KR20240093915A - Method for treating relapsed/refractory follicular lymphoma using mosunetuzumab and lenalidomide - Google Patents

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 receiving combination therapy with mosunetuzumab and lenalidomide.

Description

Method for treating relapsed/refractory follicular lymphoma using mosunetuzumab and lenalidomide

sequence list

This application contains a sequence listing that has been filed electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy created on October 29, 2021 has a file name of 50474-262WO2_Sequence_Listing_10_28_21_ST25 and a size of 23,600 bytes.

field of invention

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

background

Cancer is characterized by the uncontrolled growth of cell subpopulations. Cancer is the leading cause of death in developed countries and the second leading cause of death in developing countries, with more than 14 million new cancer cases diagnosed and more than 8 million cancer deaths occurring each year. Indolent cancers can also have a serious impact on quality of life. Cancer treatment therefore represents a significant and continuously increasing social burden.

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

Lymphomas of B-cell origin constitute a diverse set of neoplasms in the larger context of non-Hodgkin lymphoma (NHL). Follicular lymphoma (FL) is the most common subtype of inactive NHL (Al-Hamandi et al., 2015). Regardless of the biological and clinical heterogeneity of B-cell lymphoma, patients with advanced-stage B-cell malignancies are typically initially treated with monoclonal antibodies (mAbs), such as anti-CD20 MAb, rituximab (Rituxan®, MabThera®). Treatment is with intensive cytotoxic chemotherapy administered in combination. Although a durable response may be achieved in some patients, the majority of patients ultimately experience progressive or recurrent disease. FL remains an incurable disease with currently available treatments. Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP); cyclophosphamide, vincristine, and prednisone (CVP); fludarabine; Alternatively, the addition of rituximab to commonly used induction chemotherapy agents, including bendamustine (Zelenetz et al., 2014; Forstpointer et al., 2006) followed by maintenance rituximab treatment, has been associated with longer remission periods and improved patient outcomes. . However, treatment with these therapies results in only partial responses and not complete responses in the majority of patients with relapsed or refractory (R/R) FL. Therefore, multiple recurrent FL remains a disease with high unmet medical need requiring improved treatments.

Summary of the Invention

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 combination therapy. In particular, the present invention relates to R/ It relates to a method of treating a subject with R/R FL.

ligny 외, Blood. 2004; 104(5): 1258-1265.) 점수가 2-5점(예: 2, 3, 4 또는 5점)이거나, (b) 이전 항-CD20 단일클론 항체 치료에 불응성이었거나, (c) 이전 치료 시작 후 24개월 이내에 질환 진행이 있다. 일부 실시형태에서, 유효량의 모수네투주맙 및 레날리도마이드를 투여받기 전 적어도 4주(예를 들어,, 4주, 6주, 8주, 10주, 12주, 24주, 36주, 48주, 60주, 또는 그 이상) 동안 항-CD20 단일클론 항체로 치료받지 않았다. 일부 실시형태에서, 모수네투주맙과 레날리도마이드는 R/R FL에 상승작용적 효과를 갖는다. 일부 실시형태에서, 상승작용적 효과는 Lugano 2014 기준(Cheson BD, 외, J Clin Oncol 2014; 32:1-9)에서 정의된 바에 따른 부분 반응이다. 일부 실시형태에서, 상승작용적 효과는 Lugano 2014 기준(Cheson BD, 외, J Clin Oncol 2014; 32:1-9)에서 정의된 바에 따른 완전 반응이다. 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 has (a) relapsed disease that expresses CD20; or refractory follicular lymphoma (R/R FL), and (b) at least one prior chemo-immunotherapy 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., anti-CD20 Have been treated with at least one chemo-immunotherapy agent containing a monoclonal antibody (e.g., rituximab or obinutuzumab). In some embodiments, the subject has previously received only one line of systemic treatment, and (a) the Follicular Lymphoma International Prognostic Index (FLIPI; Solal-C

ligny et al., Blood . 2004; 104(5): 1258-1265.) had a score of 2 to 5 (e.g., 2, 3, 4, or 5), or (b) was refractory to previous anti-CD20 monoclonal antibody treatment, or (c) had a prior anti-CD20 monoclonal antibody treatment. There is disease progression within 24 months of starting treatment. In some embodiments, at least 4 weeks (e.g., 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks) prior to receiving an effective amount of mosunetuzumab and lenalidomide. weeks, 60 weeks, or more) have not been treated with anti-CD20 monoclonal antibodies. 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 synergistic effect is a complete response as defined by the Lugano 2014 criteria (Cheson BD, et al., J Clin Oncol 2014; 32:1-9).

In some embodiments, 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, wherein: (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab, where C1D1 and C1D2 are each greater than C1D3, and C1D1 is 0.02 mg to 4.0 mg (e.g. For example, 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, 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, 0.1 mg to 3.5 mg, 0.1 mg to 3.0 mg, 0.1 mg to 2.5 mg, 0.1 mg to 2.0 mg, 0.1 mg to 1.5 mg, 0.1 mg to 1 mg, 0.1 mg to 0.5 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 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg. 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., 0.1 mg to 20.0 mg, 0.2 mg) mg to 20.0 mg, 0.3 mg to 20.0 mg, 0.4 mg to 20.0 mg, 0.5 mg to 20.0 mg, 1.0 mg to 20.0 mg, 1.5 mg to 20.0 mg, 2.0 mg to 20.0 mg, 3.0 mg to 20.0 mg, 4.0 mg to 20.0 mg, 5.0 mg to 20.0 mg, 6.0 mg to 20.0 mg, 7.0 mg to 20.0 mg, 8.0 mg to 20.0 mg, 9.0 mg to 20.0 mg, 10.0 mg to 20.0 mg, 15.0 mg to 20.0 mg, 0.5 mg to 15.0 mg , 0.5 mg to 10.0 mg, 0.5 mg to 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 10.0 mg 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 50.0 mg) 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 to 50.0 mg, 40.0 mg to 50.0 mg, 45.0 mg to 50.0 mg, 1.0 mg to 45.0 mg, 1.0 mg to 40.0 mg, 1.0 mg to 35.0 mg, 1.0 mg to 30.0 mg, 1.0 mg to 25.0 mg, 1.0 mg to 20.0 mg, 1.0 mg to 15.0 mg, 1.0 mg to 10.0 mg, 1.0 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, 3.0 mg to 45.0 mg, 3.0 mg to 50.0 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); and (b) the second administration cycle comprises a single dose of mosunetuzumab (C2D1), wherein C2D1 is at least C1D3 and is 0.2 mg to 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 to 50.0 mg, 40.0 mg to 50.0 mg, 45.0 mg to 50.0 mg, 1.0 mg to 45.0 mg, 1.0 mg to 40.0 mg, 1.0 mg to 35.0 mg, 1.0 mg to 30.0 mg, 1.0 mg to 25.0 mg, 1.0 mg to 20.0 mg, 1.0 mg to 15.0 mg, 1.0 mg to 10.0 mg, 1.0 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, 3.0 mg to 45.0 mg, 3.0 mg to 50.0 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, (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, 3.0 mg to 20.0 mg, 4.0 mg to 20.0 mg, 5.0 mg to 20.0 mg, 6.0 mg to 20.0 mg, 7.0 mg to 20.0 mg, 8.0 mg to 20.0 mg, 9.0 mg to 20.0 mg, 10.0 mg to 20.0 mg, 15.0 mg to 20.0 mg, 1.0 mg to 15.0 mg, 1.0 mg to 10.0 mg, 1.0 mg to 9.0 mg, 1.0 mg to 8.0 mg, 1.0 mg to 7.0 mg, 1.0 mg to 6.0 mg, 1.0 mg to 5.0 mg, 1.0 mg to 4.0 mg, 1.0 mg to 3.0 mg, 1.0 mg to 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. 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 50.0 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, 3.0 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, 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; , 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) 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) 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, 3.0 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, 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; , 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, (a) C1D1 is 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; For example, 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), 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. 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 (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) 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).

In some embodiments, C1D1 and C1D2 are each less than C1D3. In some embodiments, C1D1 and C1D2 are substantially identical. In some embodiments, C1D2 is about 50% to about 250% more than C1D1 (e.g., C1D2 is about 50% to about 225% more than C1D1, or C1D2 is about 50% to about 200% more than C1D1. % more, or C1D2 is about 50% to about 175% more than C1D1, or C1D2 is about 50% to about 150% more than C1D1, or C1D2 is about 50% to about 125% more than C1D1. more, or C1D2 is about 50% to about 100% more than C1D1, or C1D2 is about 50% to about 75% more than C1D1; for example, C1D2 is about 50% more than C1D1; or C1D2 is about 100% more than C1D1, or C1D2 is about 150% more than C1D1, or C1D2 is about 200% more than C1D1, or C1D2 is about 250% more than C1D1. ).

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.

In some embodiments, the length of the first administration cycle is 21 days (±1 day). In some embodiments, the method comprises treating the subject on each of days 1, 8, and 15 of the first dosing cycle, or approximately on days 1, 8 (±1 day), and 15 days (±1 day), respectively. It involves administering C1D1, C1D2 and C1D3 to the patient. In some embodiments, the length of the second administration cycle is 28 days (±1 day). In some embodiments, comprising administering C2D1 to the subject on day 1 of the second administration cycle.

In some embodiments, the dosing regimen can be administered in 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 1 dosing cycle, 8 dosing cycles, 9 dosing cycles, 10 dosing cycles or more). In some embodiments, the dosing regimen consists of 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 aspects, each of the one or more additional dosing cycles is 28 days (±1 day) in length. In some embodiments, each of the one or more additional dosing cycles comprises an additional dose of mosunetuzumab. In some embodiments, the method comprises 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 0.2 mg to 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, 35.0 mg to 50.0 mg, 40.0 mg to 50.0 mg, 45.0 mg to 50.0 mg, 1.0 mg to 45.0 mg, 1.0 mg to 40.0 mg, 1.0 mg to 35.0 mg, 1.0 mg to 30.0 mg, 1.0 mg to 25.0 mg, 1.0 mg to 20.0 mg, 1.0 mg to 15.0 mg, 1.0 mg to 10.0 mg, 1.0 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, 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 includes 12 dosing cycles comprising mosunetuzumab and 11 dosing cycles comprising lenalidomide.

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 is the first dosing cycle of mosunetuzumab; A first dose (C1D1), a second dose (C1D2), and a third dose (C1D3), wherein C1D1 and C1D2 are each less than or equal to C1D3, and C1D1 is 0.02 mg to 4.0 mg (e.g., 0.05 mg to 4.0 mg). 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, 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, 0.1 mg to 3.5 mg, 0.1 mg to 3.0 mg, 0.1 mg to 2.5 mg, 0.1 mg to 2.0 mg, 0.1 mg to 1.5 mg, 0.1 mg to 1 mg, 0.1 mg to 0.5 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 1.0 mg 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 to 20.0 mg (e.g., 0.1 mg to 20.0 mg, 0.2 mg to 20.0 mg, 0.3 mg) mg to 20.0 mg, 0.4 mg to 20.0 mg, 0.5 mg to 20.0 mg, 1.0 mg to 20.0 mg, 1.5 mg to 20.0 mg, 2.0 mg to 20.0 mg, 3.0 mg to 20.0 mg, 4.0 mg to 20.0 mg, 5.0 mg to 20.0 mg, 6.0 mg to 20.0 mg, 7.0 mg to 20.0 mg, 8.0 mg to 20.0 mg, 9.0 mg to 20.0 mg, 10.0 mg to 20.0 mg, 15.0 mg to 20.0 mg, 0.5 mg to 15.0 mg, 0.5 mg to 10.0 mg , 0.5 mg to 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 15.0 mg 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 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 to 50.0 mg, 40.0 mg to 50.0 mg, 45.0 mg to 50.0 mg, 1.0 mg to 45.0 mg, 1.0 mg to 40.0 mg, 1.0 mg to 35.0 mg, 1.0 mg to 30.0 mg, 1.0 mg to 25.0 mg, 1.0 mg to 20.0 mg, 1.0 mg to 15.0 mg, 1.0 mg to 10.0 mg, 1.0 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, 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); and (b) the second to twelfth administration cycle each comprises a single dose (C2D1-C12D1) of mosunetuzumab, wherein the C2D1-C12D1 of each single dose is equal in amount, is at least C1D3, and is 0.2 mg to 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 to 50.0 mg, 40.0 mg to 50.0 mg, 45.0 mg to 50.0 mg , 1.0 mg to 45.0 mg, 1.0 mg to 40.0 mg, 1.0 mg to 35.0 mg, 1.0 mg to 30.0 mg, 1.0 mg to 25.0 mg, 1.0 mg to 20.0 mg, 1.0 mg to 15.0 mg, 1.0 mg to 10.0 mg, 1.0 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, 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 )am.

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, 3.0 mg to 20.0 mg, 4.0 mg to 20.0 mg, 5.0 mg to 20.0 mg, 6.0 mg to 20.0 mg, 7.0 mg to 20.0 mg, 8.0 mg to 20.0 mg, 9.0 mg to 20.0 mg, 10.0 mg to 20.0 mg, 15.0 mg to 20.0 mg, 1.0 mg to 15.0 mg, 1.0 mg to 10.0 mg, 1.0 mg to 9.0 mg, 1.0 mg to 8.0 mg, 1.0 mg to 7.0 mg, 1.0 mg to 6.0 mg, 1.0 mg to 5.0 mg, 1.0 mg to 4.0 mg, 1.0 mg to 3.0 mg, 1.0 mg to 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. 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 50.0 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, 3.0 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, 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; , 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 single dose of C2D1-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, 3.0 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, 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 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, (a) C1D1 is 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. mg to 1.1 mg; for example, 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) 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. 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-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). , 25.0 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 mg, about 30.0 mg, about 35.0 mg, about 40.0 mg, or about 45.0 mg).

In some embodiments, C1D1 and C1D2 are each less than C1D3. In some embodiments, C1D2 is about 50% to about 250% more than C1D1 (e.g., C1D2 is about 50% to about 225% more than C1D1, or C1D2 is about 50% to about 200% more than C1D1. % more, or C1D2 is about 50% to about 175% more than C1D1, or C1D2 is about 50% to about 150% more than C1D1, or C1D2 is about 50% to about 125% more than C1D1. more, or C1D2 is about 50% to about 100% more than C1D1, or C1D2 is about 50% to about 75% more than C1D1; for example, C1D2 is about 50% more than C1D1; or C1D2 is about 100% more than C1D1, or C1D2 is about 150% more than C1D1, or C1D2 is about 200% more than C1D1, or C1D2 is about 250% more than C1D1. ).

In some embodiments, (a) C1D1 is 0.8 mg, C1D2 is 2.0 mg, 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, 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, C1D3 is 30.0 mg, and each single dose C2D1-C12D1 is 30.0 mg.

In some embodiments, the length of the first administration cycle is 21 days (±1 day). In some embodiments, the method comprises treating the subject on each of days 1, 8, and 15 of the first dosing cycle, or approximately on days 1, 8 (±1 day), and 15 days (±1 day), respectively. It involves administering C1D1, C1D2 and C1D3 to the patient. In some embodiments, the length of each second through twelfth dosing cycle is 28 days (±1 day). In some embodiments, the method comprises administering each of C2D1-C12D1 to the subject on day 1 of each separate administration cycle. In some embodiments, the length of each second through twelfth dosing cycle is 28 days (±1 day).

In some embodiments, mosunetuzumab is administered intravenously.

In some embodiments, lenalidomide is administered during the second and 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 comprising administration of lenalidomide. In some embodiments, lenalidomide is not administered during 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.

In some embodiments, the subject has been previously 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.

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: (i) relapses expressing CD20; have refractory or refractory follicular lymphoma (R/R FL), and (ii) have been previously treated with at least one chemo-immunotherapy regimen including obinutuzumab; and administering the effective amount of mosunetuzumab and lenalidomide includes at least a first 21-day (± 1 day) dosing cycle and a second 28-day (± 1 day) dosing cycle of mosunetuzumab and lenalidomide. wherein: (a) the first administration cycle is administered intravenously on Day 1, Day 8 (±1 Day), and Day 15 (±1 Day), respectively, of the first administration cycle; Includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab administered within, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg. and (b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) administered intravenously on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and (c) the second dosing cycle. further comprising oral administration of lenalidomide 20 mg daily on days 1-21 of the second dosing cycle.

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: (i) relapses expressing CD20; have refractory or refractory follicular lymphoma (R/R FL), and (ii) have been previously treated with at least one chemo-immunotherapy regimen including obinutuzumab; and administering an effective amount of mosunetuzumab and lenalidomide means at least the first 21-day (± 1 day) dosing cycle and 11 subsequent 28-day (± 1 day) dosing cycles of mosunetuzumab and lenalidomide. and administering according to a dosing cycle comprising: (a) the first dosing cycle is on day 1, day 8 (±1 day), and day 15 (±1 day) respectively of the first dosing cycle; A first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab administered intravenously, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg. mg, and (b) each of the second to twelfth dosing cycles comprises a single dose (C2D1-C12D1) of mosunetuzumab administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1-C12D1 is 30 mg, and (c) each of the second through twelfth dosing cycles further comprises daily oral administration of 20 mg lenalidomide on days 1-21 of each dosing cycle.

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: (i) relapses expressing CD20; have refractory or refractory follicular lymphoma (R/R FL), and (ii) have been previously treated with at least one chemo-immunotherapy regimen containing rituximab; and administering the effective amount of mosunetuzumab and lenalidomide includes at least a first 21-day (± 1 day) dosing cycle and a second 28-day (± 1 day) dosing cycle of mosunetuzumab and lenalidomide. wherein: (a) the first administration cycle is administered on Day 1, Day 8 (±1 Day), and Day 15 (±1 Day), respectively, of the first administration cycle; A first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg, (b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) administered on Day 1 of the second dosing cycle, where C2D1 is 30 mg, and (c) the second dosing cycle comprises the second dosing cycle. It further includes lenalidomide 20 mg orally daily on days 1-21 of the cycle.

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: (i) relapses expressing CD20; have refractory or refractory follicular lymphoma (R/R FL), and (ii) have been previously treated with at least one chemo-immunotherapy regimen containing rituximab; and administering an effective amount of mosunetuzumab and lenalidomide means at least the first 21-day (± 1 day) dosing cycle and 11 subsequent 28-day (± 1 day) dosing cycles of mosunetuzumab and lenalidomide. and administering according to a dosing cycle comprising: (a) the first dosing cycle is on day 1, day 8 (±1 day), and day 15 (±1 day) respectively of the first dosing cycle; A first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab administered intravenously, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg. mg, and (b) each of the second to twelfth dosing cycles comprises a single dose (C2D1-C12D1) of mosunetuzumab administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1-C12D1 is 30 mg, and (c) each of the second through twelfth dosing cycles further comprises daily oral administration of 20 mg lenalidomide on days 1-21 of each dosing cycle.

ligny 외, Blood. 2004; 104(5): 1258-1265.) 점수가 2-5점(예: 2, 3, 4 또는 5점)이거나, (b) 이전 오비누투주맙 치료에 불응성이었거나, (c) 이전 리툭시맙 치료에 불응성이었거나, 또는 (d)이전 치료 시작 후 24개월 이내에 질환 진행이 있다. 일부 실시형태에서, 대상체는 유효량의 모수네투주맙 및 레날리도마이드를 투여받기 전 적어도 4주(예를 들어,, 4주, 6주, 8주, 10주, 12주, 24주, 36주, 48주, 60주, 또는 그 이상) 동안 오비누투주맙 또는 리툭시맙으로 치료받지 않았다.In some embodiments, the subject has previously received only one line of systemic treatment, and (a) the Follicular Lymphoma International Prognostic Index (FLIPI; Solal-C

ligny et al., Blood . 2004; 104(5): 1258-1265.) had a score of 2 to 5 (e.g., 2, 3, 4, or 5), or (b) was refractory to prior obinutuzumab treatment, or (c) had prior rituxi. has been refractory to Mab treatment, or (d) has disease progression within 24 months of starting previous treatment. In some embodiments, the subject has been treated for at least 4 weeks (e.g., 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 24 weeks, 36 weeks) before receiving an effective amount of mosunetuzumab and lenalidomide. , 48 weeks, 60 weeks, or more) have not been treated with obinutuzumab or rituximab.

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 synergistic effect is a complete response as defined by the Lugano 2014 criteria (Cheson BD, et al., J Clin Oncol 2014; 32:1-9).

In some embodiments, the FL is histologically classified as grade 1, 2, or 3a, but not grade 3b, according to the World Health Organization Classification of Lymphomatous Neoplasms (see Swerdlow SH, et al., Blood 2016; 127:2375-90). It is recorded.

In one aspect, the invention features 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, wherein each subject: (a) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and (b) have been previously treated with at least one chemo-immunotherapy regimen; and administering the effective amount of mosunetuzumab and lenalidomide includes at least a first 21-day (± 1 day) dosing cycle and a second 28-day (± 1 day) dosing cycle of mosunetuzumab and lenalidomide. wherein: (a) the first administration cycle is administered intravenously on Day 1, Day 8 (±1 Day), and Day 15 (±1 Day), respectively, of the first administration cycle; Includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab administered within, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg. and (b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) administered intravenously on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and (c) the second dosing cycle. further comprising oral administration of 20 mg lenalidomide daily on days 1-21 of the second dosing cycle. In some embodiments, the at least one chemo-immunotherapy regimen comprised an anti-CD20 monoclonal antibody (e.g., rituximab or obinutuzumab).

In one aspect, the invention features 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, wherein each subject: ( a) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and (b) have been previously treated with at least one chemo-immunotherapy regimen; and administering an effective amount of mosunetuzumab and lenalidomide means at least the first 21-day (± 1 day) dosing cycle and 11 subsequent 28-day (± 1 day) dosing cycles of mosunetuzumab and lenalidomide. and administering according to a dosing cycle comprising: (a) the first dosing cycle is on day 1, day 8 (±1 day), and day 15 (±1 day) respectively of the first dosing cycle; A first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab administered intravenously, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg. mg, and (b) each of the second to twelfth dosing cycles comprises a single dose (C2D1-C12D1) of mosunetuzumab administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1-C12D1 is 30 mg, and (c) each of the second through twelfth dosing cycles further comprises daily oral administration of 20 mg lenalidomide on days 1-21 of each dosing cycle. In some embodiments, the at least one chemo-immunotherapy regimen comprised an anti-CD20 monoclonal antibody (e.g., rituximab or obinutuzumab).

ligny 외, Blood. 2004; 104(5): 1258-1265.) 점수가 2-5점(예: 2, 3, 4 또는 5점)이거나, (b) 이전 항-CD20 단일클론 항체 치료에 불응성이었거나, (c) 이전 치료 시작 후 24개월 이내에 질환 진행이 있다.In some embodiments, each subject has previously received only one line of systemic treatment, and (a) Follicular Lymphoma International Prognostic Index (FLIPI; Solal-C

ligny et al., Blood . 2004; 104(5): 1258-1265.) had a score of 2 to 5 (e.g., 2, 3, 4, or 5), or (b) was refractory to previous anti-CD20 monoclonal antibody treatment, or (c) had a prior anti-CD20 monoclonal antibody treatment. There is disease progression within 24 months of starting treatment.

In some embodiments, each subject's FL is grade 1, 2, or 3a, but not grade 3b, according to the World Health Organization's Classification of Lymphomatous Neoplasms (see Swerdlow SH, et al., Blood 2016; 127:2375-90). Histologically recorded.

In some embodiments, each subject has been treated for at least 4 weeks (e.g., 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 24 weeks, 36 weeks) before receiving an effective amount of mosunetuzumab and lenalidomide. week, 48 weeks, 60 weeks, or more) have not been treated with anti-CD20 monoclonal antibodies.

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 synergistic effect is a complete response as defined by the Lugano 2014 criteria (Cheson BD, et al., J Clin Oncol 2014; 32:1-9).

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

In some embodiments, the incidence of adverse events is not significantly higher than if lenalidomide was not administered to the population of subjects.

In some embodiments, the incidence of cytokine release syndrome as defined by the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grade for Cytokine Release Syndrome (“ASTCT CRS Grade”; Lee et al., Biol Blood Marrow Transplant 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%; For example, between about 0% and about 50%, between about 5% and about 40%, between about 5% and about 20%, between about 5% and about 10%, between about 20% and about 45%, between about 30% and about 30%. 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%; %, 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 Grade for Cytokine Release Syndrome (“ASTCT CRS Grade”) is less than 35%. In some embodiments, the incidence of cytokine release syndrome as defined by the American Society for Transplantation and Cell Therapy (ASTCT) Consensus Grade for Cytokine Release Syndrome (“ASTCT CRS Grade”) is less than 25%.

In some embodiments, the incidence of cytokine release syndrome grade 3 or higher, as defined by the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grade for Cytokine Release Syndrome (“ASTCT CRS Grade”), 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%, for example, from 0% to 10%, from 0% to 1%; 9%, 0% to 8%, 0% to 7%, 0% to 6%, 0% to 5%, 0% to 4%, 0% to 3%, 0% to 2%, 0% to 1% , 1% to 3%, 1% to 5%, 1% to 10%, 3% to 5%, 5% to 8%, 5% to 10%, 8% to 10%). In some embodiments, the incidence of cytokine release syndrome of grade 3 or higher is less than 5%, as defined by the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grade for Cytokine Release Syndrome (“ASTCT CRS Grade”). . In some embodiments, the incidence of grade 3 or higher cytokine release syndrome is less than 3%, as defined by the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grade for Cytokine Release Syndrome (“ASTCT CRS Grade”). . In some embodiments, the incidence of cytokine release syndrome grade 3 or higher, as defined by the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grade for Cytokine Release Syndrome (“ASTCT CRS Grade”), is less than 1%. .

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%; for example, 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%, for example, 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 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; 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%; for example, 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%.

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%; %, 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%.

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

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

In some embodiments, the subject exhibits a reduction in tumor burden after receiving an effective amount of mosunetuzumab and an effective amount of lenalidomide. In some embodiments, reduction of tumor burden is determined by computed tomography (CT). In some embodiments, the reduction in tumor burden is a reduction in the sum of diameter products (SPD) of the 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; for example, 40-100%, 40-80%, 40-60%, 50-70%, 70-90%, 75-85%, 60-100%, 55-65%, 80-100%; for example, 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%.

In some embodiments, at least 45% (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; for example, between 45-100%, between 45-80%, between 45-60%, between 50-70%, between 55-65%, between 70-90% , between 70-80%, between 60-100%, between 80-100%; for example, 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%) represents a reduction in tumor burden after receiving an effective amount of mosunetuzumab and an effective amount of lenalidomide. In some embodiments, at least 60% of the subjects in the population demonstrate a reduction in tumor burden after receiving an effective amount of mosunetuzumab and an effective amount of lenalidomide. In some embodiments, at least 75% of the subjects in the population demonstrate a reduction in tumor burden after receiving an effective amount of mosunetuzumab and an effective amount of lenalidomide. In some embodiments, reduction of tumor burden is determined by computed tomography (CT).

In some embodiments, the reduction in tumor burden is a reduction in the sum of diameter products (SPD) of the 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; for example, 40-100%, 40-80%, 40-60%, 50-70%, 70-90%, 75-85%, 60-100%, 55-65%, 80-100%; for example, 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%.

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 administration cycle. In some embodiments, the first administration cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of corticosteroid. In some embodiments, C1D1, C1D2, and C1D3 of corticosteroids are administered to the subject on Day 1, Day 8 (±1 day), and Day 15 (±1 day), respectively, of the first administration cycle. In some embodiments, each single dose C1D1-C1D3 of corticosteroid is administered to the subject prior to administering each C1D1-C1D3 dose of mosunetuzumab. In some embodiments, each single dose C1D1-C1D3 of corticosteroid is administered 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, before administering each C1D1-C1D3 of mosunetuzumab. It is administered to the subject 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.

In some embodiments, the corticosteroid is administered to the subject in the first administration cycle and is not administered in the second administration cycle.

In some embodiments, the corticosteroid is administered to the subject in the second administration cycle. In some embodiments, the second administration cycle comprises a single dose of corticosteroid (C2D1). In some embodiments, C2D1 of corticosteroid is administered to the subject on day 1 of the second administration cycle. In some embodiments, C2D1 of corticosteroid is administered to the subject prior to C2D1 administration of mosunetuzumab. In some embodiments, the C2D1 of 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 prior to administering the C2D1 of mosunetuzumab. , 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 to the subject.

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 administration cycle. In some embodiments, the first administration cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of corticosteroid. In some embodiments, C1D1, C1D2, and C1D3 of corticosteroids are administered to the subject on Day 1, Day 8 (±1 day), and Day 15 (±1 day), respectively, of the first administration cycle. In some embodiments, each single dose C1D1-C1D3 of corticosteroid is administered to the subject prior to administering each C1D1-C1D3 dose of mosunetuzumab. In some embodiments, each single dose C1D1-C1D3 of corticosteroid is administered 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, before administering each C1D1-C1D3 of mosunetuzumab. It is administered to the subject 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.

In some embodiments, the corticosteroid is administered to the subject in the first administration cycle and is not administered in the second administration cycle.

In some embodiments, the corticosteroid is administered to the subject in the second administration cycle. In some embodiments, the second administration cycle comprises a single dose of corticosteroid (C2D1). In some embodiments, C2D1 of corticosteroid is administered to the subject on day 1 of the second administration cycle. In some embodiments, C2D1 of corticosteroid is administered to the subject prior to C2D1 administration of mosunetuzumab. In some embodiments, the C2D1 of 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 prior to administering the C2D1 of mosunetuzumab. , 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 to the subject.

In some embodiments, each additional administration cycle comprises administering an additional dose of corticosteroid to the subject. In some embodiments, each additional dose of corticosteroid is administered on Day 1 of each additional dosing cycle. In some embodiments, each additional dose of corticosteroid is administered to the subject prior to administration of each additional dose of mosunetuzumab. In some embodiments, each additional dose of corticosteroid is administered 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours prior to administering each additional dose of mosunetuzumab. , 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 to the subject.

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 drawing
Figure 1A is a schematic diagram of the study design described in Example 1 for the dosing regimen of combination therapy with 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=relapse or refractory. Note: One cycle is 21 days; After the 2nd cycle, it is 28 days.
Figure 1B is a schematic diagram of the dosing regimen described in Example 1. Lenalidomide is initiated in cycle 2 to minimize risk, with mosunetuzumab starting during cycle 1 when the risk of CRS is highest.
Figure 2 is a butterfly plot showing adverse events that occurred in ≥ 10% of patients subject to safety evaluation described in Example 1, classified by MedDRA organ system major categories and MedDRA representative terms. Based on MedDRA version 23.1. The grade of the abnormal case is indicated in the legend. On the left, all adverse cases are displayed. The right side shows adverse events resulting from mosunetuzumab (Mosun) or lenalidomide treatment. The clinical end date (CCOD) is April 5, 2021.
Figure 3 is a butterfly plot showing adverse events that occurred in ≥ 10% of patients subject to safety evaluation described in Example 1, classified by MedDRA organ system major categories and MedDRA representative terms. Based on MedDRA version 23.1. The grade of the abnormal case is indicated in the legend. On the left, all adverse cases are displayed. The right side shows adverse events resulting from mosunetuzumab (Mosun) treatment. CCOD on April 5, 2021.
Figure 4 is a butterfly plot showing adverse events that occurred in ≥ 10% of patients subject to safety evaluation described in Example 1, classified by MedDRA organ system major categories and MedDRA representative terms. Based on MedDRA version 23.1. The grade of the abnormal case is indicated in the legend. On the left, all adverse cases are displayed. The right side shows adverse events resulting from lenalidomide treatment. CCOD on April 5, 2021.
Figure 5 is a swimlane plot showing the development of cytokine release syndrome (CRS) events in five patients treated with the 1/2/30 mg dosing regimen of mosunetuzumab described in Example 1. The onset of grade 1 or grade 2 CRS is indicated by light or dark diamonds, respectively. CCOD on April 5, 2021.
Figure 6 is a plot showing observed concentration-time data for mosunetuzumab (in combination with lenalidomide) from study CO41942 overlaid with popPK model simulations based on mosunetuzumab monotherapy data from study GO29781; Simulations were performed with 1/2/30 mg Q4W. Filled red circles and lines represent individual and mean mosunetuzumab concentration measurements observed in study CO41942 at 1/2/30 mg IV doses combined with lenalidomide. The shaded area represents the simulated concentration-time profile for mosunetuzumab monotherapy based on a prospective population PK model simulation (5th-95th prediction interval) developed based on clinical data from study GO29781.
Figure 7 is a butterfly plot showing adverse events that occurred in ≥ 10% of patients subject to safety evaluation described in Example 3, classified by MedDRA organ system major categories and MedDRA representative terms. Based on MedDRA version 23.1. The grade of the abnormal case is indicated in the legend. On the left, all adverse cases are displayed. The right side shows adverse events resulting from mosunetuzumab (Mosun) or lenalidomide treatment. CCOD September 13, 2021.
Figure 8 is a bar graph showing cytokine release syndrome (CRS) cases according to dosing cycle (C) and primary (D) and CRS grade (Gr). The values below the graph show the dose of mosunetuzumab associated with each dosing cycle (C) and first day (D). The C1D1 dose is administered on day 1 of cycle 1, the C1D2 dose is administered on day 8 of cycle 1, and the C1D3 dose is administered on day 15 of cycle 1. Subsequent doses are administered on Day 1 of each dosing cycle (C2, C3+).
Figure 9 is a bar graph showing neutropenia and febrile neutropenia cases according to administration cycle (C) and neutropenia grade (Gr). The number of patients receiving granulocyte colony-stimulating factor (G-CSF) per administration cycle (C) is shown in the graph below.
Figure 10 is a bar graph showing anti-tumor activity in patients who had ≥1 diagnostic computed tomography (CT) scan at the time of response assessment. The number above each bar represents the percentage change compared to the baseline. Changes in tumor burden are quantified by comparing the sum of diameter products (SPD) of target lesions to baseline measurements.
Figure 11 shows the overall response rate (ORR), complete response rate (CR), and partial response rate ( This is a bar graph showing PR). Response rates are shown for 29 patients as of September 13, 2021, the data cutoff date. The 95% confidence interval (CI) for each response rate value is shown in parentheses below. The response rate is determined by positron emission tomography computed tomography (PET-CT).
Figure 12 is a swimlane plot showing the duration of response in all 29 patients treated with the mosunetuzumab 1/2/30 mg dosing regimen described in Example 3 and 20 mg oral lenalidomide. Duration of response is shown for 29 patients as of September 13, 2021, the data cutoff date.

details

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 combination therapy. In particular, the invention relates to at least one prior systemic treatment (e.g. , one prior treatment with a chemo-immunotherapy regimen) and a method of treating a subject with R/R FL who is R/R. The method includes administering an effective amount of mosunetuzumab according to a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein: (a) the first dosing cycle is a first dose of mosunetuzumab ( C1D1), a second dose (C1D2), and a third dose (C1D3), wherein C1D1 and C1D2 are each less than or equal to C1D3, C1D1 is 0.02 mg to 4.0 mg, C1D2 is 0.05 mg to 20.0 mg, and C1D3 is 0.2 mg. mg to 50.0 mg; and (b) the second administration cycle comprises a single dose of mosunetuzumab (C2D1), wherein C2D1 is greater than or equal to C1D3 and is between 0.2 mg and 50 mg.

The invention provides, in part, a combination comprising intravenous administration of mosunetuzumab and oral administration of lenalidomide over multiple dosing cycles (e.g., the first dosing cycle is an escalation, split dosing cycle). Subjects with relapsed/refractory (R/R) follicular lymphoma (FL) whose therapy shows a synergistic effect between mosunetuzumab and lenalidomide, particularly with anti-CD20 antibodies (e.g., anti- Subjects who are R/R to previous systemic therapy including a CD20 monoclonal antibody, e.g., rituximab or obinutuzumab, e.g., R-CHOP) (e.g., with regard to frequency and severity of adverse events) ) is based on the finding that it can be treated effectively while maintaining an acceptable safety profile.

I. General techniques

The techniques and procedures described or referred to herein are generally well understood and can be understood by those skilled in the art to be equivalent to traditional methodologies, such as, for example, the widely utilized methodologies described in 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 (FM Ausubel, et al., eds., (2003)); the series 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 Notebook (JE Cellis, ed., 1998) Academic Press; Animal Cell Culture (RI Freshney), ed., 1987); Introduction to Cell and Tissue Culture (JP Mather and PE Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (A. Doyle, JB Griffiths, and DG Newell, eds., 1993-8) J. Wiley and Sons; Handbook of Experimental Immunology (DM Weir and CC Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (JM Miller and M.P. Calos, eds., 1987); PCR: The Polymerase Chain Reaction , (Mullis et al., eds., 1994); Current Protocols in Immunology (JE Coligan 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 Capra, eds., Harwood Academic Publishers, 1995); and Cancer: Principles and Practice of Oncology (VT DeVita et al., eds., JB Lippincott Company, 1993).

II. Justice

Aspects and embodiments of the invention described herein are understood to include the terms “comprising,” “consisting,” and “consisting essentially of.”

As used herein, the singular forms “a” and “it” include plural references unless otherwise indicated.

As used herein, the term “about” refers to the typical margin of error for each value, as is well known to those skilled in the art. Reference to “about” a value or parameter herein includes (and describes) embodiments directed to that value or parameter per se.

The terms “cancer” and “cancerous” typically refer to or describe a physiological condition in mammals characterized by uncontrolled cell growth. Examples of cancer include, but are not limited to, hematological cancers other than Hodgkin's lymphoma, such as mature B cell cancer, relapsed or refractory DLBCL, or non-Hodgkin's lymphoma (NHL), which may be Richter's transformation. , including, for example, diffuse large B-cell lymphoma (DLBCL). Other specific examples of cancer also include germinal center B cell-like (GCB) diffuse large B-cell lymphoma (DLBCL), activated B cell-like (ABC) DLBCL, follicular lymphoma (FL), transformed FL, and 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 (thymus) large B-cell lymphoma (PMLBCL), small lymphocytic leukemia (SLL) ), lymphoplasmacytic lymphoma (LL), transformed LL, Waldenström macroglobulinemia (WM), central nervous system lymphoma (CNSL), Burkitt lymphoma (BL), B-cell prolymphocytic leukemia, splenic marginal zone lymphoma, hairy cell leukemia , Splenic lymphoma/leukemia, unclassified, splenic diffuse red medullary small B-cell lymphoma, hairy cell leukemia variant, heavy chain disease, α heavy chain disease, γ heavy chain disease, μ heavy chain disease, plasma cell myeloma, solitary plasmacytoma of bone, extraosseous traits Cytoma, extranodal marginal zone lymphoma of mucosa-related lymphoid tissue (MALT lymphoma), nodal marginal zone lymphoma, pediatric nodal marginal zone lymphoma, pediatric follicular lymphoma, primary cutaneous follicular lymphoma, T cell/histiocyte-rich type B large cell lymphoma, primary of the CNS. DLBCL, primary cutaneous DLBCL, leg type, EBV-positive DLBCL in the elderly, DLBCL associated with chronic inflammation, lymphomatoid granulomatosis, intravascular large cell B lymphoma, ALK-positive large cell B lymphoma, plasmablastic lymphoma, HHV8-related Type B large cell lymphoma arising in multifocal Castleman disease, primary exudative lymphoma: unclassifiable B-cell lymphoma with features intermediate between DLBCL and Burkitt lymphoma, and unclassifiable B-cell lymphoma with features intermediate between DLBCL and classic Hodgkin lymphoma. This is included. Additional examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and lymphoid malignancies, including leukemia or B cell lymphoma. More specific examples of such cancers include multiple myeloma (MM); low grade/parcel NHL; Small lymphocytic (SL) NHL; Intermediate grade/parcel NHL; intermediate grade diffuse NHL; High-grade immunoblastic NHL; High-grade lymphocytic NHL; High-grade small non-incised cell NHL; bulky disease NHL; AIDS-related lymphoma; and acute lymphoblastic leukemia (ALL); chronic myeloid leukemia; and post-transplant lymphoproliferative disorder (PTLD).

As used herein, “tumor” 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 disease,” “proliferative disease,” and “tumor”, as used herein, are not mutually exclusive.

“Disease” is any condition that would benefit from treatment, including, but not limited to, chronic and acute diseases or disorders, including pathological conditions that predispose a mammal to the disease in question.

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.

The term “B cell proliferative disorder” or “B cell malignancy” refers to disorders associated with some degree of abnormal B cell proliferation and includes, for example, lymphoma, leukemia, myeloma and myelodysplastic syndrome. In some embodiments, the B cell proliferative disorder is a lymphoma, e.g., non-Hodgkin lymphoma (NHL), diffuse, including follicular lymphoma (FL) (e.g., relapsed and/or refractory FL or transformed FL). 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.

“Follicular Lymphoma International Prognostic Index” or “FLIPI” refers to a scoring system or index for determining the prognostic risk of a patient (e.g., cancer, e.g., NHL, e.g., follicular lymphoma (FL)) . FLIPI scores range from 0 to 5, depending on how many of the following five conditions or risk factors the patient has: (i) age ≥ 60 years; (ii) Ann Arbor Phases III-IV; Hemoglobin level ≥ 120 g/L; Serum lactate dehydrogenase (LDH) level ≥ upper limit of normal (ULN) (e.g. > 280 units/L); (v) Number of nodal sites > 4. For example, Solal-Celigny et al., Blood . 2004; 104 (5): 1258-1265. Please refer to Table 4.

As used herein, the term “Ann Arbor staging” or “Ann Arbor staging” refers to a system for classifying lymphoma stages (e.g., non-Hodgkin lymphoma (NHL); e.g., DLBCL, FL, MCL, high grade B-cell lymphoma , PMLBCL or CLL). Lymphomas (eg, NHL) can be classified into one of four Ann Arbor stages. Stage 1 refers to lymphoma that involves a single lymph node region or an organ or site other than a single lymph node. Stage 2 refers to lymphoma that involves involvement of two or more lymph node areas on the same side of the diaphragm. Stage III refers to lymphoma showing involvement of lymph node areas on both sides of the diaphragm (III), and may be accompanied by local involvement of organs or sites other than the lymph nodes, spleen involvement, or both. Stage 4 refers to lymphoma showing diffuse or disseminated involvement of one or more extralymphatic organs or tissues, with or without associated lymph node enlargement. Since liver involvement is always considered diffuse, it is always considered Ann Arbor stage IV. Lymphatic structures include lymph nodes, thymus, spleen, appendix, Waldeyer's ring, and Peyer's patches. Carbone, P.P. et al., Cancer Res. See 1971, 31(11):1860-1861.

“Refractory disease” is defined as the absence of complete response to at least first-line therapy. In one embodiment, refractory disease is defined as no 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) with optimal response to first-line therapy, at least one first-line therapy (e.g., anti-CD20 antibody, e.g. Stable disease (SD) or optimal response following at least one anti-CD20 targeted therapy, e.g., an anti-CD20 monoclonal antibody, e.g., rituximab or obinutuzumab. partial response (PR), and biopsy-proven residual disease or disease progression after partial response. “Relapsed disease” is defined as complete response to first-line therapy. In one embodiment, disease recurrence is demonstrated by biopsy. In one embodiment, the patient has received at least one prior systemic treatment regimen (e.g., an anti-CD20 antibody, e.g., an anti-CD20 monoclonal antibody, e.g., rituximab or obinutuzumab). has relapsed or failed to respond to at least one anti-CD20-targeted therapy).

As used herein, “treatment” (and grammatical variants thereof, such as “treat” or “treating”) means clinical intervention in an attempt to alter the natural course of the subject being treated, for the purpose of prevention or It may be performed during clinical pathology procedures. The desired effects of treatment include preventing the occurrence or recurrence of the disease, alleviating symptoms, reducing any direct or indirect pathological consequences of the disease, preventing metastasis, reducing the rate of disease progression, improving or alleviating the condition of the disease, and achieving remission or These include, but are not limited to, improved prognosis. In some embodiments, the antibodies of the invention are used to delay the development or progression of a disease or disorder.

As used herein, “retarding the progression” of a disorder or condition means withholding, interfering with, retarding, arresting, stabilizing, and/or delaying the development of a disease or disorder (e.g., relapsed and/or refractory FL). It refers to doing something. This delay may vary in length depending on the medical history and/or subject being treated. As will be clear to those skilled in the art, sufficient or significant delay may include prevention, in effect, in that the individual does not develop the disease. For example, terminal cancer, such as the development of metastases, can be delayed.

“Reduce or suppress” means, for example, a total reduction of 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or more. It means the ability to cause. For clarity, this term includes reduction to zero (or below the detection limit of the analytical method), i.e. complete abolition or elimination. In certain embodiments, the reduction or inhibition is the reduction or inhibition of undesirable events, e.g., cytokine-induced toxicity, following treatment with mosunetuzumab using the escalation dosing regimen of the invention compared to a constant predetermined dose of mosunetuzumab at the target dose. (e.g., cytokine release syndrome (CRS)), infusion-related reactions (IRR), macrophage activation syndrome (MAS), neurological toxicity, severe tumor lysis syndrome (TLS), neutropenia, thrombocytopenia, elevated liver May refer to reduction or inhibition of enzyme and/or central nervous system (CNS) toxicity. In other embodiments, the reduction or inhibition is an effector function of the antibody mediated by the antibody Fc region, e.g., complement-dependent cytotoxicity (CDC), antibody-dependent cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis ( ADCP) may refer to effector functions. In other embodiments, reduction or inhibition may refer to the symptoms of R/R FL being treated, the presence or size of metastases, or the size of the primary tumor. In another embodiment, reducing or inhibiting cancer recurrence means reducing or inhibiting tumor or cancer recurrence or tumor or cancer progression.

As used herein, “administering” refers to a dose of a compound (e.g., a bispecific antibody, e.g., an anti-CD20/anti-CD3 bispecific antibody, e.g., mosunetuzumab) or a composition ( For example, it refers to a method of providing a pharmaceutical composition (e.g., a pharmaceutical composition comprising a bispecific antibody (e.g., mosunetuzumab)) to a subject. Compounds and/or compositions used in the methods described herein can be administered intravenously (e.g., by intravenous infusion).

A "fixed" or "fixed'' dose of a therapeutic agent (e.g., a bispecific antibody) herein refers to the dose administered to a patient regardless of the patient's body weight or body surface area (BSA). Therefore, fixed or fixed'' dose Dosages are not given in mg/kg doses or mg/m ² doses, but rather as absolute amounts of therapeutic agent (eg, mg).

The “subject” or “individual” is a mammal. Mammals include primates (e.g., humans and non-human primates such as monkeys), livestock (e.g., cattle, sheep, cats, dogs, and horses), rabbits, and rodents (e.g., mice and rats). It is not limited to this. In certain embodiments, the subject or individual is a human.

“Individual response” or “response” refers to (1) inhibition of disease progression (e.g., progression of R/R FL to some extent, including slowing and complete arrest); (2) reduction in tumor size; 3) Inhibition (i.e., reduction, slowing, or complete arrest) of cancer cell invasion into adjacent peripheral organs and/or tissues; (4) Inhibition (i.e., reduction, slowing, or complete arrest) of metastasis; (5) R/ Relief to some extent of one or more symptoms associated with R FL; (6) increased or prolonged survival, including overall survival and progression-free survival; and/or (9) reduced mortality at a given time point after treatment; Can be evaluated using any endpoint that indicates a benefit to the subject (but is not limited thereto).

As used herein, “complete response” or “CR” refers to the disappearance of all target lesions (i.e., all evidence of disease).

As used herein, “partial response” or “PR” means a reduction of at least 30% in SLD based on the sum of the longest diameters of baseline target lesions (SLD), or based on the sum of the products of the diameters of baseline target lesions (SPD). This refers to a decrease in SPD of at least 50%.

As used herein, “objective response rate (ORR)” refers to the sum of the complete response (CR) rate and the partial response (PR) rate.

As used herein, “duration of objective response” (DOR) is the period from the first recorded objective response until disease progression or death from any cause within 30 days of the last dose of treatment, whichever occurs first. It is defined by time.

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. do. In some embodiments, tumor burden is defined as the sum of the diameters of the target lesions or the sum of the products of the target lesions. In certain embodiments, tumor burden is defined as the sum of the diameters of target lesions (SPD). In some embodiments, the diameter of the target lesion is quantified by computed tomography (CT).

“Sustained response” refers to a sustained effect in reducing tumor growth after discontinuation of treatment. For example, tumor size may remain the same or smaller compared to its size at the beginning of the administration phase. In some embodiments, the sustained response has a duration at least equal to the treatment period, which is at least 1.5x, 2.0x, 2.5x, or 3.0x the length of the treatment period.

“Effective response” of a subject or “responsiveness” of a subject to treatment with a medication and similar expressions refers to the clinical or therapeutic benefit conferred to a subject at risk for or suffering from a disease or disorder, such as cancer. In one embodiment, these benefits include any one or more of the following: prolonged survival (including overall survival and progression-free survival); Results in an objective response (including complete or partial response); or improving signs or symptoms of cancer.

Subjects who “do not have an effective response” to treatment have prolonged survival (including overall survival and progression-free survival); Results in an objective response (including complete or partial response); or improving signs or symptoms of cancer.

As used herein, “survival” refers to patients who survive and includes overall survival and progression-free survival.

As used herein, “overall survival” (OS) refers to the percentage of subjects in a group alive at a particular time, e.g., 1 year or 5 years from diagnosis or treatment.

As used herein, “progression-free survival” (PFS) refers to the period during and following treatment during which the disease being treated (e.g., R/R FL) does not worsen. Progression-free survival may include the amount of time the patient experiences a complete or partial response and the amount of time the patient experiences stable disease.

As used herein, “stable disease” or “SD” refers to neither sufficient shrinkage of the target lesion to be considered PR nor sufficient increase to be considered PD, based on the minimum SLD since the start of treatment.

As used herein, “progressive disease” or “PD” means at least a 20% increase in the SLD of target lesions, with reference to the minimum SLD recorded since the start of treatment, or at least a 50% increase in the SPD of target lesions, with reference to the minimum SPD. or refers to the presence of one or more new lesions.

As used herein, “delaying the progression” of a disorder or disease means withholding, impeding, or inhibiting the development of a disease or disorder (e.g., relapsed and/or refractory FL (R/R) follicular lymphoma (FL)). Refers to delaying, blocking, stabilizing, and/or delaying. This delay may vary in length of time depending on the medical history and/or subject being treated. As will be apparent to those skilled in the art, sufficient or significant delay may include prevention in that the subject does not develop the disease in effect. For example, in advanced cancer, the onset of central nervous system (CNS) metastases may be delayed.

“Prolonged survival” refers to untreated patients (e.g., compared to patients not treated with a drug) or compared to patients who do not express a biomarker at a specified level, and/or compared to patients treated with an approved anticancer drug; refers to an increase in overall or progression-free survival in treated patients. “Objective response” refers to a measurable response, including a complete response (CR) or partial response (PR).

The term “antibody” is used herein in the broadest sense and includes, but is 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. Covers a variety of antibody structures, including.

An antibody fragment refers to a molecule other than an intact antibody that contains the portion of the intact antibody that binds to the antigen to which the intact antibody binds. Examples of antibody fragments include Fv, Fab, Fab', Fab'-SH, F(ab') ₂ ; Diabodies; linear antibody; single chain antibody molecule (eg, scFv); and multispecific antibodies formed from antibody fragments.

The terms “full-length antibody,” “intact antibody,” and “whole antibody” are used to refer to an antibody having a structure substantially similar to that of a native antibody or having heavy chains containing an Fc region as defined herein. Used interchangeably herein.

“Binding domain” means the portion of a compound or molecule that specifically binds to a target epitope, antigen, ligand, or receptor. Binding domains can be 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, apibodies, nanobodies and VH and/or VL domains of antibodies), receptors, ligands, aptamers and other molecules with identified binding partners.

The term “Fc region” is used herein to define the C-terminal region of an immunoglobulin heavy chain containing at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions. In one embodiment, the human IgG heavy chain Fc region extends from Cys226, or 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 explicitly stated otherwise, the numbering of amino acid residues in the Fc region or constant region follows the EU numbering system, Kabat et al., Sequences of Proteins of Immunological Interest , 5th Ed. According to the so-called EU index described in the Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

The “class” of an antibody refers to the type of constant domain or constant region possessed by the heavy chain of the antibody. There are five main classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these have subclasses (isotypes), such as IgG ₁ , IgG ₂ , IgG ₃ , IgG ₄ , and IgA _1. , and IgA ₂ . The heavy chain constant domains corresponding to the different immunoglobulin classes are called α, δ, ε, γ, and μ, respectively.

As used herein, the term IgG “isotype” or “subclass” refers to any subclass of immunoglobulin defined by the chemical and antigenic characteristics of its constant regions.

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

“Human common framework” is a framework representing the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Typically, human immunoglobulin VL or VH sequences are selected from a subgroup of variable domain sequences. In general, subgroups of sequences are described in Kabat et al., Sequences of Proteins of Immunological Interest , Fifth Edition, NIH Publication 91-3242, Bethesda MD (1991), vols. This is the same subgroup as in 1-3 . In one embodiment, for VL, the subgroup is subgroup Kappa I as in Kabat et al., supra. In one embodiment, for VH, the subgroup is subgroup III as in Kabat et al., supra.

For purposes herein, a "receptor human framework" means a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from the human immunoglobulin framework or the human common framework, as defined below. It is a framework containing amino acid sequences. A receptor "derived from" the human immunoglobulin framework or the human common framework may contain its identical amino acid sequence or may contain amino acid sequence changes. In some embodiments, the number of amino acid changes is 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, or 2 or fewer. In some embodiments, the VL receptor human framework is identical in sequence to a VL human immunoglobulin framework sequence or a human consensus framework sequence.

“Humanized” antibodies refer to chimeric antibodies that contain amino acid residues from non-human HVRs and amino acid residues from human FRs. In certain embodiments, the humanized antibody comprises substantially at least one, and typically both, variable domains, wherein all or substantially all of the HVRs (e.g., CDRs) correspond to a non-human antibody. , all or substantially all of the FRs correspond to those of human antibodies. 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, eg, a non-human antibody, refers to an antibody that has undergone humanization.

A “human antibody” is an antibody that possesses an amino acid sequence that corresponds to that of an antibody produced by a human or a human cell or derived from a non-human source using the human antibody repertoire or other human antibody-encoding sequences. The definition of human antibody specifically excludes humanized antibodies containing non-human antigen-binding moieties. Human antibodies can be produced by various techniques known in the art. Hoogenboom and Winter, J. Mol. Biol. , 227:381 (1991); Marks et al., J. Mol. Biol. , 222:581 (1991). Also, for the preparation of human monoclonal antibodies, see Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); The methods described in Boerner et al., J. Immunol., 147(1):86-95 (1991) are also available. See also van Dijk and van de Winkel, Curr. Opin. See also Pharmacol., 5: 368-74 (2001). Human antibodies have been modified to produce such antibodies in response to antigen challenge, but their endogenous loci can be produced by administering the antigen to transgenic animals, such as immunized xeno mice, in which the loci have been disabled. (See, for example, U.S. Patents 6,075,181 and 6,150,584 for XENOMOUSE™ technology). Also see, for example, Li et al., Proc., regarding human antibodies generated by human B-cell hybridoma technology. Natl. Acad. Sci. USA, 103:3557-3562 (2006).

“Variable region” or “variable domain” refers to the antibody heavy or light chain domain that is responsible for binding the antibody (i.e., mosunetuzumab) to an antigen. The variable domains of the heavy and light chains (V _H and V _L , respectively) of natural antibodies generally have a similar structure, with each domain containing four conserved framework regions (FRs) and three hypervariable regions (HVRs). do. (See, e.g., Kindt et al. Kuby Immunology , ^6th ed., WH Freeman and Co., page 91 (2007).) A single VH or VL domain may be sufficient to confer antigen-binding specificity. Moreover, antibodies that bind to a particular antigen can be isolated using the VH or VL domain of the antibody that binds the antigen to screen libraries of complementary VL or VH domains. For example, Portolano et al., J. Immunol. 150:880-887 (1993); See Clarkson et al., Nature 352:624-628 (1991).

As used herein, the term “hypervariable region” or “HVR” refers to hypervariable in sequence (“complementarity determining region” or “CDR”) and/or structurally defined loops (“hypervariable loops”) and/or antigenic contacts. Refers to each of the antibody variable domain regions that form a residue (“antigen contact”). Typically, antibodies contain six HVRs: three in the VH (H1, H2, H3), and three in the VL (L1, L2, L3). Exemplary HVRs herein include:

(a) Seconds occurring at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) variable loop (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) Antigens occurring at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) contact (MacCallum et al . J. Mol. Biol. 262: 732-745 (1996)); and

(d) HVR amino acid residues 46-56 (L2), 47-56 (L2), 48-56 (L2), 49-56 (L2), 26-35 (H1), 26-35b (H1), 49- Combinations of (a), (b) and/or (c), including 65(H2), 93-102(H3) and 94-102(H3).

Unless otherwise specified, HVR residues and other residues (e.g., FR residues) of the variable domains are numbered according to Kabat et al., supra.

An “immunoconjugate” is an antibody conjugated to one or more heterologous molecule(s), including but not limited to a cytotoxic agent.

The term “isolated antibody” when used to describe the various antibodies disclosed herein refers to an antibody that has been identified and isolated and/or recovered from the cell or cell culture in which it was expressed. Contaminants in the natural environment are substances that would normally interfere with the diagnostic or therapeutic use of the polypeptide in question and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In some embodiments, the antibody is measured, for example, by electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reversed-phase HPLC). It is purified to over 95% or 99% purity. For a review of methods for assessing antibody purity, see, e.g., Flatman et al., J. Chromatogr. See B 848:79-87 (2007). In a preferred embodiment, the antibody (i.e., mosunetuzumab) is (1) sufficient to obtain at least 15 residues of the N-terminal or internal amino acid sequence using a spinning cup sequencer, or (2) Coomassie blue. or purified until homogeneous by SDS-PAGE under non-reducing or reducing conditions, preferably using silver staining. Isolated antibodies contain antibodies in situ within recombinant cells because at least one component of the polypeptide's natural environment is absent. However, typically, the isolated polypeptide will be prepared by at least one purification step.

As used herein, the term “monoclonal antibody” refers to an antibody obtained from a substantially homogeneous population of antibodies, e.g., individual antibodies include populations that bind to the same population and/or the same epitope, but variant antibodies, e.g. There is the possibility of variant antibodies with naturally occurring mutations or mutations that arise during the manufacture of monoclonal antibody preparations, and these variants are generally present in small quantities. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody in a monoclonal antibody preparation is directed against a single determinant on the antigen. Accordingly, the modifier “monoclonal” refers to the nature of the antibody (i.e., mosunetuzumab) being obtained from a substantially homogeneous population of antibodies and should not be construed as requiring production of the antibody by any particular method. . For example, the monoclonal antibody (i.e., mosunetuzumab) used according to the present invention can be used in hybridoma methods, recombinant DNA methods, phage-display methods, and transgenic animals containing all or part of the human immunoglobulin locus. These and other exemplary methods of making monoclonal antibodies are described herein.

“Affinity” refers to the aggregate strength of non-covalent interactions between a single binding site on a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, “binding affinity” as used herein refers to intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen). The _affinity of a molecule Affinity can be measured by general methods known in the art, including those described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described below.

An “affinity matured” antibody refers to an antibody that has one or more changes in one or more hypervariable regions (HVRs) compared to a parent antibody that does not, such changes improving the affinity of the antibody for the antigen. .

The terms “anti-CD3 antibody” and “antibody that binds CD3” refer to an antibody that is capable of binding CD3 with sufficient affinity to render the antibody useful as a diagnostic and/or therapeutic agent in targeting CD3. In one embodiment, the extent of binding of the anti-CD3 antibody to an irrelevant, non-CD3 protein is less than about 10% of the antibody binding to CD3, e.g., as measured by radioimmunoassay (RIA). In certain embodiments, the antibody that binds CD3 has a concentration of ≧1 μM, ≧100 nM, ≧10 nM, ≧1 nM, ≧0.1 nM, ≧0.01 nM, or ≧0.001 nM (e.g., 10 ^-8 M or has a dissociation constant (K _D ) of less than, eg, 10 ^-8 M to 10 ^-13 M, eg, 10 ^-9 M to 10 ^-13 M). In certain embodiments, the anti-CD3 antibody binds to an epitope of CD3 that is conserved in different species of CD3.

As used herein, the term “cluster of differentiation” or “CD3” refers to any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. refers to native CD3 and includes, for example, CD3ε, CD3γ, CD3α, and CD3β chains. The term includes “full-length” unprocessed CD3 (e.g., unprocessed or unmodified CD3ε or CD3γ), as well as any form of CD3 that results from processing in a cell. The term also includes naturally occurring variants of CD3, such as 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).

The terms “anti-CD20 antibody” and “antibody that binds CD20” refer to an antibody that is capable of binding CD20 with sufficient affinity to render the antibody useful as a diagnostic and/or therapeutic agent in targeting CD20. In one embodiment, the extent of binding of the anti-CD20 antibody to an irrelevant, non-CD20 protein is less than about 10% of the antibody binding to CD20, e.g., as measured by radioimmunoassay (RIA). In certain embodiments, the antibody that binds CD20 has a concentration of ≧1 μM, ≧100 nM, ≧10 nM, ≧1 nM, ≧0.1 nM, ≧0.01 nM, or ≧0.001 nM (e.g., 10 ^-8 M or has a dissociation constant (K _D ) of less than, eg, 10 ^-8 M to 10 ^-13 M, eg, 10 ^-9 M to 10 ^-13 M). In certain embodiments, the anti-CD20 antibody binds to an epitope of CD20 that is conserved in different species of CD20. 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.

As used herein, the term “rituximab” or “RITUXAN®” refers to List 77 of the Proposed International Nonproprietary Names (Proposed INN) for the drug substance (WHO Drug Information, Vol. 11, No. 2, 1997, p. 99). or an anti-CD20 antibody (e.g., an anti-CD20 monoclonal antibody) having CAS registration number 174722-31-7.

As used herein, the term “obinutuzumab” or “GAZYVA®” refers to List 99 of the Proposed International Nonproprietary Names (Proposed INN) for the drug substance (WHO Drug Information, Vol. 22, No. 2, 2008, p. 396). ), Proposed International Nonproprietary Names (Proposed INN) List 108 for the drug substance (WHO Drug Information, Vol. 26, No. 4, 2012, p. 453) or anti-CD20 with CAS registration number 949142-50-1 Refers to an antibody (e.g., anti-CD20 monoclonal antibody).

As used herein, the term “cluster of differentiation 20” or “CD20” refers to any vertebrate, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. Refers to natural CD20 from animal sources. This term includes “full-length,” unprocessed CD20, as well as any form of CD20 that has been processed in the cell. The term also includes naturally occurring variants of CD20, such as splice variants or allelic variants. CD20 includes, for example, the human CD20 protein (see, e.g., NCBI RefSeq Nos. NP_068769.2 and NP_690605.1), which is 297 amino acids long and lacks, e.g., part of the 5' UTR may be generated from a long variant mRNA transcript (see, e.g., NCBI RefSeq No. NM_021950.3) or a longer variant mRNA transcript (see, e.g., NCBI RefSeq No. NM_152866.2).

The terms “anti-CD20/anti-CD3 bispecific antibody”, “bispecific anti-CD20/anti-CD3 antibody” and “antibody that binds CD20 and CD3” or variants thereof mean that the antibody targets CD20 and/or CD3. refers to a multispecific antibody (e.g., a bispecific antibody) that is capable of binding CD20 and CD3 with sufficient affinity to be useful as a diagnostic and/or therapeutic agent. In one embodiment, the extent of binding of a bispecific antibody that binds CD20 and CD3 to unrelated non-CD3 proteins and/or non-CD20 proteins is measured, for example, by radioimmunoassay (RIA), Less than about 10% of antibody binding to CD3 and/or CD20. In certain embodiments, the bispecific antibody that binds CD20 and CD3 has ≥ 1 μM, ≥ 100 nM, ≥ 10 nM, ≥ 1 nM, ≥ 0.1 nM, ≥ 0.01 nM, or ≥ 0.001 nM (e.g., ^10- It has a dissociation constant (K _D ) of ⁸ M or less, for example from 10 ^-8 M to 10 ^-13 M, for example from 10 ^-9 M to 10 ^-13 M). In certain embodiments, a bispecific antibody that binds CD20 and CD3 binds an epitope of CD3 that is conserved among different species of CD3 and/or an epitope of CD20 that is conserved among different species of CD20. In one embodiment, the bispecific antibody monovalently binds CD20 and monovalently binds CD3. In some embodiments, the bispecific antibody that binds CD20 and CD3 is mosunetuzumab.

As used herein, the term “mosunetuzumab” refers to the term having the International Nonproprietary Name (INN) List 117 (WHO Drug Information, Vol. 31, No. 2, 2017, p. 303) or CAS registration number 1905409-39-3. -refers to CD20/anti-CD3 bispecific antibody.

As used herein, the term "lenalidomide" refers to CAS registration number 191732-72-6 and IUPAC name (3RS)-3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole- 2-yl) refers to a compound having piperidine-2,6-dione. Lenalidomide is also known by the brand names REVLIMID®, Linamide, and Lenalid. Lenalidomide has DrugBank accession number DB00480, PubChem CID 216326, and the chemical formula C ₁₃ H ₁₃ N ₃ O ₃ .

As used herein, the term “specifically binds to” or “specific for” refers to a measurable and reproducible interaction, such as binding between a target and an antibody, which is heterogeneous in molecules, including biological molecules. Determine the existence of a target in the presence of a group. For example, an antibody that specifically binds to a target (which may be an epitope) binds to that target with greater affinity, avidity, more readily, and/or for a longer duration than it binds to other targets. It is an antibody. In one embodiment, the extent of binding of the antibody to an unrelated target is less than about 10% of the binding of the antibody to the target, e.g., as measured by radioimmunoassay (RIA). In certain embodiments, an antibody that specifically binds a target has a dissociation constant (K _D ) of ≧1 μM, ≧100 nM, ≧10 nM, ≧1 nM, or ≧0.1 nM. In certain embodiments, the antibody specifically binds to an epitope of a protein that is conserved among proteins from different species. In another embodiment, specific binding may include, but is not required to be, exclusive binding. As used herein, the term refers to, for example, a target that is less than or equal to 10 ^-4 M, alternatively less than or equal to 10 ^-5 M, alternatively less than or equal to 10 ^-6 M, alternatively less than or equal to 10 ^-7 M, alternatively with K _D of 10 ^-8 M or less, alternatively 10 ^-9 M or less, alternatively 10 ^-10 M or less, alternatively 10 ^-11 M or less, alternatively ^{10 -12} M or less. It may represent a molecule having a K _D ranging from 10 ^-6 M or 10 ^-6 M to 10 ^-10 M or 10 ^-7 M to 10 ^-9 M. As understood by those skilled in the art, affinity and K _D values are inversely proportional. High affinity for an antigen is measured by low K _D values. In one embodiment, the term “specific binding” refers to the binding of a molecule to a specific polypeptide or an epitope on a specific polypeptide without substantially binding to any other polypeptide or polypeptide epitope.

“Percent amino acid sequence identity” to a reference polypeptide sequence refers to the amino acids in a candidate sequence that are identical to amino acid residues in the reference polypeptide sequence after aligning the sequences and introducing gaps, if necessary, to achieve maximum percent sequence identity. Defined as a percentage of residues, conservative substitutions are not considered part of sequence identity. Alignments to determine percent amino acid sequence identity can be performed in a variety of ways that are within the skill in the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEGALIGN® (DNASTAR®) software. This can be done. One skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms necessary to achieve maximal 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 created by Genentech, Inc., and the source code was submitted with user documentation to the U.S. Copyright Office, Washington, D.C., 20559, U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, California, or can be compiled from source code. The ALIGN-2 program must be compiled for use on UNIX® operating systems, including Digital UNIX® V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and are not changed.

When ALIGN-2 is used for amino acid sequence comparison, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (alternatively with respect to a given amino acid sequence B) A given amino acid sequence A, which has or comprises a given % amino acid sequence identity with or against it, is calculated as follows:

100 x Fraction

At this time, X is the number of amino acid residues recorded as identical matches by the sequence alignment program ALIGN-2 in the program alignment of A and B, and Y is the total number of amino acid residues in B. If the length of amino acid sequence A is not equal to the length of amino acid sequence B, then the % amino acid sequence identity of A with respect to B is recognized as not being equal to the % amino acid sequence identity of B with respect to A. Unless otherwise specifically stated, all amino acid sequence identity percent values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.

The term “pharmaceutical formulation” refers to a preparation in a form so as to render effective the biological activity of the active ingredient contained therein, but does not contain additional ingredients that would cause unacceptable toxicity to the subject to which the preparation is administered.

“Pharmaceutically acceptable carrier” refers to an ingredient other than the active ingredient in a pharmaceutical formulation that is non-toxic to the subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

As used herein, the term “chemotherapeutic agent” refers to a compound useful in the treatment of cancer, e.g., R/R FL. Examples of chemotherapy agents include EGFR inhibitors (small molecule inhibitors (e.g., 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, ZD1839, gefitinib; (IRESSA®) 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, ZM 105180 ((6-amino) -4-(3-methylphenyl-amino)-quinazoline, Zeneca) BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl); )-pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim), PKI-166((R)-4-[4-[(1-phenylethyl)amino]-1H-p rolo[2,3-d]pyrimidin-6-yl]-phenol) (R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[ 2,3-d]pyrimidine); CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide), 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-[(3 fluorophenyl)methyl); Toxy]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 the ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual HER inhibitors, e.g., EGFR pan-HER inhibitors such as EKB-569 (available from Wyeth), which preferentially binds to but inhibits both HER2 and EGFR-overexpressing cells; 1 inhibitors, such as the antisense agent ISIS-5132 (ISIS Pharmaceuticals) that inhibits Raf-1 nephrogenesis, such as imatinib mesylate (GLEEVEC®, Glaxo SmithKline); Multi-targeted tyrosine kinase inhibitors such as sunitinib (SUTENT®, Pfizer); VEGF receptor tyrosine kinase inhibitors such as batalanib (PTK787/ZK222584, Novartis/Schering AG); inhibitors CI-1040 (Pharmacia), such as PD 153035,4-(3-chloroanilino) quinazoline; pyrimidopyrimidines, such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidine, 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidine; diferuloyl methane, 4,5-bis(4) -fluoroanilino)phthalimide); antisense molecule PD-0183805 (Warner-Lamber) containing a nitrothiophene moiety (e.g., a molecule that binds to a HER-encoding nucleic acid); Pan-HER inhibitors such as saline (U.S. Patent No. 5,804,396); ZD6474 (Astra Zeneca); CI-1033 (Pfizer); Afinitac (ISIS 3521; Isis/Lilly); PKI 166 (Novartis); GW2016 (Glaxo SmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis/Schering AG); INC-1C11 (Imclone); and rapamycin (sirolimus, RAPAMUNE®); proteasome inhibitors such as bortezomib (VELCADE®, Millennium Pharm.); disulfiram; epigallocatechin gallate; Salinosporamide A; carfilzomib; 17-AAG (geldanamycin); radicicol; lactate dehydrogenase A (LDH-A); fulvestrant (FASLODEX®, AstraZeneca); letrozole (FEMARA®, Novartis), pinasunate (VATALANIB®, Novartis); Oxaliplatin (ELOXATIN®, Sanofi); 5-FU (5-fluorouracil); leucovorin; lonafarnib (SCH 66336); sorafenib (NEXAVAR®, Bayer Labs); AG1478, alkylating agents such as thiotepa and CYTOXAN® cyclophosphamide; Alkyl sulfonates such as busulfan, improsulfan and fifosulfan; Aziridines such as benzodopa, carboquone, meturedopa and uredopa; ethyleneimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylomelamine; Acetogenins (especially bullatacin and bullatacinone); Camptothecins (including topotecan and irinotecan); bryostatin; kallistatin; CC-1065 (including synthetic analogues of adozelesin, caselesin, and bizelesin); Cryptophysins (especially cryptophysin 1 and cryptophycin 8); Adrenocorticosteroids (including prednisone and prednisolone); cyproterone acetate; 5α-reductase including finasteride and dutasteride); Vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat dolastatin; aldesleukin, talc duocarmycin (including synthetic analogs, KW-2189 and CB1-TM1); Eleutherobin; Pancratistatin; sarcodictin; Spongistatin; Nitrogen mustards, such as chlorambucil, clomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine , prednimustine, troposphamide, uracil mustard; Nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine and ranimustine; Antibiotics, such as endoyne antibiotics (e.g. calicheamicin, especially calicheamicin γ1 and calicheamicin ω1); dynemycins, including dynemycin A; Bisphosphonates such as clodronate; esferamycin; as well as the neocarzinostatin chromophore and the related chromoprotein endoyne antibiotic chromophore), aclasinomycin, actinomycin, outhramycin, azaserin, actinomycin, carabicin, caminomycin, carzinophilin, and chromophore. mycin, dactinomycin, detorubicin, 6-diazo-5-oxo-L-norleucine, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin) , epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin such as mitomycin C, mycophenolic acid, nogalamycin, olibomycin, pephlomycin, porphyromycin, puromycin, quelamycin, Rhodorubicin, streptonigrin, streptozocin, tubercidin, yubenimex, genostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); Folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; Purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; Pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, camofur, cytarabine, dideoxyuridine, doxyfluridine, enocitabine, floxuridine; Androgens such as calusterone, dromostanolone propionate, epithiostanol, mephithiostane, testolactone; Anti-adrenal agents such as aminoglutethimide, mitotane, trilostane; Folic acid supplements such as prolinic acid; Aceglaton; aldophosphamide glycoside; aminolevulinic acid; eniluracil; Amsacrine; Bestra Busil; bisantrene; edatroxate; Depopamine; demecolcine; diaziquon; Elpomitin; Elliptinium acetate; epothilone; etoglucide; gallium nitrate; hydroxyurea; lentinan; ronidanin; maytansinoids such as maytansine and ansamitocin; mitoguazone; mitoxantrone; Fur Damnol; nitraerin; pentostatin; penamet; pyrarubicin; rosoxantrone; Podophyllic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products); Razoxan; Rizoxin; Sizofuran; Spirogermanium; tenuazonic acid; triaziquon; 2,2',2''-trichlorotriethylamine; trichothecenes (especially T-2 toxin, veraculin A, loridin A, and anguidine); urethane; vindesine; Dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; achytocin; Arabinoside (“Ara-C”); thiotepa; chlorambucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; etoposide (VP-16); ifosfamide; mitoxantrone; Novantrone; teniposide; edatrexate; daunomycin; aminopterin; Capecitabine (XELODA®); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); Retinoids, such as retinoic acid; and pharmaceutically acceptable salts, acids, prodrugs and derivatives of any of the above.

Chemotherapeutic agents may also include (i) anti-hormonal agents that act to modulate or inhibit hormonal action on the tumor, such as, for example, tamoxifen (NOLVADEX®; including tamoxifen citrate), raloxifene, droloxifen, Anti-estrogens and selective estrogen receptor modulators (SERMs), including iodoxifen, 4-hydroxytamoxifen, trioxifene, ceoxifene, LY117018, onapristone, and FARESTON® (toremipine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazole, aminoglutethimide, MEGASE® (megestrol acetate) , AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) anti-androgens, such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; Buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all transrethionic acid, fenretinide, as well as troxacitabine (1,3-dioxolein new cleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, especially those that inhibit the expression of genes of the renal amenorrhea pathway involved in aberrant cell proliferation, such as, for example, PKC-alpha, Ralf and H-Ras; (vii) ribozymes, such as VEGF expression inhibitors (eg, ANGIOZYME®) and HER2 expression inhibitors; (viii) vaccines, such as gene therapy vaccines such as ALLOVECTIN®, LEUVECTIN®, and VAXID®; PROLEUKIN (ix) Vincas (e.g., vincristine and vinblastine), NAVELBINE® (vinorelbine), taxanes (e.g., paclitaxel, nab-paclitaxel, and docetaxel), topoisomerase II inhibitors (e.g. For example, 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.

The term “chemo-immunotherapy” refers to combination therapy that includes both chemotherapy drugs and immunotherapy agents. In some embodiments, chemoimmunotherapy is used to treat cancer, e.g., CD20-positive cancer, e.g., NHL, e.g., FL. In some embodiments, the immunotherapeutic agent comprises an antibody, e.g., 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.

As used herein, the term “R-CHOP” refers to a treatment comprising rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone. In some embodiments, R-CHOP is a chemotherapy treatment or regimen used in the treatment of cancer, optionally a B cell proliferative disorder (e.g., non-Hodgkin lymphoma, e.g., DLBCL, or high grade B cell lymphoma) . In some embodiments, R-CHOP is a standard treatment ( SOC) or standard therapy. In some embodiments, R-CHOP is the standard front-line or first-line therapy administered to previously untreated subjects. In some embodiments, R-CHOP is administered every 3 weeks (in a 21-day dosing cycle) for 3 to 6 dosing cycles. In some embodiments, the dosing regimen for R-CHOP therapy comprises 21 day dosing cycles, wherein during each dosing cycle the subject is administered 375 mg/m ² rituximab IV, and also cyclophosphamide, doxorubicin, Vincristine and prednisone are administered. In some embodiments, the dosing regimen for the R-CHOP therapy further comprises 750 mg/m ² cyclophosphamide IV per day, 50 mg/m ² doxorubicin IV, 1.4 mg/m ² vincristine IV per day, and 5 days of Contains 100 mg or 40 mg/m ² of prednisone orally. In some embodiments, the maximum single dose of vincristine is 2 mg.

As used herein, the term “cytotoxic agent” refers to any agent that is harmful to cells (e.g., causes cell death, inhibits proliferation, or otherwise interferes with cell function). Cytotoxic agents include radioisotopes (e.g., radioisotopes of ²¹¹ At, ¹³¹ I, ¹²⁵ I, ⁹⁰ Y, ¹⁸⁶ Re, ¹⁸⁸ Re, ¹⁵³ Sm, ²¹² Bi, ³² P, ²¹² Pb, and Lu); chemotherapy agents; Enzymes and fragments thereof, such as nucleolytic enzymes; and toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, and fragments and/or variants thereof. Exemplary cytotoxic agents include anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, signal transduction pathway inhibitors, non-receptor tyrosines. It may be selected from a kinase angiogenesis inhibitor, an immunotherapy agent, a proapoptosis agent, an LDH-A inhibitor, a fatty acid biosynthesis inhibitor, a cell cycle elongation inhibitor, an HDAC inhibitor, a proteasome inhibitor, and a cancer metabolism inhibitor. In one example, the cytotoxic agent is a platinum-based chemotherapy agent (e.g., carboplatin or cisplatin). In one example, the cytotoxic agent is an antagonist of EGFR, e.g., 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.

The term “package insert” means an inclusion customarily included in a commercial package of a therapeutic product containing information about indications, directions for use, dosage, administration, combination therapy, contraindications, and/or warnings regarding the use of the therapeutic product. It is used to refer to instructions that are used.

The term “synergistic effect” is used to refer to an effect that occurs due to the combined use of two or more therapeutic agents (e.g., mosunetuzumab and lenalidomide), and that this effect occurs when the two or more therapeutic agents are used individually. greater than the sum of the effects observed when In some embodiments, the synergistic effect is associated with relapsed and/or refractory (R/R) non-Hodgkin lymphoma (NHL) treated with combination therapy comprising mosunetuzumab and lenalidomide; e.g., R /R follicular lymphoma (FL)). In some embodiments, the population of subjects with R/R FL is more stable when treated with a combination therapy comprising mosunetuzumab and lenalidomide compared to the population of subjects treated with monotherapy of mosunetuzumab or lenalidomide. It shows a high complete response rate. In some embodiments, the population of subjects with R/R FL is more stable when treated with a combination therapy comprising mosunetuzumab and lenalidomide compared to the population of subjects treated with monotherapy of mosunetuzumab or lenalidomide. It shows a high complete response rate.

III. Treatment method

ligny 외, Blood. 2004; 104(5): 1258-1265.) 점수가 2-5점(예: 2, 3, 4 또는 5점)이거나, (b) 이전 항-CD20 단일클론 항체 치료에 불응성이었거나, (c) 이전 치료 시작 후 24개월 이내에 질환 진행이 있다. 일부 실시형태에서, 각 대상체는 유효량의 모수네투주맙 및 레날리도마이드를 투여받기 전 적어도 4주(예를 들어,, 4주, 6주, 8주, 10주, 12주, 24주, 36주, 48주, 60주, 또는 그 이상) 동안 항-CD20 단일클론 항체로 치료받지 않았다. 일부 실시형태에서, 모수네투주맙과 레날리도마이드는 R/R FL에 상승작용적 효과를 갖는다. 일부 실시형태에서, 상승작용적 효과는 Lugano 2014 기준(Cheson BD, 외, J Clin Oncol 2014; 32:1-9)에서 정의된 바에 따른 부분 반응이다. 일부 실시형태에서, 상승작용적 효과는 Lugano 2014 기준(Cheson BD, 외, J Clin Oncol 2014; 32:1-9)에서 정의된 바에 따른 완전 반응이다. Provided herein is a method of treating a subject with relapsed and/or refractory (R/R) follicular lymphoma (FL) by administering mosunetuzumab and lenalidomide as combination therapy. In particular, the invention relates to at least one prior systemic treatment (e.g. , one prior treatment with a chemo-immunotherapy regimen) and a method of treating a subject with R/R FL who is R/R. In some embodiments, the FL is a classified FL (e.g., a Class 1, 2, or 3a FL, but not a Class 3b FL). In some embodiments, each subject's FL is grade 1, 2, or 3a, but not grade 3b, according to the World Health Organization's Classification of Lymphomatous Neoplasms (see Swerdlow SH, et al., Blood 2016; 127:2375-90). Histologically recorded. In some embodiments, the subject has previously received only one line of systemic treatment, and (a) the Follicular Lymphoma International Prognostic Index (FLIPI; Solal-C

ligny et al., Blood . 2004; 104(5): 1258-1265.) had a score of 2 to 5 (e.g., 2, 3, 4, or 5), or (b) was refractory to previous anti-CD20 monoclonal antibody treatment, or (c) had a prior anti-CD20 monoclonal antibody treatment. There is disease progression within 24 months of starting treatment. In some embodiments, each subject has been treated for at least 4 weeks (e.g., 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 24 weeks, 36 weeks) before receiving an effective amount of mosunetuzumab and lenalidomide. week, 48 weeks, 60 weeks, or more) have not been treated with anti-CD20 monoclonal antibodies. 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 synergistic effect is a complete response as defined by the Lugano 2014 criteria (Cheson BD, et al., J Clin Oncol 2014; 32:1-9).

A. Treatment method for mosunetuzumab administration

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 combination therapy. In particular, the invention relates to at least one prior systemic treatment (e.g. , one prior treatment with a chemo-immunotherapy regimen) and a method of treating a subject with R/R FL who is R/R. 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 synergistic effect is a complete response as defined by the Lugano 2014 criteria (Cheson BD, et al., J Clin Oncol 2014; 32:1-9).

In some embodiments, 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, wherein: (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab, where C1D1 and C1D2 are each greater than C1D3, and C1D1 is 0.02 mg to 4.0 mg (e.g. For example, 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, 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, 0.1 mg to 3.5 mg, 0.1 mg to 3.0 mg, 0.1 mg to 2.5 mg, 0.1 mg to 2.0 mg, 0.1 mg to 1.5 mg, 0.1 mg to 1 mg, 0.1 mg to 0.5 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 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg. 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., 0.1 mg to 20.0 mg, 0.2 mg) mg to 20.0 mg, 0.3 mg to 20.0 mg, 0.4 mg to 20.0 mg, 0.5 mg to 20.0 mg, 1.0 mg to 20.0 mg, 1.5 mg to 20.0 mg, 2.0 mg to 20.0 mg, 3.0 mg to 20.0 mg, 4.0 mg to 20.0 mg, 5.0 mg to 20.0 mg, 6.0 mg to 20.0 mg, 7.0 mg to 20.0 mg, 8.0 mg to 20.0 mg, 9.0 mg to 20.0 mg, 10.0 mg to 20.0 mg, 15.0 mg to 20.0 mg, 0.5 mg to 15.0 mg , 0.5 mg to 10.0 mg, 0.5 mg to 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 10.0 mg 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 50.0 mg) 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 to 50.0 mg, 40.0 mg to 50.0 mg, 45.0 mg to 50.0 mg, 1.0 mg to 45.0 mg, 1.0 mg to 40.0 mg, 1.0 mg to 35.0 mg, 1.0 mg to 30.0 mg, 1.0 mg to 25.0 mg, 1.0 mg to 20.0 mg, 1.0 mg to 15.0 mg, 1.0 mg to 10.0 mg, 1.0 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, 3.0 mg to 45.0 mg, 3.0 mg to 50.0 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); and (b) the second administration cycle comprises a single dose of mosunetuzumab (C2D1), wherein C2D1 is at least C1D3 and is 0.2 mg to 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 to 50.0 mg, 40.0 mg to 50.0 mg, 45.0 mg to 50.0 mg, 1.0 mg to 45.0 mg, 1.0 mg to 40.0 mg, 1.0 mg to 35.0 mg, 1.0 mg to 30.0 mg, 1.0 mg to 25.0 mg, 1.0 mg to 20.0 mg, 1.0 mg to 15.0 mg, 1.0 mg to 10.0 mg, 1.0 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, 3.0 mg to 45.0 mg, 3.0 mg to 50.0 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, (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, 3.0 mg to 20.0 mg, 4.0 mg to 20.0 mg, 5.0 mg to 20.0 mg, 6.0 mg to 20.0 mg, 7.0 mg to 20.0 mg, 8.0 mg to 20.0 mg, 9.0 mg to 20.0 mg, 10.0 mg to 20.0 mg, 15.0 mg to 20.0 mg, 1.0 mg to 15.0 mg, 1.0 mg to 10.0 mg, 1.0 mg to 9.0 mg, 1.0 mg to 8.0 mg, 1.0 mg to 7.0 mg, 1.0 mg to 6.0 mg, 1.0 mg to 5.0 mg, 1.0 mg to 4.0 mg, 1.0 mg to 3.0 mg, 1.0 mg to 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. 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 50.0 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, 3.0 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, 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; , 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) 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) 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, 3.0 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, 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; , 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, (a) C1D1 is 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; For example, 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), 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. 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 (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) 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).

In some embodiments, C1D1 and C1D2 are each less than C1D3. In some embodiments, C1D1 and C1D2 are substantially identical. In some embodiments, C1D2 is about 50% to about 250% more than C1D1 (e.g., C1D2 is about 50% to about 225% more than C1D1, or C1D2 is about 50% to about 200% more than C1D1. % more, or C1D2 is about 50% to about 175% more than C1D1, or C1D2 is about 50% to about 150% more than C1D1, or C1D2 is about 50% to about 125% more than C1D1. more, or C1D2 is about 50% to about 100% more than C1D1, or C1D2 is about 50% to about 75% more than C1D1; for example, C1D2 is about 50% more than C1D1; or C1D2 is about 100% more than C1D1, or C1D2 is about 150% more than C1D1, or C1D2 is about 200% more than C1D1, or C1D2 is about 250% more than C1D1. ).

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.

In some embodiments, the length of the first administration cycle is 21 days (±1 day). In some embodiments, the method comprises treating the subject on each of days 1, 8, and 15 of the first dosing cycle, or approximately on days 1, 8 (±1 day), and 15 days (±1 day), respectively. It involves administering C1D1, C1D2 and C1D3 to the patient. In some embodiments, the length of the second administration cycle is 28 days (±1 day). In some embodiments, comprising administering C2D1 to the subject on day 1 of the second administration cycle.

In some embodiments, the dosing regimen can be administered in 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 1 dosing cycle, 8 dosing cycles, 9 dosing cycles, 10 dosing cycles or more). In some embodiments, the dosing regimen consists of 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 aspects, each of the one or more additional dosing cycles is 28 days (±1 day) in length. In some embodiments, each of the one or more additional dosing cycles comprises an additional dose of mosunetuzumab. In some embodiments, the method comprises 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 0.2 mg to 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, 35.0 mg to 50.0 mg, 40.0 mg to 50.0 mg, 45.0 mg to 50.0 mg, 1.0 mg to 45.0 mg, 1.0 mg to 40.0 mg, 1.0 mg to 35.0 mg, 1.0 mg to 30.0 mg, 1.0 mg to 25.0 mg, 1.0 mg to 20.0 mg, 1.0 mg to 15.0 mg, 1.0 mg to 10.0 mg, 1.0 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, 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, administering an effective amount of mosunetuzumab comprises administering mosunetuzumab according to a dosing regimen comprising 12 dosing cycles, wherein: (a) the first dosing cycle is the first dosing cycle of mosunetuzumab; A first dose (C1D1), a second dose (C1D2), and a third dose (C1D3), wherein C1D1 and C1D2 are each less than or equal to C1D3, and C1D1 is 0.02 mg to 4.0 mg (e.g., 0.05 mg to 4.0 mg). 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, 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, 0.1 mg to 3.5 mg, 0.1 mg to 3.0 mg, 0.1 mg to 2.5 mg, 0.1 mg to 2.0 mg, 0.1 mg to 1.5 mg, 0.1 mg to 1 mg, 0.1 mg to 0.5 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 1.0 mg 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 to 20.0 mg (e.g., 0.1 mg to 20.0 mg, 0.2 mg to 20.0 mg, 0.3 mg) mg to 20.0 mg, 0.4 mg to 20.0 mg, 0.5 mg to 20.0 mg, 1.0 mg to 20.0 mg, 1.5 mg to 20.0 mg, 2.0 mg to 20.0 mg, 3.0 mg to 20.0 mg, 4.0 mg to 20.0 mg, 5.0 mg to 20.0 mg, 6.0 mg to 20.0 mg, 7.0 mg to 20.0 mg, 8.0 mg to 20.0 mg, 9.0 mg to 20.0 mg, 10.0 mg to 20.0 mg, 15.0 mg to 20.0 mg, 0.5 mg to 15.0 mg, 0.5 mg to 10.0 mg , 0.5 mg to 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 15.0 mg 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 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 to 50.0 mg, 40.0 mg to 50.0 mg, 45.0 mg to 50.0 mg, 1.0 mg to 45.0 mg, 1.0 mg to 40.0 mg, 1.0 mg to 35.0 mg, 1.0 mg to 30.0 mg, 1.0 mg to 25.0 mg, 1.0 mg to 20.0 mg, 1.0 mg to 15.0 mg, 1.0 mg to 10.0 mg, 1.0 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, 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); and (b) the second to twelfth administration cycle each comprises a single dose (C2D1-C12D1) of mosunetuzumab, wherein the C2D1-C12D1 of each single dose is equal in amount, is at least C1D3, and is 0.2 mg to 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 to 50.0 mg, 40.0 mg to 50.0 mg, 45.0 mg to 50.0 mg , 1.0 mg to 45.0 mg, 1.0 mg to 40.0 mg, 1.0 mg to 35.0 mg, 1.0 mg to 30.0 mg, 1.0 mg to 25.0 mg, 1.0 mg to 20.0 mg, 1.0 mg to 15.0 mg, 1.0 mg to 10.0 mg, 1.0 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, 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 )am.

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, 3.0 mg to 20.0 mg, 4.0 mg to 20.0 mg, 5.0 mg to 20.0 mg, 6.0 mg to 20.0 mg, 7.0 mg to 20.0 mg, 8.0 mg to 20.0 mg, 9.0 mg to 20.0 mg, 10.0 mg to 20.0 mg, 15.0 mg to 20.0 mg, 1.0 mg to 15.0 mg, 1.0 mg to 10.0 mg, 1.0 mg to 9.0 mg, 1.0 mg to 8.0 mg, 1.0 mg to 7.0 mg, 1.0 mg to 6.0 mg, 1.0 mg to 5.0 mg, 1.0 mg to 4.0 mg, 1.0 mg to 3.0 mg, 1.0 mg to 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. 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 50.0 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, 3.0 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, 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; , 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 single dose of C2D1-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, 3.0 mg to 45.0 mg, 3.0 mg to 40.0 mg, 3.0 mg to 35.0 mg, 3.0 mg 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, 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 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, (a) C1D1 is 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. mg to 1.1 mg; for example, 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) 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. 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-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). , 25.0 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 mg, about 30.0 mg, about 35.0 mg, about 40.0 mg, or about 45.0 mg).

In some embodiments, C1D1 and C1D2 are each less than C1D3. In some embodiments, C1D2 is about 50% to about 250% more than C1D1 (e.g., C1D2 is about 50% to about 225% more than C1D1, or C1D2 is about 50% to about 200% more than C1D1. % more, or C1D2 is about 50% to about 175% more than C1D1, or C1D2 is about 50% to about 150% more than C1D1, or C1D2 is about 50% to about 125% more than C1D1. more, or C1D2 is about 50% to about 100% more than C1D1, or C1D2 is about 50% to about 75% more than C1D1, for example, C1D2 is about 50% more than C1D1; or C1D2 is about 100% more than C1D1, or C1D2 is about 150% more than C1D1, or C1D2 is about 200% more than C1D1, or C1D2 is about 250% more than C1D1. ).

In some embodiments, (a) C1D1 is 0.8 mg, C1D2 is 2.0 mg, 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, 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, C1D3 is 30.0 mg, and each single dose C2D1-C12D1 is 30.0 mg.

In some embodiments, the length of the first administration cycle is 21 days (±1 day). In some embodiments, the method comprises treating the subject on each of days 1, 8, and 15 of the first dosing cycle, or approximately on days 1, 8 (±1 day), and 15 days (±1 day), respectively. It involves administering C1D1, C1D2 and C1D3 to the patient. In some embodiments, the length of each second through twelfth dosing cycle is 28 days (±1 day). In some embodiments, the method comprises administering each of C2D1-C12D1 to the subject on day 1 of each separate administration cycle. In some embodiments, the length of each second through twelfth dosing cycle is 28 days (±1 day).

In some embodiments, mosunetuzumab is administered intravenously.

In some embodiments, lenalidomide is administered during the second and 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 comprising administration of lenalidomide. In some embodiments, lenalidomide is not administered during 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.

In some embodiments, the subject has been previously 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.

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: (i) relapses expressing CD20; have refractory or refractory follicular lymphoma (R/R FL), and (ii) have been previously treated with at least one chemo-immunotherapy regimen including obinutuzumab; and administering the effective amount of mosunetuzumab and lenalidomide includes at least a first 21-day (± 1 day) dosing cycle and a second 28-day (± 1 day) dosing cycle of mosunetuzumab and lenalidomide. wherein: (a) the first administration cycle is administered intravenously on Day 1, Day 8 (±1 Day), and Day 15 (±1 Day), respectively, of the first administration cycle; Includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab administered within, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg. and (b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) administered intravenously on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and (c) the second dosing cycle. further comprising oral administration of lenalidomide 20 mg daily on days 1-21 of the second dosing cycle.

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: (i) relapses expressing CD20; have refractory or refractory follicular lymphoma (R/R FL), and (ii) have been previously treated with at least one chemo-immunotherapy regimen including obinutuzumab; and administering an effective amount of mosunetuzumab and lenalidomide means at least the first 21-day (± 1 day) dosing cycle and 11 subsequent 28-day (± 1 day) dosing cycles of mosunetuzumab and lenalidomide. and administering according to a dosing cycle comprising: (a) the first dosing cycle is on day 1, day 8 (±1 day), and day 15 (±1 day) respectively of the first dosing cycle; A first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab administered intravenously, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg. mg, and (b) each of the second to twelfth dosing cycles comprises a single dose (C2D1-C12D1) of mosunetuzumab administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1-C12D1 is 30 mg, and (c) each of the second through twelfth dosing cycles further comprises daily oral administration of 20 mg lenalidomide on days 1-21 of each dosing cycle.

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: (i) relapses expressing CD20; have refractory or refractory follicular lymphoma (R/R FL), and (ii) have been previously treated with at least one chemo-immunotherapy regimen containing rituximab; and administering the effective amount of mosunetuzumab and lenalidomide includes at least a first 21-day (± 1 day) dosing cycle and a second 28-day (± 1 day) dosing cycle of mosunetuzumab and lenalidomide. wherein: (a) the first administration cycle is administered on Day 1, Day 8 (±1 Day), and Day 15 (±1 Day), respectively, of the first administration cycle; A first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg, (b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) administered on Day 1 of the second dosing cycle, where C2D1 is 30 mg, and (c) the second dosing cycle comprises the second dosing cycle. It additionally includes lenalidomide 20 mg orally daily on days 1-21 of the cycle.

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: (i) relapses expressing CD20; have refractory or refractory follicular lymphoma (R/R FL), and (ii) have been previously treated with at least one chemo-immunotherapy regimen containing rituximab; and administering an effective amount of mosunetuzumab and lenalidomide means at least the first 21-day (± 1 day) dosing cycle and 11 subsequent 28-day (± 1 day) dosing cycles of mosunetuzumab and lenalidomide. and administering according to a dosing cycle comprising: (a) the first dosing cycle is on day 1, day 8 (±1 day), and day 15 (±1 day) respectively of the first dosing cycle; A first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab administered intravenously, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg. mg, and (b) each of the second to twelfth dosing cycles comprises a single dose (C2D1-C12D1) of mosunetuzumab administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1-C12D1 is 30 mg, and (c) each of the second through twelfth dosing cycles further comprises daily oral administration of 20 mg lenalidomide on days 1-21 of each dosing cycle.

In one aspect, the invention features 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, wherein each subject: (a) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and (b) have been previously treated with at least one chemo-immunotherapy regimen; and administering the effective amount of mosunetuzumab and lenalidomide includes at least a first 21-day (± 1 day) dosing cycle and a second 28-day (± 1 day) dosing cycle of mosunetuzumab and lenalidomide. wherein: (a) the first administration cycle is administered intravenously on Day 1, Day 8 (±1 Day), and Day 15 (±1 Day), respectively, of the first administration cycle; Includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab administered within, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg. and (b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) administered intravenously on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and (c) the second dosing cycle. further comprises oral administration of lenalidomide 20 mg daily on days 1-21 of the second dosing cycle. In some embodiments, the at least one chemo-immunotherapy regimen comprised an anti-CD20 monoclonal antibody (e.g., rituximab or obinutuzumab).

In one aspect, the invention features 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, wherein each subject: ( a) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and (b) have been previously treated with at least one chemo-immunotherapy regimen; and administering an effective amount of mosunetuzumab and lenalidomide means at least the first 21-day (± 1 day) dosing cycle and 11 subsequent 28-day (± 1 day) dosing cycles of mosunetuzumab and lenalidomide. and administering according to a dosing cycle comprising: (a) the first dosing cycle is on day 1, day 8 (±1 day), and day 15 (±1 day) respectively of the first dosing cycle; A first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab administered intravenously, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg. mg, and (b) each of the second to twelfth dosing cycles comprises a single dose (C2D1-C12D1) of mosunetuzumab administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1-C12D1 is 30 mg, and (c) each of the second through twelfth dosing cycles further comprises daily oral administration of 20 mg lenalidomide on days 1-21 of each dosing cycle. In some embodiments, the at least one chemo-immunotherapy regimen comprised an anti-CD20 monoclonal antibody (e.g., rituximab or obinutuzumab).

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 administration cycle. In some embodiments, the first administration cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of corticosteroid. In some embodiments, C1D1, C1D2, and C1D3 of corticosteroids are administered to the subject on Day 1, Day 8 (±1 day), and Day 15 (±1 day), respectively, of the first administration cycle. In some embodiments, each single dose C1D1-C1D3 of corticosteroid is administered to the subject prior to administering each C1D1-C1D3 dose of mosunetuzumab. In some embodiments, each single dose C1D1-C1D3 of corticosteroid is administered 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, before administering each C1D1-C1D3 of mosunetuzumab. It is administered to the subject 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.

In some embodiments, the corticosteroid is administered to the subject in the first administration cycle and is not administered in the second administration cycle.

In some embodiments, the corticosteroid is administered to the subject in the second administration cycle. In some embodiments, the second administration cycle comprises a single dose of corticosteroid (C2D1). In some embodiments, C2D1 of corticosteroid is administered to the subject on day 1 of the second administration cycle. In some embodiments, C2D1 of corticosteroid is administered to the subject prior to C2D1 administration of mosunetuzumab. In some embodiments, the C2D1 of 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 prior to administering the C2D1 of mosunetuzumab. , 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 to the subject.

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 administration cycle. In some embodiments, the first administration cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of corticosteroid. In some embodiments, C1D1, C1D2, and C1D3 of corticosteroids are administered to the subject on Day 1, Day 8 (±1 day), and Day 15 (±1 day), respectively, of the first administration cycle. In some embodiments, each single dose C1D1-C1D3 of corticosteroid is administered to the subject prior to administering each C1D1-C1D3 dose of mosunetuzumab. In some embodiments, each single dose C1D1-C1D3 of corticosteroid is administered 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, before administering each C1D1-C1D3 of mosunetuzumab. It is administered to the subject 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.

In some embodiments, the corticosteroid is administered to the subject in the first administration cycle and is not administered in the second administration cycle.

In some embodiments, the corticosteroid is administered to the subject in the second administration cycle. In some embodiments, the second administration cycle comprises a single dose of corticosteroid (C2D1). In some embodiments, C2D1 of corticosteroid is administered to the subject on day 1 of the second administration cycle. In some embodiments, C2D1 of corticosteroid is administered to the subject prior to C2D1 administration of mosunetuzumab. In some embodiments, the C2D1 of 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 prior to administering the C2D1 of mosunetuzumab. , 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 to the subject.

In some embodiments, each additional administration cycle comprises administering an additional dose of corticosteroid to the subject. In some embodiments, each additional dose of corticosteroid is administered on Day 1 of each additional dosing cycle. In some embodiments, each additional dose of corticosteroid is administered to the subject prior to administration of each additional dose of mosunetuzumab. In some embodiments, each additional dose of corticosteroid is administered 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours prior to administering each additional dose of mosunetuzumab. , 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 to the subject.

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).

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; for example, 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%; for example, 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 the population of subjects with R/R FL is at least 95%. In some embodiments, the overall response rate in the population of subjects with R/R FL is at least 99%.

In some embodiments, the complete response rate in the 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 or more; for example, 65-100%, 75-100%, 85-100%, 95-100%, 65-90%, 65-80%, 65-70%, 65-75%, or 75- 85%; for example, 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 the 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%.

In some embodiments, combination therapy with mosunetuzumab and lenalidomide increases the efficacy of the therapy compared to therapy with mosunetuzumab or lenalidomide alone to treat subjects with R/R FL. It shows a direct effect. In some embodiments, a population of subjects with R/R FL treated with combination therapy with mosunetuzumab and lenalidomide has a higher overall response rate compared to a population of subjects treated with mosunetuzumab or lenalidomide monotherapy. represents. In some embodiments, a population of subjects with R/R FL treated with combination therapy with mosunetuzumab and lenalidomide has a higher complete response rate compared to a population of subjects treated with mosunetuzumab or lenalidomide monotherapy. represents.

In some embodiments, the subject exhibits a reduction in tumor burden after receiving an effective amount of mosunetuzumab and an effective amount of lenalidomide. In some embodiments, reduction of tumor burden is determined by computed tomography (CT). In some embodiments, the reduction in tumor burden is a reduction in the sum of diameter products (SPD) of the 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; for example, 40-100%, 40-80%, 40-60%, 50-70%, 70-90%, 75-85%, 60-100%, 55-65%, 80-100%; for example, 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%.

In some embodiments, at least 45% (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; for example, between 45-100%, between 45-80%, between 45-60%, between 50-70%, between 55-65%, between 70-90% , between 70-80%, between 60-100%, between 80-100%; for example, 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%) represents a reduction in tumor burden after receiving an effective amount of mosunetuzumab and an effective amount of lenalidomide. In some embodiments, at least 60% of the subjects in the population demonstrate a reduction in tumor burden after receiving an effective amount of mosunetuzumab and an effective amount of lenalidomide. In some embodiments, at least 75% of the subjects in the population demonstrate a reduction in tumor burden after receiving an effective amount of mosunetuzumab and an effective amount of lenalidomide. In some embodiments, reduction of tumor burden is determined by computed tomography (CT).

In some embodiments, the reduction in tumor burden is a reduction in the sum of diameter products (SPD) of the 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; for example, 40-100%, 40-80%, 40-60%, 50-70%, 70-90%, 75-85%, 60-100%, 55-65%, 80-100%; for example, 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%.

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

B. Dosing strategy to alleviate 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 combination therapy. In particular, the invention relates to at least one prior systemic treatment (e.g. , one prior treatment with a chemo-immunotherapy regimen) and a method of treating a subject with R/R FL who is R/R. The therapies and dosing regimens described herein provide an acceptable safety profile in subjects with R/R FL treated with the dosing regimens.

1. CRS symptoms and grades

Any of the methods described herein may include monitoring the subject for cytokine release syndrome (CRS), e.g., an event of CRS following initiation of any of the methods described above. Current clinical management focuses on treating individual signs and symptoms, providing supportive care, and attempting to alleviate the inflammatory response using high-dose corticosteroids. However, this approach is not always successful, especially when intervention is late. The CRS grading criteria used by the methods described herein are published by the American Society for Transplantation and Cell Therapy (ASTCT), which defines mild, moderate, severe, or life-threatening CRS and provides reporting throughout clinical trials. Harmonized, it enables rapid recognition and treatment of CRS (Lee et al., Biol Blood Marrow Transplantation. 25(4): 625-638, 2019). The ASTCT criteria are objective, easy to apply, and are intended to more accurately classify the severity of CRS. This CRS rating system is shown in Table 1 below.

Table 1. CRS rating system

ASTCT = American Society for Transplantation and Cellular Therapy; BiPAP = two-level positive airway pressure; CPAP = continuous positive airway pressure; CRS = cytokine release syndrome; CTCAE = Common Terminology Criteria for Adverse Events.

Fever is defined as a temperature ≥38°C that cannot be attributed to other causes. In subjects with CRS receiving antipyretics or anticytokine therapy, such as tocilizumab or steroids, fever is no longer required to grade subsequent CRS severity. In this case, the CRS grade is determined by hypotension and/or hypoxia.

CRS grade is determined by the more severe cases: hypotension or hypoxia not due to other causes. For example, a subject with a temperature of 39.5°C, hypotension requiring 1 vasopressor, and hypoxia requiring a low-flow nasal cannula would be classified as grade 3 CRS.

Low-flow nasal cannulae are defined as oxygen delivered at ≥ 6 L/min. Low flow also includes blow-by oxygen delivery, which is often used in pediatrics. High-flow nasal cannulae are defined as oxygen delivered at >6 L/min.

CRS is associated with elevations of various cytokines, including significant elevations in levels of IFN-γ, IL-6, and TNF-α. Emerging evidence suggests that IL-6 in particular is an important mediator of CRS. IL-6 is a pro-inflammatory multifunctional cytokine produced by a variety of cell types and has been shown to be involved in a variety of physiological processes, including T cell activation. Regardless of the trigger, 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), IL-6 correlates with the severity of CRS, with subjects experiencing grade 4 or 5 CRS events either not experiencing CRS or experiencing mild CRS (grade 0-3). have significantly higher IL-6 levels compared to subjects that do so (Chen et al., J. Immunol. Methods. 434:1-8, 2016).

Therefore, to manage the CRS observed in subjects during a two-step split-dose escalation regimen, blocking the inflammatory actions of IL-6 using agents that inhibit IL-6-mediated nephrotoxicity is an alternative to steroid treatment, and CD20 -Not expected to negatively affect T cell function or reduce the efficacy or clinical benefit of mosunetuzumab therapy in the treatment of benign cell proliferative disorders (e.g., B cell proliferative disorders).

If the subject has a CRS event that does not resolve or worsens within 24 hours after administration of an IL-6R antagonist to treat the symptoms of the CRS event, the method may include administering to the subject one or more additional doses of IL-6R antagonist to manage the CRS event. The step of administering a 6R antagonist may be further included. If CRS cases are not managed by administering IL-6R antagonists, the subject may be administered corticosteroids, such as methylprednisolone or dexamethasone.

2. Other adverse events and grades

Any of the methods described herein may include monitoring the subject for additional non-CRS adverse events. Incidence, nature, and severity of physical findings and adverse events, with severity determined according to the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 5 (NCI CTCAE v5.0). Besides CRS, one of the most common adverse events reported in patients treated with mosunetuzumab and/or lenalidomide is neutropenia (e.g. febrile neutropenia).

Neutropenia is characterized by an abnormally low blood count of neutrophils, a type of white blood cell. Neutropenia may increase the risk of infection. The generally accepted reference range for absolute neutrophil count (ANC) in adults is 1,500 to 8,000 cells/μL of blood. Mild neutropenia is characterized by an ANC of 1,000-1,500 cells/μL (grade 1-2); Moderate neutropenia is characterized by an ANC of 500-1,000 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 and a single temperature measurement greater than 38.3°C or a sustained temperature measurement greater than 38°C for more than 1 hour. Do it as

3. Dosing regimen with acceptable safety profile

In one aspect, the invention features 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, wherein each subject: (a) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and (b) have been previously treated with at least one chemo-immunotherapy regimen; and administering the effective amount of mosunetuzumab and lenalidomide includes at least a first 21-day (± 1 day) dosing cycle and a second 28-day (± 1 day) dosing cycle of mosunetuzumab and lenalidomide. wherein: (a) the first administration cycle is administered intravenously on Day 1, Day 8 (±1 Day), and Day 15 (±1 Day), respectively, of the first administration cycle; Includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab administered within, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg. and (b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) administered intravenously on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and (c) the second dosing cycle. further comprises oral administration of lenalidomide 20 mg daily on days 1-21 of the second dosing cycle. In some embodiments, the at least one chemo-immunotherapy regimen comprised an anti-CD20 monoclonal antibody (e.g., rituximab or obinutuzumab).

In one aspect, the invention features 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, wherein each subject: ( a) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and (b) have been previously treated with at least one chemo-immunotherapy regimen; and administering an effective amount of mosunetuzumab and lenalidomide means at least the first 21-day (± 1 day) dosing cycle and 11 subsequent 28-day (± 1 day) dosing cycles of mosunetuzumab and lenalidomide. and administering according to a dosing cycle comprising: (a) the first dosing cycle is on day 1, day 8 (±1 day), and day 15 (±1 day) respectively of the first dosing cycle; A first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab administered intravenously, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg. mg, and (b) each of the second to twelfth dosing cycles comprises a single dose (C2D1-C12D1) of mosunetuzumab administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1-C12D1 is 30 mg, and (c) each of the second through twelfth dosing cycles further comprises daily oral administration of 20 mg lenalidomide on days 1-21 of each dosing cycle. In some embodiments, the at least one chemo-immunotherapy regimen comprised an anti-CD20 monoclonal antibody (e.g., rituximab or obinutuzumab).

ligny 외, Blood. 2004; 104(5): 1258-1265.) 점수가 2-5점(예: 2, 3, 4 또는 5점)이거나, (b) 이전 항-CD20 단일클론 항체 치료에 불응성이었거나, (c) 이전 치료 시작 후 24개월 이내에 질환 진행이 있다.In some embodiments, each subject has previously received only one line of systemic treatment, and (a) Follicular Lymphoma International Prognostic Index (FLIPI; Solal-C

ligny et al., Blood . 2004; 104(5): 1258-1265.) had a score of 2 to 5 (e.g., 2, 3, 4, or 5), or (b) was refractory to previous anti-CD20 monoclonal antibody treatment, or (c) had a prior anti-CD20 monoclonal antibody treatment. There is disease progression within 24 months of starting treatment.

In some embodiments, each subject's FL is grade 1, 2, or 3a, but not grade 3b, according to the World Health Organization's Classification of Lymphomatous Neoplasms (see Swerdlow SH, et al., Blood 2016; 127:2375-90). Histologically recorded.

In some embodiments, each subject has been treated for at least 4 weeks (e.g., 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 24 weeks, 36 weeks) before receiving an effective amount of mosunetuzumab and lenalidomide. week, 48 weeks, 60 weeks, or more) have not been treated with anti-CD20 monoclonal antibodies.

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 synergistic effect is a complete response as defined by the Lugano 2014 criteria (Cheson BD, et al., J Clin Oncol 2014; 32:1-9).

In one aspect, the method of the invention features premedication with a corticosteroid to reduce the side 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 receiving a combination of mosunetuzumab and lenalidomide). reduce. 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 administration cycle. In some embodiments, the first administration cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of corticosteroid. In some embodiments, C1D1, C1D2, and C1D3 of corticosteroids are administered to the subject on Day 1, Day 8 (±1 day), and Day 15 (±1 day), respectively, of the first administration cycle. In some embodiments, each single dose C1D1-C1D3 of corticosteroid is administered to the subject prior to administering each C1D1-C1D3 dose of mosunetuzumab. In some embodiments, each single dose C1D1-C1D3 of corticosteroid is administered 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, before administering each C1D1-C1D3 of mosunetuzumab. It is administered to the subject 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. 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.

In some embodiments, the corticosteroid is administered to the subject in the first administration cycle and is not administered in the second administration cycle.

In some embodiments, the corticosteroid is administered to the subject in the second administration cycle. In some embodiments, the second administration cycle comprises a single dose of corticosteroid (C2D1). In some embodiments, C2D1 of corticosteroid is administered to the subject on day 1 of the second administration cycle. In some embodiments, C2D1 of corticosteroid is administered to the subject prior to C2D1 administration of mosunetuzumab. In some embodiments, the C2D1 of 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 prior to administering the C2D1 of mosunetuzumab. , 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 to the subject.

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 administration cycle. In some embodiments, the first administration cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of corticosteroid. In some embodiments, C1D1, C1D2, and C1D3 of corticosteroids are administered to the subject on Day 1, Day 8 (±1 day), and Day 15 (±1 day), respectively, of the first administration cycle. In some embodiments, each single dose C1D1-C1D3 of corticosteroid is administered to the subject prior to administering each C1D1-C1D3 dose of mosunetuzumab. In some embodiments, each single dose C1D1-C1D3 of corticosteroid is administered 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, before administering each C1D1-C1D3 of mosunetuzumab. It is administered to the subject 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.

In some embodiments, the corticosteroid is administered to the subject in the first administration cycle and is not administered in the second administration cycle.

In some embodiments, the corticosteroid is administered to the subject in the second administration cycle. In some embodiments, the second administration cycle comprises a single dose of corticosteroid (C2D1). In some embodiments, C2D1 of corticosteroid is administered to the subject on day 1 of the second administration cycle. In some embodiments, C2D1 of corticosteroid is administered to the subject prior to C2D1 administration of mosunetuzumab. In some embodiments, the C2D1 of 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 prior to administering the C2D1 of mosunetuzumab. , 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 to the subject.

In some embodiments, each additional administration cycle comprises administering an additional dose of corticosteroid to the subject. In some embodiments, each additional dose of corticosteroid is administered on Day 1 of each additional dosing cycle. In some embodiments, each additional dose of corticosteroid is administered to the subject prior to administration of each additional dose of mosunetuzumab. In some embodiments, each additional dose of corticosteroid is administered 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours prior to administering each additional dose of mosunetuzumab. , 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 to the subject.

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).

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

In some embodiments, the incidence of cytokine release syndrome as defined by the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grade for Cytokine Release Syndrome (“ASTCT CRS Grade”; Lee et al., Biol Blood Marrow Transplant 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%; For example, between about 0% and about 50%, between about 5% and about 40%, between about 5% and about 20%, between about 5% and about 10%, between about 20% and about 45%, between about 30% and about 30%. 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%; %, 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 Grade for Cytokine Release Syndrome (“ASTCT CRS Grade”) is less than 35%. In some embodiments, the incidence of cytokine release syndrome as defined by the American Society for Transplantation and Cell Therapy (ASTCT) Consensus Grade for Cytokine Release Syndrome (“ASTCT CRS Grade”) is less than 25%. In some embodiments, the incidence of CRS is about 30%.

In some embodiments, the incidence of cytokine release syndrome grade 3 or higher, as defined by the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grade for Cytokine Release Syndrome (“ASTCT CRS Grade”), 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%, for example, from 0% to 10%, from 0% to 1%; 9%, 0% to 8%, 0% to 7%, 0% to 6%, 0% to 5%, 0% to 4%, 0% to 3%, 0% to 2%, 0% to 1% , 1% to 3%, 1% to 5%, 1% to 10%, 3% to 5%, 5% to 8%, 5% to 10%, or 8% to 10%). In some embodiments, the incidence of cytokine release syndrome of grade 3 or higher is less than 5%, as defined by the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grade for Cytokine Release Syndrome (“ASTCT CRS Grade”). . In some embodiments, the incidence of cytokine release syndrome grade 3 or higher, as defined by the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grade for Cytokine Release Syndrome (“ASTCT CRS Grade”), is less than 3%. . In some embodiments, the incidence of cytokine release syndrome grade 3 or higher, as defined by the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grade for Cytokine Release Syndrome (“ASTCT CRS Grade”), is less than 1%. . In some embodiments, the incidence of grade 3 or higher CRS is about 0%.

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

The methods described herein may result in an acceptable safety profile for subjects with R/R mosunetuzumab being treated with combination therapy of mosunetuzumab and lenalidomide. In some instances, treatment using the methods described herein of administering mosunetuzumab intravenously in the context of a split dose escalation dosing regimen and oral administration of lenalidomide utilizes the split, dose escalation dosing regimen of the invention. Therefore, compared to treatment with mosunetuzumab using a non-fractionated dosing regimen, treatment with mosunetuzumab is associated with fewer unwanted adverse events, such as cytokine-induced toxicity (e.g., cytokine release syndrome (CRS)), and infusion. Related reactions (IRRs), macrophage activation syndrome (MAS), neurologic toxicity, severe tumor lysis syndrome (TLS), neutropenia, thrombocytopenia, elevated liver enzymes, and/or reduction in hepatotoxicity (e.g., 20% or greater) , 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 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% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60%, 20% to 50%, 20% to 40%, 20% to 30%, 40% to 100%, 60% to 100%, 80% to 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% , resulting in about 99%, or about 100%) or complete inhibition (100% reduction).

IV. remedy

A. Mosunetuzumab

The present invention provides mosunetuzumab, a bispecific antibody that binds CD20 and CD3, useful for treating relapsed and/or refractory (R/R) follicular lymphoma (FL). FL may be level 1, 2 or 3a, but not level 3b.

In some examples, the invention relates to (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) a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from HVR-L3 comprising the amino acid sequence of QQWSFNPPT (SEQ ID NO: 6). - Provides mosunetuzumab containing the CD20 arm. In some examples, mosunetuzumab comprises at least one of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4, each comprising the sequences of SEQ ID NOs: 17-20 (e.g., 1, 2, 3, or 4), and/or at least one of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4, each comprising the sequences of SEQ ID NOs: 21-24 (e.g. , 1, 2, 3, or 4). In some examples, mosunetuzumab has (a) the sequence of SEQ ID NO:7 or at least 90% sequence identity thereto (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, a heavy chain variable (VH) domain comprising an amino acid sequence with 98% or 99% sequence identity; (b) sequence of SEQ ID NO:8 or at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) a light chain variable (VL) domain comprising an amino acid sequence with sequence identity; or (c) an anti-CD20 arm comprising a first binding domain comprising the VH domain of (a) and the VL domain of (b). Accordingly, 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.

In some examples, the invention relates to (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) an anti-CD3 arm having a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 HVRs selected from HVR-L3 comprising the amino acid sequence of TQSFILRT (SEQ ID NO: 14). Provided is mosunetuzumab comprising: In some examples, mosunetuzumab comprises at least one of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4, each comprising the sequences of SEQ ID NOs: 25-28 (e.g., 1, 2 , 3, or 4), and/or at least one of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4, each comprising the sequences of SEQ ID NOs: 29-32 (e.g., 1, 2, 3, or 4). In some examples, mosunetuzumab has (a) the sequence of SEQ ID NO: 15 or at least 90% sequence identity thereto (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, a VH domain comprising an amino acid sequence with 98% or 99% sequence identity; (b) sequence of SEQ ID NO: 16 or at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) a VL domain comprising an amino acid sequence with sequence identity; or (c) an anti-CD3 arm comprising a second binding domain comprising the VH domain of (a) and the VL domain of (b). Accordingly, 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.

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

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

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

Table 2. Sequence number of mosunetuzumab

Mosunetuzumab can be produced using recombinant methods and compositions, for example, as described in U.S. Pat. No. 4,816,567.

B. Lenalidomide

Lenalidomide is an immunomodulatory (IMiD) imide drug that binds to cereblon, an E3 ubiquitin ligase protein (Gribben et al., 2015). The immunomodulatory activities of lenalidomide are not fully understood; Lenalidomide 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).

The CAS registration number for lenalidomide is 191732-72-6 and the IUPAC name is (3RS)-3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)p. It is peridine-2,6-dione. Lenalidomide is also known by the brand names REVLIMID®, Linamide, and Lenalid. Lenalidomide has DrugBank accession number DB00480, PubChem CID 216326, and the chemical formula C ₁₃ H ₁₃ N ₃ O ₃ . The present invention describes the additive/synergistic efficacy as well as potential overlapping toxicities in the combination of mosunetuzumab and lenalidomide, with respect to which patients are carefully monitored by the dosing regimen and treatment described herein. and managed.

C. Additional treatments

In some instances, the methods described herein include administering mosunetuzumab and lenalidomide in combination with one or more additional therapeutic agents.

In some instances, one or more additional therapeutic agents may reduce the incidence or severity of cytokine release syndrome (CRS). In some instances, one or more additional therapeutic agents may prevent symptoms associated with CRS. In certain instances, additional treatments used to reduce the incidence or severity of CRS or prevent symptoms associated with CRS include corticosteroids, such as dexamethasone (CAS#: 50-02-2), prednisone (CAS#: 53- 03-2), prednisolone (CAS# 50-42-8) or methylprednisolone (CAS#: 83-43-2)) or IL-6R antagonists (e.g. tocilizumab, sarilumab, bovalilizumab (ALX) -0061), satralizumab (SA) -237) and variants thereof). In some instances, the additional therapeutic agent is tocilizumab. In some instances, the additional therapeutic agent is a corticosteroid. In some instances, a corticosteroid is administered prior to administration of mosunetuzumab. In some instances, 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, or 3.5 minutes prior to administering mosunetuzumab. administered 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours before the dose. In some instances, corticosteroids are 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, It is administered to the subject 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. In some examples, the corticosteroid is methylprednisolone. In some examples, the corticosteroid is prednisone.

In some instances, one or more additional therapeutic agents may be used to treat neutropenia. In some instances, additional therapeutic agents may prevent symptoms associated with neutropenia. In some instances, additional therapeutic agents may reduce the incidence or severity of neutropenia. In certain instances, the additional therapeutic agent is granulocyte colony stimulating factor (G-CSF or GCSF) or colony stimulating factor 3 (CSF 3). The mRNA sequence of human G-CSF/CSF 3 includes, for example, NCBI RefSeq No. Protein amino acid sequences of human G-CSF/CSF 3 include NM_000759, NM_001178147, NM_172219, and NM_172220, for example, NCBI RefSeq No. Includes NP_000750, NP_001171618, NP_757373, and NP_757374.

For all methods described herein, mosunetuzumab and lenalidomide are formulated, administered, and administered in a manner consistent with good medical practice guidelines. Factors to be considered in this regard include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual subject, the cause of the disorder, the site of agent delivery, method of administration, schedule of administration, and other factors known to the medical practitioner. Mosunetuzumab and lenalidomide are optionally, but not necessarily, formulated with one or more agents currently used to prevent or treat the disorder in question. The effective amount of these other agents will vary depending on the amount of mosunetuzumab and lenalidomide present in the formulation, the type of disease or treatment, and other factors discussed above. Mosunetuzumab and lenalidomide may be administered to the subject as appropriate over a series of treatment schedules. When mosunetuzumab and lenalidomide are administered on the same day, mosunetuzumab can be administered before, simultaneously with, or after lenalidomide.

In some instances, additional therapeutic agents useful in the invention include therapeutic antibodies, e.g., also 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 ozogamycin (MYLOTARG®, Wyeth). Additional humanized monoclonal antibodies that have therapeutic potential as agents in combination with the compounds of the invention include: apolizumab, acelizumab, atlizumab, bapineuzumab, bibatuzumab mertansine, and cantuzumab mer. Tanshin, cedelizumab, certolizumab pegol, sidfucituzumab, sidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felbizumab, pontolizumab, inotu Zumab ozogamycin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motobizumab, natalizumab, nimotuzumab, nolovizumab, numabizumab, ocrelizumab, Omalizumab, palivizumab, pascolizumab, pecfucituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab, reslibizumab, reslizumab, lesibizumab, lobelizumab, ruplizumab, Sibrotuzumab, Ciplizumab, Sontuzumab, Tacatuzumab Tetraxetan, Tadocizumab, Tafasitamab, Talizumab, Tepibazumab, Tocilizumab, Toralizumab, Tucotuzumab Selmoryukin, Tucushi Tuzumab, Umabizumab, Urtoxazumab, Ustekinumab, Vicilizumab, and Briakinumab.

IV. Pharmaceutical compositions and dosage forms

Mosunetuzumab and/or lenalidomide described herein can be used in pharmaceutical compositions and formulations. Pharmaceutical compositions and dosage forms of mosunetuzumab, lenalidomide, and/or other agents described herein (e.g., dexamethasone) may be prepared by combining 1, 2, or all 3 agents with the desired purity with one or more optional pharmaceutical agents. It can be prepared in the form of a lyophilized formulation or aqueous solution by mixing with an acceptable carrier ( Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)). Lenalidomide may also be formulated according to standard formulations and/or manufacturing practices. Dexamethasone may also be formulated according to standard formulations and/or manufacturing practices. Pharmaceutically acceptable carriers are nontoxic to recipients at the dosages and concentrations employed and include, but are not limited to: buffers such as phosphate, citrate and other organic acids; Antioxidants including ascorbic acid and methionine; Preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butal or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclo hexanol; 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 counter-ions such as sodium; metal complexes (eg, Zn-protein complexes); and/or non-ionic surfactants such as polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers herein include interstitial drug dispersions, such as soluble neutral-active hyaluronidase glycoprotein (sHASEGP), such as human soluble PH-20 hyaluronidase. glycoproteins such as rHuPH20 ( ^HYLENEX® , Baxter International, Inc.). Certain exemplary sHASEGPs comprising rHuPH20 and methods of using them are described in US published patent applications 2005/0260186 and 2006/0104968. In one aspect, sHASEGP is combined with one or more additional glycosaminoglycanases, such as chondroitinase.

Exemplary lyophilized antibody formulations are described in U.S. Pat. No. 6,267,958. Aqueous antibody preparations include those described in US Pat. No. 6,171,586 and WO2006/044908, the latter preparation comprising histidine-acetate buffer.

The formulations herein may also contain two or more active ingredients as needed for the particular indication being treated, preferably ingredients with complementary activities that do not adversely affect each other. For example, it may be desirable to additionally provide additional therapeutic agents (e.g., chemotherapy agents, cytotoxic agents, growth inhibitory agents, and/or anti-hormonal agents, e.g., those mentioned herein above). there is. These active ingredients are suitably present in combination in amounts effective for the intended purpose.

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

Sustained-release formulations can be manufactured. Suitable examples of sustained-release formulations include semipermeable matrices of solid hydrophobic polymers containing the antibody, such matrices being in the form of molded articles, such as films, or microcapsules.

Formulations used for in vivo administration are generally sterile. Sterilization can be easily achieved, for example, by filtration through a sterile filtration membrane.

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.

V. Kits and Manufacturing Supplies

In another aspect of the invention, a kit or article of manufacture containing materials useful for the treatment, prevention and/or diagnosis of the disorders described above is provided. These kits or articles of manufacture include a container and a label or drug product instructions on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, etc. Containers can be formed from a variety of materials, such as glass or plastic. The container may hold the composition, alone or in combination with other compositions effective for treating, preventing and/or diagnosing a disease, and may have a sterile access port (e.g., the container may be accessed by a hypodermic needle). may be a vial with a pierceable stopper). At least one active agent in the composition is mosunetuzumab or lenalidomide described herein. The label or drug insert further includes information regarding the composition being used to treat relapsed and/or refractory (R/R) follicular lymphoma (FL) and at least one of the dosing regimens described herein. In some embodiments, the label or drug product instructions indicate that the composition has been used to treat at least one prior treatment comprising an anti-CD20 antibody (e.g., an anti-CD20 monoclonal antibody; e.g., rituximab or obinutuzumab). Indicates that it is used to treat R/R FL in patients who are R/R to (e.g., chemoimmunotherapy). Moreover, a kit or article of manufacture may comprise (a) a first container containing a composition therein, wherein the composition comprises mosunetuzumab, lenalidomide, or both mosunetuzumab and lenalidomide; and (b) a second container containing a composition therein, wherein the composition comprises an additional cytotoxic agent or other therapeutic agent. Alternatively, or additionally, the kit or article of manufacture may comprise a second pharmaceutically acceptable buffer solution, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and dextrose solution. (or a third) container may be further included. The article of manufacture may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles and syringes.

Example

The following are examples of the methods and compositions of the present invention. It is understood that various other embodiments may be practiced in accordance with the foregoing general description.

Example 1. Phase Ib, open-label, non-randomized, multicenter study evaluating the safety, pharmacokinetics, and efficacy of mosunetuzumab in combination with lenalidomide in patients with relapsed or refractory follicular lymphoma.

study design

Study CO41942 evaluated 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). This is an ongoing phase 1b, open-label, multicenter study. Patients with r/r FL who have previously received at least one systemic therapy are eligible to participate in the study. CCOD Currently, the combination of mosunetuzumab and lenalidomide is the only active treatment combination in Study CO41942, so this study focuses only on the combination of mosunetuzumab and lenalidomide. The study design is summarized in Figures 1A and 1B.

The study includes an initial dose escalation phase, including a dose escalation cohort, designed to determine the recommended phase 2 dose (RP2D) of mosunetuzumab. The initial dose escalation phase is followed by an expansion phase in which RP2D for mosunetuzumab is given.

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

Study population and treatment received

As of CCOD (April 5, 2021), all patients (N = 16) enrolled in the mosunetuzumab plus lenalidomide (IV) study arm and receiving at least one dose of mosunetuzumab. Ten patients completed the DLT evaluation period and reached D28 in cycle 2. Mosunetuzumab doses of 1/2/30 mg were used in all patients. Lenalidomide 20 mg was the dose for all patients.

Overall, 9 patients (56.3%) had a study duration of 0 to 3 months; Four patients (25.0%) had a duration of 3 to 6 months; Three patients (18.8%) had a duration of 6 to 9 months.

Patient demographics for the population assessed for safety (N = 16) are presented in Table 3. The majority of patients were female (62.5%, 10/16 patients) and the median age was 61.5 years. The Eastern Cooperative Oncology Group (ECOG) status of patients was 0 in 81.3% (13/16 patients) and 1 in 18.8% (3/16 patients).

Table 3. Demographic and baseline characteristics of patients evaluated for safety.

CCOD: April 5, 2021

CCOD Currently, all 16 patients in the safety evaluation population have received at least one dose of study treatment. Sixteen patients entered cycle 1, day 1 of treatment (and received the C1D1 dose); 14 patients entered cycle 1 day 8 (and received the C1D2 dose); 14 patients entered cycle 1 day 15 (and received the C1D3 dose); 13 patients entered cycle 2 (C2); Eight patients entered the third cycle.

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 administered was 5 (range: 1-11); The median cumulative dose administered was 93 mg (range: 1.0-273.0).

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 administered was 37 (range: 1-151); The median cumulative dose administered was 740 mg (range: 20.0-3020.0).

safety results

The safety assessment population (N = 16) included all patients enrolled in the study and receiving at least one dose of study treatment. An overview of key safety findings from the CCOD (April 5, 2021) is summarized below and further explained in Table 4.

● The proportion of patients reporting at least one adverse event (AE) was 81.3% (13/16 patients), with a total of 83 AEs reported overall.

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

● The proportion of patients reporting at least one event considered related to the study treatment was 81.3% (13/16). The proportion of patients reporting at least one event considered related to mosunetuzumab or lenalidomide treatment was 81.3% and 50.0%, respectively.

● CCOD Currently, no fatal (grade 5) AEs have been reported in this study.

● The proportion of patients reporting at least one serious adverse event (SAE) was 12.5% (2/16), of which three events were related to mosunetuzumab treatment (PT, CRS [2 cases ]; maculopapular rash).

● The proportion of patients reporting at least one grade ≥ 3 AE was 31.3% (5/16 patients).

● There were no AEs reported that resulted in discontinuation of study treatment.

● The proportion of patients reporting at least one event resulting in dose change/discontinuation of study treatment was 37.5% (6/16 patients). Among these, two patients stopped taking mosunetuzumab, and six patients stopped taking lenalidomide treatment.

● The proportion of patients reporting at least one adverse event of special interest (AESI) was 31.3% (5/16 patients).

The incidence and frequency of AEs, including AEs, SAEs, and AESIs, considered to be mosunetuzumab-related, were similar in this study to related studies of mosunetuzumab monotherapy administered at similar doses.

Table 4. Safety summary for patients eligible for CCOD current safety assessment as of April 5, 2021.

AE = Adverse Event, AESI = Adverse Event of Special Interest

^a Does not include cases of “death due to advanced disease”

^b According to ASTCT standards

^c Subject had worsening pleural effusion. Based on the International Dictionary of Medical Terminology (MedDRA) Representative Terms (PT), tumor flare is “tumor redness, tumor inflammation, tumor pain, and new or worsening pleural effusion.”

The most frequently reported adverse events:

Overall, the percentage of patients reporting at least one AE was 81.3% (13/16 patients), with a total of 83 AEs reported overall.

The most frequently reported AEs according to organ system classification (SOC) were skin and subcutaneous tissue disorders (43.8%; 7/16 patients); Gastrointestinal disorders (37.5%; 6/16 patients); Blood and lymphatic system disorders; These were general disorders and administration site conditions, immune system disorders, and neurological disorders (all 31.3%; 5/16 patients).

● The most commonly reported AEs, based on MedDRA representative terms (PT), were CRS (31.3%; 5/16 patients); constipation, and neutropenia (both 25.0%; 4/16 patients). A summary of AEs (≥ 10%) is presented in Table 5.

Table 5. Summary of adverse events ≥ 10% by patient as of April 5, 2021.

As of MedDRA version 23.1. Percentages are based on the N in the column title. Only AEs due to treatment are shown. In the case of frequency counts by representative term, if the same AE occurs multiple times in an entity, it is counted only once. CCOD on April 5, 2021.

Adverse events related to treatment

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 to be related to study treatment (e.g., related to mosunetuzumab or lenalidomide) are depicted in Figure 2.

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 following PT related to mosunetuzumab treatment was CRS (31.3%, 5/16 patients). AEs (≥ 10%) considered related to mosunetuzumab are shown in Figure 3.

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 following PT considered related to lenalidomide treatment was neutropenia (25.0%; 4/16 patients). AEs (≥ 10%) considered to be related to lenalidomide are shown in Figure 4.

Abnormal cases by intensity

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 following PT was neutropenia (25.0%; 4/16 patients; Table 6).

Table 6. Summary of grade 3-5 adverse events (AEs) as of April 5, 2021.

As of MedDRA version 23.1. Percentages are based on the N in the column title. Only AEs due to treatment are shown. In the frequency count in the 'Total number of cases' row, if the same AE occurs multiple times in an individual, it is counted separately.

Dead

CCOD Currently, no deaths have been reported in Study CO41942.

serious adverse events

Overall, the proportion of patients reporting 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 criteria, maculopapular rash) that the investigators considered to be related to mosunetuzumab. These adverse events were grade 3 in severity and resolved 9 days after discontinuation of mosunetuzumab dose. In two other cases (PT, pleural effusion, and atrial flutter) treatment (lenalidomide and mosunetuzumab, respectively) was discontinued; Both cases were grade 2 severe and resolved on day 8 of illness. All other SAEs reported were grade 1 or 2 in severity and resolved by day 9 of onset without discontinuation/change of dose of study treatment. No grade 4 or 5 SAEs were reported.

Table 7. Summary of serious adverse events (SAEs) as of April 5, 2021.

Percentages are based on the N in the column title. In the case of frequency counts by representative term, if the same SAE occurs multiple times in an entity, it is counted only once. In the frequency count in the 'Total number of cases' row, if the same SAE occurs multiple times in an entity, it is counted separately. Adverse events with missing Common Terminology Criteria for Adverse Events (CTCAE) ratings are excluded.

Adverse events that resulted in study treatment dose change or discontinuation

Overall, the proportion of patients reporting at least one event that resulted in a dose change/discontinuation of study treatment was 37.5% (6/16 patients, Table 4). Among these, two patients stopped taking mosunetuzumab, and six patients stopped taking lenalidomide treatment.

Two patients (12.5%) experienced investigator-reported events (PT, maculopapular rash [grade 3], neutropenia [grade 4], and atrial flutter [grade 2]) that led to discontinuation of mosunetuzumab. . All cases resolved within 9 days of onset after treatment of AE.

Six patients (37.5%) had cases (PT criteria, pleural effusion [grade 2]; neutropenia [grade 3 and 4, 3 cases each], erythema [grade 3], pruritus [grade 2], and maculopapular rash). [Grade 3]), which led to discontinuation of lenalidomide. Two patients (12.5%) experienced an event (PT criteria, neutropenia [grades 3 and 4]), which resulted in a dose reduction of lenalidomide. As of CCOD, all cases had resolved, but two cases of neutropenia (both grade 3 severity) were still ongoing.

Adverse Events of Special Concern (AESI)

AESI includes cases where toxicities are considered to overlap between study treatments, which 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 case of grade 1 thrombocytopenia that did not resolve at the time of CCOD; No action was taken.

Table 8. Summary of Adverse Events of Special Concern (AESI) as of April 5, 2021.

Percentages are based on the N in the column title.

Overall, the most commonly reported AESI was CRS (31.3%; 5/16 patients; 7 cases). Among patients who experienced an adverse event, 4 patients (25.0%) reported an event of grade 1 severity and 1 patient (6.3%) reported an event of grade 2 severity; All cases were considered related to mosunetuzumab treatment. Most cases were reported in patients on study day 1, and all resolved within 3 days of onset. Two patients (12.5%) reported follow-up events; One patient reported on study day 15 and the other on study day 29, with resolution within 2 and 7 days, respectively. Of the five patients reporting CRS, four (25.0%) received interventional treatment for these cases.

As assessed by the investigators, 5 patients (31.3%) had CRS cases considered related to mosunetuzumab treatment, including 4 patients (25.0%) with ASTCT grade 1 (25.0%) and 1 patient (6.3%) with grade 2. experienced (Table 9). In all five patients, their first CRS episode began between cycle 1 day 1 and cycle 1 day 7 (Figure 5). During treatment with mosunetuzumab monotherapy, one patient (6.3%, 1/14 patients) experienced a subsequent grade 1 event between Cycle 1 Day 15 and Cycle 1 Day 21, and another patient (6.3%, 1/14 patients) experienced a subsequent grade 1 event in C2 during combination treatment with mosunetuzumab and lenalidomide.

Table 9. Cases of CRS by dosing cycle for patients subject to current safety evaluation of CCOD as of April 5, 2021.

Overall, fever was the most frequent symptom of CRS, with 7 cases reported in 5 patients reporting CRS. Other signs and symptoms reported concurrently with CRS 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 the treatment of grade 2 CRS. No cases of grade ≥3 CRS were observed and no patients required tocilizumab, ICU care, high-flow oxygen, or vasopressor support.

Four patients (25.0%) reported nine cases of neutropenia (Table 4). As assessed by the investigators, two of these patients had five events considered related to mosunetuzumab and lenalidomide treatment, and two patients had four events considered related to lenalidomide treatment only. experienced. Two patients reported grade 4 severity cases, both of which resolved, one patient without any treatment and the other after G-CSF treatment. Two patients reported five grade 3 severity cases, two of which (one for each patient) had unresolved CCOD after discontinuation of G-CSF treatment and lenalidomide for those cases. Cases of neutropenia occurred between days 42 and 155 and lasted for 8 to 16 days.

preliminary efficacy

Populations assessed for efficacy include patients assessed for response at any time during the study, patients who withdrew treatment or study before reaching the primary response assessment, or reaching the scheduled primary response assessment planned as per protocol for Cycle 3, D15-21. All patients were included, including those who had been in the study long enough to complete the study. Response was assessed by investigators according to Lugano 2014 criteria (Cheson BD, et al., J Clin Oncol 2014; 32:1-9).

No formal efficacy data analysis was performed. Review of electronic databases revealed that eight patients enrolled in CCOD Current 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%). There were no patients whose disease progressed or who discontinued the study.

Pharmacokinetics

Preliminary mosunetuzumab pharmacokinetic data (N = 13) in patients receiving 1/2/30 mg Q4W doses of mosunetuzumab in Study CO41942 are summarized in Figure 6. The pharmacokinetics observed for 1/2/30 mg (IV) of mosunetuzumab in combination with lenalidomide in patients with R/R FL are similar to those of the same dose of mosunetuzumab monotherapy in patients with R/R NHL. It was similar to prediction. Preliminary results indicate that mosunetuzumab PK is similar when administered in combination with lenalidomide compared to monotherapy, and observed concentration measurements generally fall within the 5th to 95th prediction interval of the popPK model simulation.

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

conclusion

The safety profile of mosunetuzumab in combination with lenalidomide at the dose and schedule tested (1/2/30 mg, Q4W) was acceptable and there were no unexpected safety signals.

The overall frequency and severity of CRS events observed with mosunetuzumab and lenalidomide in this study (7 grade 1 to 2 events in 5 patients) were similar to the CRS events observed with mosunetuzumab monotherapy. did. 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 grade 1 CRS event in cycle 2. Four patients (25.0%) reported grade 3-4 neutropenia. CCOD Currently, of the 9 cases reported, 7 cases are resolved and 2 cases (severity level 3) are not resolved. One patient (6.3%) reported unresolved grade 1 thrombocytopenia at the time of CCOD. No patients discontinued study treatment due to AEs.

Mosunetuzumab PK exposure observed in Study CO41942 was consistent with that expected based on the PK observed with mosunetuzumab monotherapy, suggesting that combination therapy with mosunetuzumab and lenalidomide did not affect mosunetuzumab exposure. This suggests that it does not appear to be the case. The proposed dosing regimen was supported by a combination of data and exposure-response characterization based on mosunetuzumab monotherapy and the combination of mosunetuzumab and lenalidomide, which ensured an appropriate balance of clinical benefit/risk in the patient population. suggests.

In summary, the available data from study GO41942 demonstrated an acceptable safety profile and preliminary efficacy in patients with R/R FL, thus demonstrating a 1/2/30 mg escalation dose regimen of mosunetuzumab in combination with lenalidomide. Supports the continued use of

Example 2 Mosunetuzumab in combination with lenalidomide provides a manageable safety profile and encouraging activity in patients with relapsed/refractory follicular lymphoma: initial results from a phase Ib study

Presented here are initial data from an ongoing phase Ib study (NCT04246086) evaluating the safety and activity of mosunetuzumab plus lenalidomide in patients with R/R FL who have previously received at least one line of treatment. am.

method

Patients with R/R FL (grade 1-3a) and at least one prior systemic anticancer treatment were enrolled to receive 12 cycles of mosunetuzumab plus lenalidomide (cycle duration: 1 cycle, 21 days, cycles 2-12, 28 days). In cycle 1, escalating doses of mosunetuzumab (IV infusion) were administered on day 1 of cycle 1 (C1D1 dose, 1 mg) and day 2 of cycle 1 (C1D2 dose, 2 mg), with the target dose being 3 days of cycle 1. Administered on day 1 (C1D3 dose; 30 mg) and on day 1 of cycles 2 to 12 (C2D1-C12D1 doses). Lenalidomide (20 mg orally) was administered on days 1 to 21 of cycles 2 to 12. The protocol did not mandate hospitalization. The primary objective was to evaluate the safety of mosunetuzumab and lenalidomide combination therapy; Secondary objectives include response assessment and long-term efficacy outcomes. Cytokine release syndrome (CRS) was reported using ASTCT criteria (Lee et al., Biol Blood Marrow Transplant 2019). Responses are assessed by investigators with PET-CT using the Lugano 2014 criteria (Cheson BD, et al., J Clin Oncol 2014; 32:1-9).

result

At data cutoff date (May 31, 2021), 27 patients were enrolled. The average age was 59 years (range: 31-79 years); Twelve patients (44%) were male. The Eastern Cooperative Oncology Group (ECOG) performance status score for all patients was 0 (18 patients, 67%) or 1 (9 patients, 33%). The median number of prior treatment lines was 1 (range: 1-4), and 3 patients (11%) had disease progression (PD) <24 months after starting first-line treatment. At data cutoff, 16 patients (59%) had been present for 0–3 months, 8 (30%) had been admitted for 3–6 months, 2 (7%) had been admitted for 6–9 months, and 1 (4%) had been admitted for 6–9 months. > The study was conducted for 9 months.

All 27 patients were eligible for safety evaluation at the data cutoff date. Twenty patients (74%) experienced ≥ 1 adverse event (AE) of any grade (Gr); The most common AE was 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%). There were no AEs leading to withdrawal of mosunetuzumab or lenalidomide; Two patients experienced mosunetuzumab-related AEs resulting in a delay in mosunetuzumab administration, and 6 patients (22%) experienced lenalidomide-related AEs resulting in lenalidomide dosing discontinuation and/or reduction. did.

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

Populations assessed for efficacy include patients who were assessed for response at any time during the study, patients who withdrew treatment or study before reaching the primary response assessment, or patients who were enrolled in the planned primary response assessment as per protocol for Cycle 3, Days 15-21. All patients were included, including those who had been in the study long enough to reach. At data cutoff, the objective response rate in the 13 evaluable patients was 92%, with complete metabolic response observed in 10 patients (77%) and partial metabolic response (PMR) in 2 patients (15%). was observed, and in 1 patient (8%), the disease was stable. One patient who initially achieved PMR experienced PD after 8 cycles of treatment.

conclusion

Combination treatment with mosunetuzumab and lenalidomide was shown to have an acceptable safety profile in patients with R/R FL who had previously received at least one line of therapy, and preliminary antilymphoma activity was observed.

Example 3. Preliminary safety and efficacy of mosunetuzumab in combination with lenalidomide in patients with relapsed/refractory follicular lymphoma: initial results from a phase Ib study.

Presented here is 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 previously received at least one line of treatment (conducted above). This is additional data (described in Example 2).

method

Patients with R/R FL (grade 1-3a) and who had received at least one prior systemic anticancer treatment were enrolled to receive 12 dosing cycles of mosunetuzumab plus lenalidomide (cycle duration: 1 cycle; 21 days, cycle 2-12, 28 days). In cycle 1, escalating doses of mosunetuzumab (IV infusion) were administered on day 1 of cycle 1 (C1D1 dose, 1 mg) and day 2 of cycle 1 (C1D2 dose, 2 mg), with the target dose being 3 days of cycle 1. Administered on day 1 (C1D3 dose; 30 mg) and on day 1 of cycles 2 to 12 (C2D1-C12D1 doses). Lenalidomide (20 mg orally) was administered on days 1 to 21 of cycles 2 to 12. Premedication with corticosteroids was administered to patients during cycles 1 and 2 and was optional from cycle 3 onwards. For corticosteroid preadministration, patients were administered 10 mg of dexamethasone intravenously before mosunetuzumab. Depending on evaluation of additional safety data, preadministration of corticosteroids may be considered optional in an additional second cycle. The protocol did not mandate hospitalization. The primary objective was to evaluate the safety of mosunetuzumab and lenalidomide combination therapy; Secondary objectives include response assessment and long-term efficacy outcomes. Cytokine release syndrome (CRS) was reported using ASTCT criteria (Lee et al., Biol Blood Marrow Transplant 2019). Responses are assessed by investigators with PET-CT using the Lugano 2014 criteria (Cheson BD, et al., J Clin Oncol 2014; 32:1-9).

result

At data cutoff date (September 13, 2021), 29 patients were enrolled. The average age was 59 years (range: 30-79 years); Thirteen patients (44.8%) were male. The Eastern Cooperative Oncology Group (ECOG) performance status score for all patients was 0-2. Two (6.8%) patients had Ann Arbor stage I-II at study entry and 27 (93.1%) patients had Ann Arbor stage III-IV at study entry (Carbone et al., Cancer Res. 1971, 31(11): 1860-1861). Seven (24.1%) patients had 0 to 1 FLIPI risk factors at study entry, 8 (27.6%) patients had 2 FLIPI risk factors at study entry, and 14 (48.3%) patients had 0 to 1 FLIPI risk factors at study entry. There were 3 to 5 FLIPI risk factors at study entry. 18 (62.1%) patients had FL grade 1-2, 5 (17.2%) patients had FL grade 3a, and 6 (20.7%) patients had FL of unknown grade. . The median number of prior treatment lines was 1 (range: 1-6), and 3 patients (10.3%) had disease progression (PD) <24 months after starting first-line treatment (POD24). Nine (31%) patients were refractory to at least one prior therapy containing anti-CD20 monoclonal antibodies. Seven (24.1%) patients were doubly refractory to both treatment containing anti-CD20 monoclonal antibodies and treatment containing alkylating agents. At data cutoff, 1 patient (3.4%) had been diagnosed for 0–3 months, 14 (48.3%) had been diagnosed for 3–6 months, 7 (24.1%) had been diagnosed for 6–9 months, and 7 patients (24.1%) had been diagnosed for 6–9 months. > The study was conducted for 9 months. The median duration of mosunetuzumab treatment was 4.9 months (range 2-11 months) and the median duration of lenalidomide treatment was 4.3 months (range 2-10 months). The median follow-up period was 5.4 months (range 3-12 months).

All 29 patients were eligible for safety evaluation at the data cutoff date (September 13, 2021). Adverse events are summarized in Table 10 below.

Table 10. Adverse events in patients subject to safety evaluation (data cutoff date: September 13, 2021)

AE = adverse event

Twenty-nine patients (100%) experienced at least 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 resulted in withdrawal of mosunetuzumab and one AE (3.4%) resulted in withdrawal of lenalidomide; Six patients (20.7%) experienced mosunetuzumab-related AEs resulting in mosunetuzumab dose change and/or discontinuation; Twelve patients (41.4%) experienced lenalidomide-related AEs resulting in lenalidomide dose change and/or discontinuation.

Cases of cytokine release syndrome (CRS) observed in patients evaluated for safety are summarized in Table 11 below.

Table 11. Cases of CRS in patients evaluated for safety (data cutoff date: September 13, 2021)

Patient ^a experienced 2L fever and hypoxia and required nasal cannula oxygen.

In all patients who experienced at least 1 CRS event (8/29 total patients), the CRS event was grade 1 (7/8 patients) or grade 2 (1/8 patients). For most patients (6/8), the CRS event occurred in cycle 1; Two patients experienced grade 1 CRS events in cycle 2. The median time to onset of CRS was 1 day (range: 1-28 days) after primary study drug administration, and the median duration of CRS was 3 days (range: 2-5 days). All CRS cases were 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 cases of immune effector cell associated neurotoxic syndrome (ICANS) occurred. A summary of CRS cases according to administration cycle and dose is presented in Figure 8.

Cases of neutropenia and febrile neutropenia observed in patients subject to safety evaluation are summarized in Table 12 below.

Table 12. Neutropenia and febrile neutropenia cases in patients evaluated for safety (data cutoff date: September 13, 2021)

Seven patients (24.1%) reported cases of grade 3–4 neutropenia or febrile neutropenia; All neutropenia cases occurred between days 41 and 189 (median day 86), with a median duration of 9 days (range 4-29 days). All neutropenia cases resolved by data cut-off date. Febrile neutropenia (grade 3) occurred in one patient (duration: 5 days) and was considered treatment-related. A summary of neutropenia cases according to administration cycle and grade and use of granulocyte colony-stimulating factor (G-CSF) by administration cycle is shown in Figure 9.

The anti-tumor activity of the patients evaluated is shown in Figure 10. In particular, the objective response rate of 29 patients at the data cutoff was 89.7%, and complete metabolic response was observed in 65.5% of patients (see Figure 11). Specifically, 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 had responses as measured by PET-CT. Duration of response for all 29 patients as of September 13, 2021, the data cutoff date, is summarized in Figure 12.

conclusion

Combination treatment with mosunetuzumab and lenalidomide appeared to have an acceptable safety profile in patients with R/R FL who had previously received at least one line of therapy, and antilymphoma and antitumor activities were observed. Compared to mosunetuzumab monotherapy, no increase in the incidence of CRS and neutropenia was observed.

Embodiment

Some embodiments of the techniques described herein may be defined according to any one 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:

(a) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(b) have previously been treated with at least one chemo-immunotherapy regimen.

2. Mosunetuzumab for use in combination with lenalidomide in treating a subject, wherein the subject:

(a) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(b) mosunetuzumab, having previously been treated with at least one chemo-immunotherapy regimen.

3. Use of mosunetuzumab in combination with lenalidomide in treating a subject, wherein the subject:

(a) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(b) have previously been treated with at least one chemo-immunotherapy regimen.

4. Use of mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide to treat a subject, wherein the subject:

(a) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(b) have previously been treated with at least one chemo-immunotherapy regimen.

5. Use of lenalidomide in the manufacture of a medicament for use in combination with mosunetuzumab to treat a subject, wherein the subject:

(a) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(b) have previously been treated with at least one chemo-immunotherapy regimen.

6. Use of mosunetuzumab and lenalidomide in the manufacture of a medicament for treating a subject, wherein the subject:

(a) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(b) have previously been treated with at least one chemo-immunotherapy regimen.

7. The method, mosunetuzumab, or use of any one of embodiments 1 to 6, wherein the at least one chemo-immunotherapy regimen comprises an anti-CD20 monoclonal antibody.

8. The method of any one of embodiments 1 to 7, wherein the subject has previously received only one line of systemic treatment, and:

(a) Follicular Lymphoma International Prognostic Index (FLIPI; Solal-Celigny et al., Blood . 2004; 104 (5): 1258-1265.) score of 2-5;

(b) was refractory to previous anti-CD20 monoclonal antibody treatment, or

(c) with disease progression within 24 months of starting prior treatment, methods, mosunetuzumab, or uses.

9. The method of any of embodiments 7 or 8, wherein the subject has not been treated with an anti-CD20 monoclonal antibody for at least 4 weeks prior to receiving an effective amount of mosunetuzumab and lenalidomide.

10. The method of embodiment 7 or 8, wherein mosunetuzumab and lenalidomide are not administered to the subject for at least 4 weeks after the subject has been treated with the anti-CD20 monoclonal antibody. Usage.

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

12. The method of embodiment 11, wherein the synergistic effect is a partial response as defined in the Lugano 2014 criteria (Cheson BD, et al., J Clin Oncol 2014; 32:1-9), or Usage.

13. The method of embodiment 11, wherein the synergistic effect is a complete response as defined in Lugano 2014 criteria (Cheson BD, et al., J Clin Oncol 2014; 32:1-9), or mosunetuzumab, or Usage.

14. The method of any one of embodiments 1 and 7 to 9, and 11 to 13, wherein administering the effective amount of mosunetuzumab comprises at least a first dosing cycle and a second dosing cycle. Including administering:

(a) The first administration cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab, where C1D1 and C1D2 are each less than or equal to C1D3, and C1D1 is 0.02 mg to 4.0 mg, C1D2 is 0.05 mg to 20.0 mg, and C1D3 is 0.2 mg to 50.0 mg; and

(b) the second administration cycle comprises a single dose (C2D1) of mosunetuzumab, wherein C2D1 is greater than or equal to C1D3 and is between 0.2 mg and 50 mg.

15. The method of any one of embodiments 2 to 8 and 10 to 14, wherein mosunetuzumab is administered to the subject according to a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, wherein:

(a) The first administration cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab, where C1D1 and C1D2 are each less than or equal to C1D3, and C1D1 is 0.02 mg to 4.0 mg, C1D2 is 0.05 mg to 20.0 mg, and C1D3 is 0.2 mg to 50.0 mg; and

(b) the second administration cycle comprises a single dose (C2D1) of mosunetuzumab, wherein C2D1 is greater than or equal to C1D3 and is 0.2 mg to 50 mg.

16. In embodiment 14 or 15:

(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) C2D1 is 3.0 mg to 50.0 mg, method, mosunetuzumab, or use for use.

17. The method of any one of embodiments 14 to 16:

(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) C2D1 is 3.0 mg to 45.0 mg, method, mosunetuzumab, or use.

18. The method, mosunetuzumab, or use of any of embodiments 14 to 17, wherein C1D1 and C1D2 are each less than C1D3.

19. The method, mosunetuzumab, or use of any of embodiments 14 to 17, wherein C1D2 is about 50% to about 250% more than C1D1.

20. The method of any one of embodiments 14 to 17:

(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.

21. The method, mosunetuzumab, or use according to any one of embodiments 14 to 20, wherein the length of the first administration cycle is 21 days.

22. The method of embodiment 21, wherein the method comprises administering C1D1, C1D2, and C1D3 to the subject on each of Day 1, Day 8, and Day 15 of the first administration cycle, or approximately Day 1, Day 8, and Day 15, respectively. method, including that.

23. The use of embodiment 21, wherein C1D1, C1D2, and C1D3 are administered to the subject on each of Day 1, Day 8, and Day 15 of the first administration cycle, or approximately Day 1, Day 8, and Day 15, respectively. Mosunetuzumab, or uses for.

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

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

26. Mosunetuzumab, or the use of embodiment 24, wherein C2D1 is administered to the subject on day 1 of the second administration cycle.

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

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

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

30. The method, mosunetuzumab, or use according to any one of embodiments 27 to 29, wherein each of the one or more additional administration cycles is 28 days in length.

31. The method, mosunetuzumab, or use of any one of embodiments 27 to 30, wherein each of the one or more additional administration cycles comprises an additional dose of mosunetuzumab.

32. The method of embodiment 31, wherein each additional dose of mosunetuzumab is administered on Day 1 of each of one or more additional dosing cycles.

33. Mosunetuzumab, or the use, according to embodiment 31, wherein each additional dose of mosunetuzumab is administered on Day 1 of each of one or more additional dosing cycles.

34. The method of any one of embodiments 1 to 13, wherein administering the effective amount of mosunetuzumab comprises administering mosunetuzumab according to a dosing regimen comprising 12 dosing cycles, wherein:

(a) The first administration cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab, where C1D1 and C1D2 are each less than or equal to C1D3, and C1D1 is 0.02 mg to 4.0 mg, C1D2 is 0.05 mg to 20.0 mg, and C1D3 is 0.2 mg to 50.0 mg; and

(b) the second to twelfth administration cycle each comprises a single dose of mosunetuzumab (C2D1-C12D1), wherein each single dose C2D1-C12D1 is the same amount, is at least C1D3, and is 0.2 mg to 50 mg. .

35. The method of any one of embodiments 1 to 13, wherein mosunetuzumab is administered to the subject according to a dosing regimen comprising 12 dosing cycles, wherein:

(a) The first administration cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab, where C1D1 and C1D2 are each less than or equal to C1D3, and C1D1 is 0.02 mg to 4.0 mg, C1D2 is 0.05 mg to 20.0 mg, and C1D3 is 0.2 mg to 50.0 mg; and

(b) the second to twelfth administration cycles each comprise a single dose of mosunetuzumab (C2D1-C12D1), wherein each single dose C2D1-C12D1 is the same amount, is at least C1D3, and is 0.2 mg to 50 mg. Mosunetuzumab, or uses for.

36. In embodiment 34 or 35:

(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) each single dose of C2D1-C12D1 is 3.0 mg to 50.0 mg.

37. The method of any one of embodiments 34 to 36:

(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) each single dose of C2D1-C12D1 is 3.0 mg to 45.0 mg.

38. The method, mosunetuzumab, or use of any of embodiments 34 to 37, wherein C1D1 and C1D2 are each less than C1D3.

39. The method, mosunetuzumab, or use of any of embodiments 34 to 38, wherein C1D2 is about 50% to about 250% more than C1D1.

40. The method of any one of embodiments 34 to 37:

(a) C1D1 is 0.8 mg, C1D2 is 2.0 mg, 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, 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, C1D3 is 30.0 mg, and each single dose C2D1-C12D1 is 30.0 mg.

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

42. The method of embodiment 41, wherein the method comprises administering C1D1, C1D2, and C1D3 to the subject on each of Day 1, Day 8, and Day 15 of the first administration cycle, or approximately Day 1, Day 8, and Day 15, respectively. method, including that.

43. The use of embodiment 41, wherein C1D1, C1D2, and C1D3 are administered to the subject on each of Day 1, Day 8, and Day 15 of the first administration cycle, or approximately Day 1, Day 8, and Day 15, respectively. Mosunetuzumab, or uses for.

44. The method, mosunetuzumab, or use of any one of embodiments 34 to 43, wherein each of the second to twelfth administration cycles is 28 days in length.

45. The method of embodiment 44, wherein the method comprises administering each of C2D1-C12D1 to the subject on Day 1 of each respective administration cycle.

46. The method of any one of embodiments 34 to 45, wherein each of the second to twelfth administration cycles is 28 days in length.

47. The method of any one of embodiments 34 to 43, wherein each of the second to twelfth administration cycles is 21 days in length.

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

49. Mosunetuzumab, or use, according to any one of the preceding embodiments, wherein mosunetuzumab is administered intravenously.

50. The method of any one of embodiments 14 to 49, wherein lenalidomide is administered during the second and subsequent cycles.

51. The method of any one of embodiments 14 to 49, wherein lenalidomide is administered during the second and subsequent cycles.

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

53. Mosunetuzumab, or the use according to any one of embodiments 14 to 51, wherein lenalidomide is not administered during the first cycle.

54. The method of any one of embodiments 14 to 53, wherein lenalidomide is administered daily.

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

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

57. Mosunetuzumab, or Usage.

58. The method of any one of embodiments 47 to 55, wherein lenalidomide is administered daily for the first 14 days of each dosing cycle comprising administration of lenalidomide.

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

60. The method of any one of embodiments 56 to 59, wherein lenalidomide is not administered during the last 7 days of each dosing cycle comprising administration of lenalidomide.

61. Mosunetuzumab, or the use according to any one of embodiments 56 to 59, wherein lenalidomide is not administered during the last 7 days of each dosing cycle comprising administration of lenalidomide.

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

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

64. The method of any of the preceding embodiments, wherein lenalidomide is administered orally.

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

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

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

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

69. A method of treating a subject, comprising administering to the subject an effective amount of mosunetuzumab and an effective amount of lenalidomide,

Here the object is:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

wherein administering an effective amount 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; , here:

(a) The first dosing cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) administered intravenously on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and

(c) the second dosing cycle further comprises oral administration of 20 mg lenalidomide daily on days 1-21 of the second dosing cycle.

70. Mosunetuzumab for use in combination with lenalidomide to treat a subject, wherein the subject:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

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, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) to be administered intravenously on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and

(c) mosunetuzumab, wherein the second dosing cycle further comprises a daily dose of 20 mg lenalidomide, which should be administered orally on days 1 to 21 of the second dosing cycle.

71. Use of mosunetuzumab in combination with lenalidomide to treat a subject, wherein the subject:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

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, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) to be administered intravenously on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and

(c) the second administration cycle further comprises a daily dose of 20 mg lenalidomide, which should be administered orally on days 1 to 21 of the second administration cycle.

72. Use of mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide to treat a subject, wherein the subject:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

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, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) to be administered intravenously on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and

(c) the second administration cycle further comprises a daily dose of 20 mg lenalidomide, which should be administered orally on days 1 to 21 of the second administration cycle.

73. Use of lenalidomide in the manufacture of a medicament for use in combination with mosunetuzumab to treat a subject, wherein the subject:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

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, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) to be administered intravenously on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and

(c) the second administration cycle further comprises a daily dose of 20 mg lenalidomide, which should be administered orally on days 1 to 21 of the second administration cycle.

74. Use of mosunetuzumab and lenalidomide in the manufacture of a medicament for treating a subject, wherein the subject:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

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, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) to be administered intravenously on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and

(c) the second administration cycle further comprises a daily dose of 20 mg lenalidomide, which should be administered orally on days 1 to 21 of the second administration cycle.

75. A method of treating a subject, comprising administering to the subject an effective amount of mosunetuzumab and an effective amount of lenalidomide,

Here the object is:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

wherein administering an effective amount of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and 11 subsequent 28-day dosing cycles; , here:

(a) The first dosing cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second to twelfth dosing cycles each comprise a single dose of mosunetuzumab (C2D1-C12D1) administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1-C12D1 is 30 mg, and

(c) each of the second to twelfth dosing cycles further comprises daily oral administration of 20 mg lenalidomide on days 1-21 of each dosing cycle.

76. Mosunetuzumab for use in combination with lenalidomide in treating a subject, wherein the subject:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

wherein mosunetuzumab and lenalidomide shall be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and 11 subsequent 28-day dosing cycles, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second to twelfth dosing cycles each comprise a single dose of mosunetuzumab (C2D1-C12D1) to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1-C12D1 is 30 mg; and

(c) mosunetuzumab, wherein each of the second to twelfth dosing cycles further comprises a daily dose of 20 mg lenalidomide, which should be administered orally on days 1-21 of each dosing cycle.

77. Use of mosunetuzumab in combination with lenalidomide in treating a subject, wherein the subject:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

wherein mosunetuzumab and lenalidomide shall be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and 11 subsequent 28-day dosing cycles, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second to twelfth dosing cycles each comprise a single dose of mosunetuzumab (C2D1-C12D1) to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1-C12D1 is 30 mg; and

(c) the second to twelfth dosing cycles each further comprise a daily dose of 20 mg lenalidomide, which is to be administered orally on days 1-21 of each dosing cycle.

78. Use of mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide to treat a subject, wherein the subject:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

wherein mosunetuzumab and lenalidomide shall be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and 11 subsequent 28-day dosing cycles, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second to twelfth dosing cycles each comprise a single dose of mosunetuzumab (C2D1-C12D1) to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1-C12D1 is 30 mg; and

(c) the second to twelfth dosing cycles each further comprise a daily dose of 20 mg lenalidomide, which is to be administered orally on days 1-21 of each dosing cycle.

79. Use of lenalidomide in the manufacture of a medicament for use in combination with mosunetuzumab to treat a subject, wherein the subject:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

wherein mosunetuzumab and lenalidomide shall be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and 11 subsequent 28-day dosing cycles, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second to twelfth dosing cycles each comprise a single dose of mosunetuzumab (C2D1-C12D1) to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1-C12D1 is 30 mg; and

(c) the second to twelfth dosing cycles each further comprise a daily dose of 20 mg lenalidomide, which is to be administered orally on days 1-21 of each dosing cycle.

80. Use of mosunetuzumab and lenalidomide in the manufacture of a medicament for treating a subject, wherein the subject:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

wherein mosunetuzumab and lenalidomide shall be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and 11 subsequent 28-day dosing cycles, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second to twelfth dosing cycles each comprise a single dose of mosunetuzumab (C2D1-C12D1) to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1-C12D1 is 30 mg; and

(c) each of the second to twelfth dosing cycles further comprises a daily dose of 20 mg lenalidomide, which is to be administered orally on days 1-21 of each dosing cycle.

81. A method of treating a subject, comprising administering to the subject an effective amount of mosunetuzumab and an effective amount of lenalidomide,

Here the object is:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

wherein administering an effective amount 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; , here:

(a) The first dosing cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) administered intravenously on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and

(c) the second dosing cycle further comprises oral administration of 20 mg lenalidomide daily on days 1-14 of the second dosing cycle.

82. Mosunetuzumab for use in combination with lenalidomide in treating a subject, wherein the subject:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

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 21-day dosing cycle, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) to be administered intravenously on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and

(c) mosunetuzumab, wherein the second dosing cycle further comprises a daily dose of 20 mg lenalidomide, which should be administered orally on days 1 to 14 of the second dosing cycle.

83. Use of mosunetuzumab in combination with lenalidomide in treating a subject, wherein the subject:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

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 21-day dosing cycle, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) to be administered intravenously on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and

(c) the second administration cycle further comprises a daily dose of 20 mg lenalidomide, which should be administered orally on days 1 to 14 of the second administration cycle.

84. Use of mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide to treat a subject, wherein the subject:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

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 21-day dosing cycle, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) to be administered intravenously on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and

(c) the second administration cycle further comprises a daily dose of 20 mg lenalidomide, which should be administered orally on days 1 to 14 of the second administration cycle.

85. Use of lenalidomide in the manufacture of a medicament for use in combination with mosunetuzumab to treat a subject, wherein the subject:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

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 21-day dosing cycle, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) to be administered intravenously on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and

(c) the second administration cycle further comprises a daily dose of 20 mg lenalidomide, which should be administered orally on days 1 to 14 of the second administration cycle.

86. Use of mosunetuzumab and lenalidomide in the manufacture of a medicament for treating a subject, wherein the subject:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

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 21-day dosing cycle, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) to be administered intravenously on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and

(c) the second administration cycle further comprises a daily dose of 20 mg lenalidomide, which should be administered orally on days 1 to 14 of the second administration cycle.

87. A method of treating a subject, comprising administering to the subject an effective amount of mosunetuzumab and an effective amount of lenalidomide,

Here the object is:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen including obinutuzumab; and

wherein administering an effective amount of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and 11 subsequent 21-day dosing cycles; , here:

(a) The first dosing cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second to twelfth dosing cycles each comprise a single dose of mosunetuzumab (C2D1-C12D1) administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1-C12D1 is 30 mg, and

(c) each of the second to twelfth dosing cycles further comprises daily oral administration of 20 mg lenalidomide on days 1-14 of each dosing cycle.

88. Mosunetuzumab for use in combination with lenalidomide in treating a subject, wherein the subject:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

wherein mosunetuzumab and lenalidomide shall be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and 11 subsequent 21-day dosing cycles, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second to twelfth dosing cycles each comprise a single dose of mosunetuzumab (C2D1-C12D1) to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1-C12D1 is 30 mg; and

(c) mosunetuzumab, wherein the second to twelfth dosing cycles each further comprise a daily dose of 20 mg lenalidomide, which should be administered on days 1-14 of each dosing cycle.

89. Use of mosunetuzumab in combination with lenalidomide in treating a subject, wherein the subject:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

wherein mosunetuzumab and lenalidomide shall be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and 11 subsequent 21-day dosing cycles, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second to twelfth dosing cycles each comprise a single dose of mosunetuzumab (C2D1-C12D1) to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1-C12D1 is 30 mg; and

(c) the second to twelfth dosing cycles each further comprise a daily dose of 20 mg lenalidomide, which should be administered on days 1-14 of each dosing cycle.

90. Use of mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide to treat a subject, wherein the subject:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

wherein mosunetuzumab and lenalidomide shall be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and 11 subsequent 21-day dosing cycles, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second to twelfth dosing cycles each comprise a single dose of mosunetuzumab (C2D1-C12D1) to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1-C12D1 is 30 mg; and

(c) the second to twelfth dosing cycles each further comprise a daily dose of 20 mg lenalidomide, which should be administered on days 1-14 of each dosing cycle.

91. Use of lenalidomide in the manufacture of a medicament for use in combination with mosunetuzumab to treat a subject, wherein the subject:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

wherein mosunetuzumab and lenalidomide shall be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and 11 subsequent 21-day dosing cycles, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second to twelfth dosing cycles each comprise a single dose of mosunetuzumab (C2D1-C12D1) to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1-C12D1 is 30 mg; and

(c) the second to twelfth dosing cycles each further comprise a daily dose of 20 mg lenalidomide, which should be administered on days 1-14 of each dosing cycle.

92. Use of mosunetuzumab and lenalidomide in the manufacture of a medicament for treating a subject, wherein the subject:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

wherein mosunetuzumab and lenalidomide shall be administered to the subject according to a dosing regimen comprising a first 21-day dosing cycle and 11 subsequent 21-day dosing cycles, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second to twelfth dosing cycles each comprise a single dose of mosunetuzumab (C2D1-C12D1) to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1-C12D1 is 30 mg; and

(c) the second to twelfth dosing cycles each further comprise a daily dose of 20 mg lenalidomide, which should be administered on days 1-14 of each dosing cycle.

93. The method, mosunetuzumab, or use of any of embodiments 69 to 92, wherein the at least one chemo-immunotherapy regimen comprises an anti-CD20 monoclonal antibody.

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

95. The method of any one of embodiments 69-94, wherein the subject has previously received only one line of systemic treatment, and:

(a) Follicular Lymphoma International Prognostic Index (FLIPI; Solal-Celigny et al., Blood . 2004; 104 (5): 1258-1265.) score of 2-5;

(b) was refractory to previous obinutuzumab treatment;

(c) was refractory to previous rituximab treatment, or

(d) there is disease progression within 24 months of starting prior treatment, methods, mosunetuzumab, or uses for which.

96. The method of any one of embodiments 93 to 95, wherein the subject has not been treated with obinutuzumab or rituximab for at least 4 weeks prior to receiving an effective amount of mosunetuzumab and lenalidomide.

97. The parameter for 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 been treated with the anti-CD20 monoclonal antibody. Netuzumab or uses.

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

99. The method of embodiment 98, wherein the synergistic effect is a partial response as defined in Lugano 2014 criteria (Cheson BD, et al., J Clin Oncol 2014; 32:1-9), or Usage.

100. The method of embodiment 98, wherein the synergistic effect is a complete response as defined in Lugano 2014 criteria (Cheson BD, et al., J Clin Oncol 2014; 32:1-9), or mosunetuzumab, or Usage.

101. The method of any of the preceding embodiments, wherein the FL is grade 1, grade 2, or 3a according to the World Health Organization's classification of lymphoma neoplasms (see Swerdlow SH, et al., Blood 2016; 127:2375-90), but is grade 3b The grade is not histologically documented, the method, mosunetuzumab for use, or uses.

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,

Where each object:

(a) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(b) had previously been treated with at least one chemo-immunotherapy regimen; and

wherein administering an effective amount 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; , here:

(a) The first dosing cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) administered intravenously on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and

(c) the second dosing cycle further comprises oral administration of 20 mg lenalidomide daily on days 1-21 of the second dosing cycle.

103. Mosunetuzumab for use in combination with lenalidomide to treat a population of subjects, wherein each subject in the population:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

wherein mosunetuzumab and lenalidomide are 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, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) to be administered intravenously on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and

(c) mosunetuzumab, wherein the second dosing cycle further comprises a daily dose of 20 mg lenalidomide, which should be administered orally on days 1 to 21 of the second dosing cycle.

104. Use of mosunetuzumab in combination with lenalidomide to treat a population of subjects, wherein each subject in the population:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

wherein mosunetuzumab and lenalidomide are 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, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) to be administered intravenously on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and

(c) the second administration cycle further comprises a daily dose of 20 mg lenalidomide, which should be administered orally on days 1 to 21 of the second administration cycle.

105. Use of mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide to treat a population of subjects, wherein each subject in the population:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

wherein mosunetuzumab and lenalidomide are 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, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) to be administered intravenously on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and

(c) the second administration cycle further comprises a daily dose of 20 mg lenalidomide, which should be administered orally on days 1 to 21 of the second administration cycle.

106. Use of lenalidomide in the manufacture of a medicament for use in combination with mosunetuzumab to treat a population of subjects, wherein each subject in the population:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

wherein mosunetuzumab and lenalidomide are 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, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) to be administered intravenously on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and

(c) the second administration cycle further comprises a daily dose of 20 mg lenalidomide, which should be administered orally on days 1 to 21 of the second administration cycle.

107. Use of mosunetuzumab and lenalidomide in the manufacture of a medicament for the treatment of a population of subjects, wherein each subject in the population:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

wherein mosunetuzumab and lenalidomide are 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, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) to be administered intravenously on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and

(c) the second administration cycle further comprises a daily dose of 20 mg lenalidomide, which should be administered orally on days 1 to 21 of the second administration cycle.

108. 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,

Where each object:

(a) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(b) had previously been treated with at least one chemo-immunotherapy regimen containing an anti-CD20 monoclonal antibody; and

wherein administering an effective amount of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and 11 subsequent 28-day dosing cycles; , here:

(a) The first dosing cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) each of the second to twelfth dosing cycles comprises a single dose of mosunetuzumab (C2D1-C12D1) administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1-C12D1 is 30 mg, and

(c) each of the second to twelfth dosing cycles further comprises orally administering 20 mg lenalidomide daily on days 1-21 of each dosing cycle.

109. Mosunetuzumab for use in combination with lenalidomide in treating a population of subjects, wherein each subject in the population:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

wherein mosunetuzumab and lenalidomide shall be administered to the population of subjects according to a dosing regimen comprising a first 21-day dosing cycle and 11 subsequent 28-day dosing cycles, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second to twelfth dosing cycles each comprise a single dose of mosunetuzumab (C2D1-C12D1) to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1-C12D1 is 30 mg; and

(c) mosunetuzumab, wherein each of the second to twelfth dosing cycles further comprises a daily dose of 20 mg lenalidomide, which should be administered orally on days 1-21 of each dosing cycle.

110. Use of mosunetuzumab in combination with lenalidomide in treating a population of subjects, wherein each subject in the population:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

wherein mosunetuzumab and lenalidomide shall be administered to the population of subjects according to a dosing regimen comprising a first 21-day dosing cycle and 11 subsequent 28-day dosing cycles, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second to twelfth dosing cycles each comprise a single dose of mosunetuzumab (C2D1-C12D1) to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1-C12D1 is 30 mg; and

(c) mosunetuzumab, wherein each of the second to twelfth dosing cycles further comprises a daily dose of 20 mg lenalidomide, which should be administered orally on days 1-21 of each dosing cycle.

111. Use of mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide to treat a population of subjects, wherein each subject in the population:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

wherein mosunetuzumab and lenalidomide shall be administered to the population of subjects according to a dosing regimen comprising a first 21-day dosing cycle and 11 subsequent 28-day dosing cycles, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second to twelfth dosing cycles each comprise a single dose of mosunetuzumab (C2D1-C12D1) to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1-C12D1 is 30 mg; and

(c) the second to twelfth dosing cycles each further comprise a daily dose of 20 mg lenalidomide, which is to be administered orally on days 1-21 of each dosing cycle.

112. Use of lenalidomide in the manufacture of a medicament for use in combination with mosunetuzumab to treat a population of subjects, wherein each subject in the population:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

wherein mosunetuzumab and lenalidomide shall be administered to the population of subjects according to a dosing regimen comprising a first 21-day dosing cycle and 11 subsequent 28-day dosing cycles, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second to twelfth dosing cycles each comprise a single dose of mosunetuzumab (C2D1-C12D1) to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1-C12D1 is 30 mg; and

(c) the second to twelfth dosing cycles each further comprise a daily dose of 20 mg lenalidomide, which is to be administered orally on days 1-21 of each dosing cycle.

113. Use of mosunetuzumab and lenalidomide in the manufacture of a medicament for the treatment of a population of subjects, wherein each subject in the population:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

wherein mosunetuzumab and lenalidomide shall be administered to the population of subjects according to a dosing regimen comprising a first 21-day dosing cycle and 11 subsequent 28-day dosing cycles, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second to twelfth dosing cycles each comprise a single dose of mosunetuzumab (C2D1-C12D1) to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1-C12D1 is 30 mg; and

(c) the second to twelfth dosing cycles each further comprise a daily dose of 20 mg lenalidomide, which is to be administered orally on days 1-21 of each dosing cycle.

114. 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,

Where each object:

(a) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(b) had previously been treated with at least one chemo-immunotherapy regimen containing an anti-CD20 monoclonal antibody; and

wherein administering an effective amount 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; , here:

(a) The first dosing cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) administered intravenously on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and

(c) the second dosing cycle further comprises oral administration of 20 mg lenalidomide daily on days 1-14 of the second dosing cycle.

115. Mosunetuzumab for use in combination with lenalidomide in treating a population of subjects, wherein each subject in the population:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

wherein mosunetuzumab and lenalidomide are administered to the population of subjects according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 21-day dosing cycle, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) to be administered intravenously on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and

(c) mosunetuzumab, wherein the second dosing cycle further comprises a daily dose of 20 mg lenalidomide, which should be administered orally on days 1 to 14 of the second dosing cycle.

116. Use of mosunetuzumab in combination with lenalidomide in treating a population of subjects, wherein each subject in the population:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

wherein mosunetuzumab and lenalidomide are administered to the population of subjects according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 21-day dosing cycle, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) to be administered intravenously on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and

(c) the second administration cycle further comprises a daily dose of 20 mg lenalidomide, which should be administered orally on days 1 to 14 of the second administration cycle.

117. Use of mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide to treat a population of subjects, wherein each subject in the population:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

wherein mosunetuzumab and lenalidomide are administered to the population of subjects according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 21-day dosing cycle, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) to be administered intravenously on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and

(c) the second administration cycle further comprises a daily dose of 20 mg lenalidomide, which should be administered orally on days 1 to 14 of the second administration cycle.

118. Use of lenalidomide in the manufacture of a medicament for use in combination with mosunetuzumab to treat a population of subjects, wherein each subject in the population:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

wherein mosunetuzumab and lenalidomide are administered to the population of subjects according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 21-day dosing cycle, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) to be administered intravenously on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and

(c) the second administration cycle further comprises a daily dose of 20 mg lenalidomide, which should be administered orally on days 1 to 14 of the second administration cycle.

119. Use of mosunetuzumab and lenalidomide in the manufacture of a medicament for the treatment of a population of subjects, wherein each subject in the population:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

wherein mosunetuzumab and lenalidomide are administered to the population of subjects according to a dosing regimen comprising at least a first 21-day dosing cycle and a second 21-day dosing cycle, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second dosing cycle comprises a single dose of mosunetuzumab (C2D1) to be administered intravenously on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and

(c) the second administration cycle further comprises a daily dose of 20 mg lenalidomide, which should be administered orally on days 1 to 14 of the second administration cycle.

120. 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,

Where each object:

(a) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(b) had previously been treated with at least one chemo-immunotherapy regimen containing an anti-CD20 monoclonal antibody; and

wherein administering an effective amount of mosunetuzumab and lenalidomide comprises administering mosunetuzumab and lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and 11 subsequent 21-day dosing cycles; , here:

(a) The first dosing cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) each of the second to twelfth dosing cycles comprises a single dose of mosunetuzumab (C2D1-C12D1) administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1-C12D1 is 30 mg, and

(c) each of the second to twelfth dosing cycles further comprises daily oral administration of 20 mg lenalidomide on days 1-14 of each dosing cycle.

121. Mosunetuzumab for use in combination with lenalidomide in treating a population of subjects, wherein each subject in the population:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

wherein mosunetuzumab and lenalidomide shall be administered to the population of subjects according to a dosing regimen comprising a first 21-day dosing cycle and 11 subsequent 21-day dosing cycles, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second to twelfth dosing cycles each comprise a single dose of mosunetuzumab (C2D1-C12D1) to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1-C12D1 is 30 mg; and

(c) mosunetuzumab, wherein the second to twelfth dosing cycles each further comprise a daily dose of 20 mg lenalidomide, which should be administered on days 1-14 of each dosing cycle.

122. Use of mosunetuzumab in combination with lenalidomide in treating a population of subjects, wherein each subject in the population:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

wherein mosunetuzumab and lenalidomide shall be administered to the population of subjects according to a dosing regimen comprising a first 21-day dosing cycle and 11 subsequent 21-day dosing cycles, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second to twelfth dosing cycles each comprise a single dose of mosunetuzumab (C2D1-C12D1) to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1-C12D1 is 30 mg; and

(c) the second to twelfth dosing cycles each further comprise a daily dose of 20 mg lenalidomide, which should be administered on days 1-14 of each dosing cycle.

123. Use of mosunetuzumab in the manufacture of a medicament for use in combination with lenalidomide to treat a population of subjects, wherein each subject in the population:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

wherein mosunetuzumab and lenalidomide shall be administered to the population of subjects according to a dosing regimen comprising a first 21-day dosing cycle and 11 subsequent 21-day dosing cycles, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second to twelfth dosing cycles each comprise a single dose of mosunetuzumab (C2D1-C12D1) to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1-C12D1 is 30 mg; and

(c) the second to twelfth dosing cycles each further comprise a daily dose of 20 mg lenalidomide, which should be administered on days 1-14 of each dosing cycle.

124. Use of lenalidomide in the manufacture of a medicament for use in combination with mosunetuzumab to treat a population of subjects, wherein each subject in the population:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

wherein mosunetuzumab and lenalidomide shall be administered to the population of subjects according to a dosing regimen comprising a first 21-day dosing cycle and 11 subsequent 21-day dosing cycles, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second to twelfth dosing cycles each comprise a single dose of mosunetuzumab (C2D1-C12D1) to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1-C12D1 is 30 mg; and

(c) the second to twelfth dosing cycles each further comprise a daily dose of 20 mg lenalidomide, which should be administered on days 1-14 of each dosing cycle.

125. Use of mosunetuzumab and lenalidomide in the manufacture of a medicament for the treatment of a population of subjects, wherein each subject in the population:

(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20, and

(ii) had previously been treated with at least one chemo-immunotherapy regimen; and

wherein mosunetuzumab and lenalidomide shall be administered to the population of subjects according to a dosing regimen comprising a first 21-day dosing cycle and 11 subsequent 21-day dosing cycles, wherein:

(a) The first dosing cycle consists of a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab, which should be administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Includes a dose (C1D3), where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg,

(b) the second to twelfth dosing cycles each comprise a single dose of mosunetuzumab (C2D1-C12D1) to be administered intravenously on Day 1 of each dosing cycle, wherein each single dose C2D1-C12D1 is 30 mg; and

(c) the second to twelfth dosing cycles each further comprise a daily dose of 20 mg lenalidomide, which should be administered on days 1-14 of each dosing cycle.

126. The method, mosunetuzumab, or use of any one of embodiments 102 to 125, wherein the at least one chemo-immunotherapy regimen comprises an anti-CD20 monoclonal antibody.

127. The method of embodiment 126, wherein the anti-CD20 monoclonal antibody is rituximab or obinutuzumab.

128. The method of any one of embodiments 102-127, wherein each subject has previously received only one line of systemic treatment, and:

(a) Follicular Lymphoma International Prognostic Index (FLIPI) score of 2-5;

(b) was refractory to previous anti-CD20 monoclonal antibody treatment, or

(c) with disease progression within 24 months of starting prior treatment, methods, mosunetuzumab, or uses.

129. The method of any of embodiments 102 to 128, wherein each subject's FL is grade 1, grade 2, or according to the World Health Organization's classification of lymphoma neoplasms (see Swerdlow SH, et al., Blood 2016; 127:2375-90) Histologically documented as grade 3a but not grade 3b, methods, mosunetuzumab, or uses for use.

130. The method of any one of embodiments 102 to 129, wherein each subject has not been treated with an anti-CD20 monoclonal antibody for at least 4 weeks prior to receiving an effective amount of mosunetuzumab and lenalidomide.

131. The use of any one of embodiments 102 to 129, wherein mosunetuzumab and lenalidomide are not administered to each subject for at least 4 weeks after said subject has been treated with the anti-CD20 monoclonal antibody. Mosunetuzumab or for use.

132. The method of any one of embodiments 102 to 125, wherein mosunetuzumab and lenalidomide have a synergistic effect on R/R FL.

133. The method of embodiment 132, wherein 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).

134. The method of embodiment 132, wherein the synergistic effect is a complete response as defined by the Lugano 2014 criteria (Cheson BD, et al., J Clin Oncol 2014; 32:1-9).

135. The method, mosunetuzumab or use for any of embodiments 102 to 134, wherein the incidence of adverse events is not significantly higher than when mosunetuzumab is administered alone to the population of subjects.

136. The method of any one of embodiments 102 to 134, wherein the incidence of adverse events is not significantly higher than when lenalidomide is not administered to the population of subjects.

137. The method of any one of embodiments 102 to 136, wherein the American Society for Transplantation and Cell Therapy (ASTCT) Consensus Grade for Cytokine Release Syndrome (“ASTCT CRS Grade”; Lee et al., Biol Blood Marrow Transplant 2019) A method, mosunetuzumab or use for use according to the method, wherein the incidence of cytokine release syndrome is less than 45%.

138. The method of embodiment 137, wherein the incidence of cytokine release syndrome as defined by the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Scale for Cytokine Release Syndrome (“ASTCT CRS Scale”) is less than 35%. , mosunetuzumab or for use.

139. The method of embodiment 138, wherein the incidence of cytokine release syndrome as defined by the American Society for Transplantation and Cell Therapy (ASTCT) Consensus Scale for Cytokine Release Syndrome (“ASTCT CRS Scale”) is less than 25%. , mosunetuzumab or for use.

140. The method of any one of embodiments 102 to 139, wherein the cytokine release is grade 3 or higher, as defined by the American Society for Transplantation and Cell Therapy (ASTCT) Consensus Scale for Cytokine Release Syndromes (“ASTCT CRS Scale”) Methods, mosunetuzumab or purposes for use, wherein the incidence of the syndrome is less than 10%.

141. The method of embodiment 140, wherein the incidence of cytokine release syndrome of grade 3 or greater is 5, as defined by the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Scale for Cytokine Release Syndrome (“ASTCT CRS Scale”). Less than %, method, mosunetuzumab or purpose for use.

142. The method of embodiment 141, wherein the incidence of cytokine release syndrome of grade 3 or greater is 3, as defined by the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Scale for Cytokine Release Syndrome (“ASTCT CRS Scale”) Less than %, method, mosunetuzumab or purpose for use.

143. The method of embodiment 142, wherein the incidence of cytokine release syndrome grade 3 or greater is 1, as defined by the American Society for Transplantation and Cell Therapy (ASTCT) Consensus Scale for Cytokine Release Syndrome (“ASTCT CRS Scale”) Less than %, method, mosunetuzumab or purpose for use.

144. The method, mosunetuzumab or use according to any one of embodiments 102 to 143, wherein the incidence of neutropenia is less than 40%.

145. The method of embodiment 144, wherein the incidence of neutropenia is less than 30%.

146. The method of embodiment 145, wherein the incidence of neutropenia is less than 20%.

147. The method, mosunetuzumab, or use of any one of embodiments 102 to 146, wherein the overall response rate is at least 80%.

148. The method, mosunetuzumab, or use of embodiment 147, wherein the overall response rate is at least 90%.

149. The method, mosunetuzumab, or use of embodiment 148, wherein the overall response rate is at least 95%.

150. The method, mosunetuzumab, or use of embodiment 149, wherein the overall response rate is at least 99%.

151. The method, mosunetuzumab, or use of any one of embodiments 102 to 146, wherein the complete response rate is at least 65%.

152. The method, mosunetuzumab, or use of embodiment 151, wherein the complete response rate is at least 75%.

153. The method, mosunetuzumab, or use of embodiment 152, wherein the complete response rate is at least 85%.

154. The method, mosunetuzumab, or use of any one of embodiments 102 to 153, wherein the anti-CD20 monoclonal antibody is obinutuzumab or rituximab.

155. The method, mosunetuzumab, or use of any one of embodiments 1 to 101, wherein the subject is a human.

156. The method, mosunetuzumab, or use of any one of embodiments 102 to 154, wherein each subject in the population is a human.

157. The method of any one of embodiments 1 to 101, wherein the subject exhibits a reduction in tumor burden after receiving an effective amount of mosunetuzumab and an effective amount of lenalidomide.

158. Mosunetuzumab, or the use, according to any one of embodiments 1 to 101, wherein the subject exhibits a reduction in tumor burden after being treated with mosunetuzumab and lenalidomide.

159. The method, mosunetuzumab, or use of embodiment 157 or 158, wherein the reduction of tumor burden is determined by computed tomography (CT).

160. The method, mosunetuzumab, or use of any one of embodiments 157 to 159, wherein reducing tumor burden is reducing the sum of diameter products (SPD) of target lesions.

161. The method, mosunetuzumab, or use of embodiment 160, wherein the reduction of SPD is at least 40%.

162. The method of embodiment 161, wherein the reduction of SPD is at least 60%, mosunetuzumab, or use for use.

163. The method, mosunetuzumab, or use of embodiment 162, wherein the reduction of SPD is at least 80%.

164. The method of any one of embodiments 102 to 154, wherein at least 45% of the subjects in the population exhibit a reduction in tumor burden after receiving mosunetuzumab and lenalidomide, mosunetuzumab, or Usage.

165. The method, mosunetuzumab, or use of embodiment 164, wherein at least 60% of the subjects in the population exhibit a reduction in tumor burden after receiving mosunetuzumab and lenalidomide.

166. The method of embodiment 165, wherein at least 75% of the subjects in the population exhibit a reduction in tumor burden after receiving an effective amount of mosunetuzumab and an effective amount of lenalidomide. .

167. The method, mosunetuzumab, or use of any one of embodiments 164 to 166, wherein the reduction of tumor burden is determined by computed tomography (CT).

168. The method, mosunetuzumab, or use of any one of embodiments 164 to 167, wherein reducing tumor burden is reducing the sum of diameter products (SPD) of target lesions.

169. The method, mosunetuzumab, or use of embodiment 168, wherein the reduction of SPD is at least 40%.

170. The method, mosunetuzumab, or use of embodiment 169, wherein the reduction of SPD is at least 60%.

171. The method, mosunetuzumab, or use of embodiment 170, wherein the reduction of SPD is at least 80%.

172. The method, mosunetuzumab, or use of any of embodiments 8 to 54, wherein the dosing regimen further comprises administering a corticosteroid.

173. The method, mosunetuzumab, or use of embodiment 172, wherein the corticosteroid is administered or to be administered to the subject during the first administration cycle.

174. The method of embodiment 173, wherein the first administration cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of the corticosteroid, or use.

175. The method of embodiment 174, wherein the C1D1, C1D2, and C1D3 of the corticosteroids are or should be administered to the subject on each of Day 1, Day 8, and Day 15 of the first administration cycle, a method for using mosunetuzumab; or use.

176. The method of embodiment 175, wherein each single dose C1D1-C1D3 of corticosteroid is or should be administered to the subject prior to administering each C1D1-C1D3 of mosunetuzumab.

177. The method of any one of embodiments 172 to 176, wherein the corticosteroid is administered or should be administered to the subject in the first administration cycle and is not or should not be administered in the second administration cycle. or use.

178. The method, mosunetuzumab, or use of any one of embodiments 172 to 176, wherein the corticosteroid is administered or to be administered to the subject in the second administration cycle.

179. The method, mosunetuzumab, or use of embodiment 178, wherein the second administration cycle comprises a single dose of corticosteroid (C2D1).

180. The method, mosunetuzumab, or use of embodiment 179, wherein the C2D1 of the corticosteroid is or should be administered to the subject on day 1 of the second administration cycle.

181. The method of embodiment 180, wherein the C2D1 of the corticosteroid is or should be administered to the subject prior to the C2D1 administration of mosunetuzumab.

182. The method, mosunetuzumab, or use of any one of embodiments 102 to 154, wherein the dosing regimen further comprises administration of a corticosteroid.

183. The method, mosunetuzumab, or use of embodiment 182, wherein the corticosteroid is administered or to be administered to the subject during the first administration cycle.

184. The method of embodiment 183, wherein the first administration cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of the corticosteroid, or use.

185. The method of embodiment 184, wherein C1D1, C1D2, and C1D3 of the corticosteroid are or should be administered to the subject on each of Day 1, Day 8, and Day 15 of the first administration cycle, a method for using mosunetuzumab; or use.

186. The method of embodiment 185, wherein each single dose C1D1-C1D3 of corticosteroid is or should be administered to the subject prior to administering each C1D1-C1D3 of mosunetuzumab.

187. The method of any one of embodiments 182 to 186, wherein the corticosteroid is administered or should not be administered to the subject in the first administration cycle and is not or should not be administered in the second administration cycle. or use.

188. The method, mosunetuzumab, or use of any one of embodiments 182 to 186, wherein the corticosteroid is administered or to be administered to the subject in the second administration cycle.

189. The method, mosunetuzumab, or use of embodiment 188, wherein the second administration cycle comprises a single dose of corticosteroid (C2D1).

190. The method, mosunetuzumab, or use of embodiment 189, wherein the C2D1 of the corticosteroid is or should be administered to the subject on day 1 of the second administration cycle.

191. The method, mosunetuzumab, or use of embodiment 190, wherein the C2D1 of the corticosteroid is or should be administered to the subject prior to the C2D1 administration of mosunetuzumab.

192. The method, mosunetuzumab, or use of any one of embodiments 31-33, wherein each additional administration cycle comprises administration of an additional dose of corticosteroid.

193. The method, mosunetuzumab, or use of embodiment 192, wherein each additional dose of corticosteroid is administered or is to be administered on Day 1 of each additional administration cycle.

194. The method, mosunetuzumab, or use of embodiment 193, wherein each additional dose of corticosteroid is administered or is administered to the subject prior to administering each additional dose of mosunetuzumab.

195. The method, mosunetuzumab, or use of any of embodiments 172 to 194, wherein the corticosteroid is or shall be administered intravenously.

196. The method, mosunetuzumab, or use of any one of embodiments 172 to 195, wherein the corticosteroid is dexamethasone.

197. The method, mosunetuzumab, or use of embodiment 196, wherein each dose of dexamethasone is 10 mg.

Other Embodiments

Although the above-described invention has been described in detail using examples and examples for clear understanding, these examples and examples should not be construed as limiting the scope of the present invention. The contents of all patents and scientific literature cited herein are incorporated by reference in their entirety.

SEQUENCE LISTING <110> Genentech, Inc. <120> METHODS FOR TREATMENT OF RELAPSED/REFRACTORY FOLLICULAR LYMPHOMA WITH MOSUNETUZUMAB AND LENALIDOMIDE <130> 50474-262WO2 <160> 36 <170> PatentIn version 3.5 <210> 1 <211> 10 <212> PRT <213> Artificial Sequence < 220> <223> Synthetic Construct <400> 1 Gly Tyr Thr Phe Thr Ser Tyr Asn Met His 1 5 10 <210> 2 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct < 400> 2 Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe Lys 1 5 10 15 Gly <210> 3 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct < 400> 3 Val Val Tyr Tyr Ser Asn Ser Tyr Trp Tyr Phe Asp Val 1 5 10 <210> 4 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 4 Arg Ala Ser Ser Ser Val Ser Tyr Met His 1 5 10 <210> 5 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 5 Ala Pro Ser Asn Leu Ala Ser 1 5 < 210> 6 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 6 Gln Gln Trp Ser Phe Asn Pro Pro Thr 1 5 <210> 7 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 7 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Phe Thr Ile Ser Val Asp Lys Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Val Tyr Tyr Ser Asn Ser Tyr Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 8 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 8 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Pro Leu Ile Tyr 35 40 45 Ala Pro Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu 65 70 75 80 Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Phe Asn Pro Pro Thr 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 9 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 9 Asn Tyr Tyr Ile His 1 5 <210> 10 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 10 Trp Ile Tyr Pro Gly Asp Gly Asn Thr Lys Tyr Asn Glu Lys Phe Lys 1 5 10 15 Gly <210> 11 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 11 Asp Ser Tyr Ser Asn Tyr Tyr Phe Asp Tyr 1 5 10 <210> 12 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 12 Lys Ser Ser Gln Ser Leu Leu Asn Ser Arg Thr Arg Lys Asn Tyr Leu 1 5 10 15 Ala <210> 13 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 13 Trp Ala Ser Thr Arg Glu Ser 1 5 <210> 14 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 14 Thr Gln Ser Phe Ile Leu Arg Thr 1 5 <210> 15 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 15 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Trp Ile Tyr Pro Gly Asp Gly Asn Thr Lys Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Arg Ala Thr Leu Thr Ala Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Tyr Ser Asn Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 < 210> 16 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 16 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser 20 25 30 Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Thr Gln 85 90 95 Ser Phe Ile Leu Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 110 <210> 17 <211> 25 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 17 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser 20 25 <210> 18 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400 > 18 Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly 1 5 10 <210> 19 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 19 Arg Phe Thr Ile Ser Val Asp Lys Ser Lys Asn Thr Leu Tyr Leu Gln 1 5 10 15 Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30 <210> 20 <211> 11 <212> PRT < 213> Artificial Sequence <220> <223> Synthetic Construct <400> 20 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 1 5 10 <210> 21 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 21 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys 20 <210> 22 <211> 15 <212> PRT < 213> Artificial Sequence <220> <223> Synthetic Construct <400> 22 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Pro Leu Ile Tyr 1 5 10 15 <210> 23 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 23 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys 20 25 30 <210> 24 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 24 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 1 5 10 <210> 25 < 211> 30 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 25 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr 20 25 30 <210> 26 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 26 Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly 1 5 10 <210> 27 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 27 Arg Ala Thr Leu Thr Ala Asp Thr Ser Thr Ser Thr Ala Tyr Leu Glu 1 5 10 15 Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg 20 25 30 <210> 28 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 28 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 1 5 10 <210> 29 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 29 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys 20 <210> 30 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 30 Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr 1 5 10 15 <210> 31 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400 > 31 Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 1 5 10 15 Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys 20 25 30 <210> 32 <211> 10 < 212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 32 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 1 5 10 <210> 33 <211> 452 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 33 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Arg Phe Thr Ile Ser Val Asp Lys Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Val Tyr Tyr Ser Asn Ser Tyr Trp Tyr Phe Asp Val Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser 210 215 220 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 245 250 255 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 260 265 270 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 275 280 285 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr 290 295 300 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 305 310 315 320 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 325 330 335 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 340 345 350 Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 355 360 365 Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 370 375 380 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 385 390 395 400 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 405 410 415 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 420 425 430 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 435 440 445 Ser Pro Gly Lys 450 <210> 34 <211> 213 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 34 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Pro Leu Ile Tyr 35 40 45 Ala Pro Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu 65 70 75 80 Asp Phe Ala Thr Tyr Cys Gln Gln Trp Ser Phe Asn Pro Pro Thr 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210 <210> 35 <211> 449 <212 > PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 35 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Trp Ile Tyr Pro Gly Asp Gly Asn Thr Lys Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Arg Ala Thr Leu Thr Ala Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ser Tyr Ser Asn Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Ser 355 360 365 Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys <210> 36 <211> 219 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Construct <400> 36 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser 20 25 30 Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Thr Gln 85 90 95 Ser Phe Ile Leu Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 110 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 145 150 155 160 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215

Claims (125)

A method of treating a subject, comprising administering to the subject an effective amount of mosunetuzumab and an effective amount of lenalidomide,
The object is
(a) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20;
(b) having previously been treated with at least one chemo-immunotherapy regimen. The method of claim 1 , wherein the at least one chemo-immunotherapy regimen comprises an anti-CD20 monoclonal antibody. The method of claim 1 or 2, wherein the subject
Previously received only one line of systemic treatment,
(a) a Follicular Lymphoma International Prognostic Index (FLIPI) (Solal-Celigny et al., Blood. 2004, 104 (5): 1258-1265) score of 2-5;
(b) was refractory to previous anti-CD20 monoclonal antibody treatment, or
(c) wherein there is disease progression within 24 months of starting previous treatment. 4. The method of claim 2 or 3, wherein the subject has not been treated with an anti-CD20 monoclonal antibody for at least 4 weeks prior to receiving the effective amount of mosunetuzumab and lenalidomide. The method of claim 1, wherein mosunetuzumab and lenalidomide have a synergistic effect on R/R FL. The method of claim 5, wherein 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). The method of claim 5, wherein the synergistic effect is a complete response as defined by the Lugano 2014 criteria (Cheson BD, et al., J Clin Oncol 2014, 32:1-9). According to any one of claims 1 to 7,
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) the first administration cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab;
C1D1 and C1D2 are each less than or equal to C1D3;
C1D1 is 0.02 mg to 4.0 mg,
C1D2 is 0.05 mg to 20.0 mg,
C1D3 is 0.2 mg to 50.0 mg,
(b) the second administration cycle comprises a single dose of mosunetuzumab (C2D1),
C2D1 is greater than or equal to C1D3 and is 0.2 mg to 50 mg. According to clause 8,
(a) C1D1 is 0.4 mg to 4.0 mg,
C1D2 is 1.0 mg to 20.0 mg,
C1D3 is 3.0 mg to 50.0 mg,
(b) C2D1 is 3.0 mg to 50.0 mg. According to clause 8 or 9,
(a) C1D1 is 0.8 mg to 3.0 mg,
C1D2 is 1.0 mg to 6.0 mg,
C1D3 is 3.0 mg to 45.0 mg,
(b) C2D1 is 3.0 mg to 45.0 mg. 11. The method according to any one of claims 8 to 10, wherein C1D1 and C1D2 are each less than C1D3. 11. The method of any one of claims 8-10, wherein C1D2 is about 50% to about 250% more than C1D1. According to any one of claims 8 to 10,
(a) C1D1 is 0.8 mg;
C1D2 is 2.0 mg;
C1D3 is 4.2 mg;
C2D1 is 4.2 mg, or
(b) C1D1 is 1.0 mg;
C1D2 is 1.0 mg;
C1D3 is 3.0 mg;
C2D1 is 30.0 mg, or
(c) C1D1 is 1.0 mg;
C1D2 is 2.0 mg;
C1D3 is 30.0 mg;
Method where C2D1 is 30.0 mg. 14. The method of any one of claims 8-13, wherein the length of the first administration cycle is 21 days. 15. The method of claim 14, comprising administering C1D1, C1D2, and C1D3 to the subject on each of Day 1, Day 8, and Day 15 of the first administration cycle, or approximately Day 1, Day 8, and Day 15, respectively.


16. The method of any one of claims 8-15, wherein the length of the second administration cycle is 28 days. 17. The method of claim 16, comprising administering C2D1 to the subject on day 1 of the second administration cycle. 18. The method of any one of claims 8-17, wherein the dosing regimen comprises one or more additional dosing cycles. 19. The method of claim 18, wherein the dosing regimen comprises 1 to 10 additional dosing cycles. 20. The method of claim 18 or 19, wherein the dosing regimen comprises 10 additional dosing cycles. 21. The method of any one of claims 18-20, wherein each of the one or more additional administration cycles is 28 days in length. 22. The method of any one of claims 18-21, wherein each of the one or more additional administration cycles comprises an additional dose of mosunetuzumab. 23. The method of claim 22, comprising administering each additional dose of mosunetuzumab to the subject on Day 1 of each of one or more additional dosing cycles. According to any one of claims 1 to 7,
administering an effective amount of mosunetuzumab comprises administering mosunetuzumab according to a dosing regimen comprising 12 dosing cycles,
(a) the first administration cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosunetuzumab;
C1D1 and C1D2 are each less than or equal to C1D3;
C1D1 is 0.02 mg to 4.0 mg,
C1D2 is 0.05 mg to 20.0 mg,
C1D3 is 0.2 mg to 50.0 mg,
(b) each of the second to twelfth dosing cycles comprises a single dose of mosunetuzumab (C2D1-C12D1),
wherein each single dose C2D1-C12D1 is the same amount and is greater than or equal to C1D3 and is 0.2 mg to 50 mg. According to clause 24,
(a) C1D1 is 0.4 mg to 4.0 mg,
C1D2 is 1.0 mg to 20.0 mg,
C1D3 is 3.0 mg to 50.0 mg,
(b) wherein each single dose of C2D1-C12D1 is 3.0 mg to 50.0 mg. According to claim 24 or 25,
(a) C1D1 is 0.8 mg to 3.0 mg,
C1D2 is 1.0 mg to 6.0 mg,
C1D3 is 3.0 mg to 45.0 mg,
(b) wherein each single dose of C2D1-C12D1 is 3.0 mg to 45.0 mg. 27. The method of any one of claims 24-26, wherein C1D1 and C1D2 are each less than C1D3. 27. The method of any one of claims 24-26, wherein C1D2 is about 50% to about 250% more than C1D1. According to any one of claims 24 to 26,
(a) C1D1 is 0.8 mg;
C1D2 is 2.0 mg;
C1D3 is 4.2 mg;
Each single dose C2D1-C12D1 is 4.2 mg, or
(b) C1D1 is 1.0 mg;
C1D2 is 1.0 mg;
C1D3 is 3.0 mg;
Each single dose C2D1-C12D1 is 30.0 mg, or
(c) C1D1 is 1.0 mg;
C1D2 is 2.0 mg;
C1D3 is 30.0 mg;
Each single dose C2D1-C12D1 is 30.0 mg. 30. The method of any one of claims 24-29, wherein the length of the first administration cycle is 21 days. 31. The method of claim 30, comprising administering C1D1, C1D2, and C1D3 to the subject on each of Day 1, Day 8, and Day 15 of the first administration cycle, or approximately Day 1, Day 8, and Day 15, respectively. 32. The method of any one of claims 24-31, wherein each of the second to twelfth administration cycles is 28 days in length. 33. The method of claim 32, comprising administering each of C2D1-C12D1 to the subject on Day 1 of each individual administration cycle. 34. The method of any one of claims 24-33, wherein each of the second to twelfth administration cycles is 28 days in length. 35. The method of any one of claims 1-34, wherein mosunetuzumab is administered intravenously. 36. The method of any one of claims 8-35, wherein lenalidomide is administered during the second and subsequent cycles. 37. The method of any one of claims 8-36, wherein lenalidomide is not administered during the first cycle. 38. The method of any one of claims 8-37, wherein lenalidomide is administered daily. 39. The method of any one of claims 36-38, wherein lenalidomide is administered daily for the first 21 days of each dosing cycle comprising administration of lenalidomide. 40. The method of claim 39, wherein lenalidomide is not administered during the last 7 days of each dosing cycle comprising administration of lenalidomide. 41. The method according to any one of claims 8 to 40, wherein lenalidomide is administered at a dose of 20 mg. 42. The method of any one of claims 1-41, wherein lenalidomide is administered orally. 43. The method of any one of claims 1-42, wherein the subject has previously been treated with at least one anti-CD20 monoclonal antibody. 44. The method of claim 43, wherein the subject is relapsed or refractory to treatment comprising an anti-CD20 monoclonal antibody. 45. The method of claim 43 or 44, wherein the anti-CD20 monoclonal antibody is obinutuzumab or rituximab. A method of treating a subject, comprising administering to the subject an effective amount of mosunetuzumab and an effective amount of lenalidomide,
The object is
(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20;
(ii) had previously been treated with at least one chemo-immunotherapy regimen;
administering the effective amount of mosunetuzumab and lenalidomide comprises administering the 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) The first dosing cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Contains (C1D3),
C1D1 is 1 mg,
C1D2 is 2 mg,
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,
C2D1 is 30 mg;
(c) wherein the second dosing cycle further comprises oral administration of 20 mg lenalidomide daily on days 1-21 of the second dosing cycle. A method of treating a subject, comprising administering to the subject an effective amount of mosunetuzumab and an effective amount of lenalidomide,
The object is
(i) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20;
(ii) had previously been treated with at least one chemo-immunotherapy regimen;
administering the effective amount of mosunetuzumab and lenalidomide comprises administering the mosunetuzumab and lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and 11 subsequent 28-day dosing cycles;
(a) The first dosing cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Contains (C1D3),
C1D1 is 1 mg,
C1D2 is 2 mg,
C1D3 is 30 mg,
(b) each of the second to twelfth dosing cycles comprises a single dose of mosunetuzumab (C2D1-C12D1) administered intravenously on Day 1 of each dosing cycle,
Each single dose C2D1-C12D1 is 30 mg;
(c) each of the second to twelfth dosing cycles further comprises daily oral administration of 20 mg lenalidomide on days 1-21 of each dosing cycle. 48. The method of any one of claims 45-47, wherein at least one chemo-immunotherapy regimen comprises an anti-CD20 monoclonal antibody. The method of any one of claims 45 to 48, wherein the subject
Previously received only one line of systemic treatment,
(a) Follicular Lymphoma International Prognostic Index (FLIPI) score of 2-5;
(b) was refractory to previous obinutuzumab treatment;
(c) was refractory to previous rituximab treatment, or
(d) wherein there is disease progression within 24 months of starting prior treatment. The method of any one of claims 45 to 49, wherein the subject has not been treated with obinutuzumab or rituximab for at least 4 weeks prior to receiving the effective amount of mosunetuzumab and lenalidomide. . The method according to any one of claims 45 to 49, wherein mosunetuzumab and lenalidomide have a synergistic effect on R/R FL. 52. The method of claim 51, wherein 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). 52. The method of claim 51, wherein the synergistic effect is a complete response as defined by the Lugano 2014 criteria (Cheson BD, et al., J Clin Oncol 2014, 32:1-9). The method of any one of claims 1 to 53, wherein the FL is grade 1, 2 according to the World Health Organization classification of lymphoma neoplasms (as noted in Swerdlow SH, et al., Blood 2016, 127:2375-90) A method that is histologically documented as grade or grade 3a but not grade 3b. 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 object
(a) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20;
(b) had previously been treated with at least one chemo-immunotherapy regimen;
administering the effective amount of mosunetuzumab and lenalidomide comprises administering the 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) The first dosing cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Contains (C1D3),
C1D1 is 1 mg,
C1D2 is 2 mg,
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,
C2D1 is 30 mg;
(c) wherein the second dosing cycle further comprises oral administration of 20 mg lenalidomide daily on days 1-21 of the second dosing cycle. 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 object
(a) have relapsed or refractory follicular lymphoma (R/R FL) expressing CD20;
(b) had previously been treated with at least one chemo-immunotherapy regimen;
administering the effective amount of mosunetuzumab and lenalidomide comprises administering the mosunetuzumab and lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and 11 subsequent 28-day dosing cycles;
(a) The first dosing cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose of mosunetuzumab administered intravenously on days 1, 8, and 15, respectively, of the first dosing cycle. Contains (C1D3),
C1D1 is 1 mg,
C1D2 is 2 mg,
C1D3 is 30 mg,
(b) each of the second to twelfth dosing cycles comprises a single dose of mosunetuzumab (C2D1-C12D1) administered intravenously on Day 1 of each dosing cycle,
Each single dose C2D1-C12D1 is 30 mg;
(c) each of the second to twelfth dosing cycles further comprises daily oral administration of 20 mg lenalidomide on days 1-21 of each dosing cycle. 57. The method of claim 55 or 56, wherein at least one chemo-immunotherapy regimen comprises an anti-CD20 monoclonal antibody. The method of any one of claims 55 to 57, wherein each subject
Previously received only one line of systemic treatment,
(a) Follicular Lymphoma International Prognostic Index (FLIPI) score of 2-5;
(b) was refractory to previous anti-CD20 monoclonal antibody treatment, or
(c) wherein there is disease progression within 24 months of starting previous treatment. The method of any one of claims 55 to 58, wherein each subject's FL is 1 according to the World Health Organization's classification of lymphoma neoplasms (as noted in Swerdlow SH, et al., Blood 2016, 127:2375-90) Methods that are histologically documented as grade, grade 2 or grade 3a but not grade 3b. The method of any one of claims 57-59, wherein each subject has not been treated with an anti-CD20 monoclonal antibody for at least 4 weeks prior to receiving an effective amount of mosunetuzumab and lenalidomide. 61. The method of claim 60, wherein mosunetuzumab and lenalidomide have a synergistic effect on R/R FL. 62. The method of claim 61, wherein 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). 62. The method of claim 61, wherein the synergistic effect is a complete response as defined by the Lugano 2014 criteria (Cheson BD, et al., J Clin Oncol 2014, 32:1-9). 64. The method of any one of claims 55-63, wherein the incidence of adverse events is not significantly higher than when mosunetuzumab is administered alone to the population of subjects. 64. The method of any one of claims 55-63, wherein the incidence of adverse events is not significantly higher than if lenalidomide was not administered to the population of subjects. 66. The method of any one of claims 55 to 65, wherein the American Society of Transplantation and Cellular Therapy (ASTCT) Consensus Rating for Cytokine-Release Syndrome (“ASTCT CRS Grade”, Lee et al., Biol Blood Marrow Transplant 2019) with an incidence of cytokine release syndrome of less than 45%. 67. The method of claim 66, wherein the incidence of cytokine release syndrome as defined by the American Society for Transplantation and Cell Therapy (ASTCT) Consensus Grade for Cytokine Release Syndrome (“ASTCT CRS Grade”) is less than 35%. 68. The method of claim 67, wherein the incidence of cytokine release syndrome as defined by the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grade for Cytokine Release Syndrome (“ASTCT CRS Grade”) is less than 25%. 69. The method of any one of claims 55-68, wherein cytokine release is grade 3 or higher as defined by the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Scale for Cytokine Release Syndromes (“ASTCT CRS Scale”) Methods in which the incidence of the syndrome is less than 10%. The method of claim 69, wherein the incidence of grade 3 or higher cytokine release syndrome as defined by the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grade for Cytokine Release Syndrome (“ASTCT CRS Grade”) is less than 5%. . The method of claim 70, wherein the incidence of grade 3 or higher cytokine release syndrome as defined by the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grade for Cytokine Release Syndrome (“ASTCT CRS Grade”) is less than 3%. . 72. The method of claim 71, wherein the incidence of grade 3 or higher cytokine release syndrome as defined by the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grade for Cytokine Release Syndrome (“ASTCT CRS Grade”) is less than 1%. . 73. The method of any one of claims 55-72, wherein the incidence of neutropenia is less than 40%. 74. The method of claim 73, wherein the incidence of neutropenia is less than 30%. 75. The method of claim 74, wherein the incidence of neutropenia is less than 20%. 76. The method of any one of claims 55-75, wherein the overall response rate is at least 80%. 77. The method of claim 76, wherein the overall response rate is at least 90%. 78. The method of claim 77, wherein the overall response rate is at least 95%. 79. The method of claim 78, wherein the overall response rate is at least 99%. 76. The method of any one of claims 55-75, wherein the complete response rate is at least 65%. 81. The method of claim 80, wherein the complete response rate is at least 75%. 82. The method of claim 81, wherein the complete response rate is at least 85%. 83. The method of any one of claims 55-82, wherein the anti-CD20 monoclonal antibody is obinutuzumab or rituximab. 55. The method of any one of claims 1-54, wherein the subject is a human. 84. The method of any one of claims 55-83, wherein each subject in the population is a human. 55. The method of any one of claims 1-54, wherein the subject exhibits a reduction in tumor burden after receiving an effective amount of mosunetuzumab and an effective amount of lenalidomide. 87. The method of claim 86, wherein the reduction in tumor burden is determined by computed tomography (CT). 88. The method of claim 86 or 87, wherein the reduction in tumor burden is a reduction in the sum of the product of the diameters (SPD) of the target lesions. 89. The method of claim 88, wherein the reduction in SPD is at least 40%. 89. The method of claim 89, wherein the reduction in SPD is at least 60%. 91. The method of claim 90, wherein the reduction in SPD is at least 80%. 84. The method of any one of claims 55-83, wherein at least 45% of the subjects in the population demonstrate a reduction in tumor burden after receiving an effective amount of mosunetuzumab and an effective amount of lenalidomide. 93. The method of claim 92, wherein at least 60% of the subjects in the population demonstrate a reduction in tumor burden after receiving an effective amount of mosunetuzumab and an effective amount of lenalidomide. 94. The method of claim 93, wherein at least 75% of the subjects in the population demonstrate a reduction in tumor burden after receiving an effective amount of mosunetuzumab and an effective amount of lenalidomide. 95. The method of any one of claims 92-94, wherein the reduction in tumor burden is determined by computed tomography (CT). 96. The method of any one of claims 92-95, wherein the reduction in tumor burden is a reduction in the sum of diameter products (SPD) of the target lesions. 97. The method of claim 96, wherein the reduction in SPD is at least 40%. 98. The method of claim 97, wherein the reduction in SPD is at least 60%. 99. The method of claim 98, wherein the reduction in SPD is at least 80%. 55. The method of any one of claims 8-54, wherein the dosing regimen further comprises administration of a corticosteroid. 101. The method of claim 100, wherein the corticosteroid is administered to the subject during the first administration cycle. 102. The method of claim 101, wherein the first administration cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of corticosteroid. 103. The method of claim 102, wherein C1D1, C1D2, and C1D3 of corticosteroids are administered to the subject on days 1, 8, and 15, respectively, of the first administration cycle. 104. The method of claim 103, wherein each single dose C1D1-C1D3 of corticosteroid is administered to the subject prior to administering each C1D1-C1D3 dose of mosunetuzumab. 105. The method of any one of claims 100-104, wherein the corticosteroid is administered to the subject in the first administration cycle and is not administered in the second administration cycle. 105. The method of any one of claims 100-104, wherein the corticosteroid is administered to the subject in the second administration cycle. 107. The method of claim 106, wherein the second administration cycle comprises a single dose of corticosteroid (C2D1). 108. The method of claim 107, wherein C2D1 of corticosteroid is administered to the subject on Day 1 of the second administration cycle. 109. The method of claim 108, wherein C2D1 of corticosteroid is administered to the subject prior to C2D1 administration of mosunetuzumab. 84. The method of any one of claims 55-83, wherein the dosing regimen further comprises administration of a corticosteroid. 111. The method of claim 110, wherein the corticosteroid is administered to the subject during the first administration cycle. 112. The method of claim 111, wherein the first administration cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of corticosteroid. 113. The method of claim 112, wherein C1D1, C1D2, and C1D3 of corticosteroids are administered to the subject on days 1, 8, and 15, respectively, of the first administration cycle. 114. The method of claim 113, wherein each single dose C1D1-C1D3 of corticosteroid is administered to the subject prior to administering each C1D1-C1D3 dose of mosunetuzumab. 115. The method of any one of claims 110-114, wherein the corticosteroid is administered to the subject in the first administration cycle and is not administered in the second administration cycle. 116. The method of any one of claims 110-115, wherein the corticosteroid is administered to the subject in the second administration cycle. 117. The method of claim 116, wherein the second administration cycle comprises a single dose of corticosteroid (C2D1). 118. The method of claim 117, wherein C2D1 of corticosteroid is administered to the subject on Day 1 of the second administration cycle. 119. The method of claim 118, wherein C2D1 of corticosteroid is administered to the subject prior to C2D1 administration of mosunetuzumab. 24. The method of claim 22 or 23, wherein each additional administration cycle comprises administering an additional dose of corticosteroid to the subject. 121. The method of claim 120, wherein each additional dose of corticosteroid is administered on Day 1 of each additional dosing cycle. 122. The method of claim 121, wherein each additional dose of corticosteroid is administered to the subject prior to administering each additional dose of mosunetuzumab. 123. The method of any one of claims 100-122, wherein the corticosteroid is administered intravenously. 124. The method of any one of claims 100-123, wherein the corticosteroid is dexamethasone. 125. The method of claim 124, wherein each dose of dexamethasone is 10 mg.

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