg to 20.0 mg, and where C1D3 is 0.2 mg to 50.0 mg, and (b) the second dosing cycle includes a single dose (C2D1) of mosunetuzumab, where C2D1 is equal to or greater than C1D3 and is 0.2 mg to 50 mg.

[0059] The present invention is based, in part, on the discovery that combination therapy comprising intravenous administration of mosunetuzumab and oral administration of lenalidomide over multiple dosing cycles (e.g., the first dosing cycle is a step-up split dosing cycle) exhibits synergy between mosunetuzumab and lenalidomide and can effectively treat subjects with relapsed / refractory (R / R) follicular lymphoma (FL), particularly subjects who are R / R to prior systemic therapy including an anti-CD20 antibody (e.g., an anti-CD20 monoclonal antibody, e.g., rituximab or obinutuzumab; e.g., R-CHOP), while maintaining an acceptable safety profile (e.g., with respect to frequency and severity of adverse events).

[0060] I. General techniques The techniques and procedures described or referenced herein are generally well understood and may be found in, for example, Sambrook et al., Molecular Cloning: A Laboratory Manual 3d edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Current Protocols in Molecular Biology (FMA Usubel, et al. eds., (2003)); Series in Methods in Enzymology (Academic Press, Inc.): PCR 2: A Practical Approach (MJ MacPherson, BD Hames and GR Taylor eds. (1995)), Harlow and Lane, eds. (1988) Antibodies, A Laboratory Manual, 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. Notebook(JECellis,ed.,1998)Academic Press;Animal Cell Culture(RIFreshney),ed.,1987);Introduction to Cell and Tissue Culture(JPMather and PERoberts,1998)Plenum Press;Cell and Tissue Culture:Laboratory Procedures(A.Doyle,JBGriffiths,and DGNewell,eds.,1993-8)J.Wiley and Sons;Handbook of Experimental Immunology(DMWeir and CCBlackwell, eds.);Gene Transfer Vectors for Mammalian Cells(JMMiller and MPCalos, eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994); Current Protocols in Immunology (JEColigan et al., eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (CA Janeway and P.Travers,1997);Antibodies(P.Finch,1997);Antibodies A Practical Approach(D.Catty.,ed.,IRL Press,1988-1989);Monoclonal Antibodies:A Practical Approach(P.Shepherd and C.Dean,eds.,Oxford University Press,2000);Using Antibodies:A Laboratory Manual(E.Harlow and D.Lane(Cold Spring Harbor Laboratory Press,1999);The Antibodies(M.Zanetti and JD Cancer, eds., Harwood Academic Publishers, 1995); and Cancer: Principles and Practice of Oncology (VT DeVita et al., eds., JBLippincott Company, 1993), and are commonly employed by those skilled in the art.

[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 plurals unless otherwise indicated.

[0063] As used herein, the term "about" refers to a normal error range for the respective value, which is readily understood by one of ordinary skill in the art. Reference herein to a value or parameter preceded by "about" includes (and describes) embodiments that are directed to 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 mature B-cell cancers, e.g., Hodgkin's lymphoma, but not limited to non-Hodgkin's lymphoma (NHL), e.g., diffuse large B-cell lymphoma (DLBCL), which may be relapsed 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 Includes: myocardial infarction, intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, plasmablastic lymphoma, large B-cell lymphoma due to HHV8-associated multicentric Castleman disease, primary effusion lymphoma: unclassifiable B-cell lymphoma with features intermediate between DLBCL and Burkitt lymphoma, and unclassifiable B-cell lymphoma with features intermediate between DLBCL and classical Hodgkin lymphoma.Further examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and lymphoid malignancies including leukemia or B-cell lymphoma.More specific examples of such 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; bulky mass disease 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 those 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 disorder" or "B cell malignancy" refers to diseases 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, for example, non-Hodgkin's lymphoma (NHL), including follicular lymphoma (FL) (e.g., relapsed and / or refractory FL or transformed FL), diffuse large B cell lymphoma (DLBCL) (e.g., relapsed or refractory DLBCL or Richter's transformation), MCL, high-grade B cell lymphoma, or PMLBCL. In another embodiment, the B cell proliferative disorder is a leukemia, such as chronic lymphocytic leukemia (CLL). In one embodiment, the B cell proliferative disorder is relapsed and / or refractory FL.

[0069] "Follicular Lymphoma International Prognostic Index" or "FLIPI" means a scoring system or index for determining the prognostic risk of a patient (e.g., with cancer; e.g., NHL; e.g., follicular lymphoma (FL)). FLIPI scores range from 0 to 5, depending on how many of the following five symptoms or risk factors the patient may have: (i) age 60 years or older; (ii) Ann Arbor stage III-IV; hemoglobin level ≦120 g / L; serum lactate dehydrogenase (LDH) concentration ≧upper limit of normal (ULN) (e.g., >280 units / L); (v) number of nodal sites >4. See, e.g., Table 4 in Solal-Celigny et al. Blood. 2004;104(5):1258-1265.

[0070] As used herein, the term "Ann Arbor staging" or "Ann Arbor stage" refers to a system for classification of stages of lymphoma (e.g., non-Hodgkin's lymphoma (NHL); e.g., DLBCL, FL, MCL, high-grade B-cell lymphoma, PMLBCL, or CLL). Lymphoma (e.g., NHL) can be classified as one of four Ann Arbor stages. Stage I refers to lymphoma showing involvement of a single lymph node region or a single extralymphatic organ or site. Stage II refers to lymphoma showing involvement of two or more lymph node regions on the same side of the diaphragm. Stage III refers to lymphoma showing involvement of lymph node regions on both sides of the diaphragm (III) and may be accompanied by focal involvement of extralymphatic organs or sites, or involvement of the spleen, or both. Stage IV refers to lymphomas that demonstrate diffuse or disseminated involvement of one or more extranodal organs or tissues with or without associated lymphadenopathy. Liver involvement is always considered diffuse and therefore always considered Ann Arbor Stage IV. Lymphatic structures include lymph nodes, thymus, spleen, appendix, Waldeyer's rings, and Peyer's patches. See Carbone, PP et al., Cancer Res. 1971, 31(11):1860-1861.

[0071] "Refractory disease" is defined as lack of complete response 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 the following: progressive disease (PD) as best response to first line therapy, stable disease (SD) as best response after at least one first line therapy (e.g., at least one including an anti-CD20 directed therapy including an anti-CD20 antibody, e.g., an anti-CD20 monoclonal antibody, e.g., rituximab or obinutuzumab), or partial response (PR) as best response, and biopsy-proven residual disease or disease progression after partial response. "Recurrent disease" is defined as complete response to first line therapy. In one embodiment, disease recurrence is biopsy-proven. In one embodiment, the patient has relapsed after or failed to respond to at least one prior systemic treatment regimen (e.g., at least one including an anti-CD20 directed therapy including an anti-CD20 antibody, e.g., an anti-CD20 monoclonal antibody, e.g., rituximab or obinutuzumab).

[0072] As used herein, "treatment" (and grammatical variations thereof, such as "treat" or "treating") refers to a clinical intervention in an attempt to alter the natural course of the subject being treated, and can 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 of the invention are used to delay the onset of disease or to slow the progression of the disease.

[0073] 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., recurrent and / or refractory FL). This delay can be of various durations depending on the disease history 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.

[0074] "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, as compared to administration of a preset, 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 R / R FL 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.

[0075] As used herein, "administering" refers to a method of providing a dose of a compound (e.g., a bispecific antibody, e.g., an anti-CD20 / anti-CD3 bispecific antibody, e.g., mosunetuzumab) or composition (e.g., a pharmaceutical composition, e.g., a pharmaceutical composition comprising a bispecific antibody (e.g., mosunetuzumab)) to a subject. The compounds and / or compositions utilized in the methods described herein can be administered intravenously (e.g., by intravenous infusion).

[0076] A "fixed" or "flat" dose of a therapeutic agent (e.g., a bispecific antibody) herein refers to a dose administered to a patient regardless of the patient's weight or body surface area (BSA). Thus, the fixed or constant dose can 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.

[0077] 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.

[0078] "Individual response" or "response" may be evaluated using any endpoint that indicates benefit to a subject, including, but not limited to, (1) some degree of inhibition of disease progression (e.g., cancer progression), including slowing and complete halt; (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 degree of relief of one or more symptoms associated with R / R FL; (6) increased or prolonged length of survival, including overall survival and progression-free survival; and / or (9) reduction in mortality at a given time point after treatment.

[0079] As used herein, "complete response" or "CR" refers to the disappearance of all target lesions (i.e., all evidence of disease).

[0080] 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 products of diameters (SPD) of target lesions referenced to a baseline SPD.

[0081] As used herein, "objective response rate" (ORR) means the sum of the complete response (CR) rate and the partial response (PR) rate.

[0082] As used herein, "duration of objective response" (DOR) is defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause within 30 days of the last dose of treatment, whichever occurs first.

[0083] 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, e.g., NHL, e.g., FL. 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 diameter of target lesions is quantified by computed tomography (CT).

[0084] "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 phase.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.

[0085] A subject's "effective response" or a 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 any 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.

[0086] 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.

[0087] As used herein, the term "survival" refers to the patient being alive, and includes overall survival and progression-free survival.

[0088] 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.

[0089] 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., R / R FL) does not worsen. Progression-free survival can include the amount of time a patient experiences a complete or partial response, as well as the amount of time a patient experiences stable disease.

[0090] As used herein, "stable disease" or "SD" refers to neither sufficient shrinkage of target lesions to warrant PR nor sufficient increase to warrant PD, based on the smallest SLD since treatment began.

[0091] As used herein, "progressive disease" or "PD" refers to an increase in the SLD of a target lesion by at least 20% from the smallest SLD, or an increase in the SPD of a target lesion by at least 50% from the smallest SPD, or the presence of one or more new lesions recorded since the start of treatment.

[0092] 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., relapsed and / or refractory (R / R) follicular lymphoma (FL)). This delay can be of varying duration depending on the disease history and / or the subject being treated. As will be apparent to one of skill in the art, a sufficient or significant delay can in effect encompass prevention, in that the subject does not develop the disease. For example, in terminal cancer, the onset of central nervous system (CNS) metastases can be delayed.

[0093] By "prolonged survival" is meant an increase in overall survival or progression-free survival in treated patients relative to untreated patients (e.g., relative to patients not treated with a pharmaceutical agent), or relative to patients who do not express the biomarker at a specified level, and / or relative to patients treated with an approved anti-tumor agent. Objective response refers to a measurable response, including a complete response (CR) or partial response (PR).

[0094] 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.

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

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

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

[0098] 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 a 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, numbering of amino acid residues within an 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.

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

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

[0101] "Framework" or "FR" refers to variable domain residues other than hypervariable region (HVR) residues. The FR of a variable domain typically 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.

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

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

[0104] A "humanized" antibody refers to a chimeric antibody 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.

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

[0106] The term "variable region" or "variable domain" refers to the domain of an antibody heavy 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, e.g., Kindt et al. Kuby Immunology, 6 th ed., W.H. Freeman and Co., page 91 (2007).) A single VH or VL domain may be sufficient to confer antigen-binding specificity. Moreover, antibodies that bind to a specific antigen may be isolated by screening a library of complementary VL or VH domains, respectively, using the VH or VL domain of an antibody that binds the antigen. See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

[0107] The term "hypervariable region" or "HVR" as used herein refers to each 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 occurring at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)); (c) antigenic contacts occurring at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J. Mol. Biol. 262:732-745 (1996)); and (d) 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).

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

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

[0110] 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 a cell or cell culture in which the antibody 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.

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

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

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

[0114] The terms "anti-CD3 antibody" and "antibody that binds to CD3" refer to an antibody that can bind to CD3 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent targeting CD3. In one embodiment, the binding of an anti-CD3 antibody to an unrelated non-CD3 protein is less than about 10% of the binding of the antibody to CD3, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, an antibody that binds to CD3 has an affinity of 1 μM 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.

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

[0116] The terms "anti-CD20 antibody" and "antibody that binds to CD20" refer to an antibody that is capable of binding 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 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 different 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.

[0117] 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.

[0118] 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.

[0119] As used herein, the term "cluster of differentiation 20" or "CD20" 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, and any form of CD20 resulting 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 SEQ ID NOs: NP_068769.2 and NP_690605.1), which is, for example, 297 amino acids in length and can be produced from, for example, a variant mRNA transcript lacking a portion of the 5'UTR (see, e.g., NCBI Reference SEQ ID NO: NM_021950.3), or a longer mutant mRNA transcript (see, e.g., NCBI Reference SEQ ID NO: NM_152866.2).

[0120] The terms "anti-CD20 / anti-CD3 bispecific antibody," "bispecific anti-CD20 / anti-CD3 antibody" and "antibody that binds CD20 and CD3," or variants thereof, refer to a multispecific antibody (e.g., a bispecific antibody) that is capable of binding to CD20 and CD3 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting CD20 and / or CD3. In one embodiment, the extent of binding of a bispecific antibody that binds CD20 and CD3 to unrelated non-CD3 and / or non-CD20 proteins is less than about 10% of the binding of the antibody to CD3 and / or CD20, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, a bispecific antibody that binds CD20 and 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 bispecific antibody that binds CD20 and CD3 binds to an epitope of CD3 that is conserved among CD3 from different species and / or an epitope of CD20 that is conserved among CD20 from different species. In one embodiment, the bispecific antibody binds monovalently to CD20 and monovalently to CD3. In some embodiments, the bispecific antibody that binds CD20 and CD3 is mosunetuzumab.

[0121] As used herein, the term "mosunetuzumab" refers to an anti-CD20 / anti-CD3 bispecific antibody having the International Nonproprietary Name (INN) List 117 (WHO Drug Information, Vol. 31, No. 2, 2017, p. 303) or CAS Registry Number 1905409-39-3.

[0122] As used herein, the term "lenalidomide" refers to a compound having CAS Registry Number 191732-72-6 and IUPAC name (3RS)-3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione. Lenalidomide is also known by trade names including REVLIMID®, linamide, and lenalid. Lenalidomide is identified by DrugBank Accession Number DB00480, PubChem CID 216326, and chemical formula C 13 H 13 Contains N3O3.

[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, ≦100 nM, ≦10 nM, ≦1 nM, or ≦0.1 nM. D In certain embodiments, the antibody specifically binds to an epitope on a protein that is conserved among proteins from different species. In another embodiment, specific binding can include, but 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 Range of M and K 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 D In 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 for determining percent amino acid sequence identity can be obtained using various methods within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEGALIGN® (DNASTAR®) software. Those skilled in the art can determine the 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, and is hereby 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 should be compiled for use on UNIX operating systems, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.

[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 relative to a given amino acid sequence B (alternatively, it may be written as a given amino acid sequence A having or containing a particular % amino acid sequence identity to, with, or relative to a given amino acid sequence B) is calculated as follows: 100 x fraction X / Y In this case, 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 different from the length of amino acid sequence B, then the % amino acid sequence identity of A to B will differ from the % amino acid sequence identity of B to A. Unless otherwise stated, all % amino acid sequence identity values ​​as used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.

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

[0128] As used herein, the term "chemotherapeutic agent" refers to a compound useful in the treatment of cancers such as R / R FL. Examples of chemotherapeutic agents include EGFR inhibitors (including small molecule inhibitors such as erlotinib (TARCEVA®, Genentech / OSI Pharm.)); PD 183805 (CI 1033, 2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSA®) 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenylamino)-quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methylpiperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim;PKI-166((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol;(R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine;CL-387785(N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butinamide);EKB-569(N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide)(Wyeth);AG1478(Pfizer);AG1571(SU 5271; Pfizer); and dual EGFR / HER2 tyrosine kinase inhibitors such as lapatinib (TYKERB®, GSK572016 or N-[3-chloro-4-[(3fluorophenyl)methoxy]phenyl]-6[5[[[2methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine)); tyrosine kinase inhibitors (e.g., EGFR inhibitors; small molecule HER2 tyrosine kinase inhibitors such as TAK165 (Takeda);CP-724,714, an oral selective inhibitor of ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual HER inhibitors such as EKB-569 (available from Wyeth), which preferentially binds to EGFR but inhibits both HER2 and EGFR overexpressing cells; PKI-166 (Novartis); pan-HER inhibitors such as canertinib (CI-1033; Pharmacia); Raf-1 inhibitors such as the antisense agent ISIS-5132 ((ISIS 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 AG; MAPK extracellular regulated kinase I inhibitor CI-1040 (Pharmacia); quinazolines such as PD153035, 4-(3-chloroanilino)quinazoline; pyridopyrimidines; pyrimidopyrimidines; CGP 59326, CGP 60261 and CGP pyrrolopyrimidines such as 62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidines; curcumin (diferuloylmethane, 4,5-bis(4-fluoroanilino)phthalimide); tyrophostins containing a nitrothiophene moiety; PD-0183805 (Warner-Lamber); antisense molecules (e.g., those that bind to a nucleic acid encoding a HER); quinoxalines (U.S. Pat. No. 5,804,396); tryphostins (U.S. Pat. No. 5,804,396); ZD6474 (Astra Zeneca); PTK-787 (Novartis / Schering AG); pan-HER inhibitors such as CI-1033 (Pfizer); Affinitac (ISIS3521; Isis / Lilly); PKI 166 (Novartis); GW2016 (Glaxo SmithKline);CI-1033(Pfizer);EKB-569(Wyeth);Semaxinib(Pfizer);ZD6474(AstraZeneca);PTK-787 (Novartis / Schering AG); INC-1C11 (Imclone); and rapamycin (sirolimus, RAPAMUNE®); proteasome inhibitors such as bortezomib (VELCADE®, Millennium Pharm.); disulfiram; epigallocatechin gallate; salinosporamide A; carfilzomib; 17-AAG (geldanamycin); radicicol; lactate dehydrogenase A (LDH-A); fulvestrant (FASLODEX®, AstraZeneca); letrozole (FEMARA®, Novartis), finasunate (VATALANIB®, Novartis); oxaliplatin (ELOXATIN®, Sanofi); 5-FU (5-fluorouracil); leucovorin; lonafamib (SCH 66336); alkylating agents such as sorafenib (NEXAVAR®, Bayer Labs), AG1478, thiotepa and CYTOXAN® cyclophosphamide; alkylsulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa and uredopa; ethylenimines and methylamelanamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelanamine; acetogenins (especially bullatasin and bullatasinone); camptothecins (including topotecan and irinotecan); bryostatin; kallistatin; C C-1065 (including synthetic analogs of adozelesin, carzelesin and bizelesin); cryptophycins (especially cryptophycin 1 and cryptophycin 8); adrenocorticosteroids (including prednisone and prednisolone); cyproterone acetate; 5α-reductase including finasteride and dutasteride; vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat dolastatins; aldesleukin, talc duocarmycins (including synthetic analogs, KW-2189 and CB1-TM1); eletarobin; pancratistatin; sarcodictin; spongistatin;Nitrogen mustards such as chlorambucil, chromafazine, chlorophosphamide, estramustine, ifosfamide, mechlorestamine, mechlorestamine oxide hydrochloride, melphalan, nobembitine, phenesterine, prednimustine, trophosphamide, and uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics such as the enidine antibiotics (e.g., the calicheamicins, especially calicheamicin gamma 1 and calicheamicin omega 1); daphnia including dynemicin A; Inemycin; bisphosphonates such as clodronate; along with esperamicin, neocarzinostatin chromophores and related enediyne antibiotic chromophores), aclacinomycin, actinomycin, autramycin, azaserine, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycin, dactinomycin, detorubicin, 6-diazo-5-oxo-L-norleucine, morpholinodoxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolinodoxorubicin, and deoxydoxorubicin), epirubicin, mitomycins such as esorubicin, idarubicin, marcelomycin, and mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, keramycin, rodorubicin, streptonignin, streptozocin, tuberculin, ubenimex, zinostatin, and zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimetrexate; fludarabine, 6-mercaptopropionate, and other anti-metabolites. Purine analogues such as thiamiprine, thiamiprine, and thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiosteine, and testolactone; anti-adrenals such as aminoglutethimide, mitotane, and trilosteine; folic acid supplements such as floric acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid;Eniluracil; Amsacrine; Bestravcil; Bisantrene; Edatraxate; Defofamine; Demecolcine; Diaziquione; Elfomitin; Elliptine acetate; Epothilone; Etoglucide; Gallium nitrate; Hydroxyurea; Lentinan; Lonidynin; Maytansinoids such as maytansine and ansamitocin; Mitoguazone; Mitoxantrone; Mopidamunol; Nitraerin; Pentostatin; Phenamet; Pirarubicin; Rosoxantrone; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; PSK® polysaccharide complex (JHS Natural Products); Razoxane; Rhizoxin; Schizofuran; Spirogermanium; Tenuazonic acid; Triaziquone; 2,2',2''-Trichlorotriethylamine; Trichothecenes (especially T-2 toxin, veraculin A, roridin A and anguidine); Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitolactol; Pipobroman; Gacytosine; Arabinoside ("Ar a-C"); thiotepa; chlorambucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; tetoposide (VP-16); ifosfamide; mitoxantrone; nobandrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharma- ceutically 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 (Nolvadex®; including tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxyphene, ketoxifene, LY117018, onapristone, and Fairstone® (quencher). (ii) aromatase inhibitors, which inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as 4(5)-imidazole, aminoglutethimide, Megase® (megestrol acetate), Aromasin® (exemestane; Pfizer Inc.), formestany, fadrozole, RIVISOR® (vorozole), Femara® (letrozole; Novartis Inc.), and Arimidex (registered trademark). (iii) antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all trans retinoic 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, e.g., PKC-alpha, Ralf and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., Angiozyme®) and HER2 expression inhibitors; (viii) gene therapy vaccines, e.g., 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 FL. 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 or obinutuzumab. In some embodiments, the chemoimmunotherapy includes R-CHOP.

[0131] As used herein, the term "R-CHOP" refers to a treatment that includes rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. In some embodiments, R-CHOP is a chemotherapy treatment or regimen used to treat cancer, optionally a B-cell proliferative disorder (e.g., non-Hodgkin's lymphoma; e.g., DLBCL or aggressive B-cell lymphoma). In some embodiments, R-CHOP is a 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., DLBCL or aggressive B-cell lymphoma). In some embodiments, R-CHOP is a standard of care or first-line treatment administered to a previously untreated subject. In some embodiments, R-CHOP is administered every 3 weeks (with a 21-day dosing cycle) for 3-6 dosing cycles. In some embodiments, the dosing regimen for R-CHOP therapy includes 21-day dosing cycles, during each dosing cycle, the subject receives 375 mg / m 2 of rituximab IV is administered, and cyclophosphamide, doxorubicin, vincristine, and prednisone are also administered. In some embodiments, the dosing regimen for R-CHOP therapy is 750 mg / m 2 Cyclophosphamide IV, 50 mg / m 2 Doxorubicin IV, 1.4 mg / m 2 Vincristine IV, 100 mg or 40 mg / m for 5 days 2 / day oral prednisone. In some embodiments, the maximum single dose of vincristine is 2 mg.

[0132] As used herein, the term "cytotoxic agent" 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, 153Sm, 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 may 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, inhibitors of LDH-A, inhibitors of fatty acid biosynthesis, cell cycle signal transduction inhibitors, HDAC inhibitors, proteasome inhibitors, and inhibitors of cancer metabolism. 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 typically included in commercial packaging of a therapeutic product that contain information about the indications, usage, dosage, administration, concomitant therapy, contraindications and / or warnings for the use of such therapeutic product.

[0134] The term "synergy" is used to refer to an effect resulting from the combination of two or more therapeutic products (e.g., mosunetuzumab and lenalidomide) that is greater than the sum of the effects observed when the two or more therapeutic products are used individually. In some embodiments, a synergy is observed in the response rate (e.g., complete response rate or overall response rate) of a population of subjects with relapsed and / or refractory (R / R) non-Hodgkin's lymphoma (NHL; e.g., R / R follicular lymphoma (FL)) treated with a combination therapy comprising mosunetuzumab and lenalidomide. In some embodiments, a population of subjects with R / R FL shows a higher complete response rate when treated with a combination therapy comprising mosunetuzumab and lenalidomide compared to a population of subjects treated with mosunetuzumab or lenalidomide as monotherapy. In some embodiments, a population of subjects with R / R FL exhibits a higher overall response rate when treated with a combination therapy comprising mosunetuzumab and lenalidomide compared to a population of subjects treated with mosunetuzumab or lenalidomide as monotherapy.

[0135] III. Treatment method Provided herein is a method for treating a subject with relapsed and / or refractory (R / R) follicular lymphoma (FL) by administering mosunetuzumab and lenalidomide as a combination therapy. In particular, the present invention relates to a method for treating a subject with R / R FL that is R / R to at least one previous systemic therapy (e.g., one previous treatment with a chemoimmunotherapy regimen) including an anti-CD20 antibody (e.g., an anti-CD20 monoclonal antibody, e.g., rituximab or obinutuzumab) or other treatment. In some embodiments, the FL is a grade FL (e.g., grade 1, 2 or 3a, but not grade 3b FL). In some embodiments, the FL of each subject is histologically documented to be grade 1, 2 or 3a, but not 3b, according to the World Health Organization Classification of Lymphoid Neoplasms (see Swerdlow SH, et al. Blood 2016;127:2375-90). In some embodiments, the subjects have received only one prior line of systemic therapy and either (a) have a Follicular Lymphoma International Prognostic Index (FLIPI; Solal-Celigny et al.. Blood. 2004;104(5):1258-1265.) score of 2-5 (e.g., a score of 2, 3, 4, or 5), (b) are refractory to prior anti-CD20 monoclonal antibody treatment, or (c) have disease progression within 24 months after initiation of prior treatment. In some embodiments, each subject has not been treated with an anti-CD20 monoclonal antibody for at least 4 weeks (e.g., 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 60 weeks, or more) prior to administration of effective amounts of mosunetuzumab and lenalidomide. In some embodiments, mosunetuzumab and lenalidomide have a synergistic effect against R / R FL. In some embodiments, the synergy is a partial response as defined by the Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014;32:1-9).In some embodiments, the synergy is a complete response as defined by the Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014;32:1-9).

[0136] A. Therapeutic Methods for Administration of Mosunetuzumab The present invention relates to a method of treating a subject with relapsed and / or refractory (R / R) follicular lymphoma (FL) by administering mosunetuzumab and lenalidomide as a combination therapy. In particular, the present invention relates to a method of treating a subject with R / R FL that is R / R to at least one previous systemic therapy (e.g., one previous treatment with a chemoimmunotherapy regimen) including an anti-CD20 antibody (e.g., an anti-CD20 monoclonal antibody, e.g., rituximab or obinutuzumab) or other treatment. In some embodiments, mosunetuzumab and lenalidomide have a synergistic effect on R / R FL. In some embodiments, the synergistic effect is a partial response as defined by the Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014;32:1-9). In some embodiments, the synergy is a complete response as defined by the Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014;32:1-9).

[0137] In some embodiments, administering an effective amount of mosunetuzumab comprises administering mosunetuzumab according to a dosing regimen including at least a first dosing cycle and a second dosing cycle, wherein (a) the first dosing cycle includes a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of mosunetuzumab, wherein C1D1 and C1D2 are each equal to or less than C1D3, and C1D1 is between 0.02 mg and 4.0 mg (e.g., 0.05 mg to 4.0 mg, 0.1 mg to 4.0 mg, 0.2 mg to 4.0 mg, 0.3 mg to 4.0 mg). , 0.4mg~4.0mg, 0.5mg~4.0mg, 0.75mg~4.0mg, 1.0mg~4.0mg, 1.25mg~4.0mg, 1.5mg~4.0mg, 2.0mg~4.0mg, 2.5mg~4.0mg, 3.0mg~4.0mg, 3.5mg~4.0mg, 0 .1mg~3.5mg, 0.1mg~3.0mg, 0.1mg~2.5mg, 0.1mg~2.0mg, 0.1mg~1.5mg, 0.1mg~1mg, 0.1mg~0.5mg, 0.5mg~3.0mg, 0.5mg~2.0mg, 0.5mg~1.0mg, 0.75mg~1 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.75 mg, 2.0 mg, 2.25 mg, 2.5 mg, 2.75 mg, 3.0 mg, 3.5 mg, or 4.0 mg; C1D2 is 0.05 mg to 0.25 mg, 1.0 mg to 3.0 mg, 1.5 mg to 2.0 mg, 0.7 mg to 0.9 mg, or 0.9 mg to 1.1 mg; for example, about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.75 mg, about 2.0 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3.0 mg, about 3.5 mg, or about 4.0 mg. 20.0mg (e.g., 0.1mg-20.0mg, 0.2mg-20.0mg, 0.3mg-20.0mg, 0.4mg-20.0mg, 0.5mg-20.0mg, 1.0mg-20.0mg, 1.5mg-20.0mg, 2.0mg-20.0mg, 3.0mg-20.0mg, 4.0mg-20.0mg, 5.0mg-20.0mg, 6.0mg-20.0mg, 7.0mg-20.0mg, 8.0mg-20.0mg, 9.0mg-20.0mg, 10.0mg-20.0mg, 15.0mg-20.0mg, 0.5mg-15.0mg, 0.5mg-10.0mg, 0.5mg-9.0mg, 0.5mg-8.0mg, 0.5mg-7.0mg, 0.5mg-6.0mg, 0.5mg-5.0mg, 0.5mg-4.0mg, 0.5mg-3.0mg, 0.5mg-2.0mg, 0.5mg-1.0mg, 1.0mg-15.0mg, 1.0mg-10.0mg, 1.0mg-8.0mg, 1.0mg-6.0mg, 1.0mg-4.0mg, 1.0mg-3.0mg, 10.0mg-20.0mg, 15.0mg-20.0mg, 5.0mg-15.0mg, or 5.0mg-10.0mg for example, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 5.0 mg, about 6.0 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 15.0 mg, or about 20.0 mg), and C1D3 is 0.2 mg to 50.0mg (e.g., 0.3mg-50.0mg, 0.4mg-50.0mg, 0.5mg-50.0mg, 1.0mg-50.0mg, 2.0mg-50.0mg, 3.0mg-50.0mg, 4.0mg-50.0mg, 5.0mg-50.0mg, 10.0mg-50.0mg, 15.0mg-50.0mg, 20.0mg-50.0mg, 25.0mg-50.0mg, 30.0mg-50.0mg, 35.0mg-50.0mg, 40.0mg-50.0mg, 45.0mg-50.0mg, 1.0mg-45.0mg, 1.0mg-40. 0mg, 1.0mg~35.0mg, 1.0mg~30.0mg, 1.0mg~25.0mg, 1.0mg~20.0mg, 1.0mg~15.0mg, 1.0mg~10.0mg, 1.0mg~5.0mg, 10.0mg~20.0mg, 20.0mg~30.0mg, 30. 0mg~40.0mg, 5.0mg~25.0mg, 25.0mg~50.0mg, 3.0mg~45.0mg, 3.0mg~50.0mg, 4.0mg~4.5mg, 3.0mg~10.0mg, 4.0mg~5.0mg, 25.0mg~35.0mg, 28.0mg~32.0 mg, 10.0 mg to 30.0 mg, or 20.0 mg to 40.0 mg; for example, about 0.2 mg, about 0.5 mg, about 0.8 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 4.0 mg, about 4.2 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 12.0 mg, about 15.0 mg, about 20.0 mg, about 25.0 mg, about 30.0 mg, about 35.0 mg, about 40.0 mg, about 45.0 mg, or about 50.0 mg). and (b) the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab, where C2D1 is equal to or greater than C1D3 and is between 0.2 mg and 50 mg (e.g., 0.3 mg to 50.0 mg, 0.4 mg to 50.0 mg, 0.5 mg to 50.0 mg, 1.0 mg to 50.0 mg, 2.0 mg to 50.0 mg, 3.0 mg to 50.0 mg, 4.0 mg to 50.0 mg, 5.0 mg to 50.0 mg, 10.0 mg to 50.0 mg, 15.0 mg to 50.0 mg, 20.0 mg to 50.0 mg, 25.0 mg to 50.0 mg, 30.0 mg to 50.0 mg, 35.0 mg ~50.0mg, 40.0mg~50.0mg, 45.0mg~50.0mg, 1.0mg~45.0mg, 1.0mg~40.0mg, 1.0mg~35.0mg, 1.0mg~30.0mg, 1.0mg~25.0mg, 1.0mg~20.0mg, 1.0mg~15.0m g, 1.0mg~10.0mg, 1.0mg~5.0mg, 10.0mg~20.0mg, 20.0mg~30.0mg, 30.0mg~40.0mg, 5.0mg~25.0mg, 25.0mg~50.0mg, 3.0mg~45.0mg, 3.0mg~50.0mg, 4.0 mg to 4.5 mg, 3.0 mg to 10.0 mg, 4.0 mg to 5.0 mg, 25.0 mg to 35.0 mg, 28.0 mg to 32.0 mg, 10.0 mg to 30.0 mg, or 20.0 mg to 40.0 mg; for example, about 0.2 mg, about 0.5 mg, about 0.8 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 4.0 mg, about 4.2 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 12.0 mg, about 15.0 mg, about 20.0 mg, about 25.0 mg, about 30.0 mg, about 35.0 mg, about 40.0 mg, about 45.0 mg, or about 50.0 mg.

[0138] In some embodiments, (a) C1D1 is 0.4 mg to 4.0 mg (e.g., 0.5 mg to 4.0 mg, 0.75 mg to 4.0 mg, 1.0 mg to 4.0 mg, 1.25 mg to 4.0 mg, 1.5 mg to 4.0 mg, 2.0 mg to 4.0 mg, 2.5 mg to 4.0 mg, 3.0 mg to 4.0 mg, 3.5 mg to 4.0 mg, 0.5 mg to 3.5 mg, 0.5 mg to 3.0 mg, 0.5 mg to 2.0 mg, 0.5 mg to 1.0 mg, 0.75 mg to 1.25 mg, 1.0 mg to 3.0 mg, 1.5 mg to 2.0 mg, 0.7 mg to 0.9 mg, or 0 .9 mg to 1.1 mg; for example, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.75 mg, about 2.0 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3.0 mg, about 3.5 mg, or about 4.0 mg, and C1D2 is 1.0 mg to 20.0 mg (e.g., 1.1 mg to 20.0 mg, 1.2 mg to 20.0 mg, 1.3 mg to 20.0 mg, 1.4 mg to 20.0 mg, 1.5 mg to 20.0 mg, 2.0 mg to 20.0 mg, mg~20.0mg, 3.0mg~20.0mg, 4.0mg~20.0mg, 5.0mg~20.0mg, 6.0mg~20.0mg, 7.0mg~20.0mg, 8.0mg~20.0mg, 9.0mg~20.0mg, 10.0mg~20.0mg, 15.0mg~20 .0mg, 1.0mg~15.0mg, 1.0mg~10.0mg, 1.0mg~9.0mg, 1.0mg~8.0mg, 1.0mg~7.0mg, 1.0mg~6.0mg, 1.0mg~5.0mg, 1.0mg~4.0mg, 1.0mg~3.0mg, 1.0mg~2.0 mg, 10.0 mg to 20.0 mg, 15.0 mg to 20.0 mg, 5.0 mg to 15.0 mg, or 5.0 mg to 10.0 mg; for example, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 5.0 mg, about 6.0 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 15.0 mg, or about 20.0 mg) and C1D3 is 3.0 mg to 50.0mg (e.g., 4.0mg to 50.0mg, 5.0mg to 50.0mg, 10.0mg to 50.0mg, 15.0mg to 50.0mg, 20.0mg to 50.0mg, 25.0mg to 50.0mg, 30.0mg to 50.0mg, 35.0mg to 50.0mg, 40.0mg to 50.0mg, 45.0mg to 50.0mg, 3.0mg to 45.0mg, 3.0mg to 40.0mg, 3.0mg to 35.0mg, 3.0mg to 30.0mg, 3.0mg to 25.0mg, 3.0mg to 20.0mg, 3.0mg to 15.0mg, 3.0mg to 10.0mg g, 3.0 mg to 5.0 mg, 10.0 mg to 20.0 mg, 20.0 mg to 30.0 mg, 30.0 mg to 40.0 mg, 5.0 mg to 25.0 mg, 25.0 mg to 50.0 mg, 4.0 mg to 4.5 mg, 4.0 mg to 5.0 mg, 25.0 mg to 35.0 mg, 28.0 mg to 32.0 mg, 10.0 mg to 30.0 mg, or 20.0 mg to 40.0 mg; for example, about 3.0 mg, about 4.0 mg, about 4.2 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 1 and (b) C2D1 is 3.0 mg to 50.0 mg (e.g., 4.0 mg to 50.0 mg, 5.0 mg to 50.0 mg, 10.0 mg to 50.0 mg, 15.0 mg to 50.0 mg, 20.0 mg to 50.0 mg, 25.0 mg to 50.0 mg, 30.0 mg to 50.0 mg, 35.0 mg to 50.0 mg, 40.0 mg to 50.0 mg, 45.0 mg to 50.0 mg). g, 3.0mg~45.0mg, 3.0mg~40.0mg, 3.0mg~35.0mg, 3.0mg~30.0mg, 3.0mg~25.0mg, 3.0mg~20.0mg, 3.0mg~15.0mg, 3.0mg~10.0mg, 3.0mg~5.0mg, 10.0mg ~20.0mg, 20.0mg~30.0mg, 30.0mg~40.0mg, 5.0mg~25.0mg, 25.0mg~50.0mg, 4.0mg~4.5mg, 4.0mg~5.0mg, 25.0mg~35.0mg, 28.0mg~32.0mg, 10.0mg~30.0 mg, or 20.0 mg to 40.0 mg; for example, about 3.0 mg, about 4.0 mg, about 4.2 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 12.0 mg, about 15.0 mg, about 20.0 mg, about 25.0 mg, about 30.0 mg, about 35.0 mg, about 40.0 mg, about 45.0 mg, or about 50.0 mg).

[0139] In some embodiments, (a) C1D1 is in an amount of 0.8 mg to 3.0 mg (e.g., 0.9 mg to 3.0 mg, 1.0 mg to 3.0 mg, 1.25 mg to 3.0 mg, 1.5 mg to 3.0 mg, 2.0 mg to 3.0 mg, 2.5 mg to 3.0 mg, 0.8 mg to 2.5 mg, 0.8 mg to 2.0 mg, 0.5 mg to 1.5 mg, 0.8 mg to 1.0 mg, 1.0 mg to 3.0 mg, 1.5 mg to 2.0 mg, or 0.9 mg to 1.1 mg; e.g., about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, and C1D2 is 1.0 mg to 6.0 mg (e.g., 1.5 mg to 6.0 mg, 2.0 mg to 6.0 mg, 2.5 mg to 6.0 mg, 3.0 mg to 6.0 mg, 3.5 mg to 6.0 mg, 4.0 mg to 6.0 mg, 5.0 mg to 6.0 mg, 5.0 mg to 6.0 mg, 1.0 mg to 5.0 mg, 1.0 mg to 4.5 mg, 1.0 mg to 4.0 mg, 1.0 mg to 3.5 mg, 1.0 mg to 3.0 mg, 1.0 mg to 2.5 ...5.0 mg, 1.0 mg to 5.0 mg, 1.0 mg to 5.0 mg, 1.0 mg to 5.0 mg, 1.0 mg to 5.0 mg, 1.0 mg to 5.0 mg, 1.0 mg to 5.0 mg, 1.0 mg to 5.0 mg, 1.0 mg to 5.0 mg, 1.0 mg to 5.0 mg, 1.0 mg to 5.0 mg, 1.0 mg to 5 0.0mg to 2.0mg, 1.0mg to 1.5mg, 1.5mg to 2.5mg, 3.0mg to 6.0mg, 2.0mg to 4.0mg, 2.5mg to 5.0mg, or 2.5mg to 3.5mg; for example, about 1.0mg, about 1.1mg, about 1.2mg, about 1.3mg, about 1.4mg, about 1.5mg, about 1.6mg, about 1.7mg, about 1.8mg, 1.9mg, about 2.0mg, about 2.1mg, about 2.2mg, about 2.3mg, about 2.4mg, about 2.5mg, about 2.6mg, about 2.7mg, about 2.8mg, about 2.9mg, about 3.0mg, about 3.5mg, about 4.0mg , about 4.5 mg, about 5.0 mg, about 5.5 mg, or about 6.0 mg), and C1D3 is 3.0 mg to 45.0 mg (e.g., 4.0 mg to 45.0 mg, 5.0 mg to 45.0 mg, 10.0 mg to 45.0 mg, 15.0 mg to 45.0 mg, 20.0 mg to 45.0 mg, 25.0 mg to 45.0 mg, 30.0 mg to 45.0 mg, 35.0 mg to 45.0 mg, 40.0 mg to 45.0 mg, 3.0 mg to 40.0 mg, 3.0 mg to 35.0 mg, 3.0 mg to 30.0 mg, 3.0 mg to 25.0 mg, 3.0 mg to 20.0 mg, 3.0 mg to 15.0 mg, 3.0 mg to 10.0 mg, 3.0 mg to 5.0 mg, 10.0 mg to 20.0 mg, 20.0 mg to 30.0 mg, 30.0 mg to 40.0 mg, 5.0 mg to 25.0 mg, 4.0 mg to 4.5 mg, 4.0 mg to 5.0 mg, 25.0 mg to 35.0 mg, 28.0 mg to 32.0 mg, 10.0 mg to 30.0 mg, or 20.0 mg to 40.0 mg; for example, about 3.0 mg, about 4.0 mg, about 4.2 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 12.0 mg, about 15.0 mg, about 20.0 mg, about 25.0 mg, about 30.0 mg, about 35.0 mg, about 40.0 mg, or about 45.0 mg), and (b) C2D1 is 3.0 mg to 45.0 mg (for example, 4.0 mg to 45.0 mg, 5.0 mg to 45.0 mg, 10.0 mg to 45.0 mg, 15.0 mg to 45.0 mg, 20.0 mg to 45.0 mg, 25.0 mg to 45.0 mg, 30.0mg~45.0mg, 35.0mg~45.0mg, 40.0mg~45.0mg, 3.0mg~40.0mg, 3.0mg~35.0mg, 3.0mg~30.0mg, 3.0mg~25.0mg, 3.0mg~20.0mg, 3.0 mg~15.0mg, 3.0mg~10.0mg, 3.0mg~5.0mg, 10.0mg~20.0mg, 20.0mg~30.0mg, 30.0mg~40.0mg, 5.0mg~25.0mg, 4.0mg~4.5mg, 4.0mg~5.0 mg, 25.0 mg to 35.0 mg, 28.0 mg to 32.0 mg, 10.0 mg to 30.0 mg, or 20.0 mg to 40.0 mg; for example, about 3.0 mg, about 4.0 mg, about 4.2 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 12.0 mg, about 15.0 mg, about 20.0 mg, about 25.0 mg, about 30.0 mg, about 35.0 mg, about 40.0 mg, or about 45.0 mg).

[0140] In some embodiments, C1D1 and C1D2 are each smaller than C1D3. In some embodiments, C1D1 and C1D2 are approximately equal. In some embodiments, C1D2 is about 50% to about 250% larger than C1D1 (e.g., C1D2 is about 50% to about 225% larger than C1D1, C1D2 is about 50% to about 200% larger than C1D1, C1D2 is about 50% to about 175% larger than C1D1, C1D2 is about 50% to about 150% larger than C1D1, C1D2 is about 50% to about 125% larger than C1D1). greater than C1D1, C1D2 is about 50% to about 100% greater than C1D1, or C1D2 is about 50% to about 75% greater than C1D1; e.g., C1D2 is about 50% greater than C1D1, C1D2 is about 100% greater than C1D1, C1D2 is about 150% greater than C1D1, C1D2 is about 200% greater than C1D1, or C1D2 is about 250% greater than C1D1).

[0141] In some embodiments, (a) C1D1 is 0.8 mg, C1D2 is 2.0 mg, C1D3 is 4.2 mg, and C2D1 is 4.2 mg; (b) C1D1 is 1.0 mg, C1D2 is 1.0 mg, C1D3 is 3.0 mg, and C2D1 is 30.0 mg; or (c) C1D1 is 1.0 mg, C1D2 is 2.0 mg, C1D3 is 30.0 mg, and C2D1 is 30.0 mg.

[0142] In some embodiments, the length of the first dosing cycle is 21 days (± 1 day). In some embodiments, the method includes administering C1D1, C1D2, and C1D3 to the subject on days 1, 8 (± 1 day), and 15 (± 1 day), or on about days 1, about 8 (± 1 day), and about 15 (± 1 day), respectively, of the first dosing cycle. In some embodiments, the length of the second dosing cycle is 28 days (± 1 day). In some embodiments, the method includes administering C2D1 to the subject on day 1 of the second dosing cycle.

[0143] In some embodiments, the dosing regimen includes one or more additional dosing cycles (e.g., 1 dosing cycle, 2 dosing cycles, 3 dosing cycles, 4 dosing cycles, 5 dosing cycles, 6 dosing cycles, 7 dosing cycles, 8 dosing cycles, 9 dosing cycles, 10 dosing cycles, or more). In some embodiments, the dosing regimen includes 1 to 10 additional dosing cycles (e.g., 1 dosing cycle, 2 dosing cycles, 3 dosing cycles, 4 dosing cycles, 5 dosing cycles, 6 dosing cycles, 7 dosing cycles, 8 dosing cycles, 9 dosing cycles, or 10 dosing cycles). In some embodiments, the dosing regimen includes 10 additional dosing cycles. In some embodiments, the length of each of the one or more additional dosing cycles is 28 days (± 1 day). In some embodiments, each of the one or more additional dosing cycles includes an additional dose of mosunetuzumab. In some embodiments, the methods involve administering each additional dose of mosunetuzumab to the subject on day 1 of each of one or more additional dosing cycles.In some embodiments, each additional dose of mosunetuzumab is between 0.2 mg and 50.0 mg (e.g., 0.3 mg to 50.0 mg, 0.4 mg to 50.0 mg, 0.5 mg to 50.0 mg, 1.0 mg to 50.0 mg, 2.0 mg to 50.0 mg, 3.0 mg to 50.0 mg, 4.0 mg to 50.0 mg, 5.0 mg to 50.0 mg, 10.0 mg to 50.0 mg, 15.0 mg to 50.0 mg, 20.0 mg to 50.0 mg, 25.0 mg to 50.0 mg, 30.0 mg to 50.0 mg, 35 .0mg~50.0mg, 40.0mg~50.0mg, 45.0mg~50.0mg, 1.0mg~45.0mg, 1.0mg~40.0mg, 1.0mg~35.0mg, 1.0mg~30.0mg, 1.0mg~25.0mg, 1.0mg~20.0mg, 1.0mg~15.0mg, 1.0mg~10.0mg, 1.0mg~5.0mg, 10.0mg~20.0mg, 20.0mg~30.0mg, 30.0 mg to 40.0 mg, 5.0 mg to 25.0 mg, 25.0 mg to 50.0 mg, 3.0 mg to 45.0 mg, 4.0 mg to 4.5 mg, 3.0 mg to 10.0 mg, 4.0 mg to 5.0 mg, 25.0 mg to 35.0 mg, 28.0 mg to 32.0 mg, 10.0 mg to 30.0 mg, or 20.0 mg to 40.0 mg; for example, about 0.2 mg, about 0.5 mg, about 0.8 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 4.0 mg, about 4.2 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 12.0 mg, about 15.0 mg, about 20.0 mg, about 25.0 mg, about 30.0 mg, about 35.0 mg, about 40.0 mg, about 45.0 mg, or about 50.0 mg).

[0144] In some embodiments, administering an effective amount of mosunetuzumab comprises administering mosunetuzumab according to a dosing regimen comprising 12 dosing cycles, wherein (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of mosunetuzumab, wherein C1D1 and C1D2 are each equal to or less than C1D3, and C1D1 is between 0.02 mg and 4.0 mg (e.g., 0.05 mg to 4.0 mg, 0.1 mg to 4.0 mg, 0.2 mg to 4.0 mg, 0.3 mg to 4.0 mg, 0.4 mg to 4.0 mg, 0.5 mg to 4.0 mg, g~4.0mg, 0.75mg~4.0mg, 1.0mg~4.0mg, 1.25mg~4.0mg, 1.5mg~4.0mg, 2.0mg~4.0mg, 2.5mg~4.0mg, 3.0mg~4.0mg, 3.5mg~4.0mg, 0.1mg~3.5mg, 0.1mg~3 .0mg, 0.1mg~2.5mg, 0.1mg~2.0mg, 0.1mg~1.5mg, 0.1mg~1mg, 0.1mg~0.5mg, 0.5mg~3.0mg, 0.5mg~2.0mg, 0.5mg~1.0mg, 0.75mg~1.25mg, 1.0mg~3.0mg, 1.5 mg to 2.0 mg, 0.7 mg to 0.9 mg, or 0.9 mg to 1.1 mg; for example, about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.75 mg, about 2.0 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3.0 mg, about 3.5 mg, or about 4.0 mg, and C1D2 is 0.05 mg to 20.0 mg (for example, 0.1 mg to 2 0.0mg, 0.2mg~20.0mg, 0.3mg~20.0mg, 0.4mg~20.0mg, 0.5mg~20.0mg, 1.0mg~20.0mg, 1.5mg~20.0mg, 2.0mg~20.0mg, 3.0mg~20.0mg, 4.0mg~20.0mg, 5. 0mg~20.0mg, 6.0mg~20.0mg, 7.0mg~20.0mg, 8.0mg~20.0mg, 9.0mg~20.0mg, 10.0mg~20.0mg, 15.0mg~20.0mg, 0.5mg~15.0mg, 0.5mg~10.0mg, 0.5mg~9.0 mg, 0.5 mg to 8.0 mg, 0.5 mg to 7.0 mg, 0.5 mg to 6.0 mg, 0.5 mg to 5.0 mg, 0.5 mg to 4.0 mg, 0.5 mg to 3.0 mg, 0.5 mg to 2.0 mg, 0.5 mg to 1.0 mg, 1.0 mg to 15.0 mg, 1.0 mg to 10.0 mg, 1.0 mg to 8.0 mg, 1.0 mg to 6.0 mg, 1.0 mg to 4.0 mg, 1.0 mg to 3.0 mg, 10.0 mg to 20.0 mg, 15.0 mg to 20.0 mg, 5.0 mg to 15.0 mg, or 5.0 mg to 10.0 mg; for example, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 5.0 mg, about 6.0 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 15.0 mg, or about 20.0 mg), and C1D3 is 0.2 mg to 50.0 mg (e.g., 0.3 mg to 5 0.0mg, 0.4mg~50.0mg, 0.5mg~50.0mg, 1.0mg~50.0mg, 2.0mg~50.0mg, 3.0mg~50.0mg, 4.0mg~50.0mg, 5.0mg~50.0mg, 10.0mg~50.0mg, 15.0mg~50.0mg , 20.0mg~50.0mg, 25.0mg~50.0mg, 30.0mg~50.0mg, 35.0mg~50.0mg, 40.0mg~50.0mg, 45.0mg~50.0mg, 1.0mg~45.0mg, 1.0mg~40.0mg, 1.0mg~35.0mg, 1 .0mg-30.0mg, 1.0mg-25.0mg, 1.0mg-20.0mg, 1.0mg-15.0mg, 1.0mg-10.0mg, 1.0mg-5.0mg, 10.0mg-20.0mg, 20.0mg-30.0mg, 30.0mg-40.0mg, 5.0mg-25.0mg, 25.0mg-50.0mg, 3.0mg-45.0mg, 4.0mg-4.5mg, 3.0mg-10.0mg, 4.0mg-5.0mg, 25.0mg-35.0mg, 28.0mg-32.0mg, 10.0mg-30.0mg, or 20.0mg-40.0 mg; e.g., about 0.2 mg, about 0.5 mg, about 0.8 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 4.0 mg, about 4.2 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 12.0 mg, about 15.0 mg, about 20.0 mg, about 25.0 mg, about 30.0 mg, about 35.0 mg, about 40.0 mg, about 45.0 mg, or about 50.0 mg), and (b) each of the second through twelfth dosing cycles is a single dose. Each single dose C2D1-C12D1 is an equal amount, not less than C1D3, of mosunetuzumab in a dose range of 0.2 mg-50 mg (e.g., 0.3 mg-50.0 mg, 0.4 mg-50.0 mg, 0.5 mg-50.0 mg, 1.0 mg-50.0 mg, 2.0 mg-50.0 mg, 3.0 mg-50.0 mg, 4.0 mg-50.0 mg, 5.0 mg-50.0 mg, 10.0 mg-50.0 mg, 15.0 mg-50.0 mg, 20.0 mg-50.0 mg, 25.0 mg-50.0 mg, 30.0 mg-50.0 mg, 35. 0mg~50.0mg, 40.0mg~50.0mg, 45.0mg~50.0mg, 1.0mg~45.0mg, 1.0mg~40.0mg, 1.0mg~35.0mg, 1.0mg~30.0mg, 1.0mg~25.0mg, 1.0mg~20.0mg, 1.0mg~1 5.0mg, 1.0mg~10.0mg, 1.0mg~5.0mg, 10.0mg~20.0mg, 20.0mg~30.0mg, 30.0mg~40.0mg, 5.0mg~25.0mg, 25.0mg~50.0mg, 3.0mg~45.0mg, 4.0mg~4.5mg, 3.0mg to 10.0mg, 4.0mg to 5.0mg, 25.0mg to 35.0mg, 28.0mg to 32.0mg, 10.0mg to 30.0mg, or 20.0mg to 40.0mg; for example, about 0.2mg, about 0.5mg, about 0.8mg, about 1.0mg, about 1.5mg, about 2.0mg, about 2.5mg, about 3.0mg, about 4.0mg, about 4.2mg, about 4.5mg, about 5.0mg, about 5.5mg, about 6.0mg, about 6.5mg, about 7.0mg, about 8.0mg, about 9.0mg, about 10.0mg, about 12.0mg, about 15.0mg, about 20.0mg, about 25.0 mg, about 30.0 mg, about 35.0 mg, about 40.0 mg, about 45.0 mg, or about 50.0 mg.

[0145] In some embodiments, (a) C1D1 is 0.4 mg to 4.0 mg (e.g., 0.5 mg to 4.0 mg, 0.75 mg to 4.0 mg, 1.0 mg to 4.0 mg, 1.25 mg to 4.0 mg, 1.5 mg to 4.0 mg, 2.0 mg to 4.0 mg, 2.5 mg to 4.0 mg, 3.0 mg to 4.0 mg, 3.5 mg to 4.0 mg, 0.5 mg to 3.5 mg, 0.5 mg to 3.0 mg, 0.5 mg to 2.0 mg, 0.5 mg to 1.0 mg, 0.75 mg to 1.25 mg, 1.0 mg to 3.0 mg, 1.5 mg to 2.0 mg, 0.7 mg to 0.9 mg, or 0 .9 mg to 1.1 mg; for example, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.75 mg, about 2.0 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3.0 mg, about 3.5 mg, or about 4.0 mg, and C1D2 is 1.0 mg to 20.0 mg (e.g., 1.1 mg to 20.0 mg, 1.2 mg to 20.0 mg, 1.3 mg to 20.0 mg, 1.4 mg to 20.0 mg, 1.5 mg to 20.0 mg, 2.0 mg to 20.0 mg, mg~20.0mg, 3.0mg~20.0mg, 4.0mg~20.0mg, 5.0mg~20.0mg, 6.0mg~20.0mg, 7.0mg~20.0mg, 8.0mg~20.0mg, 9.0mg~20.0mg, 10.0mg~20.0mg, 15.0mg~20 .0mg, 1.0mg~15.0mg, 1.0mg~10.0mg, 1.0mg~9.0mg, 1.0mg~8.0mg, 1.0mg~7.0mg, 1.0mg~6.0mg, 1.0mg~5.0mg, 1.0mg~4.0mg, 1.0mg~3.0mg, 1.0mg~2.0 mg, 10.0 mg to 20.0 mg, 15.0 mg to 20.0 mg, 5.0 mg to 15.0 mg, or 5.0 mg to 10.0 mg; for example, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 5.0 mg, about 6.0 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 15.0 mg, or about 20.0 mg) and C1D3 is 3.0 mg to 50.0mg (e.g., 4.0mg-50.0mg, 5.0mg-50.0mg, 10.0mg-50.0mg, 15.0mg-50.0mg, 20.0mg-50.0mg, 25.0mg-50.0mg, 30.0mg-50.0mg, 35.0mg-50.0mg, 40.0mg-50.0mg, 45.0mg-50.0mg, 3.0mg-45.0mg, 3.0mg-40.0mg, 3.0mg-35.0mg, 3.0mg-30.0mg, 3.0mg-25.0mg, 3.0mg-20.0mg, 3.0mg-15.0mg, 3.0mg-10.0mg , 3.0mg to 5.0mg, 10.0mg to 20.0mg, 20.0mg to 30.0mg, 30.0mg to 40.0mg, 5.0mg to 25.0mg, 25.0mg to 50.0mg, 4.0mg to 4.5mg, 4.0mg to 5.0mg, 25.0mg to 35.0mg, 28.0mg to 32.0mg, 10.0mg to 30.0mg, or 20.0mg to 40.0mg; for example, about 3.0mg, about 4.0mg, about 4.2mg, about 4.5mg, about 5.0mg, about 5.5mg, about 6.0mg, about 6.5mg, about 7.0mg, about 8.0mg, about 9.0mg, about 10. 0 mg, about 12.0 mg, about 15.0 mg, about 20.0 mg, about 25.0 mg, about 30.0 mg, about 35.0 mg, about 40.0 mg, about 45.0 mg, or about 50.0 mg), and (b) each single dose of C2D1 to C12D1 is 3.0 mg to 50.0 mg (e.g., 4.0 mg to 50.0 mg, 5.0 mg to 50.0 mg, 10.0 mg to 50.0 mg, 15.0 mg to 50.0 mg, 20.0 mg to 50.0 mg, 25.0 mg to 50.0 mg, 30.0 mg to 50.0 mg, 35.0 mg to 50.0 mg, 40.0 mg to 50.0 mg, 45.0 mg to 50.0 mg, mg~50.0mg, 3.0mg~45.0mg, 3.0mg~40.0mg, 3.0mg~35.0mg, 3.0mg~30.0mg, 3.0mg~25.0mg, 3.0mg~20.0mg, 3.0mg~15.0mg, 3.0mg~10.0mg, 3.0mg~5.0mg , 10.0mg~20.0mg, 20.0mg~30.0mg, 30.0mg~40.0mg, 5.0mg~25.0mg, 25.0mg~50.0mg, 4.0mg~4.5mg, 4.0mg~5.0mg, 25.0mg~35.0mg, 28.0mg~32.0mg, 10.0 mg to 30.0 mg, or 20.0 mg to 40.0 mg; for example, about 3.0 mg, about 4.0 mg, about 4.2 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 12.0 mg, about 15.0 mg, about 20.0 mg, about 25.0 mg, about 30.0 mg, about 35.0 mg, about 40.0 mg, about 45.0 mg, or about 50.0 mg).

[0146] In some embodiments, (a) C1D1 is from 0.8 mg to 3.0 mg (e.g., 0.9 mg to 3.0 mg, 1.0 mg to 3.0 mg, 1.25 mg to 3.0 mg, 1.5 mg to 3.0 mg, 2.0 mg to 3.0 mg, 2.5 mg to 3.0 mg, 0.8 mg to 3.0 mg, 0.8 mg to 2.5 mg, 0.8 mg to 2.0 mg, 0.5 mg to 1.5 mg, 0.8 mg to 1.0 mg, 1.0 mg to 3.0 mg, 1.5 mg to 2.0 mg, or 0.9 mg to 1.1 mg; e.g., about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.75 mg, about 2.0 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, or about 3.0 mg), and C1D2 is 1.0 mg to 6.0 mg (e.g., 1.5 mg to 6.0 mg, 2.0 mg to 6.0 mg, 2.5 mg to 6.0 mg, 3.0 mg to 6.0 mg, 3.5 mg to 6.0 mg, 4.0 mg to 6.0 mg, 5.0 mg to 6.0 mg, 5.0 mg to 6.0 mg, 1.0 mg to 5.0 mg, 1.0 mg to 4.5 mg, 1.0 mg to 4.0 mg, 1.0 mg to 3.5 mg, 1.0 mg to 3.0 mg, 1.0 mg to 2.5 mg, 1.0 mg to 2.0 mg, 1.0 mg to 1.5 mg, 1.5 mg to 2.5 mg, 3.0 mg to 6.0 mg, 2.0 mg to 4.0 mg, 2.5 mg to 5.0 mg, or 2.5 mg to 3.5 mg; for example, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, or about 6.0 mg), and C1D3 is 3.0 mg to 45.0 mg (e.g., 4.0 mg to 45.0 mg, 5.0 mg to 45.0 mg, 10.0 mg to 45.0 mg, 15.0 mg to 45.0 mg, 20.0 mg to 45.0 mg, 25.0 mg to 45.0 mg, 30.0 mg to 45.0 mg, 35.0 mg to 45.0 mg, 40.0 mg to 45.0 mg, 3.0 mg to 40.0 mg, 3.0 mg to 35.0 mg, 3.0 mg to 30.0 mg, 3.0 mg to 25.0 mg, 3.0 mg to 20.0 mg, 3.0 mg to 15.0 mg, 3.0 mg to 10.0 mg, 3.0 mg to 5.0 mg, 10.0 mg to 20.0 mg, 20.0 mg to 30.0 mg, 30.0 mg to 40.0 mg, 5.0 mg to 25.0 mg, 4.0 mg to 4.5 mg, 4.0 mg to 5.0 mg, 25.0 mg to 35.0 mg, 28.0 mg to 32.0 mg, 10.0 mg to 30.0 mg, or 20.0 mg to 40.0 mg; for example, about 3.0 mg, about 4.0 mg, about 4.2 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 12.0 mg, about 15.0 mg, about 20.0 mg, about 25.0 mg, about 30.0 mg, about 35.0 mg, about 40.0 mg, or about 45.0 mg), and (b) each single dose of C2D1 to C12D1 is 3.0 mg to 45.0 mg (e.g., 4.0 mg to 45.0 mg, 5.0 mg to 45.0 mg, 10.0 mg to 45.0 mg, 15.0 mg to 45.0 mg, 20.0 mg to 45.0 mg, 25 .0mg~45.0mg, 30.0mg~45.0mg, 35.0mg~45.0mg, 40.0mg~45.0mg, 3.0mg~40.0mg, 3.0mg~35.0mg, 3.0mg~30.0mg, 3.0mg~25.0mg, 3.0mg~2 0.0mg, 3.0mg~15.0mg, 3.0mg~10.0mg, 3.0mg~5.0mg, 10.0mg~20.0mg, 20.0mg~30.0mg, 30.0mg~40.0mg, 5.0mg~25.0mg, 4.0mg~4.5mg, 4.0 mg to 5.0 mg, 25.0 mg to 35.0 mg, 28.0 mg to 32.0 mg, 10.0 mg to 30.0 mg, or 20.0 mg to 40.0 mg; for example, about 3.0 mg, about 4.0 mg, about 4.2 mg, about 4.5 mg, about 5.0 mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 12.0 mg, about 15.0 mg, about 20.0 mg, about 25.0 mg, about 30.0 mg, about 35.0 mg, about 40.0 mg, or about 45.0 mg).

[0147] In some embodiments, C1D1 and C1D2 are each smaller than C1D3. In some embodiments, C1D2 is about 50% to about 250% larger than C1D1 (e.g., C1D2 is about 50% to about 225% larger than C1D1, C1D2 is about 50% to about 200% larger than C1D1, C1D2 is about 50% to about 175% larger than C1D1, C1D2 is about 50% to about 150% larger than C1D1, C1D2 is about 50% to about 125% larger than C1D1). greater than C1D1, C1D2 is about 50% to about 100% greater than C1D1, or C1D2 is about 50% to about 75% greater than C1D1; e.g., C1D2 is about 50% greater than C1D1, C1D2 is about 100% greater than C1D1, C1D2 is about 150% greater than C1D1, C1D2 is about 200% greater than C1D1, or C1D2 is about 250% greater than C1D1).

[0148] In some embodiments, (a) C1D1 is 0.8 mg, C1D2 is 2.0 mg, and C1D3 is 4.2 mg, and each single dose C2D1-C12D1 is 4.2 mg; (b) C1D1 is 1.0 mg, C1D2 is 1.0 mg, and C1D3 is 3.0 mg, and each single dose C2D1-C12D1 is 30.0 mg; or (c) C1D1 is 1.0 mg, C1D2 is 2.0 mg, and C1D3 is 30.0 mg, and each single dose C2D1-C12D1 is 30.0 mg.

[0149] In some embodiments, the first dosing cycle is 21 days (± 1 day) in length. In some embodiments, the method includes administering C1D1, C1D2, and C1D3 to the subject on days 1, 8 (± 1 day), and 15 (± 1 day), or about days 1, about 8 (± 1 day), and about 15 (± 1 day), respectively, of the first dosing cycle. In some embodiments, the second through twelfth dosing cycles are each 28 days (± 1 day) in length. In some embodiments, the method includes administering each of C2D1 through C12D1 to the subject on day 1 of each respective dosing cycle. In some embodiments, the second through twelfth dosing cycles are each 28 days (± 1 day) in length.

[0150] In some embodiments, mosunetuzumab is administered intravenously.

[0151] In some embodiments, lenalidomide is administered during the second or subsequent cycles. In some embodiments, lenalidomide is not administered during the first cycle. In some embodiments, lenalidomide is administered daily. In some embodiments, lenalidomide is administered daily for the first 21 days of each dosing cycle that includes administration of lenalidomide. In some embodiments, lenalidomide is not administered for the last 7 days of each dosing cycle that includes administration of lenalidomide. In some embodiments, lenalidomide is administered at a dose of 20 mg. In some embodiments, lenalidomide is administered orally.

[0152] In some embodiments, the subject has previously been treated with at least one anti-CD20 monoclonal antibody. In some embodiments, the subject is relapsed or refractory to treatment comprising an anti-CD20 monoclonal antibody. In some embodiments, the anti-CD20 monoclonal antibody is obinutuzumab or rituximab.

[0153] In one aspect, the invention provides a method of treating a subject comprising administering to the subject an effective amount of mosunetuzumab and an effective amount of lenalidomide, wherein the subject (i) has relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20, and (ii) has previously been treated with at least one chemoimmunotherapy regimen comprising obinutuzumab, wherein administering effective amounts of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising at least a first 21 day (± 1 day) dosing cycle and a second 28 day (± 1 day) dosing cycle, wherein (a) the first dosing cycle is administered intravenously on days 1, 8 (± 1 day), and 15 (± 1 day), respectively, of the first dosing cycle. (b) the second dosing cycle comprises a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of mosunetuzumab administered intravenously on day 1 of the second dosing cycle, where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg; (b) the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab administered intravenously on day 1 of the second dosing cycle, where C2D1 is 30 mg; and (c) the second dosing cycle further comprises orally administering 20 mg of lenalidomide daily on days 1-21 of the second dosing cycle.

[0154] In one aspect, the invention provides a method of treating a subject comprising administering to the subject an effective amount of mosunetuzumab and an effective amount of lenalidomide, wherein the subject (i) has relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20, and (ii) has previously been treated with at least one chemoimmunotherapy regimen comprising obinutuzumab, wherein administering effective amounts of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising a first 21 day (± 1 day) dosing cycle and an eleventh or subsequent 28 day (± 1 day) dosing cycle, wherein (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) administered intravenously on days 1, 8 (± 1 day), and 15 (± 1 day), respectively, of the first dosing cycle. (b) a second through a twelfth dosing cycle comprise a single dose (C2D1-C12D1) of mosunetuzumab administered intravenously on day 1 of each dosing cycle, each single dose C2D1-C12D1 being 30 mg; and (c) the second through twelfth dosing cycles further comprise orally administering 20 mg of lenalidomide daily on days 1-21 of each dosing cycle, respectively.

[0155] In one aspect, the invention provides a method of treating a subject comprising administering to the subject an effective amount of mosunetuzumab and an effective amount of lenalidomide, wherein the subject (i) has relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20, and (ii) has previously been treated with at least one chemoimmunotherapy regimen comprising rituximab, wherein administering effective amounts of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising at least a first 21 day (± 1 day) dosing cycle and a second 28 day (± 1 day) dosing cycle, wherein (a) the first dosing cycle is administered on days 1, 8 (± 1 day), and 15 (± 1 day), respectively, of the first dosing cycle. (b) the second dosing cycle comprises a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of mosunetuzumab administered on day 1 of the second dosing cycle, where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg; (b) the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab administered on day 1 of the second dosing cycle, where C2D1 is 30 mg; and (c) the second dosing cycle further comprises orally administering 20 mg of lenalidomide daily on days 1-21 of the second dosing cycle.

[0156] In one aspect, the invention provides a method of treating a subject comprising administering to the subject an effective amount of mosunetuzumab and an effective amount of lenalidomide, wherein the subject (i) has relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20, and (ii) has previously been treated with at least one chemoimmunotherapy regimen comprising rituximab, wherein administering effective amounts of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising a first 21 day (± 1 day) dosing cycle and an eleventh or subsequent 28 day (± 1 day) dosing cycle, wherein (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) administered intravenously on days 1, 8 (± 1 day), and 15 (± 1 day), respectively, of the first dosing cycle. (b) a second through a twelfth dosing cycle comprise a single dose (C2D1-C12D1) of mosunetuzumab administered intravenously on day 1 of each dosing cycle, each single dose C2D1-C12D1 being 30 mg; and (c) the second through twelfth dosing cycles further comprise orally administering 20 mg of lenalidomide daily on days 1-21 of each dosing cycle, respectively.

[0157] In one aspect, the invention provides a method of treating a population of subjects comprising administering an effective amount of mosunetuzumab and an effective amount of lenalidomide to each subject in the population, wherein each subject (a) has relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20, and (b) has been previously treated with at least one chemoimmunotherapy regimen, wherein administering effective amounts of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising at least a first 21 day (± 1 day) dosing cycle and a second 28 day (± 1 day) dosing cycle, wherein (a) the first dosing cycle comprises a first dosing cycle administered intravenously on days 1, 8 (± 1 day), and 15 (± 1 day), respectively, of the first dosing cycle. (b) the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab administered intravenously on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and (c) the second dosing cycle further comprises orally administering 20 mg of lenalidomide daily on days 1-21 of the second dosing cycle. In some embodiments, at least one chemoimmunotherapeutic regimen included an anti-CD20 monoclonal antibody (e.g., rituximab or obinutuzumab).

[0158] In one aspect, the invention provides a method of treating a population of subjects comprising administering an effective amount of mosunetuzumab and an effective amount of lenalidomide to each subject in the population, wherein each subject (a) has relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20, and (b) has been previously treated with at least one chemoimmunotherapy regimen, wherein administering effective amounts of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising a first 21 day (± 1 day) dosing cycle and an eleventh or subsequent 28 day (± 1 day) dosing cycle, wherein (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3), each administered intravenously on days 1, 8 (± 1 day), and 15 (± 1 day), respectively, of the first dosing cycle. (b) a second through a twelfth dosing cycle each comprise a single dose (C2D1-C12D1) of mosunetuzumab administered intravenously on day 1 of each dosing cycle, each single dose C2D1-C12D1 being 30 mg, and (c) a second through a twelfth dosing cycle each further comprise orally administering 20 mg of lenalidomide daily on days 1-21 of each dosing cycle, in some embodiments, at least one chemoimmunotherapeutic regimen included an anti-CD20 monoclonal antibody (e.g., rituximab or obinutuzumab).

[0159] In some embodiments, the dosing regimen further comprises administration of a corticosteroid. In some embodiments, the corticosteroid is administered to the subject during a first dosing cycle. In some embodiments, the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of a corticosteroid. In some embodiments, the corticosteroids C1D1, C1D2, and C1D3 are administered to the subject on days 1, 8 (± day 1), and 15 (± day 1), respectively, of the first dosing cycle. In some embodiments, each single dose C1D1-C1D3 of the corticosteroid is administered to the subject prior to administration of C1D1-C1D3 of mosunetuzumab, respectively. In some embodiments, each single dose of corticosteroid C1D1-C1D3 is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 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 prior to administration of each of mosunetuzumab C1D1-C1D3.

[0160] In some embodiments, a corticosteroid is administered to the subject in the first dosing cycle and not in the second dosing cycle.

[0161] In some embodiments, a corticosteroid is administered to the subject in the second dosing cycle. In some embodiments, the second dosing cycle comprises a single dose (C2D1) of a corticosteroid. In some embodiments, the C2D1 corticosteroid is administered to the subject on day 1 of the second dosing cycle. In some embodiments, the C2D1 corticosteroid is administered to the subject prior to administration of C2D1 mosunetuzumab. In some embodiments, the C2D1 corticosteroid is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 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 prior to administration of the C2D1 mosunetuzumab.

[0162] In some embodiments, the dosing regimen further comprises administration of a corticosteroid. In some embodiments, the corticosteroid is administered to the subject during a first dosing cycle. In some embodiments, the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of a corticosteroid. In some embodiments, the corticosteroids C1D1, C1D2, and C1D3 are administered to the subject on days 1, 8 (± day 1), and 15 (± day 1), respectively, of the first dosing cycle. In some embodiments, each single dose C1D1-C1D3 of the corticosteroid is administered to the subject prior to administration of C1D1-C1D3 of mosunetuzumab, respectively. In some embodiments, each single dose of corticosteroid C1D1-C1D3 is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 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 prior to administration of each of mosunetuzumab C1D1-C1D3.

[0163] In some embodiments, a corticosteroid is administered to the subject in the first dosing cycle and not in the second dosing cycle.

[0164] In some embodiments, a corticosteroid is administered to the subject in the second dosing cycle. In some embodiments, the second dosing cycle comprises a single dose (C2D1) of a corticosteroid. In some embodiments, the C2D1 corticosteroid is administered to the subject on day 1 of the second dosing cycle. In some embodiments, the C2D1 corticosteroid is administered to the subject prior to administration of C2D1 mosunetuzumab. In some embodiments, the C2D1 corticosteroid is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 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 prior to administration of the C2D1 mosunetuzumab.

[0165] In some embodiments, each additional dosing cycle comprises administering an additional dose of a corticosteroid to the subject. In some embodiments, each additional dose of a corticosteroid is administered on day 1 of each additional dosing cycle. In some embodiments, each additional dose of a corticosteroid is administered to the subject prior to administration of each additional dose of mosunetuzumab. In some embodiments, each additional dose of a corticosteroid is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 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 prior to administration of each additional dose of mosunetuzumab.

[0166] In some embodiments, the corticosteroid is administered intravenously. In some embodiments, the corticosteroid is dexamethasone. In some embodiments, each dose of dexamethasone is about 10 mg (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg).

[0167] In some embodiments, the overall response rate in the population of subjects with R / R FL is at least 80% (e.g., at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more; e.g., 80%-100%, 85-100%, 87-100%, 90-100%, 95-100%, 80%-90%, 80-85%, 85-97%, 85-95%, 85-90%, 85-87%, 90-95%, or 93-97%; e.g., about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more). In some embodiments, the overall response rate in the population of subjects with R / R FL is at least 90%. In some embodiments, the overall response rate in a population of subjects with R / R FL is at least 95%. In some embodiments, the overall response rate in a population of subjects with R / R FL is at least 99%.

[0168] In some embodiments, the complete response rate in a population of subjects with R / R FL is at least 65% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more; e.g., 65-100%, 75-100%, 85-100%, 95-100%, 65-90%, 65-80%, 65-70%, 65-75%, or 75-85%; e.g., about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 80%, about 85%, about 90%, or more). In some embodiments, the complete response rate in a population of subjects with R / R FL is at least 75%. In some embodiments, the complete response rate in the population of subjects with R / R FL is at least 85%.

[0169] In some embodiments, the combination therapy of mosunetuzumab and lenalidomide shows synergistic effects in efficacy of treatment compared to mosunetuzumab or lenalidomide alone for treating subjects with R / R FL. In some embodiments, a population of subjects with R / R FL treated with the combination therapy of mosunetuzumab and lenalidomide shows a higher overall response rate compared to a population of subjects treated with mosunetuzumab or lenalidomide alone as monotherapy. In some embodiments, a population of subjects with R / R FL treated with the combination therapy of mosunetuzumab and lenalidomide shows a higher complete response rate compared to a population of subjects treated with mosunetuzumab or lenalidomide alone as monotherapy.

[0170] In some embodiments, the subject shows a reduction in tumor burden after being administered an effective amount of mosunetuzumab and an effective amount of lenalidomide.In some embodiments, the reduction in tumor burden is determined by computed tomography (CT).In some embodiments, the reduction in tumor burden is a reduction in the sum of product diameters (SPD) of target lesions. In some embodiments, the reduction in SPD is at least 40% (e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more; e.g., 40-100%, 40-80%, 40-60%, 50-70%, 70-90%, 75-85%, 60-100%, 55-65%, 80-100%; e.g., about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%). In some embodiments, the reduction in SPD is at least 60%. In some embodiments, the reduction in SPD is at least 80%.

[0171] In some embodiments, at least 45% of the subjects in the population (e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more; e.g., 45-100%, 45-80%, 45-60%, 50-70%, 55-65%, 70-90%, 70-80%, 60-100%, 80-100%; e.g., about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%) exhibit a reduction in tumor burden after being administered an effective amount of mosunetuzumab and an effective amount of lenalidomide. In some embodiments, at least 60% of the subjects in the population show a reduction in tumor burden after being administered an effective amount of mosunetuzumab and an effective amount of lenalidomide. In some embodiments, at least 75% of the subjects in the population show a reduction in tumor burden after being administered an effective amount of mosunetuzumab and an effective amount of lenalidomide. In some embodiments, the reduction in tumor burden is determined by computed tomography (CT).

[0172] In some embodiments, the reduction in tumor burden is a reduction in the sum of product diameters (SPD) of target lesions. In some embodiments, the reduction in SPD is at least 40% (e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more; e.g., 40-100%, 40-80%, 40-60%, 50-70%, 70-90%, 75-85%, 60-100%, 55-65%, 80-100%; e.g., about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%). In some embodiments, the reduction in SPD is at least 60%. In some embodiments, the reduction in SPD is at least 80%.

[0173] In some embodiments, the subject is a human. In some embodiments, each subject in the population is a human.

[0174] B. Dosing Strategies to Reduce Adverse Events The present invention relates to a method of treating a subject with relapsed and / or refractory (R / R) follicular lymphoma (FL) by administering mosunetuzumab and lenalidomide as a combination therapy. In particular, the present invention relates to a method of treating a subject with R / R FL who is R / R to at least one prior systemic therapy (e.g., one prior treatment with a chemoimmunotherapy regimen) including an anti-CD20 antibody (e.g., an anti-CD20 monoclonal antibody, e.g., rituximab or obinutuzumab) or other treatment. The treatment and dosing regimens described herein provide an acceptable safety profile in subjects with R / R FL treated with the dosing regimens described.

[0175] 1. Signs and symptoms of CRS and grading Any of the methods described herein may include 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 intended to be objective, easy to apply, and more accurately classify the severity of CRS. This CRS grading system is shown in Table 1 below. [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.

[0176] 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 receive antipyretic or anticytokine therapy, such as tocilizumab or steroids. In this case, CRS grading is determined by hypotension and / or hypoxia.

[0177] CRS grade is determined by the more severe event, hypotension or hypoxia not attributable to other causes. For example, a subject with a temperature of 39.5°C, hypotension requiring one vasopressor, and hypoxia requiring a low-flow nasal cannula is classified as having grade 3 CRS.

[0178] Low-flow nasal cannulae are defined as oxygen delivered at ≤6 L / min. Low-flow also includes blow-by oxygen delivery, sometimes used in pediatrics. High-flow nasal cannulae are defined as oxygen delivered at >6 L / min.

[0179] 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 associated with high IL-6 levels (Nagorsen et al. Cytokine. 25(1):31-5, 2004; Lee et al. Blood. 124(2):188-95, 2014; Doesegger et al. Clin. Transl. Immunology. 4(7):e39, 2015) and IL-6 correlates with CRS severity, with subjects experiencing grade 4 or 5 CRS events having much higher IL-6 levels compared to subjects not experiencing CRS or those experiencing milder CRS (grades 0-3) (Chen et al. J. Immunol. Methods. 434:1-8, 2016).

[0180] 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-escalation 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).

[0181] If the subject has a CRS event that does not resolve or worsens within 24 hours of 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.

[0182] 2. Other Adverse Events and Grading Any of the methods described herein may 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 patients undergoing treatment with mosunetuzumab and / or lenalidomide is neutropenia (e.g., febrile neutropenia).

[0183] 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.

[0184] 3. A dosing regimen with an acceptable safety profile In one aspect, the invention provides a method of treating a population of subjects comprising administering an effective amount of mosunetuzumab and an effective amount of lenalidomide to each subject in the population, wherein each subject (a) has relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20, and (b) has been previously treated with at least one chemoimmunotherapy regimen, wherein administering effective amounts of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising at least a first 21 day (± 1 day) dosing cycle and a second 28 day (± 1 day) dosing cycle, wherein (a) the first dosing cycle comprises a first dosing cycle administered intravenously on days 1, 8 (± 1 day), and 15 (± 1 day), respectively, of the first dosing cycle. (b) the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab administered intravenously on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and (c) the second dosing cycle further comprises orally administering 20 mg of lenalidomide daily on days 1-21 of the second dosing cycle. In some embodiments, at least one chemoimmunotherapeutic regimen included an anti-CD20 monoclonal antibody (e.g., rituximab or obinutuzumab).

[0185] In one aspect, the invention provides a method of treating a population of subjects comprising administering an effective amount of mosunetuzumab and an effective amount of lenalidomide to each subject in the population, wherein each subject (a) has relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20, and (b) has been previously treated with at least one chemoimmunotherapy regimen, wherein administering effective amounts of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising a first 21 day (± 1 day) dosing cycle and an eleventh or subsequent 28 day (± 1 day) dosing cycle, wherein (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) administered intravenously on days 1, 8 (± 1 day), and 15 (± 1 day) of the first dosing cycle, respectively. (b) a second through a twelfth dosing cycle comprise a single dose (C2D1-C12D1) of mosunetuzumab administered intravenously on day 1 of each dosing cycle, each single dose C2D1-C12D1 being 30 mg, and (c) the second through twelfth dosing cycles further comprise orally administering 20 mg of lenalidomide daily on days 1-21 of each dosing cycle, respectively. In some embodiments, at least one chemoimmunotherapeutic regimen included an anti-CD20 monoclonal antibody (e.g., rituximab or obinutuzumab).

[0186] In some embodiments, each subject has received only one prior line of systemic therapy and either (a) has a Follicular Lymphoma International Prognostic Index (FLIPI; Solal-Celigny et al. Blood. 2004;104(5):1258-1265.) score of 2-5 (e.g., a score of 2, 3, 4, or 5), (b) is refractory to prior anti-CD20 monoclonal antibody treatment, or (c) has progressive disease within 24 months after initiation of prior treatment.

[0187] In some embodiments, each subject's FL is histologically documented to be grade 1, 2, or 3a, but not 3b, according to the World Health Organization Classification of Lymphoid Neoplasms (referenced in Swerdlow SH, et al. Blood 2016;127:2375-90).

[0188] In some embodiments, each subject has not been treated with an anti-CD20 monoclonal antibody for at least 4 weeks (e.g., 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 24 weeks, 36 weeks, 48 ​​weeks, 60 weeks, or more) prior to administration of effective amounts of mosunetuzumab and lenalidomide.

[0189] In some embodiments, mosunetuzumab and lenalidomide have a synergistic effect on R / R FL. In some embodiments, the synergy is a partial response as defined by the Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014;32:1-9). In some embodiments, the synergy is a complete response as defined by the Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014;32:1-9).

[0190] In one aspect, the method of the present invention features premedication with a corticosteroid to reduce adverse effects of mosunetuzumab administration. In some embodiments, premedication with a corticosteroid reduces the rate of cytokine release syndrome (CRS) in subjects treated with mosunetuzumab (e.g., subjects administered a combination of mosunetuzumab and lenalidomide). In some embodiments, the dosing regimen further comprises administration of a corticosteroid. In some embodiments, the corticosteroid is administered to the subject during the first dosing cycle. In some embodiments, the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of a corticosteroid. In some embodiments, the corticosteroids C1D1, C1D2, and C1D3 are administered to the subject on days 1, 8 (± day 1), and 15 (± day 1), respectively, of the first dosing cycle. In some embodiments, each single dose of corticosteroid C1D1-C1D3 is administered to the subject prior to administration of mosunetuzumab C1D1-C1D3, respectively. In some embodiments, each single dose of corticosteroid C1D1-C1D3 is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 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 prior to administration of mosunetuzumab C1D1-C1D3, respectively. In some embodiments, the corticosteroid used is dexamethasone. In some embodiments, each dose of dexamethasone is about 10 mg (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg). In some embodiments, dexamethasone is administered intravenously.

[0191] In some embodiments, a corticosteroid is administered to the subject in the first dosing cycle and not in the second dosing cycle.

[0192] In some embodiments, a corticosteroid is administered to the subject in the second dosing cycle. In some embodiments, the second dosing cycle comprises a single dose (C2D1) of a corticosteroid. In some embodiments, the C2D1 corticosteroid is administered to the subject on day 1 of the second dosing cycle. In some embodiments, the C2D1 corticosteroid is administered to the subject prior to administration of C2D1 mosunetuzumab. In some embodiments, the C2D1 corticosteroid is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 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 prior to administration of the C2D1 mosunetuzumab.

[0193] In some embodiments, the dosing regimen further comprises administration of a corticosteroid. In some embodiments, the corticosteroid is administered to the subject during a first dosing cycle. In some embodiments, the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of a corticosteroid. In some embodiments, the corticosteroids C1D1, C1D2, and C1D3 are administered to the subject on days 1, 8 (± day 1), and 15 (± day 1), respectively, of the first dosing cycle. In some embodiments, each single dose C1D1-C1D3 of the corticosteroid is administered to the subject prior to administration of C1D1-C1D3 of mosunetuzumab, respectively. In some embodiments, each single dose of corticosteroid C1D1-C1D3 is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 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 prior to administration of each of mosunetuzumab C1D1-C1D3.

[0194] In some embodiments, a corticosteroid is administered to the subject in the first dosing cycle and not in the second dosing cycle.

[0195] In some embodiments, a corticosteroid is administered to the subject in the second dosing cycle. In some embodiments, the second dosing cycle comprises a single dose (C2D1) of a corticosteroid. In some embodiments, the C2D1 corticosteroid is administered to the subject on day 1 of the second dosing cycle. In some embodiments, the C2D1 corticosteroid is administered to the subject prior to administration of C2D1 mosunetuzumab. In some embodiments, the C2D1 corticosteroid is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 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 prior to administration of the C2D1 mosunetuzumab.

[0196] In some embodiments, each additional dosing cycle comprises administering an additional dose of a corticosteroid to the subject. In some embodiments, each additional dose of a corticosteroid is administered on day 1 of each additional dosing cycle. In some embodiments, each additional dose of a corticosteroid is administered to the subject prior to administration of each additional dose of mosunetuzumab. In some embodiments, each additional dose of a corticosteroid is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 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 prior to administration of each additional dose of mosunetuzumab.

[0197] In some embodiments, the corticosteroid is administered intravenously. In some embodiments, the corticosteroid is dexamethasone. In some embodiments, each dose of dexamethasone is about 10 mg (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg).

[0198] In some embodiments, the incidence of adverse events is not significantly higher than when mosunetuzumab is administered alone to a population of subjects with R / R FL. In some embodiments, the incidence of adverse events is not significantly higher than when lenalidomide is not administered to a population of subjects. In some embodiments, the incidence of adverse events is not significantly higher in a population of subjects with R / R FL treated with a combination therapy of mosunetuzumab and lenalidomide compared to a population of subjects with R / R FL treated with a monotherapy of mosunetuzumab or lenalidomide alone.

[0199] In some embodiments, the American Society for Transplant and Cellular Therapy (ASTCT) Consensus Grading for Cytokine Release Syndrome ("ASTCT CRS Grading"; Lee et al., Biol Blood Marrow Transplant The incidence of cytokine release syndrome as defined by the International Journal of Clinical Oncology (2019) is less than 45% (e.g., less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, less than 3%, or less than 1%; e.g., about 0% to about 50%, about 5% to about 40%, about 5% to about 20%, about 5% to about 10%, about 20% to about 45%, about 30% to about 40%, about 20% to about 40%, about 15% to about 35%, about 15% to about 25%, about 35% to about 45%, or about 25% to about 45%; e.g., about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, about 5%, about 1%, or about 0%). In some embodiments, the incidence of cytokine release syndrome as defined by the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading on Cytokine Release Syndrome ("ASTCT CRS Grading") is less than 35%. In some embodiments, the incidence of cytokine release syndrome as defined by the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading on Cytokine Release Syndrome ("ASTCT CRS Grading") is less than 25%. In some embodiments, the incidence of CRS is about 30%.

[0200] In some embodiments, the incidence of cytokine release syndrome having a grade of 3 or greater as defined by the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading on Cytokine Release Syndrome ("ASTCT CRS Grading") is less than 10% (e.g., less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%; e.g., 0%-10%, 0%-9%, 0%-8%, 0%-7%, 0%-6%, 0%-5%, 0%-4%, 0%-3%, 0%-2%, 0%-1%, 1%-3%, 1%-5%, 1%-10%, 3%-5%, 5%-8%, 5%-10%, or 8%-10%). In some embodiments, the incidence of cytokine release syndrome having a grade of 3 or greater as defined by the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading on Cytokine Release Syndrome ("ASTCT CRS Grading") is less than 5%. In some embodiments, the incidence of Grade 3 or higher cytokine release syndrome as defined by the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading on Cytokine Release Syndrome ("ASTCT CRS Grading") is less than 3%. In some embodiments, the incidence of Grade 3 or higher cytokine release syndrome as defined by the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading on Cytokine Release Syndrome ("ASTCT CRS Grading") is less than 1%. In some embodiments, the incidence of Grade 3 or higher CRS is about 0%.

[0201] In some embodiments, the incidence of neutropenia in a population of patients with R / R FL and treated with combination therapy with mosunetuzumab and lenalidomide is less than 40% (e.g., less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, less than 3%, or less than 1%; e.g., about 0% to about 40%, about 5% to about 40%, about 5% to about 20%, about 5% to about 10%, about 20% to about 40%, about 30% to about 40%, about 15% to about 35%, about 15% to about 25%, about 35% to about 40%, or about 25% to about 40%; e.g., about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, about 5%, about 3%, about 1%, or about 0%). In some embodiments, the incidence of neutropenia is less than 30%. In some embodiments, the incidence of neutropenia is less than 20%. In some embodiments, the incidence of neutropenia having grade 3 or 4 is about 19%. In some embodiments, the incidence of febrile neutropenia is about 0%.

[0202] The methods described herein may result in an acceptable safety profile for subjects with R / R mosunetuzumab being treated with a combination therapy of mosunetuzumab and lenalidomide. In some examples, treatment using the methods described herein, in which mosunetuzumab is administered intravenously and lenalidomide is administered orally in the context of a split-dose ascending dosing regimen, may result in a reduction in undesirable adverse 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 hepatotoxicity (e.g., 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 70% or more, 80% or more, 90% or more, 100% or more, 110% or more, 120% or more, 130% or more, 140% or more, 150% or more, 160% or more, 170% or more, 180% or more, 190% or more, 20% or more, 21% or more, 22% or more, 23% or more, 24% or more, 25% or more, 26% or more, 27% or more, 28% or more, 29% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 24% or more, 25% or more, 25% or more, 30% or more, 35% or more, 40% 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more; for example, 20%-100%, 20%-90%, 20%-80%, 20%-70%, 20%-60%, 20%-50%, 20%-40%, 20%-30%, 40%-100%, 60%-100%, 80%-100%, 30 % to 70%, 40% to 60%, 30% to 50%, 50% to 80%, or 90% to 100%; for example, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 97%, about 99%, or about 100%) or complete inhibition (100% reduction).

[0203] IV. Therapeutic Agents A. Mosunetuzumab The present invention provides mosunetuzumab, a bispecific antibody that binds CD20 and CD3, useful for the treatment of relapsed and / or refractory (R / R) follicular lymphoma (FL), which may be grade 1, 2 or 3a, but not grade 3b.

[0204] In some examples, the present invention provides mosunetuzumab comprising 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) HVR-H1 comprising the amino acid sequence of GYTFTSYNMH (SEQ ID NO: 1); (b) HVR-H2 comprising the amino acid sequence of AIYPGNGDTSYNQKFKG (SEQ ID NO: 2); (c) HVR-H3 comprising the amino acid sequence of VVYYSNSYWYFDV (SEQ ID NO: 3); (d) HVR-L1 comprising the amino acid sequence of RASSSVSYMH (SEQ ID NO: 4); (e) HVR-L2 comprising the amino acid sequence of APSNLAS (SEQ ID NO: 5); and (f) HVR-L3 comprising the amino acid sequence of QQWSFNPPT (SEQ ID NO: 6). In some examples, mosunetuzumab 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 having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity) to SEQ ID NO: 7 or comprising the amino acid sequence of SEQ ID NO: 7; (b) a light chain variable (VL) domain having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity) to SEQ ID NO: 8 or comprising the amino acid sequence of SEQ ID NO: 8; 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.

[0205] In some examples, the invention provides mosunetuzumab comprising an anti-CD3 arm having a second binding domain comprising at least one, two, three, four, five or six HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of NYYIH (SEQ ID NO: 9); (b) HVR-H2 comprising the amino acid sequence of WIYPGDGNTKYNEKFKG (SEQ ID NO: 10); (c) HVR-H3 comprising the amino acid sequence of DSYSNYYFDY (SEQ ID NO: 11); (d) HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 13); (f) HVR-L3 comprising the amino acid sequence of TQSFILRT (SEQ ID NO: 14). In some examples, mosunetuzumab 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: (a) a VH domain having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity) to SEQ ID NO: 15, or the amino acid sequence of SEQ ID NO: 15; (b) a VL domain having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity) to SEQ ID NO: 16, or the amino acid sequence of SEQ ID NO: 16; or (c) an anti-CD3 arm comprising 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 the amino acid sequence of SEQ ID NO: 15 and a VL domain comprising the amino acid sequence of SEQ ID NO: 16.

[0206] In some examples, the present invention provides an anti-CD20 arm having a first binding domain comprising at least one, two, three, four, five, or six HVRs selected from: (1) HVR-H1 comprising the amino acid sequence of GYTFTSYNMH (SEQ ID NO: 1); (b) HVR-H2 comprising the amino acid sequence of AIYPGNGDTSYNQKFKG (SEQ ID NO: 2); (c) HVR-H3 comprising the amino acid sequence of VVYYSNSYWYFDV (SEQ ID NO: 3); (d) HVR-L1 comprising the amino acid sequence of RASSSVSYMH (SEQ ID NO: 4); (e) HVR-L2 comprising the amino acid sequence of APSNLAS (SEQ ID NO: 5); and (f) HVR-L3 comprising the amino acid sequence of QQWSFNPPT (SEQ ID NO: 6); and (2) and 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 (1) at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 17-20, respectively, and / or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 21-24, respectively, and (2) at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 25-28, respectively, and / or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 29-32, respectively.In some examples, mosunetuzumab is an anti-CD20 antibody that comprises: (1) (a) a VH domain having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity) to SEQ ID NO: 7, or the amino acid sequence of SEQ ID NO: 7; (b) a VL domain having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity) to SEQ ID NO: 8, or the amino acid sequence of SEQ ID NO: 8; (c) an anti-CD20 antibody that comprises a first binding domain comprising a VH as in (a) and a VL as in (b). and (2) (a) a VH domain having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity) to, or the amino acid sequence of SEQ ID NO: 15; (b) a VL domain having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity) to, or the amino acid sequence of SEQ ID NO: 16; or (c) an anti-CD3 arm comprising a second binding domain comprising a VH as in (a) and a VL as in (b). In some examples, mosunetuzumab comprises (1) a first binding domain comprising a VH domain comprising the amino acid sequence of SEQ ID NO:7 and a VL domain comprising the amino acid sequence of SEQ ID NO:8, and (2) a second binding domain comprising a VH domain comprising the amino acid sequence of SEQ ID NO:15 and a VL domain comprising the amino acid sequence of SEQ ID NO:16.

[0207] 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 is an anti-CD2 antibody comprising: (1) (a) a heavy chain having an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity) to SEQ ID NO: 33, or the amino acid sequence of SEQ ID NO: 33; (b) a light chain having an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity) to SEQ ID NO: 34, or the amino acid sequence of SEQ ID NO: 34; (c) an anti-CD2 antibody comprising a first binding domain comprising a heavy chain as in (a) and a light chain as in (b). 0 arm, and (2) (a) a heavy chain having 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, or the amino acid sequence of SEQ ID NO: 35; (b) a light chain having 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, or the amino acid sequence of SEQ ID NO: 36; 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.

[0208] The amino acid sequence of mosunetuzumab is summarized in Table 2 below. [Table 2]

[0209] Mosunetuzumab can be produced using recombinant methods and compositions, for example, as described in US Pat. No. 4,816,567.

[0210] B. Lenalidomide Lenalidomide is an immunomodulatory (IMiD) imide drug that binds to the E3 ubiquitin ligase protein cereblon (Gribben et al. 2015). Although the immunomodulatory activity of lenalidomide is not fully understood, it has been shown to enhance CD4+ and CD8+ T cell costimulation, induce T cell proliferation, and enhance IL-2 and IFN-γ (Haslett et al. 1998; Davies et al. 2001).

[0211] Lenalidomide has the CAS Registry Number 191732-72-6 and the IUPAC name (3RS)-3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione. Lenalidomide is also known by trade names including REVLIMID®, linamide, and lenalid. Lenalidomide is identified by DrugBank Accession Number DB00480, PubChem CID 216326, and the chemical formula C 13 H 13 The present invention describes additive / synergistic efficacy, as well as potential overlapping toxicities, in the combination of mosunetuzumab and lenalidomide, with careful monitoring and management of patients with the dosing regimens and treatments described herein.

[0212] C. Additional Therapeutic Agents In some examples, the methods described herein include administering mosunetuzumab and lenalidomide in combination with one or more additional therapeutic agents.

[0213] 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 examples, the additional therapeutic agent used to reduce the rate or severity of CRS or prevent symptoms associated with CRS is a corticosteroid (e.g., dexamethasone (CAS number: 50-02-2), prednisone (CAS number: 53-03-2), prednisolone (CAS number: 50-42-8) or methylprednisolone (CAS#: 83-43-2)) or an IL-6R antagonist (e.g., tocilizumab, sarilumab, bovalilizumab (ALX-0061), satralizumab (SA-237), and variants thereof). 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 administered prior to administration of mosunetuzumab. In some examples, the corticosteroid is administered 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 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 prior to administration of mosunetuzumab. In some examples, the corticosteroid is administered intravenously. In some examples, the corticosteroid is dexamethasone. In some examples, 10 mg of dexamethasone is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 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 to the subject. In some examples, the corticosteroid is methylprednisolone. In some examples, the corticosteroid is prednisone.

[0214] In some examples, one or more additional therapeutic agents may be used in the treatment of neutropenia. In some examples, the additional therapeutic agent may prevent symptoms associated with neutropenia. In some examples, the additional therapeutic agent may reduce the rate or severity of neutropenia. In certain examples, the additional therapeutic agent is granulocyte colony stimulating factor (G-CSF or GCSF) or colony stimulating factor 3 (CSF3). Human G-CSF / CSF3 mRNA sequences include, for example, NCBI reference sequence numbers NM_000759, NM_001178147, NM_172219, and NM_172220, and human G-CSF / CSF3 protein amino acid sequences include, for example, NCBI reference sequence numbers NP_000750, NP_001171618, and NP_757373, NP_757374.

[0215] For all methods described herein, mosunetuzumab and lenalidomide are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this respect include the specific disease to be treated, the specific mammal to be treated, the clinical symptoms of the individual subject, the cause of the disease, the drug delivery site, the method of administration, the administration schedule, and other factors known to medical practitioners. Mosunetuzumab and lenalidomide are optionally, but not necessarily, formulated with one or more drugs currently used to prevent or treat the disorder in question. The effective amount of such other drugs depends on the amount of mosunetuzumab and / or lenalidomide present in the formulation, the type of disorder or treatment, and other factors mentioned above. Mosunetuzumab and lenalidomide can be appropriately administered to a subject over a course of treatment. If mosunetuzumab and lenalidomide are administered on the same day, mosunetuzumab can be administered before, simultaneously with, or after administration of lenalidomide.

[0216] In some examples, additional therapeutic agents useful in the present invention include therapeutic antibodies such as alemtuzumab (CAMPATH®), bevacizumab (AVASTIN®, Genentech), cetuximab (ERBITUX®, Imclone), panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech / Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (BEXXAR®, Corixia), and the antibody drug conjugate gemtuzumab ozogamicin (MYLOTARG®, Wyeth). Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the invention include apolizumab, acelizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, celelizumab pegol, cidofusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motavizumab, natalizumab, nimotuzumab, no ... These include robizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pexelizumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, reslivizumab, rovelizumab, lupizumab, sibrotuzumab, siplizumab, sontuzumab, tacatatuzumab tetraxetan, tadoxizumab, tafasitamab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumab sermoreukin, tucusituzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and briakinumab.

[0217] IV. Pharmaceutical Compositions and Formulations Mosunetuzumab and / or lenalidomide as described herein may be used in pharmaceutical compositions and formulations. Pharmaceutical compositions and formulations of mosunetuzumab, lenalidomide, and / or other agents (e.g., dexamethasone) as 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 any pharma- ceutically acceptable carriers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)). Lenalidomide may also be formulated according to standard formulation and / or manufacturing practices. Dexamethasone 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 interstitial 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).

[0218] 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.

[0219] The formulations herein may also contain two or more active ingredients as necessary for the particular indication to be 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., chemotherapeutic agents, cytotoxic agents, growth inhibitory agents, and / or antihormonal agents, such as those mentioned herein above).Such active ingredients are suitably present in combination in an amount effective for the intended purpose.

[0220] The active ingredient can be encapsulated in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methyl methacrylate) microcapsules, respectively, in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

[0221] 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.

[0222] Formulations to be used for in vivo administration are generally sterile. Sterilization may be readily accomplished, for example, by filtration through sterile filtration membranes.

[0223] In some embodiments, mosunetuzumab is formulated for intravenous administration. In some embodiments, lenalidomide is formulated for oral administration. In some embodiments, dexamethasone is formulated for intravenous administration.

[0224] V. Kits and Manufactured Products In another aspect of the present invention, a kit or article of manufacture is provided that includes materials useful for the treatment, prevention, and / or diagnosis of the above-mentioned 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, intravenous solution bags, and the like. The container can be formed from a variety of materials, such as glass or plastic. The container holds the composition alone or in combination with another composition effective for treating, preventing, and / or diagnosing a condition, and can have a sterile access port (e.g., the container can 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 lenalidomide 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 R / R FL in patients who are R / R to at least one prior treatment (e.g., chemoimmunotherapy) comprising an anti-CD20 antibody (e.g., an anti-CD20 monoclonal antibody, e.g., rituximab or obinutuzumab). Additionally, the kit or article of manufacture may include (a) a first container having a composition therein, the composition comprising mosunetuzumab, lenalidomide, or both mosunetuzumab and lenalidomide, and (b) a second container having a composition therein, the composition comprising an additional cytotoxic agent or other therapeutic agent. Alternatively, or in addition, the kit or article of manufacture may further comprise a second (or third) container comprising a pharma- ceutically acceptable buffer, e.g., 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

[0225] Working Example The following are examples of methods and compositions of the present invention. Given the general description provided above, it will be understood that other various embodiments may be practiced.

[0226] Example 1. A Phase Ib, Open-Label, Non-Randomized, Multicenter Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of Mosunetuzumab in Combination with Lenalidomide in Patients with Relapsed or Refractory Follicular Lymphoma Research Plan Study CO41942 is an ongoing Phase 1b, open-label, multicenter study evaluating the safety, pharmacokinetics, and efficacy of mosunetuzumab in combination with lenalidomide in patients with relapsed and / or refractory (e.g., R / R or r / r) follicular lymphoma (FL). Patients with r / r FL after at least one prior systemic therapy are eligible to participate in the study. At the time of CCOD, mosunetuzumab in combination with lenalidomide is the only active treatment combination in Study CO41942, therefore, this study focuses exclusively on the combination of mosunetuzumab + lenalidomide. The study design is summarized in Figure 1A and Figure 1B.

[0227] The study will include an initial dose escalation phase with dose escalation cohorts designed to determine the recommended phase 2 dose (RP2D) of mosunetuzumab. The initial dose escalation phase will be followed by an expansion phase in which the RP2D of mosunetuzumab will be given.

[0228] Study treatment will be administered for 12 cycles; cycle 1 will be 21 days in duration and cycles 2-12 will be 28 days in duration. Mosunetuzumab will be administered intravenously: in cycle 1 (21-day cycle), patients will receive 1 mg on day 1 (C1D1 dose), 2 mg on day 8 (C1D2 dose); 30 mg on day 15 (C1D3 dose). In cycles 2-12 (28-day cycle), patients will receive 30 mg on day 1 (C2D1-C12D1 dose). Lenalidomide will be administered orally (PO) at 20 mg once daily on days 1-21 of cycles 2-12 (28-day cycle). Lenalidomide will not be administered for the last 7 days of each of the 28-day cycles 2-12.

[0229] Study population and treatment received As of CCOD (April 5, 2021), all patients (N=16) enrolled in the mosunetuzumab in combination with lenalidomide (IV) arm and received at least one dose of mosunetuzumab. Ten patients completed the DLT evaluation window and reached D28 of cycle 2. Mosunetuzumab 1 / 2 / 30 mg doses were used for all patients. Lenalidomide 20 mg was the dose for all patients.

[0230] Overall, nine patients (56.3%) had a study duration of 0–3 months, four patients (25.0%) had a duration of 3–6 months, and three patients (18.8%) had a duration of 6–9 months.

[0231] Patient demographics for the safety-evaluable population (N=16) are shown in Table 3. The majority of patients were female (62.5%; 10 / 16 patients) and the median age was 61.5 years. Eastern Cooperative Oncology Group (ECOG) status was 0 in 81.3% (13 / 16 patients) and 1 in 18.8% (3 / 16 patients). [Table 3] CCOD:April 5, 2021

[0232] At the time of CCOD, all 16 patients in the safety-evaluable population had received at least one dose of study treatment: 16 patients participated in cycle 1, day 1 (and received the C1D1 dose); 14 patients participated in cycle 1, day 8 (and received the C1D2 dose); 14 patients participated in cycle 1, day 15 (and received the C1D3 dose); 13 patients participated in cycle 2 (C2); and 8 patients participated in cycle 3 of treatment.

[0233] For mosunetuzumab, the median treatment duration was 1.8 months (range: 0-7 months), the median number of treatment cycles was 3 (range: 1-9), the median number of doses received was 5 (range: 1-11), and the median cumulative dose received was 93 mg (range: 1.0-273.0).

[0234] For lenalidomide, the median treatment duration was 1.9 months (range: 0-6 months), the median number of treatment cycles was 3 (range: 1-5), the median number of doses received was 37 (range: 1-151), and the median cumulative dose received was 740 mg (range: 20.0-3020.0).

[0235] safety results

[0236] The safety-evaluable population (N=16) included all patients who were enrolled in the study and received at least one dose of study treatment. A summary of the key safety outcomes obtained by CCOD (April 5, 2021) is summarized below and further described in Table 4.

[0237] The percentage of patients who reported at least one adverse event (AE) was 81.3% (13 / 16 patients), with a total of 83 AEs reported overall.

[0238] The most commonly reported AEs by PTs were CRS (31.3%; 5 / 16 patients); constipation, and neutropenia (both 25.0%; 4 / 16 patients).

[0239] The proportion of patients who reported at least one event considered related to study treatment was 81.3% (13 / 16 patients). The proportion of patients who reported at least one event considered related to mosunetuzumab or lenalidomide treatment was 81.3% and 50.0%, respectively.

[0240] • At the time of CCOD, no fatal (grade 5) AEs were reported in this study.

[0241] The percentage of patients who reported at least one serious adverse event (SAE) was 12.5% ​​(2 / 16 patients), of which three events were related to mosunetuzumab treatment (PT, CRS [2 events]; maculopapular rash).

[0242] The proportion of patients who reported at least one grade 3 or higher AE was 31.3% (5 / 16 patients).

[0243] No AEs leading to discontinuation of study treatment were reported.

[0244] The proportion of patients reporting at least one event leading to dose modification / discontinuation of study treatment was 37.5% (6 / 16 patients). Of these, 2 patients had dose interruptions of mosunetuzumab and 6 patients had dose interruptions of lenalidomide treatment.

[0245] ●The percentage of patients reporting at least one adverse event of particular interest (AESI) was 31.3% (5 / 16 patients).

[0246] The incidence and frequency of AEs, including AEs considered to be related to mosunetuzumab, SAEs and AESIs, in this study were similar to related studies with monotherapy mosunetuzumab administered at similar doses. [Table 4] AE = adverse event, AESI = adverse event of special interest a Does not include the event of "death due to progressive disease" b According to ASTCT criteria c Subjects had worsening pleural effusion. Tumor flare based on the Medical Dictionary for Regulatory Activities (MedDRA) Essential Terminology (PT) "tumor flare, tumor inflammation, tumor pain, and new or worsening pleural effusion."

[0247] The most frequently reported adverse events were: Overall, the proportion of patients reporting at least one AE was 81.3% (13 / 16 patients), with a total of 83 AEs reported overall.

[0248] The most commonly reported AEs by system organ class (SOC) were skin and subcutaneous tissue disorders (43.8%; 7 / 16 patients); gastrointestinal disorders (37.5%; 6 / 16 patients); blood and lymphatic system disorders; general disorders and administration site symptoms, immune system disorders, and nervous system disorders (all 31.3%; 5 / 16 patients).

[0249] The most commonly reported AEs by MedDRA Preferred Terms (PT) were CRS (31.3%; 5 / 16 patients); constipation and neutropenia (both 25.0%; 4 / 16 patients). A summary of AEs (≥10%) is shown in Table 5. [Table 5] Based on MedDRA version 23.1. Percentages are based on N in column heading. Only treatment-emergent AEs are shown. In preferred term frequency counts, multiple occurrences of the same AE in an individual are counted only once. CCOD as of April 5, 2021.

[0250] Treatment-related adverse events Overall, the proportion of patients reporting at least one event considered related to study treatment was 81.3% (13 / 16 patients; Table 4). The most commonly reported treatment-related adverse events were CRS (31.3%; 5 / 16 patients) and neutropenia (25.0%; 4 / 16 patients). AEs (≥10%) considered related to study treatment (e.g., related to mosunetuzumab or lenalidomide) are shown in Figure 2.

[0251] Overall, the proportion of patients reporting at least one AE considered related to mosunetuzumab treatment was 81.3% (13 / 16 patients; Table 4). The most commonly reported AE by PTs considered related to mosunetuzumab treatment was CRS (31.3%; 5 / 16 patients). AEs considered related to mosunetuzumab (≥10%) are shown in Figure 3.

[0252] Overall, the proportion of patients reporting at least one AE considered related to lenalidomide treatment was 50.0% (8 / 16 patients; Table 4). The most commonly reported AE by PTs considered related to lenalidomide treatment was neutropenia (25.0%; 4 / 16 patients). AEs considered related to lenalidomide (≥10%) are shown in Figure 4.

[0253] Adverse events by severity Overall, the proportion of patients reporting at least one grade ≥3 AE was 31.3% (5 / 16 patients; Table 4). The most commonly reported AE by PTs was neutropenia (25.0%; 4 / 16 patients; Table 6). [Table 6] Based on MedDRA version 23.1. Percentages are based on the N in the column heading. Only treatment-emergent AEs are shown. In the frequency counts in the "Total Number of Events" row, multiple occurrences of the same AE in an individual are counted separately.

[0254] death As of CCOD, no deaths have been reported in study CO41942.

[0255] Serious Adverse Events Overall, the proportion of patients who reported at least one SAE was 12.5% ​​(2 / 16 patients; Table 4). A summary of reported serious adverse events is provided in Table 7. One patient (6.3%) experienced an SAE (PT, maculopapular rash) that was considered related to mosunetuzumab by the investigator. This event was of grade 3 severity and resolved 9 days after dose interruption of mosunetuzumab. Two other events (PT, pleural effusion; atrial flutter) led to dose interruption of treatment (lenalidomide and mosunetuzumab, respectively), both events were of grade 2 severity and had resolved by day 8 of onset. All other SAEs reported were of grade 1 or grade 2 severity and had resolved on or by day 9 of onset without dose interruption / modification of study treatment. No SAEs of grade 4 or 5 severity were reported. [Table 7] TIFF2024540044000008.tif84170Percentages are based on N in the column heading. In the frequency counts by preferred term, multiple occurrences of the same SAE in an individual are counted only once. In the frequency counts in the "Total Number of Events" row, multiple occurrences of the same SAE in an individual are counted separately. Adverse events missing Common Terminology Criteria for Adverse Events (CTCAE) grades are excluded.

[0256] Adverse events leading to modification or discontinuation of study treatment dose Overall, the proportion of patients who reported at least one event that led to dose modification / interruption of study treatment was 37.5% (6 / 16 patients; Table 4). Of these, two patients had dose interruptions of mosunetuzumab and six patients had dose interruptions of lenalidomide treatment.

[0257] Two patients (12.5%) experienced investigator-reported events that led to dose interruption of mosunetuzumab (PT: maculopapular rash [grade 3]; neutropenia [grade 4]; atrial flutter [grade 2]). All events resolved within 9 days of onset after treatment of the AE.

[0258] Six patients (37.5%) experienced events leading to lenalidomide dose interruption (PT, pleural effusion [grade 2]; neutropenia, [grade 3 and grade 4, 3 events each]; erythema [grade 3]; pruritus [grade 2]; maculopapular rash [grade 3]). Two patients (12.5%) experienced events leading to lenalidomide dose reduction (PT, neutropenia [grade 3 and grade 4]). All events resolved except for two events of neutropenia (both grade 3 severity) that were still ongoing at the time of CCOD.

[0259] Adverse Events of Special Interest (AESI) AESIs included events considered to be overlapping toxicities between study treatments and are summarized in Table 8. Overall, the proportion of patients reporting at least one AESI was 43.8% (7 / 16 patients). The most commonly reported AESIs were CRS (31.3%; 5 / 16 patients) and neutropenia (25.0%; 4 / 16 patients). One patient (6.3%) reported a grade 1 event of thrombocytopenia that had not resolved at the time of CCOD and no intervention was performed. [Table 8] Percentages are based on N in the column heading.

[0260] Overall, the most commonly reported AESI was CRS (31.3%; 5 / 16 patients; 7 events). Of the patients who experienced an event, 4 patients (25.0%) reported an event of grade 1 severity and 1 patient (6.3%) reported an event of grade 2 severity, with all events considered related to mosunetuzumab treatment. The majority of events were reported in patients on study day 1, all of which resolved within 3 days of onset. Two patients (12.5%) reported subsequent events, one on study day 15 and the other on study day 29, which resolved within 2 and 7 days, respectively. Of the 5 patients who reported CRS, 4 patients (25.0%) received intervening treatment for the event.

[0261] Five patients (31.3%) had CRS events considered related to mosunetuzumab treatment, including four patients (25.0%) with ASTCT grade 1 and one patient (6.3%) with grade 2, as assessed by the investigator (Table 9). All five patients developed their first CRS event between cycle 1 day 1 and cycle 1 day 7 (Figure 5). One patient (6.3%; 1 / 14) had a subsequent grade 1 event between cycle 1 day 15 and cycle 1 day 21 during mosunetuzumab monotherapy treatment, and another patient (6.3%; 1 / 14) had a subsequent grade 1 event at C2 during mosunetuzumab and lenalidomide combination treatment. [Table 9]

[0262] Overall, fever was the most frequent symptom of CRS, with seven events reported in the five patients who reported CRS events. Other signs and symptoms of CRS reported at the same time included chills, hypoxia, tachycardia, elevated liver enzymes (AST), elevated liver enzymes (ALT), hyperuricemia, and increased lactate dehydrogenase (LDH). One patient (6.3%) received low-flow oxygen for treatment of grade 2 CRS. No grade 3 or higher CRS events were observed, and no patients required tocilizumab, ICU management, high-flow oxygen, or vasopressor support.

[0263] Four patients (25.0%) reported 9 events of neutropenia (Table 4). Of these, 2 patients experienced 5 events considered related to mosunetuzumab and lenalidomide treatment as assessed by the investigator, and 2 patients experienced 4 events considered related to lenalidomide treatment only. Two patients reported events of grade 4 severity, all of which resolved, 1 patient did not receive any treatment, and 1 patient after treatment with G-CSF. Two patients reported 5 events of grade 3 severity, 2 of which (1 in each patient) did not resolve at the time of CCOD after treatment with G-CSF for the lenalidomide events and dose interruption. The neutropenic events occurred between days 42 and 155 and had durations between 8 and 16 days.

[0264] Preliminary Efficacy The efficacy-evaluable population included all patients who were evaluated for response at any time during the study, who withdrew from treatment or study before reaching the first response assessment, or who were on the study long enough to reach the first scheduled response assessment planned per protocol on cycle 3, days 15–21. Responses were assessed by the investigator according to the Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014;32:1-9).

[0265] No formal efficacy data analysis was performed. Review of the electronic database revealed that at the time of CCOD, eight patients enrolled in study CO41942 had at least one response assessment. Of these eight patients, two patients had a partial response and six patients had a complete response (i.e., an overall response rate (OR) of 100% and a complete response rate (CR) of 75%). No patients had disease progression or discontinued the study.

[0266] Pharmacokinetics Preliminary mosunetuzumab pharmacokinetic data (N=13) in patients receiving mosunetuzumab at 1 / 2 / 30 mg Q4W doses in study CO41942 are summarized in Figure 6. The observed pharmacokinetics of mosunetuzumab at 1 / 2 / 30 mg (IV) in combination with lenalidomide in R / R FL patients were similar to predicted mosunetuzumab pharmacokinetics of mosunetuzumab monotherapy in R / R NHL patients at the same dose. Preliminary results indicate that mosunetuzumab PK is similar when administered in combination with lenalidomide compared to monotherapy, with observed concentration measurements generally contained within the popPK model simulating the 5-95 prediction interval.

[0267] At the time of this report, lenalidomide PK data were not available. Mosunetuzumab is not expected to affect the PK of lenalidomide, which is primarily excreted in the urine (Chen N et al. Clin Pharmacokinet. 2017;56(2):139-152).

[0268] conclusion The safety profile of mosunetuzumab in combination with lenalidomide at the doses and schedules tested (1 / 2 / 30 mg Q4W) was tolerable, with no unexpected safety signals.

[0269] The overall frequency and severity of CRS events observed with mosunetuzumab in combination with lenalidomide in this study (seven events of grade 1–2 severity in five patients) were comparable to those observed with mosunetuzumab monotherapy. All CRS events were grade 1, except for one patient who experienced a grade 2 event in cycle 1 with mosunetuzumab (1 mg) monotherapy. This patient was the only patient to experience a CRS event in cycle 2 that was grade 1. Four patients (25.0%) reported grade 3–4 neutropenic events. Of the nine events reported, seven events resolved and two events (grade 3 severity) had not resolved at the time of CCOD. One patient (6.3%) reported a grade 1 thrombocytopenic event that had not resolved at the time of CCOD. No patients discontinued study treatment due to AEs.

[0270] Mosunetuzumab PK exposure observed in study CO41942 was consistent with that expected based on the PK observed with mosunetuzumab monotherapy, suggesting that the combination of mosunetuzumab with lenalidomide does not appear to affect mosunetuzumab exposure. The proposed dosing regimen was supported by the overall data and exposure-response characterization based on mosunetuzumab monotherapy and mosunetuzumab in combination with lenalidomide, suggesting an appropriate balance of clinical benefit / risk in the patient population.

[0271] In summary, available data from study GO41942 demonstrated an acceptable safety profile and preliminary efficacy for patients with R / R FL, thus supporting the continued use of a 1 / 2 / 30 mg step-up dosing regimen of mosunetuzumab in combination with lenalidomide.

[0272] Example 2. Mosunetuzumab in combination with lenalidomide has a manageable safety profile and promoting activity in patients with relapsed / refractory follicular lymphoma. Initial results of a Phase Ib study We present here initial data from an ongoing Phase Ib study (NCT04246086) evaluating the safety and activity of mosunetuzumab in combination with lenalidomide in patients with R / R FL who have received at least one prior line of therapy.

[0273] method Patients with R / R FL (grades 1–3a) and at least one prior systemic anticancer therapy were enrolled and received 12 cycles of combination therapy with mosunetuzumab and lenalidomide (cycle duration: cycle 1, 21 days; cycles 2–12, 28 days). In cycle 1, step-up doses of mosunetuzumab (IV infusion) were given on day 1 of cycle 1 (C1D1 dose; 1 mg) and day 2 of cycle 1 (C1D2 dose; 2 mg), and target doses were given on day 3 of cycle 1 (C1D3 dose; 30 mg) and day 1 of cycles 2–12 (C2D1–C12D1 dose). Lenalidomide (20 mg orally) was administered on days 1–21 of cycles 2–12. No hospitalization was mandated by the protocol. The primary objective is to evaluate the safety of the combination of mosunetuzumab and lenalidomide, and secondary objectives include evaluation of response and long-term efficacy outcomes. Cytokine release syndrome (CRS) was reported using ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Response will be assessed by the investigator using PET-CT scans using the Lugano 2014 criteria (Cheson BD,et al. J Clin Oncol 2014;32:1-9).

[0274] result At data cutoff (May 31, 2021), 27 patients had been enrolled. Median age was 59 years (range: 31-79 years), and 12 patients (44%) were male. All patients had an ECOG performance status of 0 (18 patients, 67%) or 1 (9 patients, 33%). Median number of prior lines of treatment was 1 (range: 1-4), and 3 patients (11%) had disease progression (PD) <24 months after initiation of first-line treatment. At data cutoff, 16 patients (59%) had been on study for 0-3 months, 8 (30%) for 3-6 months, 2 (7%) for 6-9 months, and 1 (4%) for >9 months.

[0275] All 27 patients were safety evaluable at data cutoff. Twenty patients (74%) experienced ≥1 adverse event (AE) of any grade (Gr), with the most common AE being CRS (8 patients, 30%). Grade 3–4 AEs occurred in 8 patients (30%), and serious AEs occurred in 8 patients (30%). No grade 5 (fatal) AEs were observed. Mosunetuzumab-related AEs occurred in 20 patients (74%), and lenalidomide-related AEs occurred in 10 patients (37%). No AEs led to mosunetuzumab or lenalidomide withdrawal, 2 patients had mosunetuzumab-related AEs resulting in mosunetuzumab dose delay, and 6 patients (22%) had lenalidomide-related AEs resulting in lenalidomide dose interruption and / or reduction.

[0276] In all patients, CRS events were grade 1 (7 / 8 patients) or grade 2 (1 / 8 patients). For most patients (6 / 8), CRS events occurred in cycle 1, and two patients experienced grade 1 CRS events in cycle 2. The median time to CRS onset was 1 day after the first study drug administration (range: 1–28 days), and the median CRS duration was 3 days (range: 2–5 days). All CRS events resolved without sequelae. No patient required tocilizumab, ICU admission, high-flow oxygen, or vasopressor support. Five patients (19%) reported 14 events of grade 3–4 neutropenia, with all neutropenic events occurring between days 41 and 218 and ranging in duration from 6 to 16 days. All neutropenic events resolved, with one patient receiving primary granulocyte-colony stimulating factor (G-CSF) prophylaxis and two patients receiving G-CSF treatment. No febrile neutropenic events occurred.

[0277] The efficacy-evaluable population included all patients who were evaluated for response at any time during the study, who withdrew from treatment or study before reaching their first response assessment, or who had been on the study long enough to reach the first scheduled response assessment planned per protocol on days 15–21 of cycle 3. The objective response rate in the 13 patients who were efficacy-evaluable at data cutoff was 92%, with complete metabolic responses observed in 10 patients (77%), partial metabolic responses (PMRs) observed in two patients (15%), and stable disease observed in one patient (8%). One patient who initially achieved a PMR experienced PD after eight cycles of treatment.

[0278] conclusion Combination treatment with mosunetuzumab and lenalidomide appeared to have a tolerable safety profile in patients with R / R FL who had received at least one prior line of therapy, and promising preliminary anti-lymphoma activity was observed.

[0279] Example 3. Preliminary safety and efficacy of mosunetuzumab in combination with lenalidomide in patients with relapsed / refractory follicular lymphoma: Early results of a Phase Ib study Additional data are presented here from an ongoing Phase Ib study (NCT04246086) (described in Example 2 above) evaluating the safety and activity of mosunetuzumab in combination with lenalidomide in patients with R / R FL who have received at least one prior line of therapy.

[0280] method Patients with R / R FL (grades 1–3a) and at least one prior systemic anticancer therapy were enrolled and received 12 dosing cycles of combination therapy with mosunetuzumab and lenalidomide (cycle duration: cycle 1, 21 days; cycles 2–12, 28 days). In cycle 1, a step-up dose of mosunetuzumab (IV infusion) was given on day 1 of cycle 1 (C1D1 dose; 1 mg) and day 2 of cycle 1 (C1D2 dose; 2 mg), and a target dose was given on day 3 of cycle 1 (C1D3 dose; 30 mg) and day 1 of cycles 2–12 (C2D1–C12D1 dose). Lenalidomide (20 mg orally) was administered on days 1–21 of cycles 2–12. Corticosteroid premedication was administered to patients during cycles 1 and 2 and was optional from cycle 3 onward. For corticosteroid premedication, 10 mg of dexamethasone was administered intravenously to patients before each dose of mosunetuzumab. Corticosteroid premedication may be further considered optional in cycle 2, depending on additional safety data evaluation. Hospitalization was not mandated by the protocol. The primary objective is to evaluate the safety of the combination of mosunetuzumab and lenalidomide, and secondary objectives include evaluation of response and long-term efficacy outcomes. Cytokine release syndrome (CRS) was reported using ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Response will be assessed by the investigator with PET-CT using the Lugano 2014 criteria (Cheson BD,et al. J Clin Oncol 2014;32:1-9).

[0281] result At the time of data cutoff (September 13, 2021), 29 patients had been enrolled. The median age was 59 years (range: 30-79 years), and 13 patients (44.8%) were male. All patients had an ECOG performance status of 0-2. Two (6.8%) patients had Ann Arbor stage I-II disease at study entry, and 27 (93.1%) patients had Ann Arbor stage III-IV disease at study entry (see Carbone et al., Cancer Res. 1971, 31(11):1860-1861). Seven (24.1%) patients had 0-1 FLIPI risk factor at study entry, eight (27.6%) patients had 2 FLIPI risk factors at study entry, and 14 (48.3%) patients had 3-5 FLIPI risk factors at study entry. Eighteen (62.1%) patients had FL grade 1–2, five (17.2%) patients had FL grade 3a, and six (20.7%) patients had FL of unknown grade. The median number of prior lines of therapy was 1 (range: 1–6), and three patients (10.3%) had progressive disease (PD) <24 months (POD24) from the start of first-line therapy. Nine (31%) patients were refractory to at least one prior therapy containing an anti-CD20 monoclonal antibody. Seven (24.1%) patients were doubly refractory to both anti-CD20 monoclonal antibody-containing therapy and alkylating agent-containing therapy. At data cutoff, one patient (3.4%) had remained on study for 0–3 months, 14 (48.3%) for 3–6 months, seven (24.1%) for 6–9 months, and seven (24.1%) for >9 months. The median duration of mosunetuzumab treatment was 4.9 months (range 2-11), and the median duration of lenalidomide treatment was 4.3 months (range 2-10). Median follow-up was 5.4 months (range 3-12).

[0282] All 29 patients were safety evaluable at data cutoff (September 13, 2021). Adverse events are summarized in Table 10 below. [Table 10] AE = adverse event

[0283] Twenty-nine patients (100%) experienced ≥1 adverse event (AE) of any grade. Common adverse events experienced by at least 10% of patients are summarized in Figure 7. Grade 3–4 AEs occurred in 13 patients (44.8%), and serious AEs occurred in 9 patients (31%). No grade 5 (fatal) AEs were observed. Mosunetuzumab-related AEs occurred in 27 patients (93.2%), and lenalidomide-related AEs occurred in 23 patients (79.3%). No AEs led to mosunetuzumab withdrawal, one AE led to lenalidomide withdrawal (3.4%), six patients (20.7%) had mosunetuzumab-related AEs leading to dose modification and / or interruption of mosunetuzumab, and 12 patients (41.4%) had lenalidomide-related AEs leading to dose modification and / or interruption of lenalidomide.

[0284] Cytokine release syndrome (CRS) events observed in safety evaluable patients are summarized in Table 11 below. [Table 11] a The patient had fever and hypoxia requiring 2 L of nasal cannula oxygen.

[0285] In all patients (8 / 29 patients total) who experienced at least one CRS event, the CRS events were grade 1 (7 / 8 patients) or grade 2 (1 / 8 patients). For most patients (6 / 8), the CRS events occurred in cycle 1, and two patients experienced a grade 1 CRS event in cycle 2. The median time to CRS onset was 1 day after the first study drug administration (range: 1–28 days), and the median CRS duration was 3 days (range: 2–5 days). All CRS events had resolved by the data cutoff date (September 13, 2021). No patients received tocilizumab, and no patients required ICU admission, high-flow oxygen, or vasopressor support. No immune effector cell-associated neurotoxicity syndrome (ICANS) events occurred. A summary of CRS events by dosing cycle and dose is shown in Figure 8.

[0286] Neutropenia and febrile neutropenic events observed in safety evaluable patients are summarized below in Table 12. [Table 12]

[0287] Seven patients (24.1%) reported grade 3-4 neutropenic or febrile neutropenic events, with all neutropenic events occurring between days 41 and 189 (median 86 days) with a median duration of 9 days (range 4-29 days). All neutropenic events had resolved by the data cutoff date. Febrile neutropenia (grade 3) occurred in one patient (duration: 5 days) and was considered treatment-related. A summary of reported neutropenic events by dosing cycle and grade by dosing cycle and granulocyte-colony stimulating factor (G-CSF) use is shown in Figure 9.

[0288] Antitumor activity in evaluable patients is shown in Figure 10. Notably, the objective response rate in 29 patients at data cutoff was 89.7%, with complete metabolic response observed in 65.5% of patients (see Figure 11). Of note, 3 / 3 patients with a history of POD24, 9 / 9 patients with anti-CD20 refractory disease, and 7 / 7 patients with dual refractory disease all demonstrated responses as measured by PET-CT. Response duration in all 29 patients as of the data cutoff date of September 13, 2021 is summarized in Figure 12.

[0289] conclusion Combination treatment with mosunetuzumab and lenalidomide appeared to have a tolerable safety profile in patients with R / R FL who had received at least one prior line of therapy, with encouraging antilymphoma and antitumor activity observed. No increase in CRS and neutropenic events was observed compared with mosunetuzumab monotherapy.

[0290] Embodiment Some embodiments of the technology described herein can be defined according to any of the following numbered embodiments. 1. A method of treating a subject, comprising administering to the subject an effective amount of mosunetuzumab and an effective amount of lenalidomide, wherein the subject is (a) Patients have relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20; (b) had been previously treated with at least one chemoimmunotherapy regimen; method.

[0291] 2. Mosunetuzumab for use in combination with lenalidomide in the treatment of a subject, wherein the subject is (a) Patients have relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20; (b) had been previously treated with at least one chemoimmunotherapy regimen; Mosunetuzumab.

[0292] 3. The use of mosunetuzumab in combination with lenalidomide in the treatment of a subject, wherein the subject has: (a) Patients have relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20; (b) had been previously treated with at least one chemoimmunotherapy regimen; use.

[0293] 4. The use of mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide to treat a subject, wherein the subject is (a) Patients have relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20; (b) had been previously treated with at least one chemoimmunotherapy regimen; use.

[0294] 5. The use of lenalidomide in the manufacture of a medicament for use in combination with mosunetuzumab to treat a subject, wherein the subject is (a) Patients have relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20; (b) had been previously treated with at least one chemoimmunotherapy regimen; use.

[0295] 6. Use of mosunetuzumab and lenalidomide in the manufacture of a medicament for treating a subject, wherein the subject is (a) Patients have relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20; (b) had been previously treated with at least one chemoimmunotherapy regimen; use.

[0296] 7. The method, the use, or the use of mosunetuzumab according to any one of embodiments 1 to 6, wherein at least one chemoimmunotherapeutic regimen comprises an anti-CD20 monoclonal antibody.

[0297] 8. The subject has received only one prior line of systemic therapy, and (a) Follicular Lymphoma International Prognostic Index (FLIPI; Solal-Celigny et al. Blood. 2004;104(5):1258-1265.) score of 2 to 5; (b) was refractory to previous anti-CD20 monoclonal antibody treatment, or (c) disease progression within 24 months after initiation of prior treatment; The method, the mosunetuzumab for use, or the use according to any one of embodiments 1 to 7,

[0298] 9. The method, mosunetuzumab for use, or use of any one of embodiments 7 or 8, wherein each subject has not been treated with an anti-CD20 monoclonal antibody for at least 4 weeks prior to administering effective amounts of mosunetuzumab and lenalidomide.

[0299] 10. Mosunetuzumab for use or the use according to embodiment 7 or 8, wherein mosunetuzumab and lenalidomide are not administered to the subject for at least 4 weeks after the subject has received treatment with an anti-CD20 monoclonal antibody.

[0300] 11. The method, mosunetuzumab for use, or use according to any one of embodiments 1 to 6, wherein mosunetuzumab and lenalidomide have a synergistic effect on R / R FL.

[0301] 12. The method, use or use of mosunetuzumab according to embodiment 11, wherein the synergy is a partial response as defined by the Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014;32:1-9).

[0302] 13. The method, use or use of mosunetuzumab according to embodiment 11, wherein the synergy is a complete response as defined by the Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014;32:1-9).

[0303] 14. Administering an effective amount of mosunetuzumab comprises administering mosunetuzumab according to 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), a second dose (C1D2) and a third dose (C1D3) of mosunetuzumab, wherein C1D1 and C1D2 are each equal to or less than C1D3, C1D1 is between 0.02 mg and 4.0 mg, C1D2 is between 0.05 mg and 20.0 mg, and C1D3 is between 0.2 mg and 50.0 mg; and (b) The method of any one of embodiments 1, 7-9, and 11-13, wherein the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab, wherein C2D1 is equal to or greater than C1D3 and is between 0.2 mg and 50 mg.

[0304] 15. Mosunetuzumab will be administered to the subject according to 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), a second dose (C1D2) and a third dose (C1D3) of mosunetuzumab, wherein C1D1 and C1D2 are each equal to or less than C1D3, C1D1 is between 0.02 mg and 4.0 mg, C1D2 is between 0.05 mg and 20.0 mg, and C1D3 is between 0.2 mg and 50.0 mg; and (b) Mosunetuzumab for use or use according to any one of embodiments 2 to 8 and 10 to 14, wherein the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab, wherein C2D1 is equal to or greater than C1D3 and is between 0.2 mg and 50 mg.

[0305] 16.(a) C1D1 is 0.4 mg to 4.0 mg, C1D2 is 1.0 mg to 20.0 mg, and C1D3 is 3.0 mg to 50.0 mg; and (b) Mosunetuzumab for use or use according to embodiment 14 or 15, wherein C2D1 is 3.0 mg to 50.0 mg.

[0306] 17.(a) C1D1 is 0.8 mg to 3.0 mg, C1D2 is 1.0 mg to 6.0 mg, and C1D3 is 3.0 mg to 45.0 mg; and (b) The method, mosunetuzumab for use, or use according to any one of embodiments 14 to 16, wherein C2D1 is between 3.0 mg and 45.0 mg.

[0307] 18. The method, mosunetuzumab for use, or method according to any one of embodiments 14-17, wherein C1D1 and C1D2 are each less than C1D3.

[0308] 19. The method, use, or use of mosunetuzumab according to any one of embodiments 14 to 17, wherein C1D2 is about 50% to about 250% greater than C1D1.

[0309] 20.(a) C1D1 is 0.8 mg, C1D2 is 2.0 mg, C1D3 is 4.2 mg, and C2D1 is 4.2 mg; or (b) C1D1 is 1.0 mg, C1D2 is 1.0 mg, C1D3 is 3.0 mg, and C2D1 is 30.0 mg; or (c) The method, use, or use of mosunetuzumab according to any one of embodiments 14 to 17, wherein C1D1 is 1.0 mg, C1D2 is 2.0 mg, C1D3 is 30.0 mg, and C2D1 is 30.0 mg.

[0310] 21. The method, the mosunetuzumab for use, or the use according to any one of embodiments 14 to 20, wherein the length of the first dosing cycle is 21 days.

[0311] 22. The method of embodiment 21, wherein the method comprises administering C1D1, C1D2, and C1D3 to the subject on, or about, days 1, 8, and 15, respectively, of the first dosing cycle.

[0312] 23. Mosunetuzumab for use or the use according to embodiment 21, wherein C1D1, C1D2 and C1D3 are administered to the subject on or about days 1, 8 and 15 of the first dosing cycle, respectively.

[0313] 24. The method, use, or use of mosunetuzumab according to any one of embodiments 14 to 23, wherein the length of the second dosing cycle is 28 days.

[0314] 25. The method of embodiment 24, wherein the method comprises administering C2D1 to the subject on day 1 of the second dosing cycle.

[0315] 26. The method, use, or use of mosunetuzumab according to embodiment 24, wherein C2D1 is administered to the subject on day 1 of the second dosing cycle.

[0316] 27. The method, the use, or the use of mosunetuzumab according to any one of embodiments 24 to 26, wherein the dosing regimen comprises one or more additional dosing cycles.

[0317] 28. The method, use, or use of mosunetuzumab according to embodiment 27, wherein the dosing regimen comprises 1 to 10 additional dosing cycles.

[0318] 29. The method, use, or use of mosunetuzumab according to embodiment 27 or 28, wherein the dosing regimen comprises 10 additional dosing cycles.

[0319] 30. The method, use, or use of mosunetuzumab according to any one of embodiments 27-29, wherein the length of each of the one or more additional dosing cycles is 28 days.

[0320] 31. The method, the mosunetuzumab for use, or the use of any one of embodiments 27-30, wherein each of the one or more additional dosing cycles comprises an additional dose of mosunetuzumab.

[0321] 32. The method of embodiment 31, wherein each additional dose of mosunetuzumab is administered to the subject on day 1 of each of one or more additional dosing cycles.

[0322] 33. Mosunetuzumab for use or the use according to embodiment 31, wherein each additional dose of mosunetuzumab is administered to the subject on day 1 of each of one or more additional dosing cycles.

[0323] 34. Administering an effective amount of mosunetuzumab comprises administering mosunetuzumab according to a dosing regimen comprising 12 dosing cycles; (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of mosunetuzumab, wherein C1D1 and C1D2 are each equal to or less than C1D3, C1D1 is between 0.02 mg and 4.0 mg, C1D2 is between 0.05 mg and 20.0 mg, and C1D3 is between 0.2 mg and 50.0 mg; and (b) The method of any one of embodiments 1 to 13, wherein the second to twelfth dosing cycles each comprise a single dose (C2D1 to C12D1) of mosunetuzumab, each single dose C2D1 to C12D1 being equivalent in amount, equal to or greater than C1D3, and ranging from 0.2 mg to 50 mg.

[0324] 35. Mosunetuzumab will be administered to the subject according to a dosing regimen that includes 12 dosing cycles; (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of mosunetuzumab, wherein C1D1 and C1D2 are each equal to or less than C1D3, C1D1 is between 0.02 mg and 4.0 mg, C1D2 is between 0.05 mg and 20.0 mg, and C1D3 is between 0.2 mg and 50.0 mg; and (b) Mosunetuzumab for use or use according to any one of embodiments 1 to 13, wherein the second to twelfth dosing cycles each comprise a single dose (C2D1 to C12D1) of mosunetuzumab, each single dose C2D1 to C12D1 being equivalent in amount, equal to or greater than C1D3 and ranging from 0.2 mg to 50 mg.

[0325] 36.(a) C1D1 is 0.4 mg to 4.0 mg, C1D2 is 1.0 mg to 20.0 mg, and C1D3 is 3.0 mg to 50.0 mg; and (b) The method, use, or use of mosunetuzumab according to embodiment 34 or 35, wherein each single dose of C2D1 to C12D1 is 3.0 mg to 50.0 mg.

[0326] 37.(a) C1D1 is 0.8 mg to 3.0 mg, C1D2 is 1.0 mg to 6.0 mg, and C1D3 is 3.0 mg to 45.0 mg; and (b) The method, the mosunetuzumab for use, or the use according to any one of embodiments 34 to 36, wherein each single dose of C2D1 to C12D1 is 3.0 mg to 45.0 mg.

[0327] 38. The method, mosunetuzumab for use, or method according to any one of embodiments 34-37, wherein C1D1 and C1D2 are each less than C1D3.

[0328] 39. The method, use, or use of mosunetuzumab according to any one of embodiments 34 to 38, wherein C1D2 is about 50% to about 250% greater than C1D1.

[0329] 40.(a) C1D1 is 0.8 mg, C1D2 is 2.0 mg, C1D3 is 4.2 mg, and each single dose of C2D1 to C12D1 is 4.2 mg; (b) C1D1 is 1.0 mg, C1D2 is 1.0 mg, C1D3 is 3.0 mg, and each single dose of C2D1 to C12D1 is 30.0 mg; or (c) The method, use, or use of mosunetuzumab according to any one of embodiments 34 to 37, wherein C1D1 is 1.0 mg, C1D2 is 2.0 mg, C1D3 is 30.0 mg, and each single dose of C2D1 to C12D1 is 30.0 mg.

[0330] 41. The method, use, or use of mosunetuzumab according to any one of embodiments 34 to 40, wherein the length of the first dosing cycle is 21 days.

[0331] 42. The method of embodiment 41, wherein the method comprises administering C1D1, C1D2, and C1D3 to the subject on, or about, days 1, 8, and 15, respectively, of the first dosing cycle.

[0332] 43. Mosunetuzumab for use or the use according to embodiment 41, wherein C1D1, C1D2 and C1D3 are administered to the subject on or about days 1, 8 and 15 of the first dosing cycle, respectively.

[0333] 44. The method, the use, or the use of mosunetuzumab according to any one of embodiments 34 to 43, wherein the length of each of the second to twelfth dosing cycles is 28 days.

[0334] 45. The method of embodiment 44, wherein the method comprises administering each of C2D1 to C12D1 to the subject on day 1 of each respective dosing cycle.

[0335] 46. ​​The method of any one of embodiments 34-45, wherein the length of each of the second through twelfth dosing cycles is 28 days.

[0336] 47. The method of any one of embodiments 34-43, wherein the length of each of the second to twelfth dosing cycles is 21 days.

[0337] 48. The method of any of the preceding embodiments, wherein mosunetuzumab is administered intravenously.

[0338] 49. Mosunetuzumab for use, or the use, according to any of the preceding embodiments, wherein the mosunetuzumab is to be administered intravenously.

[0339] 50. The method of any one of embodiments 14-49, wherein lenalidomide is administered during the second or subsequent cycle.

[0340] 51. Mosunetuzumab for use or the use according to any one of embodiments 14 to 49, wherein lenalidomide is administered during the second or subsequent cycles.

[0341] 52. The method of any one of embodiments 14-51, wherein lenalidomide is not administered during the first cycle.

[0342] 53. Mosunetuzumab for use or the use according to any one of embodiments 14 to 51, wherein lenalidomide is not administered during the second or subsequent cycles.

[0343] 54. The method of any one of embodiments 14-53, wherein lenalidomide is administered daily.

[0344] 55. Mosunetuzumab for use or the use according to any one of embodiments 14 to 53, wherein lenalidomide is to be administered daily.

[0345] 56. The method of any one of embodiments 46 and 48-55, wherein lenalidomide is administered daily during the first 21 days of each dosing cycle comprising administration of lenalidomide.

[0346] 57. Mosunetuzumab for use or the use according to any one of embodiments 46 and 48 to 55, wherein lenalidomide is administered daily during the first 21 days of each dosing cycle comprising administration of lenalidomide.

[0347] 58. The method of any one of embodiments 47-55, wherein lenalidomide is administered daily during the first 14 days of each dosing cycle comprising administration of lenalidomide.

[0348] 59. Mosunetuzumab for use or the use according to any one of embodiments 47 to 55, wherein lenalidomide is administered daily during the first 14 days of each dosing cycle comprising administration of lenalidomide.

[0349] 60. The method of any one of embodiments 56-59, wherein lenalidomide is not administered during the first 7 days of each dosing cycle comprising administration of lenalidomide.

[0350] 61. Mosunetuzumab for use or the use according to any one of embodiments 56-59, wherein lenalidomide is not administered during the last 7 days of each dosing cycle that includes administration of lenalidomide.

[0351] 62. The method of any one of embodiments 14-61, wherein lenalidomide is administered at a dose of 20 mg.

[0352] 63. Mosunetuzumab for use or the use according to any one of embodiments 14 to 61, wherein lenalidomide is to be administered in a dose of 20 mg.

[0353] 64. The method of any one of the preceding embodiments, wherein lenalidomide is administered orally.

[0354] 65. Mosunetuzumab for use, or the use according to any of the preceding embodiments, wherein lenalidomide is to be administered orally.

[0355] 66. The method, use, or use of mosunetuzumab according to any of the preceding embodiments, wherein the subject has previously been treated with at least one anti-CD20 monoclonal antibody.

[0356] 67. The method, use, or use of mosunetuzumab according to embodiment 66, wherein the subject is relapsed or refractory to treatment comprising an anti-CD20 monoclonal antibody.

[0357] 68. The method, use, or use of mosunetuzumab according to embodiment 66 or 67, wherein the anti-CD20 monoclonal antibody is obinutuzumab or rituximab.

[0358] 69. A method of treating a subject, comprising administering to the subject an effective amount of mosunetuzumab and an effective amount of lenalidomide; The target is, (i) Patients have relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20; (ii) had been previously treated with at least one chemoimmunotherapy regimen; administering effective amounts of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising at least a first 21 day dosing cycle and a second 28 day dosing cycle; (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg; (b) the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab administered intravenously on day 1 of the second dosing cycle, where C2D1 is 30 mg; and (c) the second dosing cycle further comprises orally administering 20 mg of lenalidomide daily on days 1-21 of the second dosing cycle; method.

[0359] 70. Mosunetuzumab for use in combination with lenalidomide to treat a subject, wherein the subject is (i) Patients have relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20; (ii) had been previously treated with at least one chemoimmunotherapy regimen; wherein mosunetuzumab and lenalidomide are administered to the subject according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 28-day dosing cycle; (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab to be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg; (b) the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab administered intravenously on day 1 of the second dosing cycle, where C2D1 is 30 mg; and (c) the second dosing cycle further comprises a daily dose of 20 mg of lenalidomide administered orally on days 1-21 of the second dosing cycle; Mosunetuzumab.

[0360] 71. Use of mosunetuzumab in combination with lenalidomide to treat a subject, wherein the subject is: (i) Patients have relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20; (ii) had been previously treated with at least one chemoimmunotherapy regimen; wherein mosunetuzumab and lenalidomide are administered to the subject according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 28-day dosing cycle; (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab to be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg; (b) the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab administered intravenously on day 1 of the second dosing cycle, where C2D1 is 30 mg; and (c) the second dosing cycle further comprises a daily dose of 20 mg of lenalidomide administered orally on days 1-21 of the second dosing cycle; use.

[0361] 72. The use of mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide to treat a subject, wherein the subject is (i) Patients have relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20; (ii) had been previously treated with at least one chemoimmunotherapy regimen; wherein mosunetuzumab and lenalidomide are administered to the subject according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 28-day dosing cycle; (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab to be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg; (b) the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab administered intravenously on day 1 of the second dosing cycle, where C2D1 is 30 mg; and (c) the second dosing cycle further comprises a daily dose of 20 mg of lenalidomide administered orally on days 1-21 of the second dosing cycle; use.

[0362] 73. The use of lenalidomide in the manufacture of a medicament for use in combination with mosunetuzumab to treat a subject, wherein the subject is (i) Patients have relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20; (ii) had been previously treated with at least one chemoimmunotherapy regimen; wherein mosunetuzumab and lenalidomide are administered to the subject according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 28-day dosing cycle; (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab to be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg; (b) the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab administered intravenously on day 1 of the second dosing cycle, where C2D1 is 30 mg; and (c) the second dosing cycle further comprises a daily dose of 20 mg of lenalidomide administered orally on days 1-21 of the second dosing cycle; use.

[0363] 74. Use of mosunetuzumab and lenalidomide in the manufacture of a medicament for treating a subject, wherein the subject is (i) Patients have relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20; (ii) had been previously treated with at least one chemoimmunotherapy regimen; wherein mosunetuzumab and lenalidomide are administered to the subject according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 28-day dosing cycle; (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab to be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg; (b) the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab administered intravenously on day 1 of the second dosing cycle, where C2D1 is 30 mg; and (c) the second dosing cycle further comprises a daily dose of 20 mg of lenalidomide administered orally on days 1-21 of the second dosing cycle; use.

[0364] 75. A method of treating a subject, comprising administering to the subject an effective amount of mosunetuzumab and an effective amount of lenalidomide; The target is, (i) Patients have relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20; (ii) had been previously treated with at least one chemoimmunotherapy regimen; administering effective amounts of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising a first 21 day dosing cycle and an eleventh or subsequent 28 day dosing cycle; (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg; (b) the second through twelfth dosing cycles each comprise a single dose (C2D1-C12D1) of mosunetuzumab administered intravenously on day 1 of each dosing cycle, each single dose C2D1-C12D1 being 30 mg; and (c) the second through twelfth dosing cycles each further comprise orally administering 20 mg of lenalidomide daily on days 1-21 of each dosing cycle; method.

[0365] 76. Mosunetuzumab for use in combination with lenalidomide in the treatment of a subject, wherein the subject is (i) Patients have relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20; (ii) had been previously treated with at least one chemoimmunotherapy regimen; Mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and 11th and subsequent 28-day dosing cycles; (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab to be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg; (b) the second through twelfth dosing cycles each comprise a single dose (C2D1-C12D1) of mosunetuzumab administered intravenously on day 1 of each dosing cycle, each single dose C2D1-C12D1 being 30 mg; and (c) the second through twelfth dosing cycles each further comprise a daily dose of 20 mg of lenalidomide administered on days 1-21 of each dosing cycle; Mosunetuzumab.

[0366] 77. The use of mosunetuzumab in combination with lenalidomide in the treatment of a subject, wherein the subject is (i) Patients have relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20; (ii) had been previously treated with at least one chemoimmunotherapy regimen; Mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and 11th and subsequent 28-day dosing cycles; (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab to be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg; (b) the second through twelfth dosing cycles each comprise a single dose (C2D1-C12D1) of mosunetuzumab administered intravenously on day 1 of each dosing cycle, each single dose C2D1-C12D1 being 30 mg; and (c) the second through twelfth dosing cycles each further comprise a daily dose of 20 mg of lenalidomide administered on days 1-21 of each dosing cycle; use.

[0367] 78. The use of mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide to treat a subject, wherein the subject is (i) Patients have relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20; (ii) had been previously treated with at least one chemoimmunotherapy regimen; Mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and 11th and subsequent 28-day dosing cycles; (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab to be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg; (b) the second through twelfth dosing cycles each comprise a single dose (C2D1-C12D1) of mosunetuzumab administered intravenously on day 1 of each dosing cycle, each single dose C2D1-C12D1 being 30 mg; and (c) the second through twelfth dosing cycles each further comprise a daily dose of 20 mg of lenalidomide administered on days 1-21 of each dosing cycle; use.

[0368] 79. The use of lenalidomide in the manufacture of a medicament for use in combination with mosunetuzumab to treat a subject, wherein the subject is (i) Patients have relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20; (ii) had been previously treated with at least one chemoimmunotherapy regimen; Mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and 11th and subsequent 28-day dosing cycles; (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab to be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg; (b) the second through twelfth dosing cycles each comprise a single dose (C2D1-C12D1) of mosunetuzumab administered intravenously on day 1 of each dosing cycle, each single dose C2D1-C12D1 being 30 mg; and (c) the second through twelfth dosing cycles each further comprise a daily dose of 20 mg of lenalidomide administered on days 1-21 of each dosing cycle; use.

[0369] 80. Use of mosunetuzumab and lenalidomide in the manufacture of a medicament for treating a subject, wherein the subject is (i) Patients have relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20; (ii) had been previously treated with at least one chemoimmunotherapy regimen; Mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and 11th and subsequent 28-day dosing cycles; (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab to be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg; (b) the second through twelfth dosing cycles each comprise a single dose (C2D1-C12D1) of mosunetuzumab administered intravenously on day 1 of each dosing cycle, each single dose C2D1-C12D1 being 30 mg; and (c) the second through twelfth dosing cycles each further comprise a daily dose of 20 mg of lenalidomide administered on days 1-21 of each dosing cycle; use.

[0370] 81. A method of treating a subject, comprising administering to the subject an effective amount of mosunetuzumab and an effective amount of lenalidomide; The target is, (i) Patients have relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20; (ii) had been previously treated with at least one chemoimmunotherapy regimen; administering effective amounts of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising at least a first 21 day dosing cycle and a second 21 day dosing cycle; (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg; (b) the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab administered intravenously on day 1 of the second dosing cycle, where C2D1 is 30 mg; and (c) the second dosing cycle further comprises orally administering 20 mg of lenalidomide daily on days 1-14 of the second dosing cycle; method.

[0371] 82. Mosunetuzumab for use in combination with lenalidomide in the treatment of a subject, wherein the subject is (i) Patients have relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20; (ii) had been previously treated with at least one chemoimmunotherapy regimen; wherein the mosunetuzumab and lenalidomide are administered to the subject according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 21-day dosing cycle; (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab to be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg; (b) the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab administered intravenously on day 1 of the second dosing cycle, where C2D1 is 30 mg; and (c) the second dosing cycle further comprises a daily dose of 20 mg of lenalidomide administered orally on days 1-14 of the second dosing cycle; Mosunetuzumab.

[0372] 83. The use of mosunetuzumab in combination with lenalidomide in the treatment of a subject, wherein the subject has: (i) Patients have relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20; (ii) had been previously treated with at least one chemoimmunotherapy regimen; wherein the mosunetuzumab and lenalidomide are administered to the subject according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 21-day dosing cycle; (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab to be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg; (b) the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab administered intravenously on day 1 of the second dosing cycle, where C2D1 is 30 mg; and (c) the second dosing cycle further comprises a daily dose of 20 mg of lenalidomide administered orally on days 1-14 of the second dosing cycle; use.

[0373] 84. The use of mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide to treat a subject, wherein the subject is (i) Patients have relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20; (ii) had been previously treated with at least one chemoimmunotherapy regimen; wherein the mosunetuzumab and lenalidomide are administered to the subject according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 21-day dosing cycle; (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab to be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg; (b) the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab administered intravenously on day 1 of the second dosing cycle, where C2D1 is 30 mg; and (c) the second dosing cycle further comprises a daily dose of 20 mg of lenalidomide administered orally on days 1-14 of the second dosing cycle; use.

[0374] 85. The use of lenalidomide in the manufacture of a medicament for use in combination with mosunetuzumab to treat a subject, wherein the subject is (i) Patients have relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20; (ii) had been previously treated with at least one chemoimmunotherapy regimen; wherein the mosunetuzumab and lenalidomide are administered to the subject according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 21-day dosing cycle; (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab to be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg; (b) the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab administered intravenously on day 1 of the second dosing cycle, where C2D1 is 30 mg; and (c) the second dosing cycle further comprises a daily dose of 20 mg of lenalidomide administered orally on days 1-14 of the second dosing cycle; use.

[0375] 86. Use of mosunetuzumab and lenalidomide in the manufacture of a medicament for treating a subject, wherein the subject is (i) Patients have relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20; (ii) had been previously treated with at least one chemoimmunotherapy regimen; wherein the mosunetuzumab and lenalidomide are administered to the subject according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 21-day dosing cycle; (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab to be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg; (b) the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab administered intravenously on day 1 of the second dosing cycle, where C2D1 is 30 mg; and (c) the second dosing cycle further comprises a daily dose of 20 mg of lenalidomide administered orally on days 1-14 of the second dosing cycle; use.

[0376] 87. A method of treating a subject, comprising administering to the subject an effective amount of mosunetuzumab and an effective amount of lenalidomide; The target is, (i) Patients have relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20; (ii) had been previously treated with at least one chemoimmunotherapy regimen containing obinutuzumab; administering effective amounts of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and an eleventh or subsequent 21-day dosing cycle; (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg; (b) the second through twelfth dosing cycles each comprise a single dose (C2D1-C12D1) of mosunetuzumab administered intravenously on day 1 of each dosing cycle, each single dose C2D1-C12D1 being 30 mg; and (c) the second through twelfth dosing cycles each further comprise orally administering 20 mg of lenalidomide daily on days 1-14 of each dosing cycle; method.

[0377] 88. Mosunetuzumab for use in combination with lenalidomide in the treatment of a subject, wherein the subject is (i) Patients have relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20; (ii) had been previously treated with at least one chemoimmunotherapy regimen; mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and eleventh and subsequent 21-day dosing cycles; (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab to be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg; (b) the second through twelfth dosing cycles each comprise a single dose (C2D1-C12D1) of mosunetuzumab administered intravenously on day 1 of each dosing cycle, each single dose C2D1-C12D1 being 30 mg; and (c) the second through twelfth dosing cycles each further comprise a daily dose of 20 mg of lenalidomide administered on days 1-14 of each dosing cycle; method.

[0378] 89. The use of mosunetuzumab in combination with lenalidomide in the treatment of a subject, wherein the subject has: (i) Patients have relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20; (ii) had been previously treated with at least one chemoimmunotherapy regimen; mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and eleventh and subsequent 21-day dosing cycles; (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab to be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg; (b) the second through twelfth dosing cycles each comprise a single dose (C2D1-C12D1) of mosunetuzumab administered intravenously on day 1 of each dosing cycle, each single dose C2D1-C12D1 being 30 mg; and (c) the second through twelfth dosing cycles each further comprise a daily dose of 20 mg of lenalidomide administered on days 1-14 of each dosing cycle; use.

[0379] 90. The use of mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide to treat a subject, wherein the subject is (i) Patients have relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20; (ii) had been previously treated with at least one chemoimmunotherapy regimen; mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and eleventh and subsequent 21-day dosing cycles; (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab to be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg; (b) the second through twelfth dosing cycles each comprise a single dose (C2D1-C12D1) of mosunetuzumab administered intravenously on day 1 of each dosing cycle, each single dose C2D1-C12D1 being 30 mg; and (c) the second through twelfth dosing cycles each further comprise a daily dose of 20 mg of lenalidomide administered on days 1-14 of each dosing cycle; use.

[0380] 91. The use of lenalidomide in the manufacture of a medicament for use in combination with mosunetuzumab to treat a subject, wherein the subject is (i) Patients have relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20; (ii) had been previously treated with at least one chemoimmunotherapy regimen; mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and eleventh and subsequent 21-day dosing cycles; (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab to be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg; (b) the second through twelfth dosing cycles each comprise a single dose (C2D1-C12D1) of mosunetuzumab administered intravenously on day 1 of each dosing cycle, each single dose C2D1-C12D1 being 30 mg; and (c) the second through twelfth dosing cycles each further comprise a daily dose of 20 mg of lenalidomide administered on days 1-14 of each dosing cycle; use.

[0381] 92. Use of mosunetuzumab and lenalidomide in the manufacture of a medicament for treating a subject, wherein the subject is (i) Patients have relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20; (ii) had been previously treated with at least one chemoimmunotherapy regimen; mosunetuzumab and lenalidomide are to be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and eleventh and subsequent 21-day dosing cycles; (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab to be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg; (b) the second through twelfth dosing cycles each comprise a single dose (C2D1-C12D1) of mosunetuzumab administered intravenously on day 1 of each dosing cycle, each single dose C2D1-C12D1 being 30 mg; and (c) the second through twelfth dosing cycles each further comprise a daily dose of 20 mg of lenalidomide administered on days 1-14 of each dosing cycle; use.

[0382] 93. The method, use, or use of mosunetuzumab according to any one of embodiments 69 to 92, wherein at least one chemoimmunotherapeutic regimen comprises an anti-CD20 monoclonal antibody.

[0383] 94. The method, use, or use of mosunetuzumab according to embodiment 93, wherein the anti-CD20 monoclonal antibody is rituximab or obinutuzumab.

[0384] 95. The subject has received only one prior line of systemic therapy, and (a) Follicular Lymphoma International Prognostic Index (FLIPI; Solal-Celigny et al. Blood. 2004;104(5):1258-1265.) score of 2 to 5; (b) was refractory to previous obinutuzumab treatment; (c) was refractory to previous rituximab treatment, or (d) disease progression within 24 months after initiation of prior treatment; The method, the mosunetuzumab for use, or the use according to any one of embodiments 69 to 94, wherein

[0385] 96. The method of any one of embodiments 93-95, wherein the subject has not been treated with obinutuzumab or rituximab for at least 4 weeks prior to administering effective amounts of mosunetuzumab and lenalidomide.

[0386] 97. Mosunetuzumab for use or the use according to any one of embodiments 93 to 95, wherein mosunetuzumab and lenalidomide are not administered to the subject for at least 4 weeks after the subject has received treatment with an anti-CD20 monoclonal antibody.

[0387] 98. The method, mosunetuzumab for use, or use according to any one of embodiments 69-92, wherein mosunetuzumab and lenalidomide have a synergistic effect on R / R FL.

[0388] 99. The method, use or use of mosunetuzumab according to embodiment 98, wherein the synergy is a partial response as defined by the Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014;32:1-9).

[0389] 100. The method, use or use of mosunetuzumab according to embodiment 98, wherein the synergy is a complete response as defined by the Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014;32:1-9).

[0390] 101. The method, use, or use of mosunetuzumab of any of the preceding embodiments, wherein the FL is histologically documented to be grade 1, 2 or 3a, but not 3b, according to the World Health Organization Classification of Lymphoid Neoplasms (referenced in Swerdlow SH, et al. Blood 2016;127:2375-90).

[0391] 102. A method of treating a population of subjects, comprising administering to each subject in the population an effective amount of mosunetuzumab and an effective amount of lenalidomide; Each subject, (a) Patients have relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20; (b) had been previously treated with at least one chemoimmunotherapy regimen; administering effective amounts of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising at least a first 21 day dosing cycle and a second 28 day dosing cycle; (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg; (b) the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab administered intravenously on day 1 of the second dosing cycle, where C2D1 is 30 mg; and (c) the second dosing cycle further comprises orally administering 20 mg of lenalidomide daily on days 1-21 of the second dosing cycle; method.

[0392] 103. Mosunetuzumab for use in combination with lenalidomide to treat a population of subjects, wherein each subject in the population has (i) Patients have relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20; (ii) had been previously treated with at least one chemoimmunotherapy regimen; wherein mosunetuzumab and lenalidomide are to be administered to the population of subjects according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 28-day dosing cycle; (a) a first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab to be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg; (b) the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab administered intravenously on day 1 of the second dosing cycle, where C2D1 is 30 mg; and (c) the second dosing cycle further comprises a daily dose of 20 mg of lenalidomide administered orally on days 1-21 of the second dosing cycle; Mosunetuzumab.

[0393] 104. The use of mosunetuzumab in combination with lenalidomide to treat a population of subjects, wherein each subject in the population is (i) Patients have relapsed or refractory follicular ...

Claims

1. A medicament for treating a subject, comprising mosunetuzumab, wherein mosunetuzumab is formulated for administration to the subject in combination with lenalidomide according to a dosing regimen comprising at least a first 21 day dosing cycle and a second 28 day dosing cycle; The subject (a) has relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20, and (b) has been previously treated with at least one chemoimmunotherapeutic regimen; and (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab administered intravenously on days 1, 8, and 15 of the first dosing cycle, respectively, where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg; (b) the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab administered intravenously on day 1 of the second dosing cycle, where C2D1 is 30 mg; and (c) the second dosing cycle further comprises oral administration of 20 mg of lenalidomide daily on days 1 to 21 of the second dosing cycle. Medicine.

2. A medicament for treating a subject, comprising lenalidomide, wherein the lenalidomide is formulated for administration to the subject in combination with mosunetuzumab according to a dosing regimen comprising at least a first 21 day dosing cycle and a second 28 day dosing cycle; The subject (a) has relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20, and (b) has been previously treated with at least one chemoimmunotherapeutic regimen; and (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab administered intravenously on days 1, 8, and 15 of the first dosing cycle, respectively, where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg; (b) the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab administered intravenously on day 1 of the second dosing cycle, where C2D1 is 30 mg; and (c) the second dosing cycle further comprises oral administration of 20 mg of lenalidomide daily on days 1 to 21 of the second dosing cycle. Medicine.

3. A medicament for treating a subject, comprising mosunetuzumab and lenalidomide, wherein the mosunetuzumab and lenalidomide are formulated for administration to the subject according to a dosing regimen comprising at least a first 21 day dosing cycle and a second 28 day dosing cycle; The subject (a) has relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20, and (b) has been previously treated with at least one chemoimmunotherapeutic regimen; and (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab administered intravenously on days 1, 8, and 15 of the first dosing cycle, respectively, where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg; (b) the second dosing cycle comprises a single dose (C2D1) of mosunetuzumab administered intravenously on day 1 of the second dosing cycle, where C2D1 is 30 mg; and (c) the second dosing cycle further comprises oral administration of 20 mg of lenalidomide daily on days 1 to 21 of the second dosing cycle. Medicine. (a) at least one chemoimmunotherapeutic regimen comprises an anti-CD20 monoclonal antibody; (b) the subject has received only one prior line of systemic therapy; (i) having a Follicular Lymphoma International Prognostic Index (FLIPI; Solal-Celigny et al. Blood. 2004; 104(5):1258-1265.) score of 2 to 5; (ii) was refractory to previous anti-CD20 monoclonal antibody treatment, or (iii) Disease progression within 24 months after initiation of previous treatment and / or (c) mosunetuzumab and lenalidomide have a synergistic effect on the R / R FL; The pharmaceutical composition according to any one of claims 1 to 3. (a) the subject has not been treated with the anti-CD20 monoclonal antibody for at least 4 weeks prior to administering effective amounts of mosunetuzumab and lenalidomide; and / or (b) the synergistic effect is a partial or complete response as defined by the Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014;32:1-9); The pharmaceutical composition according to claim 4.

6. The method of any one of claims 1 to 3, wherein the dosing regimen comprises one or more additional dosing cycles.

7. The method of claim 6, wherein the dosing regimen comprises 1 to 10 additional dosing cycles.

8. The dosing regimen comprises: (a) including 10 additional dosing cycles; (b) the length of each of the one or more additional dosing cycles is 28 days; (c) each of the one or more additional dosing cycles comprises an additional dose of mosunetuzumab; and / or (d) each of the one or more additional dosing cycles comprises an additional dose of lenalidomide; The pharmaceutical composition according to claim 6.

9. (a) each additional dose of mosunetuzumab is administered intravenously to the subject on day 1 of each of the one or more additional dosing cycles; (b) each additional dose of mosunetuzumab is about 30 mg: (c) lenalidomide is administered orally daily for the first 21 days of each additional dosing cycle; and / or (d) lenalidomide is administered orally at a dose of 20 mg; The pharmaceutical composition according to claim 6.

10. The pharmaceutical composition of claim 4, wherein the anti-CD20 monoclonal antibody is obinutuzumab or rituximab.

11. 1. A medicament for treating a subject, comprising mosunetuzumab, wherein the mosunetuzumab is formulated for administration to the subject in combination with lenalidomide according to a dosing regimen comprising a first 21 day dosing cycle followed by eleven 28 day dosing cycles; The subject (a) has relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20, and (b) has been previously treated with at least one chemoimmunotherapeutic regimen; and (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein the C1D1 is 1 mg, the C1D2 is 2 mg, and the C1D3 is 30 mg; (b) dosing cycles 2 through 12 each comprise a single dose (C2D1-C12D1) of mosunetuzumab administered intravenously on day 1 of each dosing cycle, each single dose C2D1-C12D1 being 30 mg; (c) the second through twelfth dosing cycles each further comprise oral administration of 20 mg of lenalidomide daily on days 1 through 21 of each dosing cycle; Medicine.

12. A pharmaceutical composition for treating a subject, comprising lenalidomide, wherein the lenalidomide is formulated for administration to the subject in combination with mosunetuzumab according to a dosing regimen comprising a first 21-day dosing cycle followed by eleven subsequent 28-day dosing cycles; The subject (a) has relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20, and (b) has been previously treated with at least one chemoimmunotherapeutic regimen; and (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein the C1D1 is 1 mg, the C1D2 is 2 mg, and the C1D3 is 30 mg; (b) dosing cycles 2 through 12 each comprise a single dose (C2D1-C12D1) of mosunetuzumab administered intravenously on day 1 of each dosing cycle, each single dose C2D1-C12D1 being 30 mg; (c) the second through twelfth dosing cycles each further comprise daily oral administration of 20 mg of lenalidomide on days 1 through 21 of each dosing cycle; Medicine.

13. A pharmaceutical composition for treating a subject, comprising mosunetuzumab and lenalidomide, wherein the mosunetuzumab and lenalidomide are formulated for administration to the subject according to a dosing regimen comprising a first 21-day dosing cycle followed by eleven subsequent 28-day dosing cycles; and The subject (a) has relapsed or refractory follicular lymphoma (R / R FL) that expresses CD20, and (b) has been previously treated with at least one chemoimmunotherapeutic regimen; and (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle, wherein the C1D1 is 1 mg, the C1D2 is 2 mg, and the C1D3 is 30 mg; (b) dosing cycles 2 through 12 each comprise a single dose (C2D1-C12D1) of mosunetuzumab administered intravenously on day 1 of each dosing cycle, each single dose C2D1-C12D1 being 30 mg; (c) the second through twelfth dosing cycles each further comprise daily oral administration of 20 mg of lenalidomide on days 1 through 21 of each dosing cycle; Medicine.

14. (a) at least one chemoimmunotherapeutic regimen comprises an anti-CD20 monoclonal antibody; (b) the subject has received only one prior line of systemic therapy; (i) having a Follicular Lymphoma International Prognostic Index (FLIPI) score of 2 to 5; (ii) was refractory to previous obinutuzumab treatment; (iii) was refractory to previous rituximab treatment; (iv) Disease progression within 24 months after initiation of previous treatment Either (c) the subject has not been treated with obinutuzumab or rituximab for at least 4 weeks prior to administering effective amounts of mosunetuzumab and lenalidomide; and / or (d) mosunetuzumab and lenalidomide have a synergistic effect on the R / R FL; The pharmaceutical composition according to any one of claims 11 to 13.

15. The pharmaceutical agent of claim 14, wherein the synergistic effect is a partial or complete response as defined by the Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014;32:1-9).

16. The medicament of any one of claims 1 to 3 and 11 to 13, wherein the FL is histologically documented to be grade 1, 2 or 3a, but not 3b, according to the World Health Organization Classification of Lymphoid Neoplasms (referenced in Swerdlow SH, et al. Blood 2016; 127: 2375-90).

17. A pharmaceutical agent described in any one of claims 1 to 3 and 11 to 13, wherein the incidence of adverse events in subjects administered mosunetuzumab and lenalidomide in accordance with the dosing regimen is not significantly higher than the incidence of adverse events in subjects administered mosunetuzumab without lenalidomide.

18. (a) In subjects administered mosunetuzumab and lenalidomide in accordance with the dosing regimen, the incidence of cytokine release syndrome as defined by the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading on Cytokine Release Syndrome ("ASTCT CRS Grading"; Lee et al., Biol Blood Marrow Transplant 2019) is less than 45%, less than 35%, or less than 25%; (b) the incidence of Grade 3 or greater cytokine release syndrome as defined by ASTCT CRS grading is less than 10%, less than 3%, or less than 1%; and / or (c) the incidence of neutropenia in subjects administered mosunetuzumab and lenalidomide according to the dosing regimen is less than 40%, less than 30%, or less than 20%. The pharmaceutical composition according to any one of claims 1 to 3 and 11 to 13.

19. (a) the overall response rate in subjects administered mosunetuzumab and lenalidomide according to the dosing regimen is at least 80%, at least 90%, at least 95%, or at least 99%; and / or (b) the complete response rate in subjects administered mosunetuzumab and lenalidomide according to said dosing regimen is at least 65%, at least 75%, or at least 85%. The pharmaceutical composition according to any one of claims 1 to 3 and 11 to 13.

20. The pharmaceutical composition according to any one of claims 1 to 3 and 11 to 13, wherein the subject is a human.

21. The medicament of any one of claims 1 to 3 and 11 to 13, wherein the subject exhibits a reduction in tumor burden after being administered an effective amount of mosunetuzumab and an effective amount of lenalidomide.

22. 22. The pharmaceutical of claim 21, wherein the reduction in tumor burden is determined by computed tomography (CT) and / or the reduction in tumor burden is a reduction in the sum of product diameters (SPD) of target lesions.

23. 23. The method of claim 22, wherein the reduction in SPD is at least 40%, at least 60%, or at least 80%.

24. A pharmaceutical agent described in any one of claims 1 to 3 and 11 to 13, wherein at least 45%, at least 60%, or at least 75% of subjects administered mosunetuzumab and lenalidomide in accordance with the dosing regimen exhibit a reduction in tumor burden after being administered an effective amount of mosunetuzumab and an effective amount of lenalidomide.

25. 25. The pharmaceutical of claim 24, wherein the reduction in tumor burden is determined by computed tomography (CT) and / or the reduction in tumor burden is a reduction in the sum of product diameters (SPD) of target lesions.

26. 26. The method of claim 25, wherein the reduction in SPD is at least 40%, at least 60%, or at least 80%.

27. The method of any one of claims 1 to 3 and 11 to 13, wherein the dosing regimen further comprises administration of a corticosteroid.

28. 28. The pharmaceutical composition of claim 27, wherein the corticosteroid is administered to the subject during the first dosing cycle.

29. 29. The medicament of claim 28, wherein the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2) and a third dose (C1D3) of the corticosteroid.

30. 30. The pharmaceutical composition of claim 29, wherein the corticosteroids C1D1, C1D2 and C1D3 are administered to the subject on days 1, 8 and 15, respectively, of the first dosing cycle, and / or each single dose of the corticosteroids C1D1 to C1D3 is administered to the subject prior to administration of the mosunetuzumab C1D1 to C1D3, respectively.

31. 28. The method of claim 27, wherein the corticosteroid is administered to the subject in the first dosing cycle and is not administered in the second dosing cycle.

32. 28. The method of claim 27, wherein the corticosteroid is administered to the subject in the second dosing cycle.

33. 33. The method of claim 32, wherein the second dosage cycle comprises a single dose (C2D1) of the corticosteroid.

34. The pharmaceutical composition of claim 33, wherein the corticosteroid of C2D1 is administered to the subject on day 1 of the second dosing cycle and / or the corticosteroid of C2D1 is administered to the subject prior to administration of mosunetuzumab of C2D1.

35. 7. The method of claim 6, wherein each additional dosing cycle comprises administration of an additional dose of the corticosteroid.

36. 36. The method of claim 35, wherein each additional dose of the corticosteroid is administered on day 1 of each additional dosing cycle and / or each additional dose of the corticosteroid is administered to the subject prior to administration of each additional dose of mosunetuzumab.

37. 28. The method of claim 27, wherein the corticosteroid is administered intravenously.

38. The pharmaceutical composition of claim 37, wherein the corticosteroid is dexamethasone.

39. 39. The method of claim 38, wherein each dose of dexamethasone is 10 mg.

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