Treatment methods for relapsed / refractory follicular lymphoma using mosnetuzumab and lenalidomide

Abstract

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

Description

[Technical Field]

[0001] Sequence List This application includes a sequence listing submitted electronically in ASCII format, which is incorporated herein by reference in its entirety. The ASCII copy, created on 29 October 2021, is named 50474-262WO2_Sequence_Listing_10_28_21_ST25 and has a size of 23,600 bytes.

[0002] Field of Invention The present invention relates to the treatment of subjects having relapsed and / or refractory (R / R) follicular lymphoma (FL). More specifically, the present invention relates to the combined treatment of subjects having R / R FL who may have received prior treatment or other treatment with an anti-CD20 antibody (e.g., an anti-CD20 monoclonal antibody, e.g., rituximab or obinutuzumab) with mosnetuzumab and lenalidomide. [Background technology]

[0003] background Cancer is characterized by the uncontrolled proliferation of cell subpopulations. It is the leading cause of death in developed countries and the second leading cause of death in developing countries, with over 14 million new cases diagnosed annually and over 8 million cancer deaths each year. Slowly progressing cancers can also have a profound impact on quality of life. Therefore, cancer care represents a significant and ever-increasing social burden.

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

[0005] B cell - derived lymphomas constitute a diverse series of neoplasms within the broader context of non - Hodgkin lymphoma (NHL). Follicular lymphoma (FL) is the most common subtype of indolent NHL (Al - Hamandi et al., 2015). Despite the biological and clinical heterogeneity of B cell lymphomas, patients with advanced B cell malignancies are typically initially treated with intensive cytotoxic chemotherapy in combination with monoclonal antibodies (mAbs) such as anti - CD20 mAb, rituximab (Rituxan®, MabThera®). Durable responses can be achieved in some patients, but most patients will ultimately experience progressive or relapsed disease. FL remains an incurable disease with currently available therapies. The addition of rituximab to commonly used induction chemotherapy including cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP); cyclophosphamide, vincristine, and prednisone (CVP); fludarabine; or bendamustine (Zelenetz et al., 2014, Forstpointer et al., 2006), followed by rituximab maintenance therapy, has led to long - term remissions and improved patient outcomes. However, treatment with these therapies results in only partial responses, not complete responses, in most patients with relapsed or refractory (R / R) FL. Thus, multiple relapsed FL remains a disease with a high unmet medical need, requiring improved therapies.

Summary of the Invention

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

[0007] In one embodiment, the present invention is a method of treating a subject, comprising administering an effective dose of mosnetuzumab and an effective dose of lenalidomide to the subject, wherein the subject (a) has relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, and (b) has been previously treated with at least one chemoimmunotherapy regimen (e.g., R-CHP (rituximab, cyclophosphamide, doxorubicin and prednisone), R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone), CVP (cyclophosphamide, vincristine and prednisone), or BR (bendamustine and rituximab)) (e.g., at least one chemoimmunotherapy comprising an anti-CD20 monoclonal antibody (e.g., rituximab or obinutuzumab)). In some embodiments, subjects have received only one prior line of systemic therapy and either (a) have a Follicular Lymphoma International Prognostic Index (FLIPI; Solar-Celigny et al..Blood.2004;104(5):1258-1265.) score of 2–5 (e.g., a score of 2, 3, 4, or 5), (b) are refractory to prior anti-CD20 monoclonal antibody treatment, or (c) have experienced disease progression within 24 months of initiation of prior treatment. In some embodiments, subjects have not been treated with anti-CD20 monoclonal antibodies for at least 4 weeks prior to administration of an effective dose of mosnetuzumab and lenalidomide (e.g., 4, 6, 8, 10, 12, 24, 36, 48, 60 weeks, or longer). In some embodiments, mosnetuzumab 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).

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

[0009] In some embodiments, (a) C1D1 is 0.4 mg to 4.0 mg (e.g., 0.5 mg to 4.0 mg, 0.75 mg to 4.0 mg, 1.0 mg to 4.0 mg, 1.25 mg to 4.0 mg, 1.5 mg to 4.0 mg, 2.0 mg to 4.0 mg, 2.5 mg to 4.0 mg, 3.0 mg to 4.0 mg, 3.5 mg to 4.0 mg, 0.5 mg to 3.5 mg, 0.5 mg to 3.0 mg, 0.5 mg to 2.0 mg, 0.5 mg to 1.0 mg, 0.75 mg to 1.25 mg, 1.0 mg to 3.0 mg, 1.5 mg to 2.0 mg, 0.7 mg to 0.9 mg, or 0 0.9mg~1.1mg; for example, approximately 0.5mg, approximately 0.6mg, approximately 0.7mg, approximately 0.8mg, approximately 0.9mg, approximately 1.0mg, approximately 1.1mg, approximately 1.2mg, approximately 1.3mg, approximately 1.4mg, approximately 1.5mg, approximately 1.75mg, approximately 2.0mg, approximately 2.25mg, approximately 2.5mg, approximately 2.75mg, approximately 3.0mg, approximately 3.5mg, or approximately 4.0mg), and C1D2 is 1.0mg~20.0mg (for example, 1.1mg~20.0mg, 1.2mg~20.0mg, 1.3mg~20.0mg, 1.4mg~20.0mg, 1.5mg~20.0mg, 2.0 mg~20.0mg, 3.0mg~20.0mg, 4.0mg~20.0mg, 5.0mg~20.0mg, 6.0mg~20.0mg, 7.0mg~20.0mg, 8.0mg~20.0mg, 9.0mg~20.0mg, 10.0mg~20.0mg, 15.0mg~20 .0mg, 1.0mg~15.0mg, 1.0mg~10.0mg, 1.0mg~9.0mg, 1.0mg~8.0mg, 1.0mg~7.0mg, 1.0mg~6.0mg, 1.0mg~5.0mg, 1.0mg~4.0mg, 1.0mg~3.0mg, 1.0mg~2.0 (mg, 10.0mg-20.0mg, 15.0mg-20.0mg, 5.0mg-15.0mg, or 5.0mg-10.0mg; for example, approximately 1.0mg, 1.1mg, 1.2mg, 1.3mg, 1.4mg, 1.5mg, 1.6mg, 1.7mg, 1.8mg, 1.9mg, 2.0mg, 2.5mg, 3.0mg, 3.5mg, 4.0mg, 5.0mg, 6.0mg, 7.0mg, 8.0mg, 9.0mg, 10.0mg, 15.0mg, or 20.0mg), and C1D3 is 3.0mg-50mg.0mg (for example, 4.0mg~50.0mg, 5.0mg~50.0mg, 10.0mg~50.0mg, 15.0mg~50.0mg, 20.0mg~50.0mg, 25.0mg~50.0mg, 30.0mg~50.0mg, 35.0mg~50.0mg, 40.0mg~50.0mg, 45.0mg~50.0mg, 3.0mg~45.0mg, 3.0mg~40.0mg, 3.0mg~35.0mg, 3.0mg~30.0mg, 3.0mg~25.0mg, 3.0mg~20.0mg, 3.0mg~15.0mg, 3.0mg~10.0mg) g, 3.0mg~5.0mg, 10.0mg~20.0mg, 20.0mg~30.0mg, 30.0mg~40.0mg, 5.0mg~25.0mg, 25.0mg~50.0mg, 4.0mg~4.5mg, 4.0mg~5.0mg, 25.0mg~35.0mg, 28.0mg~32.0mg, 10.0mg~30.0mg, or 20.0mg~40.0mg; for example, approximately 3.0mg, approximately 4.0mg, approximately 4.2mg, approximately 4.5mg, approximately 5.0mg, approximately 5.5mg, approximately 6.0mg, approximately 6.5mg, approximately 7.0mg, approximately 8.0mg, approximately 9.0mg, approximately 1 (b) C2D1 is 3.0 mg to 50.0 mg (e.g., 4.0 mg to 50.0 mg, 5.0 mg to 50.0 mg, 10.0 mg to 50.0 mg, 15.0 mg to 50.0 mg, 20.0 mg to 50.0 mg, 25.0 mg to 50.0 mg, 30.0 mg to 50.0 mg, 35.0 mg to 50.0 mg, 40.0 mg to 50.0 mg, 45.0 mg to 50.0 mg) g, 3.0mg~45.0mg, 3.0mg~40.0mg, 3.0mg~35.0mg, 3.0mg~30.0mg, 3.0mg~25.0mg, 3.0mg~20.0mg, 3.0mg~15.0mg, 3.0mg~10.0mg, 3.0mg~5.0mg, 10.0mg ~20.0mg, 20.0mg~30.0mg, 30.0mg~40.0mg, 5.0mg~25.0mg, 25.0mg~50.0mg, 4.0mg~4.5mg, 4.0mg~5.0mg, 25.0mg~35.0mg, 28.0mg~32.0mg, 10.0mg~30.0 mg, or 20.0 mg to 40.0 mg; for example, approximately 3.0 mg, 4.0 mg, 4.2 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 8.0 mg, 9.0 mg, 10.0 mg, 12.0 mg, 15.0 mg, 20.0 mg, 25.0 mg, 30.0 mg, 35.0 mg, 40.0 mg, 45.0 mg, or 50.0 mg).

[0010] 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, The amounts are approximately 1.5 mg, 1.75 mg, 2.0 mg, 2.25 mg, 2.5 mg, 2.75 mg, or 3.0 mg, and C1D2 is 1.0 mg to 6.0 mg (for example, 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 0.0mg~2.0mg, 1.0mg~1.5mg, 1.5mg~2.5mg, 3.0mg~6.0mg, 2.0mg~4.0mg, 2.5mg~5.0mg, or 2.5mg~3.5mg; for example, approximately 1.0mg, approximately 1.1mg, approximately 1.2mg, approximately 1.3mg, approximately 1.4mg, approximately 1.5mg, approximately 1.6mg, approximately 1.7mg, approximately 1.8mg, 1.9mg, approximately 2.0mg, approximately 2.1mg, approximately 2.2mg, approximately 2.3mg, approximately 2.4mg, approximately 2.5mg, approximately 2.6mg, approximately 2.7mg, approximately 2.8mg, approximately 2.9mg, approximately 3.0mg, approximately 3.5mg, approximately 4.0mg (approximately 4.5 mg, approximately 5.0 mg, approximately 5.5 mg, or approximately 6.0 mg), and C1D3 is 3.0 mg to 45.0 mg (for example, 4.0 mg to 45.0 mg, 5.0 mg to 45.0 mg, 10.0 mg to 45.0 mg, 15.0 mg to 45.0 mg, 20.0 mg to 45.0 mg, 25.0 mg to 45.0 mg, 30.0 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, 3.0mg-15.0mg, 3.0mg-10.0mg, 3.0mg-5.0mg, 10.0mg-20.0mg, 20.0mg-30.0mg, 30.0mg-40.0mg, 5.0mg-25.0mg, 4.0mg-4.5mg, 4.0mg-5.0mg, 25.0mg-35.0mg, 28.0mg-32.0mg, 10.0mg-30.0mg, or 20.0mg-40.0mg; for example, approximately 3.0mg, approximately 4.0mg, approximately 4.2mg, approximately 4.5mg, approximately 5.0mg, approximately 5.5mg, approximately (b) C2D1 is 3.0 mg to 45.0 mg (for example, 4.0 mg to 45.0 mg, 5.0 mg to 45.0 mg, 10.0 mg to 45.0 mg, 15.0 mg to 45.0 mg, 15.0 mg to 45.0 mg, 20.0 mg to 45.0 mg, 25.0 mg to 45.0 mg, 30.0mg~45.0mg, 35.0mg~45.0mg, 40.0mg~45.0mg, 3.0mg~40.0mg, 3.0mg~35.0mg, 3.0mg~30.0mg, 3.0mg~25.0mg, 3.0mg~20.0mg, 3.0 mg~15.0mg, 3.0mg~10.0mg, 3.0mg~5.0mg, 10.0mg~20.0mg, 20.0mg~30.0mg, 30.0mg~40.0mg, 5.0mg~25.0mg, 4.0mg~4.5mg, 4.0mg~5.0 mg, 25.0 mg to 35.0 mg, 28.0 mg to 32.0 mg, 10.0 mg to 30.0 mg, or 20.0 mg to 40.0 mg; for example, approximately 3.0 mg, 4.0 mg, 4.2 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 8.0 mg, 9.0 mg, 10.0 mg, 12.0 mg, 15.0 mg, 20.0 mg, 25.0 mg, 30.0 mg, 35.0 mg, 40.0 mg, or 45.0 mg).

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

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

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

[0014] In some embodiments, the drug regimen includes one or more additional drug cycles (e.g., one, two, three, four, five, six, seven, eight, nine, ten, or more drug cycles). In some embodiments, the drug regimen includes one to ten additional drug cycles (e.g., one, two, three, four, five, six, seven, eight, nine, or ten drug cycles). In some embodiments, the drug regimen includes ten additional drug cycles. In some embodiments, the length of each of the one or more additional drug cycles is 28 days (±1 day). In some embodiments, each of the one or more additional drug cycles includes an additional dose of mosnetuzumab. In some embodiments, the method includes administering each additional dose of mosnetuzumab to the subject on day 1 of each of one or more additional dosing cycles.In some embodiments, each additional dose of mosnetuzumab ranges from 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 mg). .0mg~50.0mg, 30.0mg~50.0mg, 35.0mg~50.0mg, 40.0mg~50.0mg, 45.0mg~50.0mg, 1.0mg~45.0mg, 1.0mg~40.0mg, 1. 0mg~35.0mg, 1.0mg~30.0mg, 1.0mg~25.0mg, 1.0mg~20.0mg, 1.0mg~15.0mg, 1.0mg~10.0mg, 1.0mg~5.0mg, 10.0mg~20 0.0mg, 20.0mg-30.0mg, 30.0mg-40.0mg, 5.0mg-25.0mg, 25.0mg-50.0mg, 3.0mg-45.0mg, 4.0mg-4.5mg, 3.0mg-10.0mg, 4.0mg-5.0mg, 25.0mg-35.0mg, 28.0mg-32.0mg, 10.0mg-30.0mg, or 20.0mg-40.0mg; for example, approximately 0.2mg, approximately 0.5mg, approximately 0.8mg These are approximately 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 4.0 mg, 4.2 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 8.0 mg, 9.0 mg, 10.0 mg, 12.0 mg, 15.0 mg, 20.0 mg, 25.0 mg, 30.0 mg, 35.0 mg, 40.0 mg, 45.0 mg, or 50.0 mg). In some embodiments, the dosing regimen includes 12 dosing cycles containing mosnetuzumab and 11 dosing cycles containing lenalidomide.

[0015] In some embodiments, administering an effective dose of mosnetuzumab involves administering mosnetuzumab according to a dosing regimen comprising 12 dosing cycles, where (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab, where C1D1 and C1D2 are less than or equal to C1D3, and C1D1 is between 0.02 mg and 4.0 mg (e.g., 0.05 mg to 4.0 mg, 0.1 mg to 4.0 mg, 0.2 mg to 4.0 mg, 0.3 mg to 4.0 mg, 0.4 mg to 4.0 mg, 0.5 mg mg~4.0mg, 0.75mg~4.0mg, 1.0mg~4.0mg, 1.25mg~4.0mg, 1.5mg~4.0mg, 2.0mg~4.0mg, 2.5mg~4.0mg, 3.0mg~4.0mg, 3.5mg~4.0mg, 0.1mg~3.5mg, 0.1mg ~3.0mg, 0.1mg~2.5mg, 0.1mg~2.0mg, 0.1mg~1.5mg, 0.1mg~1mg, 0.1mg~0.5mg, 0.5mg~3.0mg, 0.5mg~2.0mg, 0.5mg~1.0mg, 0.75mg~1.25mg, 1.0mg~3.0m g, 1.5mg~2.0mg, 0.7mg~0.9mg, or 0.9mg~1.1mg; for example, about 0.05mg, about 0.1mg, about 0.2mg, about 0.3mg, about 0.4mg, about 0.5mg, about 0.6mg, about 0.7mg, about 0.8mg, about 0.9mg, about 1.0mg, about 1.1mg, about 1.2mg, about 1.3mg, about 1.4mg, about 1.5mg, about 1.75mg, about 2.0mg, about 2.25mg, about 2.5mg, about 2.75mg, about 3.0mg, about 3.5mg, or about 4.0mg), and C1D2 is 0.05mg~20.0mg (for example, 0 .1mg~20.0mg, 0.2mg~20.0mg, 0.3mg~20.0mg, 0.4mg~20.0mg, 0.5mg~20.0mg, 1.0mg~20.0mg, 1.5mg~20.0mg, 2.0mg~20.0mg, 3.0mg~20.0mg, 4.0mg~20. 0mg, 5.0mg~20.0mg, 6.0mg~20.0mg, 7.0mg~20.0mg, 8.0mg~20.0mg, 9.0mg~20.0mg, 10.0mg~20.0mg, 15.0mg~20.0mg, 0.5mg~15.0mg, 0.5mg~10.0mg, 0.5mg-9.0mg, 0.5mg-8.0mg, 0.5mg-7.0mg, 0.5mg-6.0mg, 0.5mg-5.0mg, 0.5mg-4.0mg, 0.5mg-3.0mg, 0.5mg-2.0mg, 0.5mg-1.0mg, 1.0mg-15.0mg, 1.0mg-10.0mg, 1.0mg-8.0mg, 1.0mg-6.0mg, 1.0mg-4.0mg, 1.0mg-3.0mg, 10.0mg-20.0mg, 15.0mg-20.0mg, 5.0mg-15.0mg, or 5.0mg-10.0mg; for example, about 0.1mg, about 0.2mg, approximately 0.3mg, approximately 0.4mg, approximately 0.5mg, approximately 0.6mg, approximately 0.7mg, approximately 0.8mg, approximately 0.9mg, approximately 1.0mg, approximately 1.1mg, approximately 1.2mg, approximately 1.3mg, approximately 1.4mg, approximately 1.5mg, approximately 1.6mg, approximately 1.7mg, approximately 1.8mg, approximately 1.9mg, approximately 2.0mg, approximately 2.5mg, approximately 3.0mg, approximately 3.5mg, approximately 4.0mg, approximately 5.0mg, approximately 6.0mg, approximately 7.0mg, approximately 8.0mg, approximately 9.0mg, approximately 10.0mg, approximately 15.0mg, or approximately 20.0mg), and C1D3 is 0.2mg to 50.0mg (for example, 0 .3mg~50.0mg, 0.4mg~50.0mg, 0.5mg~50.0mg, 1.0mg~50.0mg, 2.0mg~50.0mg, 3.0mg~50.0mg, 4.0mg~50.0mg, 5.0mg~50.0mg, 10.0mg~50.0mg, 15.0mg~ 50.0mg, 20.0mg~50.0mg, 25.0mg~50.0mg, 30.0mg~50.0mg, 35.0mg~50.0mg, 40.0mg~50.0mg, 45.0mg~50.0mg, 1.0mg~45.0mg, 1.0mg~40.0mg, 1.0mg~35 0.0mg, 1.0mg~30.0mg, 1.0mg~25.0mg, 1.0mg~20.0mg, 1.0mg~15.0mg, 1.0mg~10.0mg, 1.0mg~5.0mg, 10.0mg~20.0mg, 20.0mg~30.0mg, 30.0mg~40.0mg, 5.0mg~25.0mg, 25.0mg~50.0mg, 3.0mg~45.0mg, 4.0mg~4.5mg, 3.0mg~10.0mg, 4.0mg~5.0mg, 25.0mg~35.0mg, 28.0mg~32.0mg, 10.0mg~30.0mg, or 20.0mg to 40.0mg; for example, approximately 0.2mg, approximately 0.5mg, approximately 0.8mg, approximately 1.0mg, approximately 1.5mg, approximately 2.0mg, approximately 2.5mg, approximately 3.0mg, approximately 4.0mg, approximately 4.2mg, approximately 4.5mg, approximately 5.0mg, approximately 5.5mg, approximately 6.0mg, approximately 6.5mg, approximately 7.0mg, approximately 8.0mg, approximately 9.0mg, approximately 10.0mg, approximately 12.0mg, approximately 15.0mg, approximately 20.0mg, approximately 25.0mg, approximately 30.0mg, approximately 35.0mg, approximately 40.0mg, approximately 45.0mg, or approximately 50.0mg), and (b) the 2nd to 12th dosing cycles are Each package contains a single dose (C2D1-C12D1) of mosnetuzumab, with each single dose (C2D1-C12D1) being equivalent, and the dosage ranges from 0.2mg to 50mg (e.g., 0.3mg-50.0mg, 0.4mg-50.0mg, 0.5mg-50.0mg, 1.0mg-50.0mg, 2.0mg-50.0mg, 3.0mg-50.0mg, 4.0mg-50.0mg, 5.0mg-50.0mg, 10.0mg-50.0mg, 15.0mg-50.0mg, 20.0mg-50.0mg, 25.0mg-50.0mg, 30.0mg-50. 0mg, 35.0mg~50.0mg, 40.0mg~50.0mg, 45.0mg~50.0mg, 1.0mg~45.0mg, 1.0mg~40.0mg, 1.0mg~35.0mg, 1.0mg~30.0mg, 1.0mg~25.0mg, 1.0mg~20.0mg, 1.0mg~15.0mg, 1.0mg~10.0mg, 1.0mg~5.0mg, 10.0mg~20.0mg, 20.0mg~30.0mg, 30.0mg~40.0mg, 5.0mg~25.0mg, 25.0mg~50.0mg, 3.0mg~45.0mg, 4.0mg ~4.5mg, 3.0mg~10.0mg, 4.0mg~5.0mg, 25.0mg~35.0mg, 28.0mg~32.0mg, 10.0mg~30.0mg, or 20.0mg~40.0mg; for example, approximately 0.2mg, approximately 0.5mg, approximately 0.8mg, approximately 1.0mg, approximately 1.5mg, approximately 2.0mg, approximately 2.5mg, approximately 3.0mg, approximately 4.0mg, approximately 4.2mg, approximately 4.5mg, approximately 5.0mg, approximately 5.5mg, approximately 6.0mg, approximately 6.5mg, approximately 7.0mg, approximately 8.0mg, approximately 9.0mg, approximately 10.0mg, approximately 12.0mg, approximately 15.0mg, approximately 20.(0 mg, approximately 25.0 mg, approximately 30.0 mg, approximately 35.0 mg, approximately 40.0 mg, approximately 45.0 mg, or approximately 50.0 mg).

[0016] In some embodiments, (a) C1D1 is 0.4 mg to 4.0 mg (e.g., 0.5 mg to 4.0 mg, 0.75 mg to 4.0 mg, 1.0 mg to 4.0 mg, 1.25 mg to 4.0 mg, 1.5 mg to 4.0 mg, 2.0 mg to 4.0 mg, 2.5 mg to 4.0 mg, 3.0 mg to 4.0 mg, 3.5 mg to 4.0 mg, 0.5 mg to 3.5 mg, 0.5 mg to 3.0 mg, 0.5 mg to 2.0 mg, 0.5 mg to 1.0 mg, 0.75 mg to 1.25 mg, 1.0 mg to 3.0 mg, 1.5 mg to 2.0 mg, 0.7 mg to 0.9 mg, or 0 0.9mg~1.1mg; for example, approximately 0.5mg, approximately 0.6mg, approximately 0.7mg, approximately 0.8mg, approximately 0.9mg, approximately 1.0mg, approximately 1.1mg, approximately 1.2mg, approximately 1.3mg, approximately 1.4mg, approximately 1.5mg, approximately 1.75mg, approximately 2.0mg, approximately 2.25mg, approximately 2.5mg, approximately 2.75mg, approximately 3.0mg, approximately 3.5mg, or approximately 4.0mg), and C1D2 is 1.0mg~20.0mg (for example, 1.1mg~20.0mg, 1.2mg~20.0mg, 1.3mg~20.0mg, 1.4mg~20.0mg, 1.5mg~20.0mg, 2.0 mg~20.0mg, 3.0mg~20.0mg, 4.0mg~20.0mg, 5.0mg~20.0mg, 6.0mg~20.0mg, 7.0mg~20.0mg, 8.0mg~20.0mg, 9.0mg~20.0mg, 10.0mg~20.0mg, 15.0mg~20 .0mg, 1.0mg~15.0mg, 1.0mg~10.0mg, 1.0mg~9.0mg, 1.0mg~8.0mg, 1.0mg~7.0mg, 1.0mg~6.0mg, 1.0mg~5.0mg, 1.0mg~4.0mg, 1.0mg~3.0mg, 1.0mg~2.0 (mg, 10.0mg-20.0mg, 15.0mg-20.0mg, 5.0mg-15.0mg, or 5.0mg-10.0mg; for example, approximately 1.0mg, 1.1mg, 1.2mg, 1.3mg, 1.4mg, 1.5mg, 1.6mg, 1.7mg, 1.8mg, 1.9mg, 2.0mg, 2.5mg, 3.0mg, 3.5mg, 4.0mg, 5.0mg, 6.0mg, 7.0mg, 8.0mg, 9.0mg, 10.0mg, 15.0mg, or 20.0mg), and C1D3 is 3.0mg-50mg.0mg (for example, 4.0mg~50.0mg, 5.0mg~50.0mg, 10.0mg~50.0mg, 15.0mg~50.0mg, 20.0mg~50.0mg, 25.0mg~50.0mg, 30.0mg~50.0mg, 35.0mg~50.0mg, 40.0mg~50.0mg, 45.0mg~50.0mg, 3.0mg~45.0mg, 3.0mg~40.0mg, 3.0mg~35.0mg, 3.0mg~30.0mg, 3.0mg~25.0mg, 3.0mg~20.0mg, 3.0mg~15.0mg, 3.0mg~10.0mg) 3.0mg~5.0mg, 10.0mg~20.0mg, 20.0mg~30.0mg, 30.0mg~40.0mg, 5.0mg~25.0mg, 25.0mg~50.0mg, 4.0mg~4.5mg, 4.0mg~5.0mg, 25.0mg~35.0mg, 28.0mg~32.0mg, 10.0mg~30.0mg, or 20.0mg~40.0mg; for example, approximately 3.0mg, approximately 4.0mg, approximately 4.2mg, approximately 4.5mg, approximately 5.0mg, approximately 5.5mg, approximately 6.0mg, approximately 6.5mg, approximately 7.0mg, approximately 8.0mg, approximately 9.0mg, approximately 10. (b) Each single dose C2D1 to C12D1 is 3.0 mg to 50.0 mg (e.g., 4.0 mg to 50.0 mg, 5.0 mg to 50.0 mg, 10.0 mg to 50.0 mg, 15.0 mg to 50.0 mg, 20.0 mg to 50.0 mg, 25.0 mg to 50.0 mg, 30.0 mg to 50.0 mg, 35.0 mg to 50.0 mg, 40.0 mg to 50.0 mg, 45.0 mg mg~50.0mg, 3.0mg~45.0mg, 3.0mg~40.0mg, 3.0mg~35.0mg, 3.0mg~30.0mg, 3.0mg~25.0mg, 3.0mg~20.0mg, 3.0mg~15.0mg, 3.0mg~10.0mg, 3.0mg~5.0mg , 10.0mg~20.0mg, 20.0mg~30.0mg, 30.0mg~40.0mg, 5.0mg~25.0mg, 25.0mg~50.0mg, 4.0mg~4.5mg, 4.0mg~5.0mg, 25.0mg~35.0mg, 28.0mg~32.0mg, 10.The dosage ranges from 0 mg to 30.0 mg, or 20.0 mg to 40.0 mg; for example, approximately 3.0 mg, 4.0 mg, 4.2 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 8.0 mg, 9.0 mg, 10.0 mg, 12.0 mg, 15.0 mg, 20.0 mg, 25.0 mg, 30.0 mg, 35.0 mg, 40.0 mg, 45.0 mg, or 50.0 mg.

[0017] 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 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 The amounts are 1.3mg, approximately 1.4mg, approximately 1.5mg, approximately 1.75mg, approximately 2.0mg, approximately 2.25mg, approximately 2.5mg, approximately 2.75mg, or approximately 3.0mg), and C1D2 is 1.0mg to 6.0mg (for example, 1.5mg to 6.0mg, 2.0mg to 6.0mg, 2.5mg to 6.0mg, 3.0mg to 6.0mg, 3.5mg to 6.0mg, 4.0mg to 6.0mg, 5.0mg to 6.0mg, 5.0mg to 6.0mg, 1.0mg to 5.0mg, 1.0mg to 4.5mg, 1.0mg to 4.0mg, 1.0mg to 3.5mg, 1.0mg to 3.0mg, 1.0mg~2.5mg, 1.0mg~2.0mg, 1.0mg~1.5mg, 1.5mg~2.5mg, 3.0mg~6.0mg, 2.0mg~4.0mg, 2.5mg~5.0mg, or 2.5mg~3.5mg; for example, approximately 1.0mg, approximately 1.1mg, approximately 1.2mg, approximately 1.3mg, approximately 1.4mg, approximately 1.5mg, approximately 1.6mg, approximately 1.7mg, approximately 1.8mg, 1.9mg, approximately 2.0mg, approximately 2.1mg, approximately 2.2mg, approximately 2.3mg, approximately 2.4mg, approximately 2.5mg, approximately 2.6mg, approximately 2.7mg, approximately 2.8mg, approximately 2.9mg, approximately 3.0mg. The amounts are approximately 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, or 6.0 mg, and C1D3 is 3.0 mg to 45.0 mg (for example, 4.0 mg to 45.0 mg, 5.0 mg to 45.0 mg, 10.0 mg to 45.0 mg, 15.0 mg to 45.0 mg, 20.0 mg to 45.0 mg, 25.0 mg to 45.0 mg, 30.0 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, 3.0mg-20.0mg, 3.0mg-15.0mg, 3.0mg-10.0mg, 3.0mg-5.0mg, 10.0mg-20.0mg, 20.0mg-30.0mg, 30.0mg-40.0mg, 5.0mg-25.0mg, 4.0mg-4.5mg, 4.0mg-5.0mg, 25.0mg-35.0mg, 28.0mg-32.0mg, 10.0mg-30.0mg, or 20.0mg-40.0mg; for example, approximately 3.0mg, approximately 4.0mg, approximately 4.2mg, approximately 4.5mg, approximately 5.0mg, approximately (b) Each single dose C2D1 to C12D1 is 3.0 mg to 45.0 mg (for example, 4.0 mg to 45.0 mg, 5.0 mg to 45.0 mg, 10.0 mg to 45.0 mg, 15.0 mg to 45.0 mg, 15.0 mg to 45.0 mg, 20.0 mg to 45.0 mg, 25.0 mg to 45.0 mg) and (b) each single dose C2D1 to C12D1 is 3.0 mg to 45.0 mg (for example, 4.0 mg to 45.0 mg, 5.0 mg to 45.0 mg, 10.0 mg to 45.0 mg, 15.0 mg to 45.0 mg, 20.0 mg to 45.0 mg, 25 .0mg~45.0mg, 30.0mg~45.0mg, 35.0mg~45.0mg, 40.0mg~45.0mg, 3.0mg~40.0mg, 3.0mg~35.0mg, 3.0mg~30.0mg, 3.0mg~25.0mg, 3.0mg~2 0.0mg, 3.0mg~15.0mg, 3.0mg~10.0mg, 3.0mg~5.0mg, 10.0mg~20.0mg, 20.0mg~30.0mg, 30.0mg~40.0mg, 5.0mg~25.0mg, 4.0mg~4.5mg, 4.0 (For example, approximately 3.0 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, approximately 3.0 mg, approximately 4.0 mg, approximately 4.2 mg, approximately 4.5 mg, approximately 5.0 mg, approximately 5.5 mg, approximately 6.0 mg, approximately 6.5 mg, approximately 7.0 mg, approximately 8.0 mg, approximately 9.0 mg, approximately 10.0 mg, approximately 12.0 mg, approximately 15.0 mg, approximately 20.0 mg, approximately 25.0 mg, approximately 30.0 mg, approximately 35.0 mg, approximately 40.0 mg, or approximately 45.0 mg).

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

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

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

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

[0022] 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 that includes lenalidomide administration. In some embodiments, lenalidomide is not administered for the last 7 days of each dosing cycle that includes lenalidomide administration. In some embodiments, lenalidomide is administered in a dose of 20 mg. In some embodiments, lenalidomide is administered orally.

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

[0024] In one embodiment, the present invention relates to a method of treating a subject comprising administering an effective dose of mosnetuzumab and an effective dose of lenalidomide to the subject, wherein the subject (i) has relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, and (ii) has been previously treated with at least one chemoimmunotherapy regimen comprising obinutuzumab, and the administration of an effective dose of mosnetuzumab and lenalidomide comprises administering the mosnetuzumab and lenalidomide according to a dosing regimen comprising at least a first dosing cycle of 21 days (±1 days) and a second dosing cycle of 28 days (±1 days), wherein the first dosing cycle is administered intravenously on day 1, day 8 (±1 days), and day 15 (±1 days), respectively. The method is characterized by comprising (a) a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg, (b) a second dosing cycle comprising a single dose (C2D1) of mosnetuzumab administered intravenously on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and (c) a second dosing cycle comprising the oral administration of 20 mg of lenalidomide daily from day 1 to day 21 of the second dosing cycle.

[0025] In one embodiment, the present invention relates to a method of treating a subject comprising administering an effective amount of mosnetuzumab and an effective amount of lenalidomide to the subject, wherein the subject (i) has relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, and (ii) has been previously treated with at least one chemoimmunotherapy regimen comprising obinutuzumab, and the administration of an effective amount of mosnetuzumab and lenalidomide comprises administering mosnetuzumab and lenalidomide according to a dosing regimen comprising a first 21-day (±1-day) dosing cycle and subsequent 28-day (±1-day) dosing cycles, wherein the first dosing cycle comprises a first dose (C1D1) administered intravenously on day 1, day 8 (±1-day), and day 15 (±1-day), respectively of the first dosing cycle, and a second dose ( The method is characterized by comprising (a) a dose (C1D2) and a third dose (C1D3) of mosnetuzumab, where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg, and (b) each of the second to twelfth drug cycles comprises a single dose (C2D1 to C12D1) of mosnetuzumab administered intravenously on day 1 of each drug cycle, where each single dose C2D1 to C12D1 is 30 mg, and (c) each of the second to twelfth drug cycles comprises the oral administration of 20 mg of lenalidomide daily on days 1 to 21 of each drug cycle.

[0026] In one embodiment, the present invention relates to a method of treating a subject comprising administering an effective dose of mosnetuzumab and an effective dose of lenalidomide to the subject, wherein the subject (i) has relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, and (ii) has been previously treated with at least one chemoimmunotherapy regimen comprising rituximab, and the administration of an effective dose of mosnetuzumab and lenalidomide comprises administering the mosnetuzumab and lenalidomide according to a drug regimen comprising at least a first 21-day (±1-day) drug cycle and a second 28-day (±1-day) drug cycle, wherein the first drug cycle is administered on day 1, day 8 (±1-day), and day 15 (±1-day), respectively. The method is characterized by comprising (a) a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg, and (b) a second dosing cycle comprising a single dose (C2D1) of mosnetuzumab administered on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and (c) a second dosing cycle further comprising the oral administration of 20 mg of lenalidomide daily from day 1 to day 21 of the second dosing cycle.

[0027] In one embodiment, the present invention relates to a method of treating a subject comprising administering an effective amount of mosnetuzumab and an effective amount of lenalidomide to the subject, wherein the subject (i) has relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, and (ii) has been previously treated with at least one chemoimmunotherapy regimen comprising rituximab, and the administration of an effective amount of mosnetuzumab and lenalidomide comprises administering mosnetuzumab and lenalidomide according to a dosing regimen comprising a first 21-day (±1-day) dosing cycle and subsequent 28-day (±1-day) dosing cycles, wherein the first dosing cycle comprises a first dose (C1D1) administered intravenously on day 1, day 8 (±1-day), and day 15 (±1-day), respectively of the first dosing cycle, and a second dose (C1D1), respectively. The method is characterized by comprising (a) a dose (C1D2) and a third dose (C1D3) of mosnetuzumab, where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg, and (b) each of the second to twelfth drug cycles comprises a single dose (C2D1 to C12D1) of mosnetuzumab administered intravenously on day 1 of each drug cycle, where each single dose C2D1 to C12D1 is 30 mg, and (c) each of the second to twelfth drug cycles comprises the oral administration of 20 mg of lenalidomide daily on days 1 to 21 of each drug cycle.

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

[0029] In some embodiments, mosnetuzumab 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).

[0030] In some embodiments, FL has been histologically demonstrated to be grade 1, 2, or 3a, but not 3b, according to the World Health Organization's classification of lymphoid neoplasms (referenced in Swerdlow SH, et al. Blood 2016;127:2375-90).

[0031] In one embodiment, the present invention relates to a method for treating a target population, comprising administering an effective dose of mosnetuzumab and an effective dose of lenalidomide to each subject in the population, wherein each subject (a) has relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, and (b) has been previously treated with at least one chemoimmunotherapy regimen, and the administration of an effective dose of mosnetuzumab and lenalidomide comprises administering mosnetuzumab and lenalidomide according to a dosing regimen comprising at least a first dosing cycle of 21 days (±1 days) and a second dosing cycle of 28 days (±1 days), wherein the first dosing cycle is administered intravenously on day 1, day 8 (±1 days), and day 15 (±1 days), respectively of the first dosing cycle. The method is characterized by comprising (a) a dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab, where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg, and (b) a second dosing cycle comprising a single dose (C2D1) of mosnetuzumab administered intravenously on day 1 of the second dosing cycle, where C2D1 is 30 mg, and (c) a second dosing cycle further comprising the oral administration of 20 mg of lenalidomide daily from day 1 to day 21 of the second dosing cycle. In some embodiments, at least one chemoimmunotherapy regimen included an anti-CD20 monoclonal antibody (e.g., rituximab or obinutuzumab).

[0032] In one embodiment, the present invention relates to a method for treating a target population, comprising administering an effective dose of mosnetuzumab and an effective dose of lenalidomide to each subject in the population, wherein each subject (a) has relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, and (b) has been previously treated with at least one chemoimmunotherapy regimen, and the administration of an effective dose of mosnetuzumab and lenalidomide comprises administering mosnetuzumab and lenalidomide according to a dosing regimen comprising a first 21-day (±1) dosing cycle and subsequent 28-day (±1) dosing cycles, wherein the first dosing cycle comprises a first dose (C1D1) and a second dose (C1D1), administered intravenously on day 1, day 8 (±1), and day 15 (±1), respectively, of the first dosing cycle. (2) comprising a third dose (C1D3) of mosnetuzumab, 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 (C2D1 to C12D1) of mosnetuzumab administered intravenously on day 1 of each dosing cycle, where each single dose (C2D1 to C12D1) is 30 mg; and (c) each of the second to twelfth dosing cycles comprises an oral dose of 20 mg of lenalidomide daily on days 1 to 21 of each dosing cycle. In some embodiments, at least one chemoimmunotherapy regimen comprises an anti-CD20 monoclonal antibody (e.g., rituximab or obinutuzumab).

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

[0034] In some embodiments, each target FL has been histologically demonstrated to be grade 1, 2, or 3a, but not 3b, according to the World Health Organization's classification of lymphoid neoplasms (referenced in Swerdlow SH, et al. Blood 2016;127:2375-90).

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

[0036] In some embodiments, mosnetuzumab 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).

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

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

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

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

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

[0042] In some embodiments, the overall response rate is at least 80% (for example, 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 higher; for example, 8 0%~100%, 85~100%, 87~100%, 90~100%, 95~100%, 80%~90%, 80~85%, 85~97%, 85~95%, 85~90%, 85~87%, 90~95%, or 93~97%; 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%.

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

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

[0045] In some embodiments, the subjects are human. In some embodiments, each subject in the group is human.

[0046] In some embodiments, subjects exhibit a reduction in tumor burden after administration of an effective dose of mosnetuzumab and an effective dose of lenalidomide. In some embodiments, the reduction in tumor burden is determined by computed tomography (CT). In some embodiments, the reduction in tumor burden is a decrease in the sum of products of diameter (SPD) of the target lesion. In some embodiments, the reduction in SPD is at least 40% (e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more; e.g., 40-100%, 40-80%, 40-60%, 50-70%, 70-90%, 75-85%, 60-100%, 55-65%, 80-100%; e.g., about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%). In some embodiments, the reduction in SPD is at least 60%. In some embodiments, the reduction in SPD is at least 80%.

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

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

[0049] In some embodiments, the drug regimen further includes the administration of corticosteroids. In some embodiments, the corticosteroids are administered to the subject during a first drug cycle. In some embodiments, the first drug cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of corticosteroids. 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 drug cycle. In some embodiments, each single dose of corticosteroid C1D1-C1D3 is administered to the subject before the administration of mosnetuzumab C1D1-C1D3. In some embodiments, each single dose of corticosteroid C1D1-C1D3 is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours prior to the administration of each mosnetuzumab dose C1D1-C1D3.

[0050] In some embodiments, corticosteroids are administered to the subject in the first medication cycle but not in the second medication cycle.

[0051] In some embodiments, the corticosteroid is administered to the subject in a second dosing cycle. In some embodiments, the second dosing cycle includes a single dose (C2D1) of the corticosteroid. In some embodiments, the C2D1 dose of the corticosteroid is administered to the subject on day 1 of the second dosing cycle. In some embodiments, the C2D1 dose of the corticosteroid is administered to the subject before the administration of C2D1 dose of mosnetuzumab. In some embodiments, a C2D1 corticosteroid is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours prior to the administration of C2D1 mosnetuzumab.

[0052] In some embodiments, the drug regimen further includes the administration of corticosteroids. In some embodiments, the corticosteroids are administered to the subject during a first drug cycle. In some embodiments, the first drug cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of corticosteroids. 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 drug cycle. In some embodiments, each single dose of corticosteroid C1D1-C1D3 is administered to the subject before the administration of mosnetuzumab C1D1-C1D3. In some embodiments, each single dose of corticosteroid C1D1-C1D3 is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours prior to the administration of each mosnetuzumab dose C1D1-C1D3.

[0053] In some embodiments, corticosteroids are administered to the subject in the first medication cycle but not in the second medication cycle.

[0054] In some embodiments, the corticosteroid is administered to the subject in a second dosing cycle. In some embodiments, the second dosing cycle includes a single dose (C2D1) of the corticosteroid. In some embodiments, the C2D1 dose of the corticosteroid is administered to the subject on day 1 of the second dosing cycle. In some embodiments, the C2D1 dose of the corticosteroid is administered to the subject before the administration of C2D1 dose of mosnetuzumab. In some embodiments, a C2D1 corticosteroid is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours prior to the administration of C2D1 mosnetuzumab.

[0055] In some embodiments, each additional dosing cycle includes 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 before the administration of each additional dose of mosnetuzumab. In some embodiments, each additional dose of corticosteroid is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours before the administration of each additional dose of mosnetuzumab.

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

[0057] [Figure 1A] Figure 1A is a schematic diagram of the study plan described in Example 1 for the combination therapy regimen of mosnetuzumab and lenalidomide. C=Cycle; D=Day; FL=Follicular lymphoma; IMC=Internal Monitoring Committee; IV=Intravenous; Len=Lenalidomide; Mosun=Mosnetuzumab; RP2D=Recommended Phase II dose; R / R=Relapsed or refractory. Note: Cycle 1 is 21 days; Cycle 2 and subsequent cycles are 28 days. [Figure 1B] Figure 1B is a schematic diagram of the drug regimen described in Example 1. Lenalidomide is initiated in Cycle 2 to minimize the risks associated with starting mosnetuzumab in Cycle 1, especially in cases of the highest CRS risk. [Figure 2] Figure 2 is a butterfly plot showing adverse events that occurred in ≥10% of safety-evaluable patients described in Example 1, categorized by MedDRA organ-specific major classifications and MedDRA basic terminology. Based on MedDRA version 23.1. The grade of the adverse event is shown in the legend. The left side shows all adverse events. The right side shows adverse events attributable to treatment with mosnetuzumab (Mosun) or lenalidomide. Clinical cutoff date (CCOD) was April 5, 2021. [Figure 3]Figure 3 is a butterfly plot showing adverse events that occurred in ≥10% of safety-evaluable patients described in Example 1, categorized by MedDRA organ-specific major classifications and MedDRA basic terminology. Based on MedDRA version 23.1. The legend indicates the grade of the adverse event. The left side shows all adverse events. The right side shows adverse events attributable to treatment with mosnetuzumab (Mosun). CCOD as of April 5, 2021. [Figure 4] Figure 4 is a butterfly plot showing adverse events that occurred in 10% or more of the safety-evaluable patients described in Example 1, categorized by MedDRA organ-specific major classification and MedDRA basic terminology. Based on MedDRA version 23.1. The legend shows the grade of the adverse event. The left side shows all adverse events. The right side shows adverse events attributable to lenalidomide treatment. CCOD as of April 5, 2021. [Figure 5] Figure 5 is a swimlane plot showing the incidence of cytokine release syndrome (CRS) events in five patients treated with the 1 / 2 / 30 mg mosnetuzumab dosing regimen described in Example 1. The onset of Grade 1 or Grade 2 CRS is indicated by light or dark diamonds, respectively. CCOD as of April 5, 2021. [Figure 6] Figure 6 is a plot showing observed concentration-time data of mosnetuzumab (in combination with lenalidomide) from study CO41942, overlaid with a popPK model simulation based on mosnetuzumab monotherapy data from study GO29781, with the simulation performed at 1 / 2 / 30 mg Q4W. Filled red circles and lines represent individual observed mosnetuzumab concentration measurements and mean observed values ​​from study CO41942 at 1 / 2 / 30 mg IV doses in combination with lenalidomide. The shaded area represents the simulated concentration-time profile of mosnetuzumab monotherapy based on a population PK model simulation (prediction interval of 5–95) developed based on clinical data from study GO29781. [Figure 7]Figure 7 is a butterfly plot showing adverse events that occurred in ≥10% of safety-evaluable patients described in Example 3, categorized by MedDRA organ-specific major classifications and MedDRA basic terminology. Based on MedDRA version 23.1. The grade of the adverse event is shown in the legend. The left side shows all adverse events. The right side shows adverse events attributable to treatment with mosnetuzumab (Mosun) or lenalidomide. CCOD dated September 13, 2021. [Figure 8] Figure 8 is a bar graph showing cytokine release syndrome (CRS) events by medication cycle (C) and day (D), as well as CRS grade (Gr). The values ​​below the graph indicate the mosnetuzumab dose associated with each medication cycle (C) and (D) day. The C1D1 dose is administered on day 1 of the first cycle, the C1D2 dose on day 8 of the first cycle, and the C1D3 dose on day 15 of the first cycle. Subsequent doses are administered on day 1 of each respective medication cycle (C2, C3+). [Figure 9] Figure 9 is a bar graph showing neutropenia and febrile neutropenia events by medication cycle (C) and neutropenia grade (Gr). The number of patients who received granulocyte colony-stimulating factor (G-CSF) per medication cycle (C) is shown below the graph. [Figure 10] Figure 10 is a bar graph showing antitumor activity in patients who underwent one or more diagnostic computed tomography (CT) scans at the time of response evaluation. The number above each bar indicates the percentage change from baseline. The change in tumor burden is quantified by comparing the sum of products of target lesion diameters (SPD) with baseline measurements. [Figure 11]Figure 11 is a bar graph showing the overall response rate (ORR), complete response rate (CR), and partial response rate (PR) for 29 patients treated with the 1 / 2 / 30 mg mosnetuzumab and 20 mg oral lenalidomide regimen described in Example 3. Response rates are shown for 29 patients as of the data cutoff date of September 13, 2021. The 95% confidence interval (CI) for each response rate value is shown in parentheses below. Response rates were determined by positron emission tomography-computed tomography (PET-CT). [Figure 12] Figure 12 is a swimlane plot showing the duration of response in all 29 patients treated with the 1 / 2 / 30 mg mosnetuzumab and 20 mg oral lenalidomide regimen described in Example 3. The duration of response is shown for all 29 patients as of the data cutoff date of September 13, 2021. [Modes for carrying out the invention]

[0058] Detailed explanation The present invention relates to a method for treating subjects having relapsed and / or refractory (R / R) follicular lymphoma (FL) by administering mosnetuzumab and lenalidomide as combination therapy. In particular, the present invention relates to a method for treating subjects having R / R FL that is R / R to at least one prior systemic therapy (e.g., one prior treatment with a chemoimmunotherapy regimen) including an anti-CD20 antibody (e.g., an anti-CD20 monoclonal antibody, e.g., rituximab or obinutuzumab) or other treatment. This method involves administering an effective dose of mosnetuzumab according to a drug regimen comprising at least a first and second drug cycle, wherein (a) the first drug cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab, where C1D1 and C1D2 are less than or equal to C1D3, C1D1 is between 0.02 mg and 4.0 mg, C1D2 is between 0.05 mg and 20.0 mg, and C1D3 is between 0.2 mg and 50.0 mg, and (b) the second drug cycle comprises a single dose (C2D1) of mosnetuzumab, where C2D1 is greater than or equal to C1D3, and is between 0.2 mg and 50 mg.

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

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

[0061] II. Definition The aspects and embodiments of the present invention described herein are understood to include "including," "consisting of," and "essentially consisting of."

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

[0063] As used herein, the term “about” refers to the normal range of error for each value, as would be readily understood by those skilled in the art. References to values ​​or parameters following “about” herein include (and describe) embodiments relating to the value or parameter itself.

[0064] The terms "cancer" and "malignant" refer to or describe physiological conditions in mammals typically characterized by uncontrolled cell growth. Examples of cancer include, but are not limited to, hematological cancers such as mature B-cell carcinoma, and non-Hodgkin lymphomas (NHL), such as diffuse large B-cell lymphoma (DLBCL), which may be relapsed or refractory DLBCL or Richter's transformation, with the exception of Hodgkin lymphoma, for example. Other specific examples of cancer include germinal center B-cell-like (GCB) diffuse large B-cell lymphoma (DLBCL), activated B-cell-like (ABC) DLBCL, follicular lymphoma (FL), transformed FL, mantle cell lymphoma (MCL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), marginal zone lymphoma (MZL), transformed MZL, high-grade B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma (PMLBCL), Small lymphocytic leukemia (SLL), lymphoplasmacytic lymphoma (LL), transformed LL, Waldenström macroglobulinemia (WM), central nervous system lymphoma (CNSL), Burkitt lymphoma (BL), B-cell prelymphocytic leukemia, splenic marginal zone lymphoma, hairy cell leukemia, splenic lymphoma / leukemia, unclassified, diffuse red pulp small B-cell lymphoma of the spleen, hairy cell leukemia variant, heavy chain leukemia, α-heavy chain disease, γ-heavy chain disease, μ Heavy chain disease, plasmacytosis, solitary plasmacytoma of bone, extraskeletal plasmacytoma, extranodal marginal zone lymphoma (MALT lymphoma) of mucosa-associated lymphoid tissue, nodular marginal zone lymphoma, pediatric nodular marginal zone lymphoma, pediatric follicular lymphoma, primary cutaneous follicular central lymphoma, T-cell / histiocyte-rich large B-cell lymphoma, primary CNS DLBCL, primary cutaneous DLBCL, leg type, EBV-positive DLBCL in the elderly, DLBCL associated with chronic inflammation, phosphorus This includes granulomatous pamanoid disease, intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, plasmablastic lymphoma, large B-cell lymphoma resulting from HHV8-associated multicentric Castleman disease, and primary exudative lymphoma: unclassifiable B-cell lymphoma with intermediate features between DLBCL and Burkitt lymphoma, and unclassifiable B-cell lymphoma with intermediate features between DLBCL and classical Hodgkin lymphoma.Furthermore, examples of cancer include, but are not limited to, carcinomas, lymphomas, blastomas, sarcomas, and lymphoid malignancies, including leukemia or B-cell lymphoma. More specific examples of cancers like these include, but are not limited to, multiple myeloma (MM); low-grade / follicular NHL; small lymphocytic (SL) NHL; intermediate-grade / follicular NHL; intermediate-grade diffuse NHL; high-grade immunoblastic NHL; high-grade lymphocytic NHL; high-grade small undivided cell NHL; giant mass lesion NHL; AIDS-associated lymphoma; and acute lymphoblastic leukemia (ALL); chronic myeloblastic leukemia; and post-transplant lymphoproliferative disorder (PTLD).

[0065] Where used herein, “tumor” refers to the growth and proliferation of all neoplastic cells, whether malignant or benign, as well as all precancerous and cancerous cells and tissues. Where used herein, the terms “cancer,” “cancerous,” “proliferative disorder,” “proliferative disorder,” and “tumor” are not mutually exclusive.

[0066] "Disorder" is any condition from which a mammal would benefit from treatment, including but not limited to chronic and acute disorders or diseases, including the symptoms that cause the disorder in question.

[0067] The terms "proliferative disorder" and "proliferative disorder" refer to disorders related to a certain degree of abnormal cell proliferation. In one embodiment, the proliferative disorder is cancer. In other embodiments, the proliferative disorder is a tumor.

[0068] The terms “B-cell proliferative disorder” or “B-cell malignancy” refer to diseases associated with some degree of abnormal B-cell proliferation, including, for example, lymphoma, leukemia, myeloma, and myelodysplastic syndromes. In some examples, B-cell proliferative disorder is lymphoma such as non-Hodgkin lymphoma (NHL), including, for example, follicular lymphoma (FL) (e.g., relapsed and / or refractory FL or transformed FL), diffuse large B-cell lymphoma (DLBCL) (e.g., relapsed or refractory DLBCL or Richter transformed), MCL, high-grade B-cell lymphoma, or PMLBCL. In another embodiment, B-cell proliferative disorder is leukemia such as chronic lymphocytic leukemia (CLL). In one embodiment, B-cell proliferative disorder is relapsed and / or refractory FL.

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

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

[0071] "Refractory disease" is defined as the absence of complete remission to at least one first-line treatment. In one embodiment, refractory disease is defined as the absence of response to prior treatment or relapse within six months of prior treatment. In one embodiment, refractory disease is characterized by one or more of the following: progressive disease (PD) as the best response to first-line treatment; stable disease (SD) as the best response after at least one first-line treatment (e.g., at least one anti-CD20 targeted therapy including an anti-CD20 antibody, e.g., anti-CD20 monoclonal antibody, e.g., rituximab or obinutuzumab); or partial response (PR) as the best response; and residual disease or disease progression as demonstrated by biopsy after partial response. "Relapsing disease" is defined as complete remission to first-line treatment. In one embodiment, disease relapse is demonstrated by biopsy. In one embodiment, the patient had relapsed or failed to respond to at least one prior systemic treatment regimen (e.g., at least one including anti-CD20 targeted therapy, such as anti-CD20 antibodies, e.g., anti-CD20 monoclonal antibodies, e.g., rituximab or obinutuzumab).

[0072] As used herein, “treatment” (and its grammatical variations such as “treat” or “treating”) refers to a clinical intervention in an attempt to alter the natural course of the subject being treated, which may be carried out for preventive purposes or during the course of clinicopathology. Desired effects of treatment include, but are not limited to, preventing the onset or recurrence of disease, reducing symptoms, attenuating any direct or indirect pathological consequences of the disease, preventing metastasis, slowing the rate of disease progression, remission or mitigation of symptoms, and recovery or improvement of prognosis. In some embodiments, the antibodies of the present invention are used to delay the onset of disease or to delay the progression of disease.

[0073] As used herein, “delaying the progression” of a disorder or disease means delaying, interfering with, slowing, stabilizing, and / or postponing the onset of a disease or disorder (e.g., recurrent and / or refractory FL). This delay may vary in duration depending on the disease history and / or the individual being treated. As will be apparent to those skilled in the art, a sufficient or significant delay can effectively encompass prevention in that the individual does not develop the disease. For example, it can delay the progression of terminal cancer, such as the development of metastases.

[0074] "Reduce" or "inhibit" means the ability to cause an overall reduction of, for example, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or more. For clarity, this term also includes reduction to 0 (or below the detection limit of the analytical method), i.e., complete disappearance or elimination. In certain embodiments, reduction or inhibition may refer to the reduction or inhibition of undesirable events such as cytokine-driven toxicity (e.g., cytokine release syndrome (CRS)), infusion-related reactions (IRRs), macrophage activation syndrome (MAS), neurotoxicity, severe oncolytic syndrome (TLS), neutropenia, thrombocytopenia, elevated liver enzymes, and / or central nervous system (CNS) toxicity after treatment with mostuzumab using the step-up dosing regimen of the present invention, compared to administration at a preset dose without alteration of the target dose of mostuzumab. In other embodiments, reducing or inhibiting may refer to the effector function of an antibody mediated by the antibody Fc region, such effector function specifically includes complement-dependent cell-mediated cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and antibody-dependent cell-mediated phagocytosis (ADCP). In other embodiments, reducing or inhibiting may refer to the symptoms of the treated R / R FL, the presence or size of metastases, or the size of the primary tumor. In yet another embodiment, reducing or inhibiting cancer recurrence means reducing or inhibiting the recurrence of tumor or cancer, or the progression of tumor or cancer.

[0075] As used herein, “administer” means a method of giving a subject a dose of a compound (e.g., a bispecific antibody, e.g., an anti-CD20 / anti-CD3 bispecific antibody, e.g., mosnetuzumab) or a composition (e.g., a pharmaceutical composition, e.g., a pharmaceutical composition containing a bispecific antibody (e.g., mosnetuzumab)). The compounds and / or compositions used in the methods described herein may be administered intravenously (e.g., by intravenous infusion).

[0076] In this specification, a “fixed” or “flat” dose of a therapeutic agent (e.g., a bispecific antibody) refers to a dose administered to a patient regardless of their body weight or body surface area (BSA). Therefore, this fixed or constant dose is expressed in mg / kg or mg / m². 2 It is provided not as a dosage, but rather as an absolute amount of the therapeutic agent (e.g., mg).

[0077] The "subject" or "individual" is a mammal. Mammals include, but are not limited to, primates (e.g., humans and non-human primates, e.g., monkeys), domestic animals (e.g., cattle, sheep, cats, dogs, and horses), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the subject or individual is a human.

[0078] "Individual response" or "response" may be evaluated using any endpoint demonstrating a benefit to the subject, including, but not limited to, (1) some degree of inhibition of disease progression (e.g., cancer progression), including slowing and complete cessation; (2) reduction of tumor size; (3) inhibition of cancer cell invasion into adjacent peripheral organs and / or tissues (i.e., reduction, slowing, or complete cessation); (4) inhibition of metastasis (i.e., reduction, slowing, or complete cessation); (5) some degree of reduction of one or more R / R FL-related symptoms; (6) increase or extension of overall survival and progression-free survival; and / or (9) reduction of mortality at a given time point after treatment.

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

[0080] As used herein, “partial response” or “PR” means a reduction of at least 30% of the sum of the longest diameters (SLDs) of target lesions, relative to reference SLD, or a reduction of at least 50% of the sum of the product diameters (SPD) of target lesions, relative to reference SPD.

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

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

[0083] As used herein, “tumor load” refers to the total amount of tumor (e.g., tumor cells or tumor mass) in an object (e.g., a human object) having cancer, e.g., NHL, e.g., FL. In some embodiments, tumor load is defined as the sum of the diameters of target lesions or the sum of the products of target lesions. In certain embodiments, tumor load is defined as the sum of the products of the diameters of target lesions (SPD). In some embodiments, the diameter of target lesions is quantified by computed tomography (CT).

[0084] "Sustained response" refers to a sustained effect of reducing tumor growth after discontinuation of treatment. For example, tumor size may remain the same as or become smaller compared to the size at the start of the treatment phase. In some embodiments, the sustained response lasts for at least the same duration as the treatment period, or at least 1.5, 2.0, 2.5, or 3.0 times the treatment period.

[0085] The terms "effective response" or "responsiveness" and similar words to those used in medical treatment refer to the clinical or therapeutic benefit bestowed upon a subject who is at risk of or suffering from a disease or disorder such as cancer. In one embodiment, such benefit may include one or more of the following: extension of survival (including overall survival and progression-free survival), achieving an objective response (including complete or partial response), or improving the signs or symptoms of cancer.

[0086] A patient who "does not show an effective response" to treatment is one who does not experience any of the following: an extension of survival (including overall survival and progression-free survival), an objective response (including complete or partial response), or an improvement in signs or symptoms of cancer.

[0087] As used herein, the term “survival” means that a patient is alive, and includes overall survival and progression-free survival.

[0088] As used herein, "overall survival" (OS) refers to the proportion of subjects who are still alive at a specific time, for example, one year or five years after diagnosis or treatment.

[0089] As used herein, “progression-free survival” (PFS) refers to the length of time during and after treatment in which the treated disease (e.g., R / R FL) does not worsen. Progression-free survival may include the amount of time the patient experienced complete or partial response, as well as the amount of time the patient experienced stable disease.

[0090] As used herein, “stable disease” or “SD” refers to a state where, based on the minimum SLD since the start of treatment, there is neither sufficient shrinkage of the target lesion to be considered a partial response (PR) nor sufficient increase to be considered a progressive disease (PD).

[0091] As used herein, “progressive disease” or “PD” means that, since the initiation of treatment, the SLD of the target lesion has increased by at least 20% from the lowest SLD, or the SPD of the target lesion has increased by at least 50% from the lowest SPD, or the presence of one or more new lesions.

[0092] As used herein, “delaying the progression” of a disorder or disease means delaying, interfering with, slowing, stabilizing, and / or postponing the onset of the disease or disorder (e.g., relapsed and / or refractory (R / R) follicular lymphoma (FL)). This delay may be of varying duration depending on the medical history and / or the subject being treated. As will be apparent to those skilled in the art, a sufficient or significant delay may substantially encompass prevention in that the subject does not develop the disease. For example, in terminal cancer, the development of central nervous system (CNS) metastases may be delayed.

[0093] "Prolonged survival" means an increase in overall survival or progression-free survival in treated patients compared to untreated patients (e.g., patients not treated with medication), or patients not expressing a specified level of biomarker, and / or patients treated with an approved antitumor agent. Objective response refers to a measurable response, including complete response (CR) or partial response (PR).

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

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

[0096] The terms “full-length antibody,” “intact antibody,” and “whole antibody” are used herein synonymously to refer to antibodies having a structure substantially similar to that of a native antibody or having a heavy chain containing an Fc region as defined herein.

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

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

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

[0100] As used herein, the terms IgG “isotype” or “subclass” mean any of the subclasses of immunoglobulins defined by the chemical and antigenic properties of their constant regions.

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

[0102] The "Human Consensus Framework" is a framework representing the most commonly occurring amino acid residues in the selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from subgroups of variable domain sequences. Generally, the sequence subgroups are those found in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda MD (1991), vols. 1-3. In one embodiment, for VL, the subgroup is subgroup Kappa I in Kabat et al. (see above). In one embodiment, for VH, the subgroup is subgroup III in Kabat et al. (see above).

[0103] For the purposes of this specification, “acceptor human framework” means a framework comprising the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or a human consensus framework, as defined below. An acceptor human framework “derived” from a human immunoglobulin framework or a human consensus framework may contain the same amino acid sequence or may contain a modification of the amino acid sequence. In some embodiments, the number of amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, the VL acceptor human framework is sequence-identical to the VL human immunoglobulin framework sequence or the human consensus framework sequence.

[0104] A “humanized” antibody refers to a chimeric antibody containing amino acid residues derived from non-human HVR and amino acid residues derived from human FR. In certain embodiments, a humanized antibody contains substantially all of at least one, typically two, variable domains, where all or substantially all of the HVR (e.g., CDR) corresponds to a non-human antibody and all or substantially all of the FR corresponds to a human antibody. A humanized antibody may optionally contain at least a portion of the antibody constant region derived from a human antibody. The “humanized form” of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization.

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

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

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

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

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

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

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

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

[0113] An "affinity-mature" antibody refers to an antibody that, compared to a parent antibody without any modifications, has one or more modifications in one or more hypervariable regions (HVRs), and in which such modifications improve the antibody's affinity for the antigen.

[0114] The terms "anti-CD3 antibody" and "antibody that binds to CD3" refer to an antibody that can bind to CD3 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent targeting CD3. In one embodiment, the binding of the anti-CD3 antibody to non-related non-CD3 proteins is, for example, less than about 10% of the binding of the antibody to CD3 as measured by, for example, radioimmunoassay (RIA). In certain embodiments, the antibody that binds to CD3 has a dissociation constant (K -8 ) of 1 μM or less, 100 nM or less, 10 nM or less, 1 nM or less, 0.1 nM or less, 0.01 nM or less, or 0.001 nM or less (e.g., 10 -8 M or less, e.g., 10 -13 M to 10 -9 M, e.g., 10 -13 M). In certain embodiments, the anti-CD3 antibody binds to an epitope of CD3 that is conserved among CD3s from different species.

[0115] The term "surface antigen classification 3" or "CD3", as used herein, refers to any native CD3 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated, and includes, for example, CD3ε, CD3γ, CD3α, and CD3β chains. This term encompasses "full-length" unprocessed CD3 (e.g., unprocessed or unmodified CD3ε or CD3γ), as well as any form of CD3 obtained from intracellular processing. This term also encompasses naturally occurring variants of CD3, including, for example, splice variants or allelic variants. CD3 includes, for example, the human CD3ε protein that is 207 amino acids long (NCBI reference sequence number NP_000724), and the human CD3γ protein that is 182 amino acids long (NCBI reference sequence number NP_000064).

[0116] ​​The terms “anti-CD20 antibody” and “CD20-binding antibody” refer to an antibody capable of binding to CD20 with sufficient affinity to be useful as a diagnostic and / or therapeutic agent in targeting CD20. In one embodiment, the degree of binding of an anti-CD20 antibody to unrelated non-CD20 proteins is less than about 10% of the binding of the antibody to CD20, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, the antibody that binds to CD20 is less than 1 μM, less than 100 nM, less than 10 nM, less than 1 nM, less than 0.1 nM, less than 0.01 nM, or less than 0.001 nM (e.g., 10 -8 M or less, for example, 10 -8 M~10 -13 M, for example 10 -9 M~10 -13 The dissociation constant (K) of M D ) has. In certain embodiments, the anti-CD20 antibody binds to an epitope of CD20 that is conserved among CD20s from different species. In some embodiments, the anti-CD20 antibody is a monoclonal antibody. In some embodiments, the anti-CD20 antibody or anti-CD20 monoclonal antibody is rituximab. In some embodiments, the anti-CD20 antibody or anti-CD20 monoclonal antibody is obinutuzumab.

[0117] As used herein, the terms “rituximab” or “RITUXAN®” refer to an anti-CD20 antibody (e.g., an anti-CD20 monoclonal antibody) having Proposed International Nonproprietary Names for Pharmaceutical Substances (Proposed INN) List 77 (WHO Drug Information, Vol. 11, No. 2, 1997, p. 99) or CAS Registry Number 174722-31-7.

[0118] As used herein, the terms “obinutuzumab” or “GAZYVA®” refer to an anti-CD20 antibody (e.g., an anti-CD20 monoclonal antibody) having Proposed International Nonproprietary Name for Pharmaceutical Substances (Proposed INN) List 99 (WHO Drug Information, Vol. 22, No. 2, 2008, p. 396), Proposed International Nonproprietary Name for Pharmaceutical Substances (Proposed INN) List 108 (WHO Drug Information, Vol. 26, No. 4, 2012, p. 453), or CAS Registry Number 949142-50-1.

[0119] As used herein, the terms “Surface Antigen Classification 20” or “CD20” refer to any natural CD20 derived from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise specified. The term encompasses “full-length,” untreated CD20, and any form of CD20 resulting from intracellular processing. The term also encompasses naturally occurring variants of CD20, including, for example, splice variants or allele variants. CD20 includes, for example, the human CD20 protein (see, e.g., NCBI reference sequence numbers NP_068769.2 and NP_690605.1), which is, for example, 297 amino acids long and can be produced from, for example, a variant mRNA transcript lacking a portion of the 5'UTR (see, e.g., NCBI reference sequence number NM_021950.3) or a longer mutant mRNA transcript (see, e.g., NCBI reference sequence number NM_152866.2).

[0120] The terms “anti-CD20 / anti-CD3 bispecific antibody,” “bispecific anti-CD20 / anti-CD3 antibody,” and “antibody that binds to CD20 and CD3,” or their variants, refer to a polyspecific antibody (e.g., a bispecific antibody) that is capable of binding to CD20 and CD3 with sufficient affinity so that it is useful as a diagnostic and / or therapeutic agent when the antibody targets CD20 and / or CD3. In one embodiment, the degree of binding of a CD20 and CD3-binding bispecific antibody to unrelated non-CD3 proteins and / or non-CD20 proteins is less than about 10% of the binding of the antibody to CD3 and / or CD20, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, the CD20 and CD3-binding bispecific antibody may have a concentration of 1 μM or less, 100 nM or less, 10 nM or less, 1 nM or less, 0.1 nM or less, 0.01 nM or less, or 0.001 nM or less (e.g., 10 -8 M or less, for example, 10 -8 M~10 -13 M, for example 10 -9 M~10 -13 The dissociation constant (K) of M D ) has. In certain embodiments, the bispecific antibody that binds to CD20 and CD3 binds to an epitope of CD3 that is conserved between CD3s from different species and / or an epitope of CD20 that is conserved between CD20s from different species. In one embodiment, the bispecific antibody binds monovalently to CD20 and monovalently to CD3. In some embodiments, the bispecific antibody that binds to CD20 and CD3 is mosnetuzumab.

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

[0122] As used herein, the term "lenalidomide" refers to the compound having CAS Registry Number 191732-72-6 and IUPAC Name (3RS)-3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione. Lenalidomide is also known by trade names including REVLIMID®, Linamide, and Lenalid. Lenalidomide has DrugBank accession number DB00480, PubChem CID 216326, and chemical formula C 13 H 13 It contains N3O3.

[0123] As used herein, the terms “binding,” “specifically binding to,” or “specific to” refer to measurable and reproducible interactions, such as binding between a target and an antibody, which determine the presence of the target in the presence of a heterogeneous population of molecules, including biomolecules. For example, an antibody that specifically binds to a target (which may be an epitope) is an antibody that binds to this target more readily and / or for a longer duration with higher affinity and binding strength than an antibody that binds to other targets. In one embodiment, the extent to which an antibody binds to an unrelated target is less than about 10% of the antibody’s binding to the target, as measured by radioimmunoassay (RIA). In certain embodiments, an antibody that specifically binds to a target has a dissociation constant (K) of ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, or ≤0.1 nM. D ) has. In certain embodiments, the antibody specifically binds to an epitope on a protein that is conserved between proteins of different species. In other embodiments, specific binding may include, but is not required, exclusive binding. The terms used herein are, for example, 10 against a target. -4 M or less, or 10 -5 M or less, or 10 -6 M or less, or 10 -7 M or less, or 10 -8 M or less, or 10 -9 M or less, or 10 -10 M or less, or 10 -11 M or less, or 10-12 K below M D , or 10 -4 M~10 -6 M, or 10 -6 M~10 -10 M, or 10 -7 M~10 -9 M range K D This can be represented by molecules having affinity and K. As will be understood by those skilled in the art, affinity and K D The values ​​are inversely correlated. High affinity for the antigen is associated with low K D It is measured by a value. In one embodiment, the term “specific binding” refers to binding where a molecule binds to a specific polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptide or polypeptide epitope.

[0124] The "amino acid sequence identity percentage (%)" for a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues of the reference polypeptide, after the sequences have been aligned and gaps introduced if necessary to obtain the maximum percentage of sequence identity, and no conservative substitutions are considered part of the sequence identity. Alignment for determining the amino acid sequence identity percentage can be obtained using various methods within the scope of the art, such as commonly available computer software like BLAST, BLAST-2, ALIGN, or MEGALIGN® (DNASTAR®) software. Those skilled in the art can determine appropriate parameters for sequence alignment, including any algorithm necessary to achieve the maximum alignment over the entire length of the sequences being compared. However, for the purposes of this specification, the amino acid sequence identity % value is generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was created by Genentech, Inc., and its source code, along with user documentation, has been filed with the U.S. Copyright Office, Washington DC, 20559, and is hereby registered under U.S. Copyright Registration Number TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc. (South San Francisco, California) or can be compiled from its source code. The ALIGN-2 program should be compiled for use with UNIX® operating systems, including Digital UNIX® V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and remain unchanged.

[0125] In situations where ALIGN-2 is used for amino acid sequence comparison, the amino acid sequence identity percentage of a given amino acid sequence A to, with, or relative to a given amino acid sequence B (or, a given amino acid sequence A may be described as having or containing a specific amino acid sequence identity percentage to, with, or relative to a given amino acid sequence B) is calculated as follows: 100 x fraction X / Y In this case, X is the number of amino acid residues scored as identical matches in the alignment of A and B by the sequence alignment program ALIGN-2, and Y is the total number of amino acid residues in B. It will be understood that if the length of amino acid sequence A is different from the length of amino acid sequence B, the % amino acid sequence identity of A to B will be different from the % amino acid sequence identity of B to A. Unless otherwise specified, all % amino acid sequence identity values ​​used herein are obtained using the ALIGN-2 computer program as described in the preceding paragraph.

[0126] The term "pharmaceutical preparation" refers to a preparation in which the biological activity of the active ingredient contained in the preparation is effective, and which does not contain any additional components that are unacceptably toxic to the person to whom the preparation is administered.

[0127] A "pharmaceutically acceptable carrier" refers to a component in a pharmaceutical preparation other than the active ingredient that is non-toxic to the target substance. Pharmaceutically acceptable carriers include, but are not limited to, buffers, additives, stabilizers, or preservatives.

[0128] As used herein, the term “chemotherapeutic agent” refers to compounds useful for treating cancers such as R / R FL. Examples of chemotherapeutic agents include EGFR inhibitors (including 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, Pfizer Inc.); ZD1839, gefitinib (IRESSA®) 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180((6-amino-4-(3-methylphenylamino)-quinazoline, Zeneca); BIBX-1382(N8-(3-chloro-4-fluorophenyl)-N2-(1-methylpiperidine-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim); PKI-166((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidine-6-yl]-phenol); (R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine); CL-387785(N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butinamide); EKB-569(N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide)(Wyeth); AG1478(Pfizer); AG1571(SU Dual EGFR / HER2 tyrosine kinase inhibitors such as 5271; Pfizer; and lapatinib (TYKERB®, GSK572016 or N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6[5[[[2-methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine)); tyrosine kinase inhibitors (e.g., EGFR inhibitors; small molecule HER2 tyrosine kinase inhibitors such as TAK165 (Takeda);Oral selective inhibitors of ErbB2 receptor tyrosine kinases (Pfizer and OSI) such as CP-724, 714; dual HER inhibitors such as EKB-569 (available from Wyeth) (which preferentially bind to EGFR but inhibit both HER2 and EGFR overexpressing cells); pan-HER inhibitors such as PKI-166 (Novartis); canertinib (CI-1033; Pharmacia); Raf-1 inhibitors such as antisense agents that inhibit Raf-1 signaling, such as ISIS-5132 (ISIS Pharmaceuticals); non-HER-targeted tyrosine kinase inhibitors such as imatinib mesylate (GLEEVEC®, Glaxo SmithKline); multi-target tyrosine kinase inhibitors such as sunitinib (SUTENT®, Pfizer); batalanib (PTK787 / ZK222584, Novartis / Schering VEGF receptor tyrosine kinase inhibitors such as AG; MAPK extracellular regulatory kinase I inhibitor CI-1040 (Pharmacia); quinazolins such as PD153035, 4-(3-chloroanilino)quinazoline; pyridopyrimidines; pyrimidopyrimidines; CGP 59326, CGP 60261 and CGP Pyrropyrimidines such as 62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidines; curcumin (diferloylmethane, 4,5-bis(4-fluoroanilino)phthalimide); tyrofostine containing the nitrothiophene moiety; PD-0183805 (Warner-Lamber); antisense molecules (e.g., those that bind to nucleic acids encoding HER); quinoxaline (US Patent No. 5,804,396); triphostine (US Patent No. 5,804,396); pan-HER inhibitors such as ZD6474 (Astra Zeneca); PTK-787 (Novartis / Schering AG); CI-1033 (Pfizer); Affinitac (ISIS3521; Isis / Lilly); PKI 166 (Novartis); GW2016 (Glaxo SmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474 (AstraZeneca);Proteasome inhibitors such as PTK-787 (Novartis / Schering AG); INC-1C11 (Imclone); and rapamycin (sirolimus, RAPAMUNE®); 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), finasnate (VATALANIB®, Novartis); oxaliplatin (ELOXATIN®, Sanofi); 5-FU (5-fluorouracil); leucovorin; ronafamib (SCH 66336); alkylating agents such as sorafenib (NEXAVAR®, Bayer Labs), AG1478, thiotepa, and CYTOXAN® cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and pigosulfan; aziridines such as benzodopa, carboquan, methuredopa, and uredopa; ethyleneimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylomellamine; acetogenins (especially bratacin and bratacinone); camptothecin (including topotecan and irinotecan); bryostatin; callistatin; C C-1065 (including synthetic analogs of adzeresin, karzeresin, and bizeresin); cryptophycin (especially cryptophycin 1 and cryptophycin 8); adrenocorticosteroids (including prednisone and prednisolone); cyproterone acetate; 5α-reductase including finasteride and dutasteride; vorinostat, romidepsin, panobinostat, valproic acid, mosetinostat, dorastatin; aldesleukin, talc duocalmycin (including synthetic analogs, KW-2189, and CB1-TM1); eletarin; pancratistatin; sarcodicin; spongistatin;Nitrogen mustards such as chlorambucil, chromafazine, chlorophosphamide, estramustine, ifosfamide, mechlorestamine, mechlorestamine oxide hydrochloride, melphalan, nobenbitin, fenesterine, prednimustine, trophosphamide, and uracil mustard; nitrosoureas such as carmustine, chlorozotosine, fotemustine, lomustine, nimustine and ranimustine; antibiotics such as enidine antibiotics (e.g., calichemycin, especially calichemycin γ1 and calichemycin ω1); and dynemycin A. Along with inemycin; bisphosphonates such as clodronate; esperamycin, neocardinostatin chromophores and related chromophores (endiin antibiotic chromophores), acrasinomycin, actinomycin, autoramycin, azaserin, kakutinomycin, carabicin, kaminomycin, cardinophilin, chromomycin, dactinomycin, detrubicin, 6-diazo-5-oxo-L-norleucine, morpholinodoxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolidoxorubicin and deoxydoxorubicin), epirubicin Mitomycins such as esorubicin, idarubicin, marcelomycin, and mitomycin C, mycophenolates, nogaramycin, olibomycin, peplomycin, porphyromycin, puromycin, keramycin, rhodorubicin, streptonignin, streptozocin, tuberculin, ubenimex, dinostatin, and zolubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimethrexate; fludarabine, 6-mercaptopramine Phosphorus, thiamiprine, thioguanine and other purine analogs; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, phloxlyzine and other pyrimidine analogs; carsterone, dromostanolone propionate, epithiostanol, mepitiosteine, testolactone and other androgens; anti-adrenal drugs such as aminoglutethimide, mitotane, and trilosteine; folic acid supplements such as phloric acid; acegraton; aldofsphamide glycosides; aminolevulinic acid;Eniluracil; Amsacrin; Bestrabusil; Bisanthren; Edatraxate; Defofamine; Demecolsin; Diazykion; Elfomitin; Elliptin acetate; Epotilon; Etoglucid; Gallium nitrate; Hydroxyurea; Lentinan; Ronidinin; Maytansinoids such as Maytansine and Ansamitosine; Mitoguazone; Maitoxantrone; Mopidamnol; Nitraerin; Pentostatin; Fenamet; Pirarubicin; Rosoxantrone; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; PSK (registered trademark) polysaccharide complex (JHS Natural) Products); Lazoxane; Rhizoxin; Schizofuran; Spirogermanium; Tenuazonic acid; Triazykion; 2,2',2''-Trichlorotriethylamine; Trichothecene (especially T-2 toxin, veraculin A, loridine A and anguidin); Urethane; Vindesine; Dacarbazine; Mannomustine; Maitobronitol; Maitractol; Pipobroman; Gacitosine; Arabinoside ("Ar a-C); Thiotepa; Chlorambucil; GEMZAR® (Gemcitabine); 6-Thiogunine; Mercaptopurine; Methotrexate; Tetoposide (VP-16); Ifosfamide; Mitoxantrone; Nobandron; Teniposide; Edatrexate; Daunomycin; Aminopterin; Capecitabine (XELODA®); Ibandronate; CPT-11; Topoisomerase inhibitor RFS 2000; Difluoromethylornithine (DMFO); Retinoids such as retinoic acid; and any pharmaceutically acceptable salts, acids, prodrugs, and derivatives of the above.

[0129] Chemotherapy agents also include (i) anti-hormone agents that act to modulate or inhibit the hormonal effects on tumors, such as anti-estrogens and selective estrogen receptor modulators (SERMs), (tamoxifen (Nolvadex®; including tamoxifen citrate), raloxifene, droloxifene, iodoxifene, 4-hydroxytamoxifen, trioxyfen, keoxyfen, LY117018, onapristone, and Fareston® (citric acid) (ii) including toremifine acid); (ii) aromatase inhibitors that inhibit aromatase, an enzyme that regulates estrogen production in the adrenal gland, such as 4(5)-imidazole, aminoglutethimide, Megase® (megestrol acetate), Aromasin® (exemestane; Pfizer), Formestany, Fadrozol, Rivisor® (borozol), Femara® (letrozole; Novartis), and Arimidex® (Registered Trademark) (Anastrozole; AltraZeneca); (iii) Antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; buserelin, trypterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all trans-retionic acids, fenretinide, and troxacitabine (1,3-dioxolane nucleoside cytosine analog); (iv) Protein kinase inhibitors; (v) Lipid kinase inhibitors; (vi) Antisense oligonucleotides, particularly those that inhibit gene expression in signaling pathways involved in abnormal cell proliferation, e.g., PKC-alpha, Ralf, and H-Ras; (vii) Ribozymes such as VEGF expression inhibitors (e.g., Angiozyme®) and HER2 expression inhibitors; (viii) Gene therapy vaccines, e.g., vaccines such as ALLOVECTIN®, leubectin®, and VAXID®;(ix) Growth inhibitors comprising vinca (e.g., vincristine and vinblastine), navelbine® (vinorelbine), taxanes (e.g., paclitaxel, nab-paclitaxel, and docetaxel), topoisomerase II inhibitors (e.g., doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin), and DNA alkylating agents (e.g., tamoxigen, dacarbazine, mechloretamine, cisplatin, methotrexate, 5-fluorouracil, and ara-C); and (x) any pharmaceutically acceptable salts, acids, prodrugs, and derivatives of any of the above.

[0130] The term "chemoimmunotherapy" refers to a combination therapy that includes both chemotherapeutic agents and immunotherapeutic agents. In some embodiments, chemoimmunotherapy is used to treat cancer, such as CD20-positive cancers, such as NHL and FL. In some embodiments, the immunotherapeutic agent is an antibody, such as an anti-CD20 antibody (e.g., an anti-CD20 monoclonal antibody). In some embodiments, the anti-CD20 antibody or anti-CD20 monoclonal antibody is rituximab or obinutuzumab. In some embodiments, chemoimmunotherapy includes R-CHOP.

[0131] As used herein, the term “R-CHOP” refers to a treatment comprising rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. In some embodiments, R-CHOP is a chemotherapy treatment or regimen used to treat cancer, optionally, B-cell proliferative disorders (e.g., non-Hodgkin lymphoma; e.g., DLBCL or high-grade B-cell lymphoma). In some embodiments, R-CHOP is a standard of care (SOC) or standard therapy administered to a subject to treat cancer, optionally, B-cell proliferative disorders (e.g., non-Hodgkin lymphoma; e.g., DLBCL or high-grade B-cell lymphoma). In some embodiments, R-CHOP is a standard state-of-the-art treatment or first-line treatment administered to a previously untreated subject. In some embodiments, R-CHOP is administered every three weeks (in 21-day dosing cycles) for three to six dosing cycles. In some embodiments, the dosing regimen for R-CHOP therapy includes a 21-day dosing cycle, during which the subject receives 375 mg / m². 2 Rituximab IV is administered, along with cyclophosphamide, doxorubicin, vincristine, and prednisone. In some embodiments, the drug regimen for R-CHOP therapy is 750 mg / m². 2 Cyclophosphamide IV, 50 mg / m² 2 Doxorubicin IV, 1.4 mg / m² 2 Vincristine IV, and 100 mg or 40 mg / m² for 5 days. 2 The formula further includes oral prednisone daily. In some embodiments, the maximum single dose of vincristine is 2 mg.

[0132] As used herein, the term “cytotoxic agent” refers to any agent that is harmful to cells (e.g., causes cell death, inhibits proliferation, or otherwise interferes with cellular function). Examples of cytotoxic agents include radioisotopes (e.g., 211 At, 131 I, 125 I, 90 Y, 186 Re, 188 Re, 153Sm, 212 Bi, 32 P, 212 Examples of cytotoxic agents include, but are not limited to, radioisotopes of Pb and Lu; chemotherapeutic agents; enzymes such as nucleases and their fragments; and toxins, such as small molecule toxins or enzymatically active toxins (including their fragments and / or variants) of bacterial, fungal, plant, or animal origin. Exemplary cytotoxic agents may be selected from antimicrotubule agents, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, signaling pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, apoptosis promoters, LDH-A inhibitors, fatty acid biosynthesis inhibitors, cell cycle signaling inhibitors, HDAC inhibitors, proteasome inhibitors, and cancer metabolism inhibitors. In one example, a cytotoxic agent is a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin). In one example, the cytotoxic agent is an EGFR antagonist, e.g., N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazoline-4-amine (e.g., erlotinib). In another example, the cytotoxic agent is a RAF inhibitor, e.g., a BRAF and / or CRAF inhibitor. In yet another example, the RAF inhibitor is vemurafenib. In yet another example, the cytotoxic agent is a PI3K inhibitor.

[0133] The term “package insert” is used to refer to instructions that are typically included in the market packaging of therapeutic products and that contain information about indications, usage, dosage, administration, combination therapy, contraindications and / or warnings relating to the use of such therapeutic products.

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

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

[0136] A. Treatment methods for administering mosnetuzumab The present invention relates to a method for treating subjects having relapsed and / or refractory (R / R) follicular lymphoma (FL) by administering mosnetuzumab and lenalidomide as combination therapy. In particular, the present invention relates to a method for treating subjects having R / R FL that is R / R to at least one prior systemic therapy (e.g., one prior treatment with a chemoimmunotherapy regimen) including an anti-CD20 antibody (e.g., an anti-CD20 monoclonal antibody, e.g., rituximab or obinutuzumab) or other treatment. In some embodiments, mosnetuzumab 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 complete response as defined by the Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014;32:1-9).

[0137] In some embodiments, administering an effective dose of mosnetuzumab comprises administering mosnetuzumab according to a dosing regimen comprising at least a first dosing cycle and a second dosing cycle, where (a) the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab, where C1D1 and C1D2 are each less than or equal to C1D3, and C1D1 is between 0.02 mg and 4.0 mg (e.g., 0.05 mg to 4.0 mg, 0.1 mg to 4.0 mg, 0.2 mg to 4.0 mg, 0.3 mg to 4.0 mg) , 0.4mg~4.0mg, 0.5mg~4.0mg, 0.75mg~4.0mg, 1.0mg~4.0mg, 1.25mg~4.0mg, 1.5mg~4.0mg, 2.0mg~4.0mg, 2.5mg~4.0mg, 3.0mg~4.0mg, 3.5mg~4.0mg, 0 .1mg~3.5mg, 0.1mg~3.0mg, 0.1mg~2.5mg, 0.1mg~2.0mg, 0.1mg~1.5mg, 0.1mg~1mg, 0.1mg~0.5mg, 0.5mg~3.0mg, 0.5mg~2.0mg, 0.5mg~1.0mg, 0.75mg~1 0.25mg, 1.0mg-3.0mg, 1.5mg-2.0mg, 0.7mg-0.9mg, or 0.9mg-1.1mg; for example, approximately 0.05mg, approximately 0.1mg, approximately 0.2mg, approximately 0.3mg, approximately 0.4mg, approximately 0.5mg, approximately 0.6mg, approximately 0.7mg, approximately 0.8mg, approximately 0.9mg, approximately 1.0mg, approximately 1.1mg, approximately 1.2mg, approximately 1.3mg, approximately 1.4mg, approximately 1.5mg, approximately 1.75mg, approximately 2.0mg, approximately 2.25mg, approximately 2.5mg, approximately 2.75mg, approximately 3.0mg, approximately 3.5mg, or approximately 4.0mg), C1D2 is 0.05mg- 20.0mg (for example, 0.1mg~20.0mg, 0.2mg~20.0mg, 0.3mg~20.0mg, 0.4mg~20.0mg, 0.5mg~20.0mg, 1.0mg~20.0mg, 1.5mg~20.0mg, 2.0mg~20.0mg, 3.0mg~20.0mg, 4.0mg~20.0mg, 5.0mg~20.0mg, 6.0mg~20.0mg, 7.0mg~20.0mg, 8.0mg~20.0mg, 9.0mg~20.0mg, 10.0mg~20.0mg, 15.0mg~20.0mg, 0.5mg~15.0mg, 0.5mg-10.0mg, 0.5mg-9.0mg, 0.5mg-8.0mg, 0.5mg-7.0mg, 0.5mg-6.0mg, 0.5mg-5.0mg, 0.5mg-4.0mg, 0.5mg-3.0mg, 0.5mg-2.0mg, 0.5mg-1.0mg, 1.0mg-15.0mg, 1.0mg-10.0mg, 1.0mg-8.0mg, 1.0mg-6.0mg, 1.0mg-4.0mg, 1.0mg-3.0mg, 10.0mg-20.0mg, 15.0mg-20.0mg, 5.0mg-15.0mg, or 5.0mg-10.0mg For example, approximately 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 5.0 mg, 6.0 mg, 7.0 mg, 8.0 mg, 9.0 mg, 10.0 mg, 15.0 mg, or 20.0 mg), and C1D3 is 0.2 mg~ 50.0mg (for example, 0.3mg~50.0mg, 0.4mg~50.0mg, 0.5mg~50.0mg, 1.0mg~50.0mg, 2.0mg~50.0mg, 3.0mg~50.0mg, 4.0mg~50.0mg, 5.0mg~50.0mg, 10.0mg~50.0mg, 15.0mg~50.0mg, 20.0mg~50.0mg, 25.0mg~50.0mg, 30.0mg~50.0mg, 35.0mg~50.0mg, 40.0mg~50.0mg, 45.0mg~50.0mg, 1.0mg~45.0mg, 1.0mg~40. 0mg, 1.0mg~35.0mg, 1.0mg~30.0mg, 1.0mg~25.0mg, 1.0mg~20.0mg, 1.0mg~15.0mg, 1.0mg~10.0mg, 1.0mg~5.0mg, 10.0mg~20.0mg, 20.0mg~30.0mg, 30. 0mg~40.0mg, 5.0mg~25.0mg, 25.0mg~50.0mg, 3.0mg~45.0mg, 3.0mg~50.0mg, 4.0mg~4.5mg, 3.0mg~10.0mg, 4.0mg~5.0mg, 25.0mg~35.0mg, 28.0mg~32.0 mg, 10.0 mg to 30.0 mg, or 20.0 mg to 40.0 mg; for example, approximately 0.2 mg, approximately 0.5 mg, approximately 0.8 mg, approximately 1.0 mg, approximately 1.5 mg, approximately 2.0 mg, approximately 2.5 mg, approximately 3.0 mg, approximately 4.0 mg, approximately 4.2 mg, approximately 4.5 mg, approximately 5.0 mg, approximately 5.5 mg, approximately 6.0 mg, approximately 6.5 mg, approximately 7.0 mg, approximately 8.0 mg, approximately 9.0 mg, approximately 10.0 mg, approximately 12.0 mg, approximately 15.0 mg, approximately 20.0 mg, approximately 25.0 mg, approximately 30.0 mg, approximately 35.0 mg, approximately 40.0 mg, approximately 45.0 mg, or approximately 50.0 mg) (b) The second medication cycle includes a single dose (C2D1) of mosnetuzumab, where C2D1 is C1D3 or higher, and the dose ranges from 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 ~50.0mg, 40.0mg~50.0mg, 45.0mg~50.0mg, 1.0mg~45.0mg, 1.0mg~40.0mg, 1.0mg~35.0mg, 1.0mg~30.0mg, 1.0mg~25.0mg, 1.0mg~20.0mg, 1.0mg~15.0m g, 1.0mg~10.0mg, 1.0mg~5.0mg, 10.0mg~20.0mg, 20.0mg~30.0mg, 30.0mg~40.0mg, 5.0mg~25.0mg, 25.0mg~50.0mg, 3.0mg~45.0mg, 3.0mg~50.0mg, 4.0 mg~4.5mg, 3.0mg~10.0mg, 4.0mg~5.0mg, 25.0mg~35.0mg, 28.0mg~32.0mg, 10.0mg~30.0mg, or 20.0mg~40.0mg; for example, approximately 0.2mg, approximately 0.5mg, approximately 0.8mg, approximately 1.0mg, approximately 1.5mg, approximately 2.0mg, approximately 2.5mg, approximately 3.0mg, approximately 4.0mg, approximately 4.2mg, approximately 4.5mg, approximately 5.0mg, approximately 5.5mg, approximately 6.0mg, approximately 6.5mg, approximately 7.0mg, approximately 8.0mg, approximately 9.0mg, approximately 10.0mg, approximately 12.0mg, approximately 15.0mg, approximately 20.(0 mg, approximately 25.0 mg, approximately 30.0 mg, approximately 35.0 mg, approximately 40.0 mg, approximately 45.0 mg, or approximately 50.0 mg).

[0138] In some embodiments, (a) C1D1 is 0.4 mg to 4.0 mg (e.g., 0.5 mg to 4.0 mg, 0.75 mg to 4.0 mg, 1.0 mg to 4.0 mg, 1.25 mg to 4.0 mg, 1.5 mg to 4.0 mg, 2.0 mg to 4.0 mg, 2.5 mg to 4.0 mg, 3.0 mg to 4.0 mg, 3.5 mg to 4.0 mg, 0.5 mg to 3.5 mg, 0.5 mg to 3.0 mg, 0.5 mg to 2.0 mg, 0.5 mg to 1.0 mg, 0.75 mg to 1.25 mg, 1.0 mg to 3.0 mg, 1.5 mg to 2.0 mg, 0.7 mg to 0.9 mg, or 0 0.9mg~1.1mg; for example, approximately 0.5mg, approximately 0.6mg, approximately 0.7mg, approximately 0.8mg, approximately 0.9mg, approximately 1.0mg, approximately 1.1mg, approximately 1.2mg, approximately 1.3mg, approximately 1.4mg, approximately 1.5mg, approximately 1.75mg, approximately 2.0mg, approximately 2.25mg, approximately 2.5mg, approximately 2.75mg, approximately 3.0mg, approximately 3.5mg, or approximately 4.0mg), and C1D2 is 1.0mg~20.0mg (for example, 1.1mg~20.0mg, 1.2mg~20.0mg, 1.3mg~20.0mg, 1.4mg~20.0mg, 1.5mg~20.0mg, 2.0 mg~20.0mg, 3.0mg~20.0mg, 4.0mg~20.0mg, 5.0mg~20.0mg, 6.0mg~20.0mg, 7.0mg~20.0mg, 8.0mg~20.0mg, 9.0mg~20.0mg, 10.0mg~20.0mg, 15.0mg~20 .0mg, 1.0mg~15.0mg, 1.0mg~10.0mg, 1.0mg~9.0mg, 1.0mg~8.0mg, 1.0mg~7.0mg, 1.0mg~6.0mg, 1.0mg~5.0mg, 1.0mg~4.0mg, 1.0mg~3.0mg, 1.0mg~2.0 (mg, 10.0mg-20.0mg, 15.0mg-20.0mg, 5.0mg-15.0mg, or 5.0mg-10.0mg; for example, approximately 1.0mg, 1.1mg, 1.2mg, 1.3mg, 1.4mg, 1.5mg, 1.6mg, 1.7mg, 1.8mg, 1.9mg, 2.0mg, 2.5mg, 3.0mg, 3.5mg, 4.0mg, 5.0mg, 6.0mg, 7.0mg, 8.0mg, 9.0mg, 10.0mg, 15.0mg, or 20.0mg), and C1D3 is 3.0mg-50mg.0mg (for example, 4.0mg~50.0mg, 5.0mg~50.0mg, 10.0mg~50.0mg, 15.0mg~50.0mg, 20.0mg~50.0mg, 25.0mg~50.0mg, 30.0mg~50.0mg, 35.0mg~50.0mg, 40.0mg~50.0mg, 45.0mg~50.0mg, 3.0mg~45.0mg, 3.0mg~40.0mg, 3.0mg~35.0mg, 3.0mg~30.0mg, 3.0mg~25.0mg, 3.0mg~20.0mg, 3.0mg~15.0mg, 3.0mg~10.0mg) g, 3.0mg~5.0mg, 10.0mg~20.0mg, 20.0mg~30.0mg, 30.0mg~40.0mg, 5.0mg~25.0mg, 25.0mg~50.0mg, 4.0mg~4.5mg, 4.0mg~5.0mg, 25.0mg~35.0mg, 28.0mg~32.0mg, 10.0mg~30.0mg, or 20.0mg~40.0mg; for example, approximately 3.0mg, approximately 4.0mg, approximately 4.2mg, approximately 4.5mg, approximately 5.0mg, approximately 5.5mg, approximately 6.0mg, approximately 6.5mg, approximately 7.0mg, approximately 8.0mg, approximately 9.0mg, approximately 1 (b) C2D1 is 3.0 mg to 50.0 mg (e.g., 4.0 mg to 50.0 mg, 5.0 mg to 50.0 mg, 10.0 mg to 50.0 mg, 15.0 mg to 50.0 mg, 20.0 mg to 50.0 mg, 25.0 mg to 50.0 mg, 30.0 mg to 50.0 mg, 35.0 mg to 50.0 mg, 40.0 mg to 50.0 mg, 45.0 mg to 50.0 mg) g, 3.0mg~45.0mg, 3.0mg~40.0mg, 3.0mg~35.0mg, 3.0mg~30.0mg, 3.0mg~25.0mg, 3.0mg~20.0mg, 3.0mg~15.0mg, 3.0mg~10.0mg, 3.0mg~5.0mg, 10.0mg ~20.0mg, 20.0mg~30.0mg, 30.0mg~40.0mg, 5.0mg~25.0mg, 25.0mg~50.0mg, 4.0mg~4.5mg, 4.0mg~5.0mg, 25.0mg~35.0mg, 28.0mg~32.0mg, 10.0mg~30.0 mg, or 20.0 mg to 40.0 mg; for example, approximately 3.0 mg, 4.0 mg, 4.2 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 8.0 mg, 9.0 mg, 10.0 mg, 12.0 mg, 15.0 mg, 20.0 mg, 25.0 mg, 30.0 mg, 35.0 mg, 40.0 mg, 45.0 mg, or 50.0 mg).

[0139] 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, The amounts are approximately 1.5 mg, 1.75 mg, 2.0 mg, 2.25 mg, 2.5 mg, 2.75 mg, or 3.0 mg, and C1D2 is 1.0 mg to 6.0 mg (for example, 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 0.0mg~2.0mg, 1.0mg~1.5mg, 1.5mg~2.5mg, 3.0mg~6.0mg, 2.0mg~4.0mg, 2.5mg~5.0mg, or 2.5mg~3.5mg; for example, approximately 1.0mg, approximately 1.1mg, approximately 1.2mg, approximately 1.3mg, approximately 1.4mg, approximately 1.5mg, approximately 1.6mg, approximately 1.7mg, approximately 1.8mg, 1.9mg, approximately 2.0mg, approximately 2.1mg, approximately 2.2mg, approximately 2.3mg, approximately 2.4mg, approximately 2.5mg, approximately 2.6mg, approximately 2.7mg, approximately 2.8mg, approximately 2.9mg, approximately 3.0mg, approximately 3.5mg, approximately 4.0mg (approximately 4.5 mg, approximately 5.0 mg, approximately 5.5 mg, or approximately 6.0 mg), and C1D3 is 3.0 mg to 45.0 mg (for example, 4.0 mg to 45.0 mg, 5.0 mg to 45.0 mg, 10.0 mg to 45.0 mg, 15.0 mg to 45.0 mg, 20.0 mg to 45.0 mg, 25.0 mg to 45.0 mg, 30.0 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, 3.0mg-15.0mg, 3.0mg-10.0mg, 3.0mg-5.0mg, 10.0mg-20.0mg, 20.0mg-30.0mg, 30.0mg-40.0mg, 5.0mg-25.0mg, 4.0mg-4.5mg, 4.0mg-5.0mg, 25.0mg-35.0mg, 28.0mg-32.0mg, 10.0mg-30.0mg, or 20.0mg-40.0mg; for example, approximately 3.0mg, approximately 4.0mg, approximately 4.2mg, approximately 4.5mg, approximately 5.0mg, approximately 5.5mg, approximately (b) C2D1 is 3.0 mg to 45.0 mg (for example, 4.0 mg to 45.0 mg, 5.0 mg to 45.0 mg, 10.0 mg to 45.0 mg, 15.0 mg to 45.0 mg, 15.0 mg to 45.0 mg, 20.0 mg to 45.0 mg, 25.0 mg to 45.0 mg, 30.0mg~45.0mg, 35.0mg~45.0mg, 40.0mg~45.0mg, 3.0mg~40.0mg, 3.0mg~35.0mg, 3.0mg~30.0mg, 3.0mg~25.0mg, 3.0mg~20.0mg, 3.0 mg~15.0mg, 3.0mg~10.0mg, 3.0mg~5.0mg, 10.0mg~20.0mg, 20.0mg~30.0mg, 30.0mg~40.0mg, 5.0mg~25.0mg, 4.0mg~4.5mg, 4.0mg~5.0 mg, 25.0 mg to 35.0 mg, 28.0 mg to 32.0 mg, 10.0 mg to 30.0 mg, or 20.0 mg to 40.0 mg; for example, approximately 3.0 mg, 4.0 mg, 4.2 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 8.0 mg, 9.0 mg, 10.0 mg, 12.0 mg, 15.0 mg, 20.0 mg, 25.0 mg, 30.0 mg, 35.0 mg, 40.0 mg, or 45.0 mg).

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

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

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

[0143] In some embodiments, the drug regimen includes one or more additional drug cycles (e.g., one, two, three, four, five, six, seven, eight, nine, ten, or more drug cycles). In some embodiments, the drug regimen includes one to ten additional drug cycles (e.g., one, two, three, four, five, six, seven, eight, nine, or ten drug cycles). In some embodiments, the drug regimen includes ten additional drug cycles. In some embodiments, the length of each of the one or more additional drug cycles is 28 days (±1 day). In some embodiments, each of the one or more additional drug cycles includes an additional dose of mosnetuzumab. In some embodiments, the method includes administering each additional dose of mosnetuzumab to the subject on day 1 of each of one or more additional dosing cycles.In some embodiments, each additional dose of mosnetuzumab ranges from 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 mg). .0mg~50.0mg, 40.0mg~50.0mg, 45.0mg~50.0mg, 1.0mg~45.0mg, 1.0mg~40.0mg, 1.0mg~35.0mg, 1.0mg~30.0mg, 1.0mg~25.0mg, 1.0mg~20.0mg, 1.0mg~15.0mg, 1.0mg~10.0mg, 1.0mg~5.0mg, 10.0mg~20.0mg, 20.0mg~30.0mg, 30.0mg~40.0mg, 5.0mg~25.0mg, 25.0mg~50.0mg, 3.0mg~45.0mg, 4.0mg~4.5mg, 3.0mg~10.0mg, 4.0mg~5.0mg, 25.0mg~35.0mg, 28.0mg~32.0mg, 10.0mg~30.0mg, or 20.0mg~40.0mg; for example, approximately 0.2mg, approximately 0.5mg, approximately 0.8mg, approximately 1.0mg, approximately These amounts are approximately 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 4.0 mg, 4.2 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 8.0 mg, 9.0 mg, 10.0 mg, 12.0 mg, 15.0 mg, 20.0 mg, 25.0 mg, 30.0 mg, 35.0 mg, 40.0 mg, 45.0 mg, or 50.0 mg.

[0144] In some embodiments, administering an effective dose of mosnetuzumab involves administering mosnetuzumab according to a dosing regimen comprising 12 dosing cycles, (a) the first dosing cycle comprising a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab, where C1D1 and C1D2 are less than or equal to C1D3, respectively, and C1D1 is between 0.02 mg and 4.0 mg (e.g., 0.05 mg to 4.0 mg, 0.1 mg to 4.0 mg, 0.2 mg to 4.0 mg, 0.3 mg to 4.0 mg, 0.4 mg to 4.0 mg, 0.5 mg) g~4.0mg, 0.75mg~4.0mg, 1.0mg~4.0mg, 1.25mg~4.0mg, 1.5mg~4.0mg, 2.0mg~4.0mg, 2.5mg~4.0mg, 3.0mg~4.0mg, 3.5mg~4.0mg, 0.1mg~3.5mg, 0.1mg~3 .0mg, 0.1mg~2.5mg, 0.1mg~2.0mg, 0.1mg~1.5mg, 0.1mg~1mg, 0.1mg~0.5mg, 0.5mg~3.0mg, 0.5mg~2.0mg, 0.5mg~1.0mg, 0.75mg~1.25mg, 1.0mg~3.0mg, 1.5mg~2.0mg, 0.7mg~0.9mg, or 0.9mg~1.1mg; for example, approximately 0.05mg, approximately 0.1mg, approximately 0.2mg, approximately 0.3mg, approximately 0.4mg, approximately 0.5mg, approximately 0.6mg, approximately 0.7mg, approximately 0.8mg, approximately 0.9mg, approximately 1.0mg, approximately 1.1mg, approximately 1.2mg, approximately 1.3mg, approximately 1.4mg, approximately 1.5mg, approximately 1.75mg, approximately 2.0mg, approximately 2.25mg, approximately 2.5mg, approximately 2.75mg, approximately 3.0mg, approximately 3.5mg, or approximately 4.0mg), C1D2 is 0.05mg~20.0mg (for example, 0.1mg~2 0.0mg, 0.2mg~20.0mg, 0.3mg~20.0mg, 0.4mg~20.0mg, 0.5mg~20.0mg, 1.0mg~20.0mg, 1.5mg~20.0mg, 2.0mg~20.0mg, 3.0mg~20.0mg, 4.0mg~20.0mg, 5. 0mg~20.0mg, 6.0mg~20.0mg, 7.0mg~20.0mg, 8.0mg~20.0mg, 9.0mg~20.0mg, 10.0mg~20.0mg, 15.0mg~20.0mg, 0.5mg~15.0mg, 0.5mg~10.0mg, 0.5mg~9.0mg, 0.5mg-8.0mg, 0.5mg-7.0mg, 0.5mg-6.0mg, 0.5mg-5.0mg, 0.5mg-4.0mg, 0.5mg-3.0mg, 0.5mg-2.0mg, 0.5mg-1.0mg, 1.0mg-15.0mg, 1.0mg-10.0mg, 1.0mg-8.0mg, 1.0mg-6.0mg, 1.0mg-4.0mg, 1.0mg-3.0mg, 10.0mg-20.0mg, 15.0mg-20.0mg, 5.0mg-15.0mg, or 5.0mg-10.0mg; for example, approximately 0.1mg, approximately 0.2mg, The amounts are approximately 0.3mg, 0.4mg, 0.5mg, 0.6mg, 0.7mg, 0.8mg, 0.9mg, 1.0mg, 1.1mg, 1.2mg, 1.3mg, 1.4mg, 1.5mg, 1.6mg, 1.7mg, 1.8mg, 1.9mg, 2.0mg, 2.5mg, 3.0mg, 3.5mg, 4.0mg, 5.0mg, 6.0mg, 7.0mg, 8.0mg, 9.0mg, 10.0mg, 15.0mg, or 20.0mg), and C1D3 is 0.2mg to 50.0mg (for example, 0.3mg to 5 0.0mg, 0.4mg~50.0mg, 0.5mg~50.0mg, 1.0mg~50.0mg, 2.0mg~50.0mg, 3.0mg~50.0mg, 4.0mg~50.0mg, 5.0mg~50.0mg, 10.0mg~50.0mg, 15.0mg~50.0mg , 20.0mg~50.0mg, 25.0mg~50.0mg, 30.0mg~50.0mg, 35.0mg~50.0mg, 40.0mg~50.0mg, 45.0mg~50.0mg, 1.0mg~45.0mg, 1.0mg~40.0mg, 1.0mg~35.0mg, 1 0.0mg~30.0mg, 1.0mg~25.0mg, 1.0mg~20.0mg, 1.0mg~15.0mg, 1.0mg~10.0mg, 1.0mg~5.0mg, 10.0mg~20.0mg, 20.0mg~30.0mg, 30.0mg~40.0mg, 5.0mg~25.0mg, 25.0mg~50.0mg, 3.0mg~45.0mg, 4.0mg~4.5mg, 3.0mg~10.0mg, 4.0mg~5.0mg, 25.0mg~35.0mg, 28.0mg~32.0mg, 10.0mg~30.0mg, or 20.0mg~40.0 mg; for example, approximately 0.2 mg, approximately 0.5 mg, approximately 0.8 mg, approximately 1.0 mg, approximately 1.5 mg, approximately 2.0 mg, approximately 2.5 mg, approximately 3.0 mg, approximately 4.0 mg, approximately 4.2 mg, approximately 4.5 mg, approximately 5.0 mg, approximately 5.5 mg, approximately 6.0 mg, approximately 6.5 mg, approximately 7.0 mg, approximately 8.0 mg, approximately 9.0 mg, approximately 10.0 mg, approximately 12.0 mg, approximately 15.0 mg, approximately 20.0 mg, approximately 25.0 mg, approximately 30.0 mg, approximately 35.0 mg, approximately 40.0 mg, approximately 45.0 mg, or approximately 50.0 mg), and (b) each of the 2nd to 12th dosing cycles is a single dose. The product contains mosnetuzumab in doses (C2D1~C12D1), with each single dose C2D1~C12D1 being equivalent, and C1D3 or higher, ranging from 0.2mg to 50mg (e.g., 0.3mg~50.0mg, 0.4mg~50.0mg, 0.5mg~50.0mg, 1.0mg~50.0mg, 2.0mg~50.0mg, 3.0mg~50.0mg, 4.0mg~50.0mg, 5.0mg~50.0mg, 10.0mg~50.0mg, 15.0mg~50.0mg, 20.0mg~50.0mg, 25.0mg~50.0mg, 30.0mg~50.0mg, 35. 0mg~50.0mg, 40.0mg~50.0mg, 45.0mg~50.0mg, 1.0mg~45.0mg, 1.0mg~40.0mg, 1.0mg~35.0mg, 1.0mg~30.0mg, 1.0mg~25.0mg, 1.0mg~20.0mg, 1.0mg~1 5.0mg, 1.0mg~10.0mg, 1.0mg~5.0mg, 10.0mg~20.0mg, 20.0mg~30.0mg, 30.0mg~40.0mg, 5.0mg~25.0mg, 25.0mg~50.0mg, 3.0mg~45.0mg, 4.0mg~4.5mg, 3.0mg-10.0mg, 4.0mg-5.0mg, 25.0mg-35.0mg, 28.0mg-32.0mg, 10.0mg-30.0mg, or 20.0mg-40.0mg; for example, approximately 0.2mg, 0.5mg, 0.8mg, 1.0mg, 1.5mg, 2.0mg, 2.5mg, 3.0mg, 4.0mg, 4.2mg, 4.5mg, 5.0mg, 5.5mg, 6.0mg, 6.5mg, 7.0mg, 8.0mg, 9.0mg, 10.0mg, 12.0mg, 15.0mg, 20.0mg, 25.(0 mg, approximately 30.0 mg, approximately 35.0 mg, approximately 40.0 mg, approximately 45.0 mg, or approximately 50.0 mg).

[0145] In some embodiments, (a) C1D1 is 0.4 mg to 4.0 mg (e.g., 0.5 mg to 4.0 mg, 0.75 mg to 4.0 mg, 1.0 mg to 4.0 mg, 1.25 mg to 4.0 mg, 1.5 mg to 4.0 mg, 2.0 mg to 4.0 mg, 2.5 mg to 4.0 mg, 3.0 mg to 4.0 mg, 3.5 mg to 4.0 mg, 0.5 mg to 3.5 mg, 0.5 mg to 3.0 mg, 0.5 mg to 2.0 mg, 0.5 mg to 1.0 mg, 0.75 mg to 1.25 mg, 1.0 mg to 3.0 mg, 1.5 mg to 2.0 mg, 0.7 mg to 0.9 mg, or 0 0.9mg~1.1mg; for example, approximately 0.5mg, approximately 0.6mg, approximately 0.7mg, approximately 0.8mg, approximately 0.9mg, approximately 1.0mg, approximately 1.1mg, approximately 1.2mg, approximately 1.3mg, approximately 1.4mg, approximately 1.5mg, approximately 1.75mg, approximately 2.0mg, approximately 2.25mg, approximately 2.5mg, approximately 2.75mg, approximately 3.0mg, approximately 3.5mg, or approximately 4.0mg), and C1D2 is 1.0mg~20.0mg (for example, 1.1mg~20.0mg, 1.2mg~20.0mg, 1.3mg~20.0mg, 1.4mg~20.0mg, 1.5mg~20.0mg, 2.0 mg~20.0mg, 3.0mg~20.0mg, 4.0mg~20.0mg, 5.0mg~20.0mg, 6.0mg~20.0mg, 7.0mg~20.0mg, 8.0mg~20.0mg, 9.0mg~20.0mg, 10.0mg~20.0mg, 15.0mg~20 .0mg, 1.0mg~15.0mg, 1.0mg~10.0mg, 1.0mg~9.0mg, 1.0mg~8.0mg, 1.0mg~7.0mg, 1.0mg~6.0mg, 1.0mg~5.0mg, 1.0mg~4.0mg, 1.0mg~3.0mg, 1.0mg~2.0 (mg, 10.0mg-20.0mg, 15.0mg-20.0mg, 5.0mg-15.0mg, or 5.0mg-10.0mg; for example, approximately 1.0mg, 1.1mg, 1.2mg, 1.3mg, 1.4mg, 1.5mg, 1.6mg, 1.7mg, 1.8mg, 1.9mg, 2.0mg, 2.5mg, 3.0mg, 3.5mg, 4.0mg, 5.0mg, 6.0mg, 7.0mg, 8.0mg, 9.0mg, 10.0mg, 15.0mg, or 20.0mg), and C1D3 is 3.0mg-50mg.0mg (for example, 4.0mg~50.0mg, 5.0mg~50.0mg, 10.0mg~50.0mg, 15.0mg~50.0mg, 20.0mg~50.0mg, 25.0mg~50.0mg, 30.0mg~50.0mg, 35.0mg~50.0mg, 40.0mg~50.0mg, 45.0mg~50.0mg, 3.0mg~45.0mg, 3.0mg~40.0mg, 3.0mg~35.0mg, 3.0mg~30.0mg, 3.0mg~25.0mg, 3.0mg~20.0mg, 3.0mg~15.0mg, 3.0mg~10.0mg) 3.0mg~5.0mg, 10.0mg~20.0mg, 20.0mg~30.0mg, 30.0mg~40.0mg, 5.0mg~25.0mg, 25.0mg~50.0mg, 4.0mg~4.5mg, 4.0mg~5.0mg, 25.0mg~35.0mg, 28.0mg~32.0mg, 10.0mg~30.0mg, or 20.0mg~40.0mg; for example, approximately 3.0mg, approximately 4.0mg, approximately 4.2mg, approximately 4.5mg, approximately 5.0mg, approximately 5.5mg, approximately 6.0mg, approximately 6.5mg, approximately 7.0mg, approximately 8.0mg, approximately 9.0mg, approximately 10. (b) Each single dose C2D1 to C12D1 is 3.0 mg to 50.0 mg (e.g., 4.0 mg to 50.0 mg, 5.0 mg to 50.0 mg, 10.0 mg to 50.0 mg, 15.0 mg to 50.0 mg, 20.0 mg to 50.0 mg, 25.0 mg to 50.0 mg, 30.0 mg to 50.0 mg, 35.0 mg to 50.0 mg, 40.0 mg to 50.0 mg, 45.0 mg mg~50.0mg, 3.0mg~45.0mg, 3.0mg~40.0mg, 3.0mg~35.0mg, 3.0mg~30.0mg, 3.0mg~25.0mg, 3.0mg~20.0mg, 3.0mg~15.0mg, 3.0mg~10.0mg, 3.0mg~5.0mg , 10.0mg~20.0mg, 20.0mg~30.0mg, 30.0mg~40.0mg, 5.0mg~25.0mg, 25.0mg~50.0mg, 4.0mg~4.5mg, 4.0mg~5.0mg, 25.0mg~35.0mg, 28.0mg~32.0mg, 10.The dosage ranges from 0 mg to 30.0 mg, or 20.0 mg to 40.0 mg; for example, approximately 3.0 mg, 4.0 mg, 4.2 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 8.0 mg, 9.0 mg, 10.0 mg, 12.0 mg, 15.0 mg, 20.0 mg, 25.0 mg, 30.0 mg, 35.0 mg, 40.0 mg, 45.0 mg, or 50.0 mg.

[0146] 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 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 The amounts are 1.3mg, approximately 1.4mg, approximately 1.5mg, approximately 1.75mg, approximately 2.0mg, approximately 2.25mg, approximately 2.5mg, approximately 2.75mg, or approximately 3.0mg), and C1D2 is 1.0mg to 6.0mg (for example, 1.5mg to 6.0mg, 2.0mg to 6.0mg, 2.5mg to 6.0mg, 3.0mg to 6.0mg, 3.5mg to 6.0mg, 4.0mg to 6.0mg, 5.0mg to 6.0mg, 5.0mg to 6.0mg, 1.0mg to 5.0mg, 1.0mg to 4.5mg, 1.0mg to 4.0mg, 1.0mg to 3.5mg, 1.0mg to 3.0mg, 1.0mg~2.5mg, 1.0mg~2.0mg, 1.0mg~1.5mg, 1.5mg~2.5mg, 3.0mg~6.0mg, 2.0mg~4.0mg, 2.5mg~5.0mg, or 2.5mg~3.5mg; for example, approximately 1.0mg, approximately 1.1mg, approximately 1.2mg, approximately 1.3mg, approximately 1.4mg, approximately 1.5mg, approximately 1.6mg, approximately 1.7mg, approximately 1.8mg, 1.9mg, approximately 2.0mg, approximately 2.1mg, approximately 2.2mg, approximately 2.3mg, approximately 2.4mg, approximately 2.5mg, approximately 2.6mg, approximately 2.7mg, approximately 2.8mg, approximately 2.9mg, approximately 3.0mg. The amounts are approximately 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, or 6.0 mg, and C1D3 is 3.0 mg to 45.0 mg (for example, 4.0 mg to 45.0 mg, 5.0 mg to 45.0 mg, 10.0 mg to 45.0 mg, 15.0 mg to 45.0 mg, 20.0 mg to 45.0 mg, 25.0 mg to 45.0 mg, 30.0 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, 3.0mg-20.0mg, 3.0mg-15.0mg, 3.0mg-10.0mg, 3.0mg-5.0mg, 10.0mg-20.0mg, 20.0mg-30.0mg, 30.0mg-40.0mg, 5.0mg-25.0mg, 4.0mg-4.5mg, 4.0mg-5.0mg, 25.0mg-35.0mg, 28.0mg-32.0mg, 10.0mg-30.0mg, or 20.0mg-40.0mg; for example, approximately 3.0mg, approximately 4.0mg, approximately 4.2mg, approximately 4.5mg, approximately 5.0mg, approximately (b) Each single dose C2D1 to C12D1 is 3.0 mg to 45.0 mg (for example, 4.0 mg to 45.0 mg, 5.0 mg to 45.0 mg, 10.0 mg to 45.0 mg, 15.0 mg to 45.0 mg, 15.0 mg to 45.0 mg, 20.0 mg to 45.0 mg, 25.0 mg to 45.0 mg) and (b) each single dose C2D1 to C12D1 is 3.0 mg to 45.0 mg (for example, 4.0 mg to 45.0 mg, 5.0 mg to 45.0 mg, 10.0 mg to 45.0 mg, 15.0 mg to 45.0 mg, 20.0 mg to 45.0 mg, 25 .0mg~45.0mg, 30.0mg~45.0mg, 35.0mg~45.0mg, 40.0mg~45.0mg, 3.0mg~40.0mg, 3.0mg~35.0mg, 3.0mg~30.0mg, 3.0mg~25.0mg, 3.0mg~2 0.0mg, 3.0mg~15.0mg, 3.0mg~10.0mg, 3.0mg~5.0mg, 10.0mg~20.0mg, 20.0mg~30.0mg, 30.0mg~40.0mg, 5.0mg~25.0mg, 4.0mg~4.5mg, 4.0 (For example, approximately 3.0 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, approximately 3.0 mg, approximately 4.0 mg, approximately 4.2 mg, approximately 4.5 mg, approximately 5.0 mg, approximately 5.5 mg, approximately 6.0 mg, approximately 6.5 mg, approximately 7.0 mg, approximately 8.0 mg, approximately 9.0 mg, approximately 10.0 mg, approximately 12.0 mg, approximately 15.0 mg, approximately 20.0 mg, approximately 25.0 mg, approximately 30.0 mg, approximately 35.0 mg, approximately 40.0 mg, or approximately 45.0 mg).

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

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

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

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

[0151] 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 that includes lenalidomide administration. In some embodiments, lenalidomide is not administered for the last 7 days of each dosing cycle that includes lenalidomide administration. In some embodiments, lenalidomide is administered in a dose of 20 mg. In some embodiments, lenalidomide is administered orally.

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

[0153] In one embodiment, the present invention relates to a method of treating a subject comprising administering an effective dose of mosnetuzumab and an effective dose of lenalidomide to the subject, wherein the subject (i) has relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, and (ii) has been previously treated with at least one chemoimmunotherapy regimen comprising obinutuzumab, and the administration of an effective dose of mosnetuzumab and lenalidomide comprises administering the mosnetuzumab and lenalidomide according to a dosing regimen comprising at least a first dosing cycle of 21 days (±1 days) and a second dosing cycle of 28 days (±1 days), wherein the first dosing cycle is administered intravenously on day 1, day 8 (±1 days), and day 15 (±1 days), respectively. The method is characterized by comprising (a) a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg, (b) a second dosing cycle comprising a single dose (C2D1) of mosnetuzumab administered intravenously on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and (c) a second dosing cycle comprising the oral administration of 20 mg of lenalidomide daily from day 1 to day 21 of the second dosing cycle.

[0154] In one embodiment, the present invention relates to a method of treating a subject comprising administering an effective amount of mosnetuzumab and an effective amount of lenalidomide to the subject, wherein the subject (i) has relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, and (ii) has been previously treated with at least one chemoimmunotherapy regimen comprising obinutuzumab, and the administration of an effective amount of mosnetuzumab and lenalidomide comprises administering mosnetuzumab and lenalidomide according to a dosing regimen comprising a first 21-day (±1-day) dosing cycle and subsequent 28-day (±1-day) dosing cycles, wherein the first dosing cycle comprises a first dose (C1D1) administered intravenously on day 1, day 8 (±1-day), and day 15 (±1-day), respectively of the first dosing cycle, and a second dose ( The method is characterized by comprising (a) a dose (C1D2) and a third dose (C1D3) of mosnetuzumab, where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg, and (b) each of the second to twelfth drug cycles comprises a single dose (C2D1 to C12D1) of mosnetuzumab administered intravenously on day 1 of each drug cycle, where each single dose C2D1 to C12D1 is 30 mg, and (c) each of the second to twelfth drug cycles comprises the oral administration of 20 mg of lenalidomide daily on days 1 to 21 of each drug cycle.

[0155] In one embodiment, the present invention relates to a method of treating a subject comprising administering an effective dose of mosnetuzumab and an effective dose of lenalidomide to the subject, wherein the subject (i) has relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, and (ii) has been previously treated with at least one chemoimmunotherapy regimen comprising rituximab, and the administration of an effective dose of mosnetuzumab and lenalidomide comprises administering the mosnetuzumab and lenalidomide according to a drug regimen comprising at least a first 21-day (±1-day) drug cycle and a second 28-day (±1-day) drug cycle, wherein the first drug cycle is administered on day 1, day 8 (±1-day), and day 15 (±1-day), respectively. The method is characterized by comprising (a) a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg, and (b) a second dosing cycle comprising a single dose (C2D1) of mosnetuzumab administered on day 1 of the second dosing cycle, wherein C2D1 is 30 mg, and (c) a second dosing cycle further comprising the oral administration of 20 mg of lenalidomide daily from day 1 to day 21 of the second dosing cycle.

[0156] In one embodiment, the present invention relates to a method of treating a subject comprising administering an effective amount of mosnetuzumab and an effective amount of lenalidomide to the subject, wherein the subject (i) has relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, and (ii) has been previously treated with at least one chemoimmunotherapy regimen comprising rituximab, and the administration of an effective amount of mosnetuzumab and lenalidomide comprises administering mosnetuzumab and lenalidomide according to a dosing regimen comprising a first 21-day (±1-day) dosing cycle and subsequent 28-day (±1-day) dosing cycles, wherein the first dosing cycle comprises a first dose (C1D1) administered intravenously on day 1, day 8 (±1-day), and day 15 (±1-day), respectively of the first dosing cycle, and a second dose (C1D1), respectively. The method is characterized by comprising (a) a dose (C1D2) and a third dose (C1D3) of mosnetuzumab, where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg, and (b) each of the second to twelfth drug cycles comprises a single dose (C2D1 to C12D1) of mosnetuzumab administered intravenously on day 1 of each drug cycle, where each single dose C2D1 to C12D1 is 30 mg, and (c) each of the second to twelfth drug cycles comprises the oral administration of 20 mg of lenalidomide daily on days 1 to 21 of each drug cycle.

[0157] In one embodiment, the present invention relates to a method for treating a target population, comprising administering an effective dose of mosnetuzumab and an effective dose of lenalidomide to each subject in the population, wherein each subject (a) has relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, and (b) has been previously treated with at least one chemoimmunotherapy regimen, and the administration of an effective dose of mosnetuzumab and lenalidomide comprises administering mosnetuzumab and lenalidomide according to a dosing regimen comprising at least a first dosing cycle of 21 days (±1 days) and a second dosing cycle of 28 days (±1 days), wherein the first dosing cycle is administered intravenously on day 1, day 8 (±1 days), and day 15 (±1 days), respectively of the first dosing cycle. The method is characterized by comprising (a) a dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab, where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg, and (b) a second dosing cycle comprising a single dose (C2D1) of mosnetuzumab administered intravenously on day 1 of the second dosing cycle, where C2D1 is 30 mg, and (c) a second dosing cycle further comprising the oral administration of 20 mg of lenalidomide daily from day 1 to day 21 of the second dosing cycle. In some embodiments, at least one chemoimmunotherapy regimen included an anti-CD20 monoclonal antibody (e.g., rituximab or obinutuzumab).

[0158] In one embodiment, the present invention relates to a method for treating a target population, comprising administering an effective dose of mosnetuzumab and an effective dose of lenalidomide to each subject in the population, wherein each subject (a) has relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, and (b) has been previously treated with at least one chemoimmunotherapy regimen, and the administration of an effective dose of mosnetuzumab and lenalidomide comprises administering mosnetuzumab and lenalidomide according to a dosing regimen comprising a first 21-day (±1) dosing cycle and subsequent 28-day (±1) dosing cycles, wherein the first dosing cycle comprises a first dose (C1D1) and a second dose (C1D1), administered intravenously on day 1, day 8 (±1), and day 15 (±1), respectively, of the first dosing cycle. (2) comprising a third dose (C1D3) of mosnetuzumab, 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 (C2D1 to C12D1) of mosnetuzumab administered intravenously on day 1 of each dosing cycle, where each single dose (C2D1 to C12D1) is 30 mg; and (c) each of the second to twelfth dosing cycles comprises an oral dose of 20 mg of lenalidomide daily on days 1 to 21 of each dosing cycle. In some embodiments, at least one chemoimmunotherapy regimen comprises an anti-CD20 monoclonal antibody (e.g., rituximab or obinutuzumab).

[0159] In some embodiments, the drug regimen further includes the administration of corticosteroids. In some embodiments, the corticosteroids are administered to the subject during a first drug cycle. In some embodiments, the first drug cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of corticosteroids. 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 drug cycle. In some embodiments, each single dose of corticosteroid C1D1-C1D3 is administered to the subject before the administration of mosnetuzumab C1D1-C1D3. In some embodiments, each single dose of corticosteroid C1D1-C1D3 is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours prior to the administration of each mosnetuzumab dose C1D1-C1D3.

[0160] In some embodiments, corticosteroids are administered to the subject in the first medication cycle but not in the second medication cycle.

[0161] In some embodiments, the corticosteroid is administered to the subject in a second dosing cycle. In some embodiments, the second dosing cycle includes a single dose (C2D1) of the corticosteroid. In some embodiments, the C2D1 dose of the corticosteroid is administered to the subject on day 1 of the second dosing cycle. In some embodiments, the C2D1 dose of the corticosteroid is administered to the subject before the administration of C2D1 dose of mosnetuzumab. In some embodiments, a C2D1 corticosteroid is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours prior to the administration of C2D1 mosnetuzumab.

[0162] In some embodiments, the drug regimen further includes the administration of corticosteroids. In some embodiments, the corticosteroids are administered to the subject during a first drug cycle. In some embodiments, the first drug cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of corticosteroids. 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 drug cycle. In some embodiments, each single dose of corticosteroid C1D1-C1D3 is administered to the subject before the administration of mosnetuzumab C1D1-C1D3. In some embodiments, each single dose of corticosteroid C1D1-C1D3 is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours prior to the administration of each mosnetuzumab dose C1D1-C1D3.

[0163] In some embodiments, corticosteroids are administered to the subject in the first medication cycle but not in the second medication cycle.

[0164] In some embodiments, the corticosteroid is administered to the subject in a second dosing cycle. In some embodiments, the second dosing cycle includes a single dose (C2D1) of the corticosteroid. In some embodiments, the C2D1 dose of the corticosteroid is administered to the subject on day 1 of the second dosing cycle. In some embodiments, the C2D1 dose of the corticosteroid is administered to the subject before the administration of C2D1 dose of mosnetuzumab. In some embodiments, a C2D1 corticosteroid is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours prior to the administration of C2D1 mosnetuzumab.

[0165] In some embodiments, each additional dosing cycle includes 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 before the administration of each additional dose of mosnetuzumab. In some embodiments, each additional dose of corticosteroid is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours before the administration of each additional dose of mosnetuzumab.

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

[0167] In some embodiments, the overall response rate in a population of subjects having 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 higher; 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%.

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

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

[0170] In some embodiments, subjects exhibit a reduction in tumor burden after administration of an effective dose of mosnetuzumab and an effective dose of lenalidomide. In some embodiments, the reduction in tumor burden is determined by computed tomography (CT). In some embodiments, the reduction in tumor burden is a decrease in the sum of products of diameter (SPD) of the target lesion. In some embodiments, the reduction in SPD is at least 40% (e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more; e.g., 40-100%, 40-80%, 40-60%, 50-70%, 70-90%, 75-85%, 60-100%, 55-65%, 80-100%; e.g., about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%). In some embodiments, the reduction in SPD is at least 60%. In some embodiments, the reduction in SPD is at least 80%.

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

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

[0173] In some embodiments, the subjects are human. In some embodiments, each subject in the group is human.

[0174] B. Dosage strategies to mitigate adverse events The present invention relates to a method for treating subjects having relapsed and / or refractory (R / R) follicular lymphoma (FL) by administering mosnetuzumab and lenalidomide as combination therapy. In particular, the present invention relates to a method for treating subjects having R / R FL that is R / R to at least one prior systemic therapy (e.g., one prior treatment with a chemoimmunotherapy regimen) including an anti-CD20 antibody (e.g., an anti-CD20 monoclonal antibody, e.g., rituximab or obinutuzumab) or other treatment. The treatment and drug regimens described herein provide an acceptable safety profile in subjects having R / R FL treated with the drug regimens described herein.

[0175] 1. Symptoms and grading of CRS Any of the methods described herein may include monitoring subjects for cytokine release syndrome (CRS) (e.g., CRS events after the initiation of any of the methods described above). Current clinical responses focus on treating individual signs and symptoms, providing supportive care, and attempting to reduce inflammatory responses using high doses of corticosteroids. However, this approach is not always successful, especially in cases of late intervention. The CRS grading criteria used by the methods described herein define mild, moderate, severe, or life-threatening CRS and have been published by the American Society for Transplantation and Cell Therapy (ASTCT) to harmonize reports across clinical trials and enable 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 intended to more accurately classify the severity of CRS. This CRS grading system is shown in Table 1 below. [Table 1] ASTCT = American Society for Transplantation and Cell Therapy; BiPAP = Bilevel Positive Airway Pressure; CPAP = Continuous Positive Airway Pressure; CRS Cytokine Release Syndrome; CTCAE = Common Terminology Criteria for Adverse Events.

[0176] Fever is defined as a body temperature of 38°C or higher that is not caused by other factors. Subsequently, in subjects with CRS, if antipyretic or anti-cytokine therapy such as tocilizumab or steroids is administered, fever is no longer required for grading the subsequent CRS severity. In this case, CRS grading is determined by hypotension and / or hypoxia.

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

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

[0179] CRS is associated with elevated levels of various cytokines, including significant increases in IFNγ, IL-6, and TNF-α levels. The evidence that has emerged particularly links CRS to IL-6 as a central mediator. IL-6 is a pro-inflammatory, multifunctional cytokine produced by various cell types, and this cytokine has been shown to be involved in a wide range of physiological processes involving T cell activation. Regardless of the induction agent, 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 levels also correlate with the severity of CRS, with subjects experiencing grade 4 or 5 CRS events having significantly higher IL-6 levels compared to subjects who do not experience CRS or those experiencing milder CRS (grades 0-3) (Chen et al. J. Immunol. Methods. 434:1-8, 2016).

[0180] Therefore, blocking the inflammatory effects of IL-6 by using agents that inhibit IL-6-mediated signaling to manage CRS observed in subjects during a two-stage fractionated dose-escalation regimen is considered an alternative to steroid treatment in the treatment of CD20-positive cell proliferation disorders (e.g., B cell proliferation disorders) that is not expected to adversely affect T cell function or reduce the efficacy or clinical benefit of mosnetuzumab therapy.

[0181] If a subject has a CRS event that does not resolve or worsens within 24 hours of administration of an IL-6R antagonist to treat the symptoms of a CRS event, the method may further include administering one or more additional doses of the IL-6R antagonist to the subject to manage the CRS event. If the CRS event is not managed through administration of the IL-6R antagonist, the subject may be administered a corticosteroid such as methylprednisolone or dexamethasone.

[0182] 2. Other adverse events and grading Any of the methods described herein may include monitoring subjects for additional non-CRS adverse events, including the incidence, nature, and severity of physical findings and adverse events, as determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events, 5th Edition (NCI CTCAE v5.0). In addition to CRS, one of the most common adverse events reported in patients treated with mosnetuzumab and / or lenalidomide is neutropenia (e.g., febrile neutropenia).

[0183] Neutropenia is characterized by an abnormally low concentration of neutrophils, a type of white blood cell, in the blood. Neutropenia can lead to an increased risk of infection. The generally accepted reference range for absolute neutrophil count (ANC) in adults is 1,500 to 8,000 cells / μL of blood. Mild neutropenia is characterized by an ANC of 1,000 to 1,500 cells / μL (grade 1 to 2); moderate neutropenia is characterized by an ANC of 500 to 1,000 cells / μL (grade 3); and severe neutropenia is characterized by an ANC of less than 500 cells / μL (grade 4). Febrile neutropenia (grade 3+ neutropenia) is characterized by an ANC of less than 1,000 cells / μL in addition to either a single temperature measurement exceeding 38.3°C or a continuous temperature measurement exceeding 38°C.

[0184] 3. Medication regimens with an acceptable safety profile In one embodiment, the present invention relates to a method for treating a target population, comprising administering an effective dose of mosnetuzumab and an effective dose of lenalidomide to each subject in the population, wherein each subject (a) has relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, and (b) has been previously treated with at least one chemoimmunotherapy regimen, and the administration of an effective dose of mosnetuzumab and lenalidomide comprises administering mosnetuzumab and lenalidomide according to a dosing regimen comprising at least a first dosing cycle of 21 days (±1 days) and a second dosing cycle of 28 days (±1 days), wherein the first dosing cycle is administered intravenously on day 1, day 8 (±1 days), and day 15 (±1 days), respectively of the first dosing cycle. The method is characterized by comprising (a) a dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab, where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg, and (b) a second dosing cycle comprising a single dose (C2D1) of mosnetuzumab administered intravenously on day 1 of the second dosing cycle, where C2D1 is 30 mg, and (c) a second dosing cycle further comprising the oral administration of 20 mg of lenalidomide daily from day 1 to day 21 of the second dosing cycle. In some embodiments, at least one chemoimmunotherapy regimen included an anti-CD20 monoclonal antibody (e.g., rituximab or obinutuzumab).

[0185] In one embodiment, the present invention relates to a method for treating a target population, comprising administering an effective dose of mosnetuzumab and an effective dose of lenalidomide to each subject in the population, wherein each subject (a) has relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, and (b) has been previously treated with at least one chemoimmunotherapy regimen, and the administration of an effective dose of mosnetuzumab and lenalidomide comprises administering mosnetuzumab and lenalidomide according to a drug regimen comprising a first 21-day (±1-day) drug cycle and subsequent 11th and subsequent 28-day (±1-day) drug cycles, wherein the first drug cycle comprises a first dose (C1D1) administered intravenously on day 1, day 8 (±1-day), and day 15 (±1-day), respectively of the first drug cycle, and a second dose The method is characterized by comprising (a) a dose (C1D2) and a third dose (C1D3) of mosnetuzumab, where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg, and (b) each of the second to twelfth dosing cycles comprises a single dose (C2D1 to C12D1) of mosnetuzumab administered intravenously on day 1 of each dosing cycle, where each single dose C2D1 to C12D1 is 30 mg, and (c) each of the second to twelfth dosing cycles comprises the oral administration of 20 mg of lenalidomide daily on days 1 to 21 of each dosing cycle. In some embodiments, at least one chemoimmunotherapy regimen comprises an anti-CD20 monoclonal antibody (e.g., rituximab or obinutuzumab).

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

[0187] In some embodiments, each target FL has been histologically demonstrated to be grade 1, 2, or 3a, but not 3b, according to the World Health Organization's classification of lymphoid neoplasms (referenced in Swerdlow SH, et al. Blood 2016;127:2375-90).

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

[0189] In some embodiments, mosnetuzumab 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).

[0190] In one embodiment, the method of the present invention is characterized by corticosteroid premedication to mitigate the adverse effects of mosnetuzumab administration. In some embodiments, corticosteroid premedication reduces the rate of cytokine release syndrome (CRS) in subjects treated with mosnetuzumab (e.g., subjects administered with a combination of mosnetuzumab and lenalidomide). In some embodiments, the dosing regimen further comprises the administration of corticosteroids. In some embodiments, the corticosteroids are administered to the subjects during a first dosing cycle. In some embodiments, the first dosing cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of corticosteroids. In some embodiments, C1D1, C1D2, and C1D3 of corticosteroids are administered to the subjects on day 1, day 8 (±1 day), and day 15 (±1 day), respectively, of the first dosing cycle. In some embodiments, each single dose of corticosteroid C1D1–C1D3 is administered to the subject before the administration of mosnetuzumab C1D1–C1D3. In some embodiments, each single dose of corticosteroid C1D1–C1D3 is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours before the administration of mosnetuzumab C1D1–C1D3. In some embodiments, the corticosteroid used is dexamethasone. In some embodiments, each dose of dexamethasone is approximately 10 mg (for example, approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg). In some embodiments, dexamethasone is administered intravenously.

[0191] In some embodiments, corticosteroids are administered to the subject in the first medication cycle but not in the second medication cycle.

[0192] In some embodiments, the corticosteroid is administered to the subject in a second dosing cycle. In some embodiments, the second dosing cycle includes a single dose (C2D1) of the corticosteroid. In some embodiments, the C2D1 dose of the corticosteroid is administered to the subject on day 1 of the second dosing cycle. In some embodiments, the C2D1 dose of the corticosteroid is administered to the subject before the administration of C2D1 dose of mosnetuzumab. In some embodiments, a C2D1 corticosteroid is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours prior to the administration of C2D1 mosnetuzumab.

[0193] In some embodiments, the drug regimen further includes the administration of corticosteroids. In some embodiments, the corticosteroids are administered to the subject during a first drug cycle. In some embodiments, the first drug cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of corticosteroids. 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 drug cycle. In some embodiments, each single dose of corticosteroid C1D1-C1D3 is administered to the subject before the administration of mosnetuzumab C1D1-C1D3. In some embodiments, each single dose of corticosteroid C1D1-C1D3 is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours prior to the administration of each mosnetuzumab dose C1D1-C1D3.

[0194] In some embodiments, corticosteroids are administered to the subject in the first medication cycle but not in the second medication cycle.

[0195] In some embodiments, the corticosteroid is administered to the subject in a second dosing cycle. In some embodiments, the second dosing cycle includes a single dose (C2D1) of the corticosteroid. In some embodiments, the C2D1 dose of the corticosteroid is administered to the subject on day 1 of the second dosing cycle. In some embodiments, the C2D1 dose of the corticosteroid is administered to the subject before the administration of C2D1 dose of mosnetuzumab. In some embodiments, a C2D1 corticosteroid is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours prior to the administration of C2D1 mosnetuzumab.

[0196] In some embodiments, each additional dosing cycle includes 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 before the administration of each additional dose of mosnetuzumab. In some embodiments, each additional dose of corticosteroid is administered to the subject 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours before the administration of each additional dose of mosnetuzumab.

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

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

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

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

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

[0202] The methods described herein may result in an acceptable safety profile for subjects with R / R mosnetuzumab being treated with combination therapy of mosnetuzumab and lenalidomide. In some cases, treatment using the methods described herein, in which mosnetuzumab is administered intravenously and lenalidomide orally in the context of a divided dose escalation regimen, shows a reduction in undesirable adverse events such as cytokine-driven toxicity (e.g., cytokine release syndrome (CRS)), infusion-related reactions (IRR), macrophage activation syndrome (MAS), neurotoxicity, severe oncolytic syndrome (TLS), neutropenia, thrombocytopenia, elevated liver enzymes and / or hepatotoxicity (e.g., ≥20%, ≥25%, ≥30%, ≥35%, ≥40%, ≥45%, ≥50%, ≥55%, ≥60%) after treatment with mosnetuzumab using the divided dose escalation regimen of the present invention, compared with treatment with mosnetuzumab using a non-divided dose regimen. 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more; for example, 20%~100%, 20%~90%, 20%~80%, 20%~70%, 20%~60%, 20%~50%, 20%~40%, 20%~30%, 40%~100%, 60%~100%, 80%~100%, 30 %~70%, 40%~60%, 30%~50%, 50%~80%, or 90%~100%; for example, approximately 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99%, or 100%) or result in complete inhibition (100% reduction).

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

[0204] In some examples, the present invention provides a mosnetuzumab comprising an anti-CD20 arm having a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence GYTFTSYNMH (SEQ ID NO: 1); (b) HVR-H2 comprising the amino acid sequence AIYPGNGDTSYNQKFKG (SEQ ID NO: 2); (c) HVR-H3 comprising the amino acid sequence VVYYSNSYWYFDV (SEQ ID NO: 3); (d) HVR-L1 comprising the amino acid sequence RASSSVSYMH (SEQ ID NO: 4); (e) HVR-L2 comprising the amino acid sequence APSNLAS (SEQ ID NO: 5); and (f) HVR-L3 comprising the amino acid sequence QQWSFNPPT (SEQ ID NO: 6). In some cases, mosnetuzumab includes at least one of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 (e.g., one, two, three, or four) containing sequences of sequence numbers 17–20, respectively, and / or at least one of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 (e.g., one, two, three, or four) containing sequences of sequence numbers 21–24, respectively. In some cases, mosnetuzumab includes (a) a heavy chain variable (VH) domain containing an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 7 (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) or the amino acid sequence of SEQ ID NO: 7; (b) a light chain variable (VL) domain containing an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 8 (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) or the amino acid sequence of SEQ ID NO: 8; or (c) an anti-CD20 arm containing a first binding domain containing a VH domain as in (a) and a VL domain as in (b). Thus, in some cases, the first binding domain contains a VH domain containing the amino acid sequence of SEQ ID NO: 7 and a VL domain containing the amino acid sequence of SEQ ID NO: 8.

[0205] In some examples, the present invention provides a mosnetuzumab comprising an anti-CD3 arm having a second binding domain comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence NYYIH (SEQ ID NO: 9); (b) HVR-H2 comprising the amino acid sequence WIYPGDGNTKYNEKFKG (SEQ ID NO: 10); (c) HVR-H3 comprising the amino acid sequence DSYSNYYFDY (SEQ ID NO: 11); (d) HVR-L1 comprising the amino acid sequence KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) HVR-L2 comprising the amino acid sequence WASTRES (SEQ ID NO: 13); and (f) HVR-L3 comprising the amino acid sequence TQSFILRT (SEQ ID NO: 14). In some cases, mosnetuzumab contains at least one of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 (e.g., one, two, three, or four) containing sequences of sequence numbers 25–28, respectively, and / or at least one of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 (e.g., one, two, three, or four) containing sequences of sequence numbers 29–32, respectively. In some cases, mosnetuzumab includes (a) a VH domain containing an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 15 (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%), or the amino acid sequence of SEQ ID NO: 15; (b) a VL domain containing an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 16 (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%), or the amino acid sequence of SEQ ID NO: 16; or (c) an anti-CD3 arm containing a second binding domain containing a VH domain as in (a) and a VL domain as in (b). Thus, in some cases, the second binding domain contains a VH domain containing the amino acid sequence of SEQ ID NO: 15 and a VL domain containing the amino acid sequence of SEQ ID NO: 16.

[0206] In some examples, the present invention relates to an anti-CD20 arm having a first binding domain comprising at least one, two, three, four, five, or six HVRs selected from (1) HVR-H1 comprising the amino acid sequence GYTFTSYNMH (SEQ ID NO: 1); (b) HVR-H2 comprising the amino acid sequence AIYPGNGDTSYNQKFKG (SEQ ID NO: 2); (c) HVR-H3 comprising the amino acid sequence VVYYSNSYWYFDV (SEQ ID NO: 3); (d) HVR-L1 comprising the amino acid sequence RASSSVSYMH (SEQ ID NO: 4); (e) HVR-L2 comprising the amino acid sequence APSNLAS (SEQ ID NO: 5); and (f) HVR-L3 comprising the amino acid sequence QQWSFNPPT (SEQ ID NO: 6); and (2) The present invention provides a mosnetuzumab comprising an anti-CD3 arm having a second binding domain comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence NYYIH (SEQ ID NO: 9); (b) HVR-H2 comprising the amino acid sequence WIYPGDGNTKYNEKFKG (SEQ ID NO: 10); (c) HVR-H3 comprising the amino acid sequence DSYSNYYFDY (SEQ ID NO: 11); (d) HVR-L1 comprising the amino acid sequence KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) HVR-L2 comprising the amino acid sequence WASTRES (SEQ ID NO: 13); and (f) HVR-L3 comprising the amino acid sequence TQSFILRT (SEQ ID NO: 14). In some examples, mosnetuzumab comprises (1) at least one heavy chain framework region FR-H1, FR-H2, FR-H3, and FR-H4 (e.g., 1, 2, 3, or 4) containing sequences of sequence numbers 17-20, and / or at least one light chain framework region FR-L1, FR-L2, FR-L3, and FR-L4 (e.g., 1, 2, 3, or 4) containing sequences of sequence numbers 21-24, and (2) at least one heavy chain framework region FR-H1, FR-H2, FR-H3, and FR-H4 (e.g., 1, 2, 3, or 4) containing sequences of sequence numbers 25-28, and / or at least one light chain framework region FR-L1, FR-L2, FR-L3, and FR-L4 (e.g., 1, 2, 3, or 4) containing sequences of sequence numbers 29-32, respectively.In some cases, mosnetuzumab contains (1)(a) an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 7 (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%), or a VH domain containing the amino acid sequence of SEQ ID NO: 7; (b) an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 8 (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%), or a VL domain containing the amino acid sequence of SEQ ID NO: 8; (c) an anti-CD20 domain containing a first binding domain comprising VH as in (a) and VL as in (b). The anti-CD3 arm comprises (2)(a) an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 15 (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity), or a VH domain containing the amino acid sequence of SEQ ID NO: 15; (b) an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 16 (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity), or a VL domain containing the amino acid sequence of SEQ ID NO: 16; or (c) an anti-CD3 arm comprising a second binding domain comprising VH as in (a) and VL as in (b). In some cases, mosnetuzumab comprises (1) a first binding domain comprising a VH domain containing the amino acid sequence of SEQ ID NO: 7 and a VL domain containing the amino acid sequence of SEQ ID NO: 8, and (2) a second binding domain comprising a VH domain containing the amino acid sequence of SEQ ID NO: 15 and a VL domain containing the amino acid sequence of SEQ ID NO: 16.

[0207] In some cases, mosnetuzumab has International Name of Drug (INN) List 117 (WHO Drug Information, Vol.31, No.2, 2017, p.303) or CAS Registry Number 1905409-39-3 and has (1) an anti-CD20 arm containing the heavy chain and light chain sequences of SEQ ID NOs. 33 and 34, respectively, and (2) an anti-CD3 arm containing the heavy chain and light chain sequences of SEQ ID NOs. 35 and 36, respectively. In some cases, mosnetuzumab contains (1)(a) an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 33 (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%), or a heavy chain containing the amino acid sequence of SEQ ID NO: 33; (b) an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 34 (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%), or a light chain containing the amino acid sequence of SEQ ID NO: 34; (c) an anti-CD2 binding domain containing a heavy chain as in (a) and a light chain as in (b). The invention comprises an 0 arm and (2)(a) a heavy chain containing an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 35 (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity), or the amino acid sequence of SEQ ID NO: 35; (b) a light chain containing an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 36 (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity), or the amino acid sequence of SEQ ID NO: 36; or (c) an anti-CD3 arm containing a second binding domain comprising a heavy chain as in (a) and a light chain as in (b). In some examples, mosnetuzumab comprises an anti-CD20 arm comprising (1) a first binding domain comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 33 and a light chain containing the amino acid sequence of SEQ ID NO: 34, and (2) an anti-CD3 arm comprising a second binding domain comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 35 and a light chain containing the amino acid sequence of SEQ ID NO: 36.

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

[0209] Mosnetuzumab can be produced using recombinant methods and compositions, for example, as described in U.S. Patent No. 4,816,567.

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

[0211] Lenalidomide has CAS registry number 191732-72-6 and IUPAC name (3RS)-3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)piperidine-2,6-dione. Lenalidomide is also known by trade names including REVLIMID®, Linamide, and Lenalidomide. Lenalidomide has DrugBank accession number DB00480, PubChem CID 216326, and chemical formula C 13 H 13 It contains N3O3. This invention describes the additive / synergistic efficacy of the combination of mosnetuzumab and lenalidomide, as well as potential overlapping toxicity, in order to carefully monitor and manage patients with the drug regimens and treatments described herein.

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

[0213] In some cases, one or more additional therapeutic agents may reduce the rate or severity of cytokine release syndrome (CRS). In some cases, one or more additional therapeutic agents may prevent symptoms associated with CRS. In specific cases, additional therapeutic agents used to reduce the rate or severity of CRS or to prevent symptoms associated with CRS are corticosteroids (e.g., dexamethasone (CAS number: 50-02-2), prednisone (CAS number: 53-03-2), prednisolone (CAS number: 50-42-8), or methylprednisolone (CAS number: 83-43-2)) or IL-6R antagonists (e.g., tocilizumab, sarilumab, bovalilizumab (ALX-0061), satralizumab (SA-237), and their variants). In some cases, the additional therapeutic agent is tocilizumab. In some cases, the additional therapeutic agent is a corticosteroid. In some cases, corticosteroids are administered before mosnetuzumab administration. In some cases, corticosteroids are administered 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours before mosnetuzumab administration. In some cases, corticosteroids are administered intravenously. In some cases, the corticosteroid is dexamethasone. In some cases, the subject is administered 10 mg of dexamethasone 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours prior to the administration of mosnetuzumab to the subject. In some cases, the corticosteroid is methylprednisolone. In some cases, the corticosteroid is prednisone.

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

[0215] For all methods described herein, mosnetuzumab and lenalidomide are formulated, administered, and given in a manner consistent with good medical practice. Factors to be considered in this regard include the specific disease being treated, the specific mammal being treated, the clinical symptoms of the individual subject, the cause of the disease, the site of drug delivery, the method of administration, the schedule of administration, and other factors known to the healthcare professional. Mosnetuzumab and lenalidomide are optionally, but not necessarily, formulated together with one or more drugs currently used to prevent or treat the disorder in question. The effective dose of such other drugs depends on the amount of mosnetuzumab and / or lenalidomide present in the formulation, the type of disorder or treatment, and the other factors mentioned above. Mosnetuzumab and lenalidomide may be appropriately administered to a subject over a series of treatments. When mosnetuzumab and lenalidomide are administered on the same day, mosnetuzumab may be administered before, concurrently with, or after the administration of lenalidomide.

[0216] In some examples, additional therapeutic agents useful in the present invention include 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 therapeutic antibodies such as gemtuzumab-ozogamicin (MYLOTARG®, Wyeth), which is an antibody-drug conjugate. Additional humanized monoclonal antibodies that have therapeutic potential as drugs in combination with the compounds of the present invention include apolizumab, aselizumab, atlizumab, bapinuzumab, vibatuzumab meltansine, cantuzumab meltansine, sedelizumab, cerorizumab pegol, sidofcituzumab, sidotuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erulizumab, felbizumab, fontrizumab, inotuzumab ozogamicin, ipilimumab, rabetuzumab, lintuzumab, matzumab, mepolizumab, motabizumab, motobizumab, natalizumab, nimotuzumab, and no Examples include lovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecufcituzumab, pexelizumab, pexelizumab, larivizumab, ranibizumab, reslivizumab, reslizumab, reslivizumab, loverizumab, lupizumab, cibrotuzumab, cyprizumab, sontuzumab, takatatuzumab tetraxetan, tadoxizumab, tafacitamab, talizumab, tefibazumab, tocilizumab, tralizumab, tucotsuzumab cermoreukin, tucucituzumab, umabizumab, urtoxazumab, ustekinumab, vizilizumab, and briakinumab.

[0217] IV. Pharmaceutical Compositions and Formulations Mosnetuzumab and / or lenalidomide as described herein may be used in pharmaceutical compositions and formulations. Pharmaceutical compositions and formulations of mosnetuzumab, lenalidomide, and / or other agents (e.g., dexamethasone) as described herein may be prepared in the form of lyophilized formulations or aqueous solutions by mixing one, two, or all three agents of the desired purity with one or more pharmaceutically acceptable carriers (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. Pharmacochemically acceptable carriers are generally non-toxic to the recipient at the doses and concentrations used, and include buffers such as phosphoric acid, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzylammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride; phenol, butyl, or benzyl alcohol; alkylparabens such as methyl or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); and low molecular weight (less than approximately 10 residues) polypeptides. Examples of nonionic surfactants include, but are not limited to: 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 dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants such as polyethylene glycol (PEG).Exemplary pharmaceutically acceptable carriers herein further include intervening drug dispersants such as soluble neutral active hyaluronidase glycoproteins (sHASEGP), e.g., human soluble PH-20 hyaluronidase glycoproteins such as rHuPH20 (HYLENEX®, Baxter International, Inc.). Several exemplary sHASEGPs, including rHuPH20, and methods of use are described in U.S. Patent Applications Publications 2005 / 0260186 and 2006 / 0104968. In one embodiment, sHASEGP is combined with one or more additional glycosaminoglycans (e.g., chondroitinases).

[0218] An example of a lyophilized antibody preparation is described in U.S. Patent No. 6,267,958. Examples of aqueous antibody preparations are described in U.S. Patent No. 6,171,586 and International Publication No. 2006 / 044908, the latter of which contains histidine acetate buffer.

[0219] The formulations described herein may also contain two or more active ingredients as needed for the specific indication being treated, preferably those having complementary activities that do not adversely affect each other. For example, it may be desirable to provide additional therapeutic agents (e.g., chemotherapeutic agents, cytotoxic agents, growth inhibitors, and / or antihormone agents, e.g., those mentioned above herein). Such active ingredients are preferably present in combination in amounts effective for the intended purpose.

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

[0221] Sustained-release preparations may be prepared. A suitable example of a sustained-release preparation is a semipermeable matrix of a solid hydrophobic polymer containing the antibody, which may be in the form of a molded article, such as a film or microcapsule.

[0222] Preparations used for in vivo administration are generally sterilized. Sterilization can be easily achieved, for example, by filtration through a sterile filtration membrane.

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

[0224] V. Kits and manufactured products In another aspect of the present invention, a kit or product is provided comprising materials useful for the treatment, prevention and / or diagnosis of the aforementioned disorders. The kit or product comprises a container and a label or packaging insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, intravenous solution pouches, etc. The container may be formed from a variety of materials such as glass or plastic. The container may hold the composition alone or in combination with another composition effective for treating, preventing and / or diagnosing the symptoms and may have a sterile access port (for example, the container may be a vial with a stopper that can be punctured by a subcutaneous needle). At least one activator in the composition is mosnetuzumab or lenalidomide as described herein. The label or accompanying information indicates that the composition is used to treat relapsed and / or refractory (R / R) follicular lymphoma (FL) and further includes information relating to at least one of the drug regimens described herein. In some embodiments, the label or accompanying information indicates that the composition is used to treat R / R FL in patients who are R / R to at least one prior treatment (e.g., chemoimmunotherapy) containing an anti-CD20 antibody (e.g., anti-CD20 monoclonal antibody, e.g., rituximab or obinutuzumab). Furthermore, the kit or product may include (a) a first container containing a composition comprising mosnetuzumab, lenalidomide, or both mosnetuzumab and lenalidomide, and (b) a second container containing a composition comprising a further cytotoxic agent or other therapeutic agent. Alternatively, or in addition thereto, the kit or product may further include a second (or third) container containing pharmaceutically acceptable buffers, e.g., bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and dextrose solution. The manufactured product may further comprise other materials desirable from a commercial and user perspective, including other buffers, diluents, filters, needles, and syringes. [Examples]

[0225] Examples The following are examples of the methods and compositions of the present invention. It is understood that various other embodiments may be implemented based on the general description provided above.

[0226] Example 1. A Phase Ib open-label, non-randomized, multicenter study evaluating the safety, pharmacokinetics, and efficacy of mosnetuzumab in combination with lenalidomide in patients with relapsed or refractory follicular lymphoma. Research plan Study CO41942 is an ongoing Phase 1b, open-label, multicenter study evaluating the safety, pharmacokinetics, and efficacy of mosnetuzumab in combination with lenalidomide in patients with relapsed and / or refractory (e.g., R / R or r / r) follicular lymphoma (FL). Patients with r / r FL after at least one prior systemic therapy are eligible to participate in the study. As of CCOD, mosnetuzumab in combination with lenalidomide is the only effective treatment combination in Study CO41942; therefore, this study focuses solely on the mosnetuzumab + lenalidomide combination. The study plan is summarized in Figures 1A and 1B.

[0227] This study includes an initial dose escalation phase, which includes a dose escalation cohort designed to determine the recommended phase 2 dose (RP2D) of mosnetuzumab. The initial dose escalation phase is followed by an expansion phase in which the RP2D of mosnetuzumab is given.

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

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

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

[0231] Table 3 shows the patient demographics for the safety evaluable population (N=16). The majority of patients were female (62.5%; 10 / 16 patients), and the median age was 61.5 years. In the East Coast Cancer Group (ECOG), the patient status was 0 for 81.3% (13 / 16 patients) and 1 for 18.8% (3 / 16 patients). [Table 3] CCOD:April 5, 2021

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

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

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

[0235] safety results

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

[0237] ● 81.3% of patients (13 out of 16 patients) reported at least one adverse event (AE), with a total of 83 AEs reported overall.

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

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

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

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

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

[0243] ● No adverse events (AEs) were reported that led to the discontinuation of the research procedure.

[0244] ● 37.5% of patients (6 out of 16 patients) reported at least one event that resulted in a dose change / discontinuation of the study treatment. Of these, 2 patients experienced dose discontinuation of mosnetuzumab and 6 patients experienced dose discontinuation of lenalidomide treatment.

[0245] ● The proportion of patients who reported at least one particularly noteworthy adverse event (AESI) was 31.3% (5 / 16 patients).

[0246] The incidence and frequency of adverse events (AEs), including those thought to be associated with mosnetuzumab, SAEs, and AESIs, were similar in this study to those observed in related studies using monotherapy with mosnetuzumab administered at similar doses. [Table 4] AE = Adverse event, AESI = Adverse event of particular note a Excluding the event "death due to progressive disease" b According to ASTCT criteria c The patient had worsening pleural effusion. Tumor flare is defined as "tumor flare, tumor inflammation, tumor pain, and new or worsening pleural effusion" in the Medical Dictionary for Regulatory Activities (MedDRA) Basic Terminology (PT).

[0247] Most frequently reported adverse events: Overall, the percentage of patients who reported at least one AE was 81.3% (13 / 16 patients), and a total of 83 AEs were reported overall.

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

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

[0250] Treatment-related adverse events Overall, the percentage of patients who reported at least one event considered to be related to the 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 the study treatment (e.g., related to mosunetuzumab or lenalidomide) are shown in Figure 2.

[0251] Overall, 81.3% of patients (13 / 16 patients; Table 4) reported at least one adverse event (AE) thought to be related to mosnetuzumab treatment. The most commonly reported AE by physical therapists thought to be related to mosnetuzumab treatment was CRS (31.3%; 5 / 16 patients). Figure 3 shows AEs thought to be related to mosnetuzumab (≥10%).

[0252] Overall, 50.0% of patients (8 / 16 patients; Table 4) reported at least one adverse event (AE) thought to be related to lenalidomide treatment. The most commonly reported AE by physical therapists thought to be related to lenalidomide treatment was neutropenia (25.0%; 4 / 16 patients). Figure 4 shows AEs thought to be related to lenalidomide (≥10%).

[0253] Adverse events by severity Overall, 31.3% of patients (5 / 16 patients; Table 4) reported at least one grade 3 or higher adverse event (AE). The most commonly reported AE by physical therapists was neutropenia (25.0%; 4 / 16 patients; Table 6). [Table 6] Based on MedDRA version 23.1. Percentages are based on N in the column header. Only treated emergency AEs are displayed. In the frequency count in the "Total Number of Events" row, multiple occurrences of the same AE in an individual are counted separately.

[0254] death As of the time of the CO41942 study, no deaths have been reported.

[0255] Serious adverse events Overall, 12.5% ​​of patients reported at least one SAE (2 / 16 patients; Table 4). A summary of reported serious adverse events is provided in Table 7. One patient (6.3%) experienced a mosnetuzumab-related SAE (maculopapular rash due to PT). This event was grade 3 in severity and resolved 9 days after dose discontinuation of mosnetuzumab. Two other events (pleural effusion and atrial flutter due to PT) resulted in dose discontinuation of the treatment (lenalidomide and mosnetuzumab, respectively), both of which were grade 2 in severity and resolved by day 8 of onset. All other reported SAEs were grade 1 or grade 2 in severity and resolved by day 9 of onset or by day 9 without dose discontinuation / modification of the study treatment. No grade 4 or 5 SAEs were reported. [Table 7] TIFF0007846761000008.tif84170 Percentages are based on N in the column header. In frequency counts by basic terminology, multiple occurrences of the same SAE in an individual are counted only once. In frequency counts in the "Total Number of Events" row, multiple occurrences of the same SAE in an individual are counted separately. Adverse events lacking a Common Terminology Criteria for Adverse Events (CTCAE) grade are excluded.

[0256] Adverse events that resulted in a change or discontinuation of the study treatment dose Overall, 37.5% of patients reported at least one event resulting in a dose change / discontinuation of the study treatment (6 / 16 patients; Table 4). Of these, two patients experienced dose discontinuation of mosnetuzumab and six patients experienced dose discontinuation of lenalidomide treatment.

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

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

[0259] Particularly noteworthy adverse events (AESIs) AESIs, including events where toxicity was considered to overlap between study procedures, are summarized in Table 8. Overall, 43.8% (7 / 16 patients) of patients reported at least one AESI. The most commonly reported AESIs were CRS (31.3%; 5 / 16 patients) and neutropenia (25.0%; 4 / 16 patients). One patient (6.3%) reported a grade 1 thrombocytopenia event that had not resolved by the time of CCOD, and no intervention was performed. [Table 8] The percentage is based on N in the column header.

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

[0261] Five patients (31.3%), including 4 patients (25.0%) with ASTCT grade 1 and 1 patient (6.3%) with grade 2, had CRS events considered related to mosunetuzumab treatment as evaluated by the study responsible physician (Table 9). All 5 patients had their first CRS event between day 1 and day 7 of cycle 1 (Figure 5). One patient (6.3%; 1 / 14) had a subsequent grade 1 event between day 15 and day 21 of cycle 1 during mosunetuzumab monotherapy treatment, and another patient (6.3%; 1 / 14) had a subsequent grade 1 event at C2 during combination treatment with mosunetuzumab and lenalidomide.

Table 9

[0262] Overall, fever was the most frequent symptom of CRS, with seven events reported in five patients who reported CRS events. Other signs and symptoms of CRS reported concurrently included chills, hypoxia, tachycardia, elevated liver enzymes (AST), elevated liver enzymes (ALT), hyperuricemia, and elevated lactate dehydrogenase (LDH). One patient (6.3%) received low-flow oxygen for treatment of grade 2 CRS. No grade 3 or higher CRS events were observed, and patients did not require support from tocilizumab, ICU management, high-flow oxygen, or vasopressors.

[0263] Four patients (25.0%) reported nine neutropenia events (Table 4). Of these, two patients experienced five events thought to be related to mosnetuzumab and lenalidomide treatment, as assessed by the investigator, and two patients experienced four events thought to be related solely to lenalidomide treatment. Two patients reported grade 4 severity events, all of which resolved, one patient received no treatment, and one patient received G-CSF treatment. Two patients reported five grade 3 severity events, two of which (one in each patient) did not resolve at the time of CCOD after lenalidomide events and G-CSF treatment for dose discontinuation. The neutropenia events occurred between days 42 and 155 and had durations between 8 and 16 days.

[0264] Preliminary effectiveness The efficacy evaluable population included all patients who were evaluated for response at any point in the study, who withdrew from the treatment or study before reaching the first response evaluation, or who had undergone a study long enough to reach the first planned response evaluation planned for each protocol on days 15–21 of cycle 3. Response was evaluated by the principal investigator according to the Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014;32:1-9).

[0265] Formal efficacy data analysis was not performed. A review of the electronic database revealed that, at the time of CCOD, eight patients enrolled in study CO41942 had received at least one response evaluation. Of these eight patients, two showed a partial response and six showed a complete response (i.e., 100% overall response rate (OR) and 75% complete response rate (CR)). None of the patients experienced disease progression or discontinued the study.

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

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

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

[0269] In this study, the overall frequency and severity of CRS events (7 events of grade 1–2 severity in 5 patients) observed with mosnetuzumab in combination with lenalidomide were comparable to those observed with mosnetuzumab monotherapy. All CRS events were grade 1, with the exception of one patient who experienced a grade 2 event in cycle 1 with mosnetuzumab (1 mg) monotherapy. This patient was the only one to experience a grade 1 CRS event in cycle 2. Four patients (25.0%) reported grade 3–4 neutropenia events. Of the nine reported events, seven resolved, and two (grade 3 severity) remained resolved by the time of CCOD. One patient (6.3%) reported a grade 1 thrombocytopenia event that had not resolved by the time of CCOD. No patients discontinued the study treatment due to adverse events (AEs).

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

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

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

[0273] method Patients with R / R FL (grade 1-3a) and at least one prior systemic anticancer therapy were enrolled and received 12 cycles of combination therapy with mosnetuzumab and lenalidomide (cycle duration: cycle 1, 21 days; cycles 2-12, 28 days). In cycle 1, step-up doses of mosnetuzumab (IV infusion) were administered on day 1 of cycle 1 (C1D1 dose; 1 mg) and day 2 of cycle 1 (C1D2 dose; 2 mg), and the target dose was administered on day 3 of cycle 1 (C1D3 dose; 30 mg) and day 1 of cycles 2-12 (C2D1-C12D1 doses). Lenalidomide (20 mg orally) was administered on days 1-21 of cycles 2-12. Hospitalization was not compulsory by protocol. The primary objective is to evaluate the safety of combination therapy with mosnetuzumab and lenalidomide, with secondary objectives including evaluation of response and long-term efficacy outcomes. Cytokine release syndrome (CRS) was reported using the ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Response was assessed by the principal investigator using PET-CT with the Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014;32:1-9).

[0274] result At the data cutoff date (May 31, 2021), 27 patients were enrolled. The median age was 59 years (range: 31–79 years), and 12 patients (44%) were male. All patients had an ECOG (East Coast Cancer Group) performance status of 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) less than 24 months after initiating first-line treatment. At the data cutoff date, 16 patients (59%) had continued the study for 0–3 months, 8 patients (30%) for 3–6 months, 2 patients (7%) for 6–9 months, and 1 patient (4%) for more than 9 months.

[0275] All 27 patients were eligible for safety evaluation at the data cutoff. Twenty patients (74%) experienced one or more adverse events (AEs) of any grade (Gr), with CRS being the most common AE (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. Mosnetuzumab-related AEs occurred in 20 patients (74%), and lenalidomide-related AEs occurred in 10 patients (37%). There were no AEs leading to withdrawal from mosnetuzumab or lenalidomide. Two patients had mosnetuzumab-related AEs resulting in mosnetuzumab dose delay, and six patients (22%) had lenalidomide-related AEs resulting in lenalidomide dose interruption and / or reduction.

[0276] In all patients, CRS events were grade 1 (7 / 8 patients) or grade 2 (1 / 8 patients). For most patients (6 / 8), CRS events occurred in cycle 1, and two patients experienced grade 1 CRS events in cycle 2. The median time to CRS onset was 1 day after the first administration of the study drug (range: 1–28 days), and the median duration of CRS was 3 days (range: 2–5 days). All CRS events resolved without complications. Patients did not require support from tocilizumab, ICU admission, high-flow oxygen, or vasopressors. Five patients (19%) reported 14 events of grade 3–4 neutropenia, all of which occurred between days 41 and 218, with durations of 6–16 days. All neutropenia events resolved, one patient received primary granulocyte colony-stimulating factor (G-CSF) prophylaxis, and two patients received G-CSF treatment. No febrile neutropenia events occurred.

[0277] The efficacy evaluable population included all patients who were evaluated for response at any point in the study, who withdrew from treatment or the study before reaching the first response evaluation, or who had undergone a study long enough to reach the first planned response evaluation planned for each protocol on days 15–21 of cycle 3. The objective response rate in the 13 patients who were efficacy evaluable at the data cutoff was 92%, with complete metabolic response observed in 10 patients (77%), partial metabolic response (PMR) observed in 2 patients (15%), and stable disease observed in 1 patient (8%). The one patient who first achieved PMR experienced disease progression (PD) after 8 cycles of treatment.

[0278] conclusion The combination therapy of mosnetuzumab and lenalidomide appears to have an acceptable safety profile in R / R FL patients who have received at least one prior treatment line, and promising preliminary anti-lymphoma activity has been observed.

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

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

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

[0282] 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] AE = Adverse Event

[0283] 29 patients (100%) experienced an adverse event (AE) of any grade 1 or higher. Common adverse events experienced by at least 10% of patients are summarized in the 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. Mosnetuzumab-related AEs occurred in 27 patients (93.2%), and lenalidomide-related AEs occurred in 23 patients (79.3%). There were no AEs leading to mosnetuzumab withdrawal, one AE leading to lenalidomide withdrawal, six patients (20.7%) had mosnetuzumab-related AEs resulting in mosnetuzumab dose modification and / or discontinuation, and 12 patients (41.4%) had lenalidomide-related AEs resulting in lenalidomide dose modification and / or discontinuation.

[0284] The cytokine release syndrome (CRS) events observed in patients whose safety could be evaluated are summarized in Table 11 below. [Table 11] a The patient had fever and hypoxia requiring 2 liters of nasal cannula oxygen.

[0285] In all patients who experienced at least one CRS event (8 / 29 patients in total), the CRS event was either Grade 1 (7 / 8 patients) or Grade 2 (1 / 8 patients). For most patients (6 / 8), the CRS event occurred in Cycle 1, and two patients experienced a Grade 1 CRS event in Cycle 2. The median time to CRS onset was 1 day after the first administration of the study drug (range: 1–28 days), and the median duration of CRS was 3 days (range: 2–5 days). All CRS events 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 immunoeffector cell-associated neurotoxicity syndrome (ICANS) events occurred. A summary of CRS events by administration cycle and dose is shown in Figure 8.

[0286] Neutropenia and febrile neutropenia events observed in patients whose safety could be evaluated are summarized in Table 12 below. [Table 12]

[0287] Seven patients (24.1%) reported grade 3–4 neutropenia or febrile neutropenia events. All neutropenia events occurred between days 41 and 189 (median day 86), with a median duration of 9 days (range 4–29 days). All neutropenia events resolved by the data cutoff date. One patient (duration: 5 days) experienced febrile neutropenia (grade 3), which was considered treatment-related. Figure 9 summarizes the reported neutropenia events by medication cycle, grade by medication cycle, and use of granulocyte colony-stimulating factor (G-CSF).

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

[0289] conclusion The combination therapy of mosnetuzumab and lenalidomide appeared to have an acceptable safety profile in R / R FL patients who had received at least one prior treatment line, and promising anti-lymphoma and antitumor activity was observed. No increase in CRS or neutropenic events was observed compared to mosnetuzumab monotherapy.

[0290] Embodiment Some embodiments of the technology described herein can be defined according to any of the embodiments numbered below. 1. A method of treating a subject, comprising administering an effective dose of mosnetuzumab and an effective dose of lenalidomide to the subject, (a) Having relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, (b) previously treated with at least one chemoimmunotherapy regimen, method.

[0291] 2. Mosnetuzumab for use in combination with lenalidomide in the treatment in question, and the subject is (a) Having relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, (b) previously treated with at least one chemoimmunotherapy regimen, Mosnetsumab.

[0292] 3. The use of mosnetuzumab in combination with lenalidomide in the treatment in question, where the subject is (a) Having relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, (b) previously treated with at least one chemoimmunotherapy regimen, use.

[0293] 4. Use of mosnetuzumab in the manufacture of a pharmaceutical product for use in combination with lenalidomide to treat a subject, where the subject is (a) Having relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, (b) previously treated with at least one chemoimmunotherapy regimen, use.

[0294] 5. The use of lenalidomide in the manufacture of a pharmaceutical product for use in combination with mosnetuzumab to treat a subject, where the subject is (a) Having relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, (b) previously treated with at least one chemoimmunotherapy regimen, use.

[0295] 6. The use of mosnetuzumab and lenalidomide in the manufacture of a pharmaceutical product for treating a subject, where the subject is (a) Having relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, (b) previously treated with at least one chemoimmunotherapy regimen, use.

[0296] 7. The method according to any one of Embodiments 1 to 6, mosnetuzumab for use, or use, wherein at least one chemoimmunotherapy regimen comprises an anti-CD20 monoclonal antibody.

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

[0298] 9. Each subject has not been treated with an anti-CD20 monoclonal antibody for at least four weeks prior to the administration of an effective dose of mosnetuzumab and lenalidomide, according to the method of either Embodiment 7 or 8, mosnetuzumab for use, or use.

[0299] 10. Mosnetuzumab or use according to Embodiment 7 or 8, wherein mosnetuzumab and lenalidomide are not administered to the subject for at least 4 weeks after the subject has been treated with an anti-CD20 monoclonal antibody.

[0300] 11. Mosnetuzumab for use, or use according to any one of Embodiments 1 to 6, wherein mosnetuzumab and lenalidomide have a synergistic effect on R / R FL.

[0301] 12. Mosnetuzumab for use, as described in Embodiment 11, or for use, 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).

[0302] 13. Mosnetuzumab for use, as described in Embodiment 11, or for use, 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).

[0303] 14. Administering an effective dose of mosnetuzumab includes administering mosnetuzumab in accordance with a drug regimen that includes at least a first and second drug cycle. (a) The first medication cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab, where C1D1 and C1D2 are each less than or equal to C1D3, where C1D1 is between 0.02 mg and 4.0 mg, C1D2 is between 0.05 mg and 20.0 mg, and C1D3 is between 0.2 mg and 50.0 mg, and (b) The method according to any one of Embodiments 1 and 7-9 and 11-13, wherein the second drug cycle comprises a single dose (C2D1) of mosnetuzumab, where C2D1 is C1D3 or higher and between 0.2 mg and 50 mg.

[0304] 15. Mosnetuzumab will be administered to the subject according to a drug regimen that includes at least a first and second drug cycle. (a) The first medication cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab, where C1D1 and C1D2 are each less than or equal to C1D3, where C1D1 is between 0.02 mg and 4.0 mg, C1D2 is between 0.05 mg and 20.0 mg, and C1D3 is between 0.2 mg and 50.0 mg, and (b) Mosnetuzumab for use according to any one of embodiments 2-8 and 10-14, wherein the second dosing cycle comprises a single dose (C2D1) of mosnetuzumab, where C2D1 is C1D3 or greater and is between 0.2 mg and 50 mg.

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

[0306] 17.(a) C1D1 is 0.8 mg to 3.0 mg, C1D2 is 1.0 mg to 6.0 mg, C1D3 is 3.0 mg to 45.0 mg, and (b) Mosnetuzumab for use according to any one of Embodiments 14 to 16, wherein C2D1 is 3.0 mg to 45.0 mg.

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

[0308] 19. Mosnetuzumab for use, according to any one of Embodiments 14-17, wherein C1D2 is approximately 50% to approximately 250% greater than C1D1.

[0309] 20.(a) Is C1D1 0.8 mg, C1D2 2.0 mg, C1D3 4.2 mg, and C2D1 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) Mosnetuzumab for use, according to any one of Embodiments 14 to 17, wherein C1D1 is 1.0 mg, C1D2 is 2.0 mg, C1D3 is 30.0 mg, and C2D1 is 30.0 mg.

[0310] 21. The method according to any one of Embodiments 14-20, mosnetuzumab for use, or use, wherein the length of the first drug cycle is 21 days.

[0311] 22. The method according to Embodiment 21, wherein the method comprises administering C1D1, C1D2, and C1D3 to a subject on day 1, day 8, and day 15, or approximately day 1, approximately day 8, and approximately day 15, respectively, of the first drug-dosing cycle.

[0312] 23. Mosnetuzumab for use as described in Embodiment 21, or for use as described in Embodiment 21, wherein C1D1, C1D2, and C1D3 are administered to the subject on day 1, day 8, and day 15, or approximately day 1, approximately day 8, and approximately day 15, respectively, of the first drug-dosing cycle.

[0313] 24. Mosnetuzumab for use according to any one of Embodiments 14-23, wherein the length of the second medication cycle is 28 days.

[0314] 25. The method according to Embodiment 24, wherein the method includes administering C2D1 to the subject on the first day of the second medication cycle.

[0315] 26. Mosnetuzumab for use, as described in Embodiment 24, or for use, wherein C2D1 is administered to the subject on day 1 of the second dosing cycle.

[0316] 27. The method according to any one of embodiments 24-26, mosnetuzumab for use, or use thereof, wherein the drug regimen includes one or more additional drug cycles.

[0317] 28. Mosnetuzumab for use, as described in Embodiment 27, or for use, wherein the drug regimen includes 1 to 10 additional drug cycles.

[0318] 29. Mosnetuzumab for use, according to the method of Embodiment 27 or 28, wherein the drug regimen includes 10 additional drug cycles.

[0319] 30. Mosnetuzumab for use according to any one of Embodiments 27-29, wherein the length of each of the 30.1 or more additional drug administration cycles is 28 days.

[0320] 31. Each of 1 or more additional dosing cycles comprises an additional dose of mosnetuzumab, according to any one of Embodiments 27-30, mosnetuzumab for use, or use.

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

[0322] 33. Mosnetuzumab for use as described in Embodiment 31, or for use as described in Embodiment 31, wherein each additional dose of mosnetuzumab is administered to the subject on day 1 of each of one or more additional dosing cycles.

[0323] 34. Administering an effective dose of mosnetuzumab includes administering mosnetuzumab according to a drug regimen comprising 12 drug cycles. (a) The first medication cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab, where C1D1 and C1D2 are each less than or equal to C1D3, where C1D1 is between 0.02 mg and 4.0 mg, C1D2 is between 0.05 mg and 20.0 mg, and C1D3 is between 0.2 mg and 50.0 mg, and (b) The method according to any one of Embodiments 1 to 13, wherein each of the second to twelfth drug cycles contains a single dose (C2D1 to C12D1) of mosnetuzumab, and each single dose C2D1 to C12D1 is equivalent in quantity, C1D3 or higher, and is between 0.2 mg and 50 mg.

[0324] 35. Mosnetuzumab will be administered to the subjects according to a drug regimen that includes 12 drug cycles. (a) The first medication cycle includes a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab, where C1D1 and C1D2 are each less than or equal to C1D3, where C1D1 is between 0.02 mg and 4.0 mg, C1D2 is between 0.05 mg and 20.0 mg, and C1D3 is between 0.2 mg and 50.0 mg, and (b) Mosnetuzumab for use as described in any one of Embodiments 1 to 13, wherein each of the second to twelfth dosing cycles comprises a single dose (C2D1 to C12D1) of mosnetuzumab, each single dose C2D1 to C12D1 being equivalent in quantity, C1D3 or higher, and ranging from 0.2 mg to 50 mg.

[0325] 36.(a) C1D1 is 0.4 mg to 4.0 mg, C1D2 is 1.0 mg to 20.0 mg, and C1D3 is 3.0 mg to 50.0 mg, and (b) Mosnetuzumab for use, as described in Embodiment 34 or 35, wherein each single dose C2D1 to C12D1 is 3.0 mg to 50.0 mg.

[0326] 37.(a) C1D1 is 0.8 mg to 3.0 mg, C1D2 is 1.0 mg to 6.0 mg, C1D3 is 3.0 mg to 45.0 mg, and (b) Mosnetuzumab for use, as described in any one of Embodiments 34 to 36, wherein each single dose C2D1 to C12D1 is 3.0 mg to 45.0 mg.

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

[0328] 39. Mosnetuzumab for use, according to any one of embodiments 34-38, wherein C1D2 is approximately 50% to approximately 250% greater than C1D1.

[0329] 40.(a) Is C1D1 0.8 mg, C1D2 2.0 mg, C1D3 4.2 mg, and each single dose C2D1 to C12D1 4.2 mg? (b) C1D1 is 1.0 mg, C1D2 is 1.0 mg, C1D3 is 3.0 mg, and each single dose C2D1 to C12D1 is 30.0 mg, or (c) Mosnetuzumab for use, according to any one of Embodiments 34 to 37, wherein C1D1 is 1.0 mg, C1D2 is 2.0 mg, C1D3 is 30.0 mg, and each single dose C2D1 to C12D1 is 30.0 mg.

[0330] 41. Mosnetuzumab for use according to any one of Embodiments 34-40, wherein the length of the first drug-dosing cycle is 21 days.

[0331] 42. The method according to Embodiment 41, wherein the method includes administering C1D1, C1D2, and C1D3 to a subject on day 1, day 8, and day 15, or approximately day 1, approximately day 8, and approximately day 15, respectively.

[0332] 43. Mosnetuzumab for use as described in Embodiment 41, or for use as described in Embodiment 41, wherein C1D1, C1D2, and C1D3 are administered to the subject on day 1, day 8, and day 15, or approximately day 1, approximately day 8, and approximately day 15, respectively, of the first dosing cycle.

[0333] 44. Mosnetuzumab for use according to any one of Embodiments 34-43, wherein the length of each of the second to twelfth drug-dosing cycles is 28 days.

[0334] 45. The method according to Embodiment 44, wherein the method includes administering each of C2D1 to C12D1 to the subject on the first day of each respective drug cycle.

[0335] 46. ​​The method according to any one of embodiments 34 to 45, wherein the length of each of the second to twelfth drug administration cycles is 28 days.

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

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

[0338] 49. Mosnetuzumab for use as described in any of the preceding embodiments, wherein mosnetuzumab is administered intravenously.

[0339] 50. The method according to any one of Embodiments 14 to 49, wherein lenalidomide is administered during the second and subsequent cycles.

[0340] 51. Mosnetuzumab for use according to any one of Embodiments 14-49, or for use in which lenalidomide is administered during the second and subsequent cycles.

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

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

[0343] 54. The method according to any one of Embodiments 14 to 53, wherein lenalidomide is administered daily.

[0344] 55. Mosnetuzumab for use according to any one of Embodiments 14 to 53, wherein lenalidomide is administered daily.

[0345] 56. The method according to any one of Embodiments 46 and 48-55, wherein lenalidomide is administered daily for the first 21 days of each medication cycle that includes the administration of lenalidomide.

[0346] 57. Mosnetuzumab for use according to any one of Embodiments 46 and 48-55, wherein lenalidomide is administered daily for the first 21 days of each dosing cycle including the administration of lenalidomide.

[0347] 58. The method according to any one of Embodiments 47 to 55, wherein lenalidomide is administered daily for the first 14 days of each medication cycle that includes the administration of lenalidomide.

[0348] 59. Mosnetuzumab for use according to any one of Embodiments 47-55, wherein lenalidomide is administered daily for the first 14 days of each dosing cycle, which includes the administration of lenalidomide.

[0349] 60. The method according to any one of embodiments 56 to 59, wherein lenalidomide is not administered during the first seven days of each medication cycle that includes the administration of lenalidomide.

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

[0351] 62. The method according to any one of Embodiments 14 to 61, wherein lenalidomide is administered in a dose of 20 mg.

[0352] 63. Mosnetuzumab for use according to any one of Embodiments 14 to 61, wherein lenalidomide is administered in a dose of 20 mg.

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

[0354] 65. Mosnetuzumab for use as described in any of the preceding embodiments, wherein lenalidomide is administered orally.

[0355] 66. The method of any of the preceding embodiments, mosnetuzumab for use, or use of a subject that has been previously treated with at least one anti-CD20 monoclonal antibody.

[0356] 67. Mosnetuzumab for use, according to Embodiment 66, or for use in a subject who is relapsed or refractory to treatment including an anti-CD20 monoclonal antibody.

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

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

[0359] 70. Mosnetuzumab for use in combination with lenalidomide to treat a subject, (i) Having relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, (ii) Having been previously treated with at least one chemoimmunotherapy regimen, Mosnetuzumab and lenalidomide are to be administered to the subjects according to a drug regimen that includes at least a first 21-day drug cycle and a second 28-day drug cycle. (a) The first medication cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab, which will be administered intravenously on days 1, 8, and 15 of the first medication cycle, respectively, with C1D1 being 1 mg, C1D2 being 2 mg, and C1D3 being 30 mg. (b) The second medication cycle includes a single dose (C2D1) of mosnetuzumab to be administered intravenously on day 1 of the second medication cycle, with C2D1 being 30 mg, and (c) The second medication cycle further comprises a daily dose of 20 mg of lenalidomide, which will be administered orally on days 1 through 21 of the second medication cycle. Mosnetsumab.

[0360] 71. Use of mosnetuzumab in combination with lenalidomide to treat a subject, wherein the subject is (i) Having relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, (ii) Having been previously treated with at least one chemoimmunotherapy regimen, Mosnetuzumab and lenalidomide are to be administered to the subjects according to a drug regimen that includes at least a first 21-day drug cycle and a second 28-day drug cycle. (a) The first medication cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab, which will be administered intravenously on days 1, 8, and 15 of the first medication cycle, respectively, with C1D1 being 1 mg, C1D2 being 2 mg, and C1D3 being 30 mg. (b) The second medication cycle includes a single dose (C2D1) of mosnetuzumab to be administered intravenously on day 1 of the second medication cycle, with C2D1 being 30 mg, and (c) The second medication cycle further comprises a daily dose of 20 mg of lenalidomide, which will be administered orally on days 1 through 21 of the second medication cycle. use.

[0361] 72. Use of mosnetuzumab in the manufacture of a pharmaceutical product for use in combination with lenalidomide to treat a subject, where the subject is (i) Having relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, (ii) Having been previously treated with at least one chemoimmunotherapy regimen, Mosnetuzumab and lenalidomide are to be administered to the subjects according to a drug regimen that includes at least a first 21-day drug cycle and a second 28-day drug cycle. (a) The first medication cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab, which will be administered intravenously on days 1, 8, and 15 of the first medication cycle, respectively, with C1D1 being 1 mg, C1D2 being 2 mg, and C1D3 being 30 mg. (b) The second medication cycle includes a single dose (C2D1) of mosnetuzumab to be administered intravenously on day 1 of the second medication cycle, with C2D1 being 30 mg, and (c) The second medication cycle further comprises a daily dose of 20 mg of lenalidomide, which will be administered orally on days 1 through 21 of the second medication cycle. use.

[0362] 73. Use of lenalidomide in the manufacture of a pharmaceutical product for use in combination with mosnetuzumab to treat a subject, where the subject is (i) Having relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, (ii) Having been previously treated with at least one chemoimmunotherapy regimen, Mosnetuzumab and lenalidomide are to be administered to the subjects according to a drug regimen that includes at least a first 21-day drug cycle and a second 28-day drug cycle. (a) The first medication cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab, which will be administered intravenously on days 1, 8, and 15 of the first medication cycle, respectively, with C1D1 being 1 mg, C1D2 being 2 mg, and C1D3 being 30 mg. (b) The second medication cycle includes a single dose (C2D1) of mosnetuzumab to be administered intravenously on day 1 of the second medication cycle, with C2D1 being 30 mg, and (c) The second medication cycle further comprises a daily dose of 20 mg of lenalidomide, which will be administered orally on days 1 through 21 of the second medication cycle. use.

[0363] 74. Use of mosnetuzumab and lenalidomide in the manufacture of a pharmacopoeia for treating a subject, where the subject is (i) Having relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, (ii) Having been previously treated with at least one chemoimmunotherapy regimen, Mosnetuzumab and lenalidomide are to be administered to the subjects according to a drug regimen that includes at least a first 21-day drug cycle and a second 28-day drug cycle. (a) The first medication cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab, which will be administered intravenously on days 1, 8, and 15 of the first medication cycle, respectively, with C1D1 being 1 mg, C1D2 being 2 mg, and C1D3 being 30 mg. (b) The second medication cycle includes a single dose (C2D1) of mosnetuzumab to be administered intravenously on day 1 of the second medication cycle, with C2D1 being 30 mg, and (c) The second medication cycle further comprises a daily dose of 20 mg of lenalidomide, which will be administered orally on days 1 through 21 of the second medication cycle. use.

[0364] 75. A method of treating a subject, comprising administering an effective dose of mosnetuzumab and an effective dose of lenalidomide to the subject. The target is, (i) Having relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, (ii) Having been previously treated with at least one chemoimmunotherapy regimen, Administering an effective dose of mosnetuzumab and lenalidomide includes administering mosnetuzumab and lenalidomide according to a drug regimen that includes a first 21-day drug cycle and subsequent 28-day drug cycles. (a) The first medication cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab administered intravenously on days 1, 8, and 15 of the first medication cycle, respectively, where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg. (b) Each of the 2nd to 12th drug cycles contains a single dose (C2D1 to C12D1) of mosnetuzumab administered intravenously on day 1 of each drug cycle, and each single dose C2D1 to C12D1 is 30 mg, (c) Each of the 2nd to 12th medication cycles further comprises administering 20 mg of lenalidomide orally daily on days 1 to 21 of each medication cycle. method.

[0365] 76. Mosnetuzumab for use in combination with lenalidomide in the treatment of the subject, (i) Having relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, (ii) Having been previously treated with at least one chemoimmunotherapy regimen, Mosnetuzumab and lenalidomide are to be administered to the subjects according to a drug regimen that includes the first 21-day drug cycle and subsequent 28-day drug cycles. (a) The first medication cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab, which will be administered intravenously on days 1, 8, and 15 of the first medication cycle, respectively, with C1D1 being 1 mg, C1D2 being 2 mg, and C1D3 being 30 mg. (b) Each of the 2nd to 12th drug cycles contains a single dose (C2D1 to C12D1) of mosnetuzumab to be administered intravenously on day 1 of each drug cycle, and each single dose C2D1 to C12D1 is 30 mg, (c) Each of the 2nd to 12th drug cycles further comprises a daily dose of 20 mg of lenalidomide, which will be administered fluorescently on days 1 to 21 of each drug cycle. Mosnetsumab.

[0366] 77. Use of mosnetuzumab in combination with lenalidomide in the treatment in question, where the subject is (i) Having relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, (ii) Having been previously treated with at least one chemoimmunotherapy regimen, Mosnetuzumab and lenalidomide are to be administered to the subjects according to a drug regimen that includes the first 21-day drug cycle and subsequent 28-day drug cycles. (a) The first medication cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab, which will be administered intravenously on days 1, 8, and 15 of the first medication cycle, respectively, with C1D1 being 1 mg, C1D2 being 2 mg, and C1D3 being 30 mg. (b) Each of the 2nd to 12th drug cycles contains a single dose (C2D1 to C12D1) of mosnetuzumab to be administered intravenously on day 1 of each drug cycle, and each single dose C2D1 to C12D1 is 30 mg, (c) Each of the 2nd to 12th drug cycles further comprises a daily dose of 20 mg of lenalidomide, which will be administered fluorescently on days 1 to 21 of each drug cycle. use.

[0367] 78. Use of mosnetuzumab in the manufacture of a pharmaceutical product for use in combination with lenalidomide to treat a subject, where the subject is (i) Having relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, (ii) Having been previously treated with at least one chemoimmunotherapy regimen, Mosnetuzumab and lenalidomide are to be administered to the subjects according to a drug regimen that includes the first 21-day drug cycle and subsequent 28-day drug cycles. (a) The first medication cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab, which will be administered intravenously on days 1, 8, and 15 of the first medication cycle, respectively, with C1D1 being 1 mg, C1D2 being 2 mg, and C1D3 being 30 mg. (b) Each of the 2nd to 12th drug cycles contains a single dose (C2D1 to C12D1) of mosnetuzumab to be administered intravenously on day 1 of each drug cycle, and each single dose C2D1 to C12D1 is 30 mg, (c) Each of the 2nd to 12th drug cycles further comprises a daily dose of 20 mg of lenalidomide, which will be administered fluorescently on days 1 to 21 of each drug cycle. use.

[0368] 79. Use of lenalidomide in the manufacture of a pharmaceutical product for use in combination with mosnetuzumab to treat a subject, where the subject is (i) Having relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, (ii) Having been previously treated with at least one chemoimmunotherapy regimen, Mosnetuzumab and lenalidomide are to be administered to the subjects according to a drug regimen that includes the first 21-day drug cycle and subsequent 28-day drug cycles. (a) The first medication cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab, which will be administered intravenously on days 1, 8, and 15 of the first medication cycle, respectively, with C1D1 being 1 mg, C1D2 being 2 mg, and C1D3 being 30 mg. (b) Each of the 2nd to 12th drug cycles contains a single dose (C2D1 to C12D1) of mosnetuzumab to be administered intravenously on day 1 of each drug cycle, and each single dose C2D1 to C12D1 is 30 mg, (c) Each of the 2nd to 12th drug cycles further comprises a daily dose of 20 mg of lenalidomide, which will be administered fluorescently on days 1 to 21 of each drug cycle. use.

[0369] 80. Use of mosnetuzumab and lenalidomide in the manufacture of a pharmacopoeia for treating a subject, where the subject is (i) Having relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, (ii) Having been previously treated with at least one chemoimmunotherapy regimen, Mosnetuzumab and lenalidomide are to be administered to the subjects according to a drug regimen that includes the first 21-day drug cycle and subsequent 28-day drug cycles. (a) The first medication cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab, which will be administered intravenously on days 1, 8, and 15 of the first medication cycle, respectively, with C1D1 being 1 mg, C1D2 being 2 mg, and C1D3 being 30 mg. (b) Each of the 2nd to 12th drug cycles contains a single dose (C2D1 to C12D1) of mosnetuzumab to be administered intravenously on day 1 of each drug cycle, and each single dose C2D1 to C12D1 is 30 mg, (c) Each of the 2nd to 12th drug cycles further comprises a daily dose of 20 mg of lenalidomide, which will be administered fluorescently on days 1 to 21 of each drug cycle. use.

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

[0371] 82. Mosnetuzumab for use in combination with lenalidomide in the treatment of the subject, (i) Having relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, (ii) Having been previously treated with at least one chemoimmunotherapy regimen, Mosnetuzumab and lenalidomide are to be administered to the subjects according to a drug regimen that includes at least a first 21-day drug cycle and a second 21-day drug cycle. (a) The first medication cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab, which will be administered intravenously on days 1, 8, and 15 of the first medication cycle, respectively, with C1D1 being 1 mg, C1D2 being 2 mg, and C1D3 being 30 mg. (b) The second medication cycle includes a single dose (C2D1) of mosnetuzumab to be administered intravenously on day 1 of the second medication cycle, with C2D1 being 30 mg, and (c) The second medication cycle further comprises a daily dose of 20 mg of lenalidomide, which will be administered orally on days 1 through 14 of the second medication cycle. Mosnetsumab.

[0372] 83. Use of mosnetuzumab in combination with lenalidomide in the treatment in question, where the subject is (i) Having relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, (ii) Having been previously treated with at least one chemoimmunotherapy regimen, Mosnetuzumab and lenalidomide are to be administered to the subjects according to a drug regimen that includes at least a first 21-day drug cycle and a second 21-day drug cycle. (a) The first medication cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab, which will be administered intravenously on days 1, 8, and 15 of the first medication cycle, respectively, with C1D1 being 1 mg, C1D2 being 2 mg, and C1D3 being 30 mg. (b) The second medication cycle includes a single dose (C2D1) of mosnetuzumab to be administered intravenously on day 1 of the second medication cycle, with C2D1 being 30 mg, and (c) The second medication cycle further comprises a daily dose of 20 mg of lenalidomide, which will be administered orally on days 1 through 14 of the second medication cycle. use.

[0373] 84. Use of mosnetuzumab in the manufacture of a pharmaceutical product for use in combination with lenalidomide to treat a subject, where the subject is (i) Having relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, (ii) Having been previously treated with at least one chemoimmunotherapy regimen, Mosnetuzumab and lenalidomide are to be administered to the subjects according to a drug regimen that includes at least a first 21-day drug cycle and a second 21-day drug cycle. (a) The first medication cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab, which will be administered intravenously on days 1, 8, and 15 of the first medication cycle, respectively, with C1D1 being 1 mg, C1D2 being 2 mg, and C1D3 being 30 mg. (b) The second medication cycle includes a single dose (C2D1) of mosnetuzumab to be administered intravenously on day 1 of the second medication cycle, with C2D1 being 30 mg, and (c) The second medication cycle further comprises a daily dose of 20 mg of lenalidomide, which will be administered orally on days 1 through 14 of the second medication cycle. use.

[0374] 85. Use of lenalidomide in the manufacture of a pharmaceutical product for use in combination with mosnetuzumab to treat a subject, where the subject is (i) Having relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, (ii) Having been previously treated with at least one chemoimmunotherapy regimen, Mosnetuzumab and lenalidomide are to be administered to the subjects according to a drug regimen that includes at least a first 21-day drug cycle and a second 21-day drug cycle. (a) The first medication cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab, which will be administered intravenously on days 1, 8, and 15 of the first medication cycle, respectively, with C1D1 being 1 mg, C1D2 being 2 mg, and C1D3 being 30 mg. (b) The second medication cycle includes a single dose (C2D1) of mosnetuzumab to be administered intravenously on day 1 of the second medication cycle, with C2D1 being 30 mg, and (c) The second medication cycle further comprises a daily dose of 20 mg of lenalidomide, which will be administered orally on days 1 through 14 of the second medication cycle. use.

[0375] 86. Use of mosnetuzumab and lenalidomide in the manufacture of a pharmacopoeia for treating a subject, where the subject is (i) Having relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, (ii) Having been previously treated with at least one chemoimmunotherapy regimen, Mosnetuzumab and lenalidomide are to be administered to the subjects according to a drug regimen that includes at least a first 21-day drug cycle and a second 21-day drug cycle. (a) The first medication cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab, which will be administered intravenously on days 1, 8, and 15 of the first medication cycle, respectively, with C1D1 being 1 mg, C1D2 being 2 mg, and C1D3 being 30 mg. (b) The second medication cycle includes a single dose (C2D1) of mosnetuzumab to be administered intravenously on day 1 of the second medication cycle, with C2D1 being 30 mg, and (c) The second medication cycle further comprises a daily dose of 20 mg of lenalidomide, which will be administered orally on days 1 through 14 of the second medication cycle. use.

[0376] 87. A method of treating a subject, comprising administering an effective dose of mosnetuzumab and an effective dose of lenalidomide to the subject. The target is, (i) Having relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, (ii) Having been previously treated with at least one chemoimmunotherapy regimen including obinutuzumab, Administering an effective dose of mosnetuzumab and lenalidomide includes administering mosnetuzumab and lenalidomide according to a drug regimen that includes a first 21-day drug cycle and subsequent 21-day drug cycles. (a) The first medication cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab administered intravenously on days 1, 8, and 15 of the first medication cycle, respectively, where C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg. (b) Each of the 2nd to 12th drug cycles contains a single dose (C2D1 to C12D1) of mosnetuzumab administered intravenously on day 1 of each drug cycle, and each single dose C2D1 to C12D1 is 30 mg, (c) Each of the 2nd to 12th medication cycles further comprises administering 20 mg of lenalidomide orally daily on days 1 to 14 of each medication cycle. method.

[0377] 88. Mosnetuzumab for use in combination with lenalidomide in the treatment of the subject, (i) Having relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, (ii) Having been previously treated with at least one chemoimmunotherapy regimen, Mosnetuzumab and lenalidomide are to be administered to the subjects according to a drug regimen that includes the first 21-day drug cycle and subsequent 21-day drug cycles. (a) The first medication cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab, which will be administered intravenously on days 1, 8, and 15 of the first medication cycle, respectively, with C1D1 being 1 mg, C1D2 being 2 mg, and C1D3 being 30 mg. (b) Each of the 2nd to 12th drug cycles contains a single dose (C2D1 to C12D1) of mosnetuzumab to be administered intravenously on day 1 of each drug cycle, and each single dose C2D1 to C12D1 is 30 mg, (c) Each of the 2nd to 12th medication cycles further comprises a daily dose of 20 mg of lenalidomide, which will be administered on days 1 to 14 of each medication cycle. method.

[0378] 89. Use of mosnetuzumab in combination with lenalidomide in the treatment in question, where the subject is (i) Having relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, (ii) Having been previously treated with at least one chemoimmunotherapy regimen, Mosnetuzumab and lenalidomide are to be administered to the subjects according to a drug regimen that includes the first 21-day drug cycle and subsequent 21-day drug cycles. (a) The first medication cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab, which will be administered intravenously on days 1, 8, and 15 of the first medication cycle, respectively, with C1D1 being 1 mg, C1D2 being 2 mg, and C1D3 being 30 mg. (b) Each of the 2nd to 12th drug cycles contains a single dose (C2D1 to C12D1) of mosnetuzumab to be administered intravenously on day 1 of each drug cycle, and each single dose C2D1 to C12D1 is 30 mg, (c) Each of the 2nd to 12th medication cycles further comprises a daily dose of 20 mg of lenalidomide, which will be administered on days 1 to 14 of each medication cycle. use.

[0379] 90. Use of mosnetuzumab in the manufacture of a pharmaceutical product for use in combination with lenalidomide to treat a subject, the subject is (i) Having relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, (ii) Having been previously treated with at least one chemoimmunotherapy regimen, Mosnetuzumab and lenalidomide are to be administered to the subjects according to a drug regimen that includes the first 21-day drug cycle and subsequent 21-day drug cycles. (a) The first medication cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab, which will be administered intravenously on days 1, 8, and 15 of the first medication cycle, respectively, with C1D1 being 1 mg, C1D2 being 2 mg, and C1D3 being 30 mg. (b) Each of the 2nd to 12th drug cycles contains a single dose (C2D1 to C12D1) of mosnetuzumab to be administered intravenously on day 1 of each drug cycle, and each single dose C2D1 to C12D1 is 30 mg, (c) Each of the 2nd to 12th medication cycles further comprises a daily dose of 20 mg of lenalidomide, which will be administered on days 1 to 14 of each medication cycle. use.

[0380] 91. Use of lenalidomide in the manufacture of a pharmaceutical product for use in combination with mosnetuzumab to treat a subject, where the subject is (i) Having relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, (ii) Having been previously treated with at least one chemoimmunotherapy regimen, Mosnetuzumab and lenalidomide are to be administered to the subjects according to a drug regimen that includes the first 21-day drug cycle and subsequent 21-day drug cycles. (a) The first medication cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab, which will be administered intravenously on days 1, 8, and 15 of the first medication cycle, respectively, with C1D1 being 1 mg, C1D2 being 2 mg, and C1D3 being 30 mg. (b) Each of the 2nd to 12th drug cycles contains a single dose (C2D1 to C12D1) of mosnetuzumab to be administered intravenously on day 1 of each drug cycle, and each single dose C2D1 to C12D1 is 30 mg, (c) Each of the 2nd to 12th medication cycles further comprises a daily dose of 20 mg of lenalidomide, which will be administered on days 1 to 14 of each medication cycle. use.

[0381] 92. Use of mosnetuzumab and lenalidomide in the manufacture of a pharmaceutical product for treating a subject, where the subject is (i) Having relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, (ii) Having been previously treated with at least one chemoimmunotherapy regimen, Mosnetuzumab and lenalidomide are to be administered to the subjects according to a drug regimen that includes the first 21-day drug cycle and subsequent 21-day drug cycles. (a) The first medication cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab, which will be administered intravenously on days 1, 8, and 15 of the first medication cycle, respectively, with C1D1 being 1 mg, C1D2 being 2 mg, and C1D3 being 30 mg. (b) Each of the 2nd to 12th drug cycles contains a single dose (C2D1 to C12D1) of mosnetuzumab to be administered intravenously on day 1 of each drug cycle, and each single dose C2D1 to C12D1 is 30 mg, (c) Each of the 2nd to 12th medication cycles further comprises a daily dose of 20 mg of lenalidomide, which will be administered on days 1 to 14 of each medication cycle. use.

[0382] 93. Mosnetuzumab for use, according to any one of Embodiments 69-92, wherein at least one chemoimmunotherapy regimen comprises an anti-CD20 monoclonal antibody.

[0383] 94. The method according to Embodiment 93, for use of mosnetuzumab, or for use of the anti-CD20 monoclonal antibody, which is rituximab or obinutuzumab.

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

[0385] 96. The method according to any one of embodiments 93 to 95, wherein the subject has not been treated with obinutuzumab or rituximab for at least four weeks prior to administration of an effective dose of mosnetuzumab and lenalidomide.

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

[0387] 98. Mosnetuzumab, lenalidomide, and mosnetuzumab according to any one of Embodiments 69 to 92, for use, or for use, wherein mosnetuzumab and lenalidomide have a synergistic effect on R / R FL.

[0388] 99. Mosnetuzumab for use, as described in Embodiment 98, or for use, 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).

[0389] 100. Mosnetuzumab for use, as described in Embodiment 98, or for use, 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).

[0390] 101. Mosnetuzumab for use, or use, as described in any of the preceding embodiments, if FL is histologically demonstrated to be grade 1, 2, or 3a, but not 3b, according to the World Health Organization's classification of lymphoid neoplasms (referenced in Swerdlow SH, et al. Blood 2016;127:2375-90).

[0391] 102. A method for treating a target population, comprising administering an effective dose of mosnetuzumab and an effective dose of lenalidomide to each subject in the population, Each target, (a) Having relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, (b) previously treated with at least one chemoimmunotherapy regimen, Administering an effective dose of mosnetuzumab and lenalidomide includes administering mosnetuzumab and lenalidomide according to a drug regimen that includes at least a first 21-day drug cycle and a second 28-day drug cycle. (a) The first medication cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab administered intravenously on days 1, 8, and 15 of the first medication cycle, respectively, where C1D1 is 1 mg, C1...

Claims

1. A pharmaceutical product comprising mosnetuzumab for treating a subject, wherein mosnetuzumab is formulated to be administered to the subject in combination with lenalidomide according to a dosing regimen comprising a first 21-day dosing cycle and eleven subsequent 28-day dosing cycles. The subject (a) has relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, and (b) has been previously treated with at least one chemoimmunotherapy regimen; and (a) The first drug cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab administered intravenously on day 1, day 8, and day 15 of the first drug cycle, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg. (b) Each of the 2nd to 12th drug cycles contains a single dose (C2D1 to C12D1) of mosnetuzumab administered intravenously on day 1 of each drug cycle, with each single dose C2D1 to C12D1 being 30 mg. (c) Each of the second to twelfth drug cycles further comprises a daily oral administration of 20 mg of lenalidomide on days 1 to 21 of each drug cycle. The subject is a human, and the drug regimen further includes the administration of corticosteroids. Pharmaceuticals.

2. A pharmaceutical product comprising lenalidomide for treating a subject, wherein lenalidomide is formulated to be administered to the subject in combination with mosnetuzumab according to a dosing regimen comprising a first 21-day dosing cycle and eleven subsequent 28-day dosing cycles. The subject (a) has relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, and (b) has been previously treated with at least one chemoimmunotherapy regimen; and (a) The first drug cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab administered intravenously on day 1, day 8, and day 15 of the first drug cycle, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg. (b) Each of the 2nd to 12th drug cycles contains a single dose (C2D1 to C12D1) of mosnetuzumab administered intravenously on day 1 of each drug cycle, with each single dose C2D1 to C12D1 being 30 mg. (c) Each of the second to twelfth drug cycles further comprises a daily oral administration of 20 mg of lenalidomide on days 1 to 21 of each drug cycle. The subject is a human, and the drug regimen further includes the administration of corticosteroids. Pharmaceuticals.

3. A pharmaceutical formulation comprising mosnetuzumab and lenalidomide for treating a subject, wherein mosnetuzumab and lenalidomide are formulated for administration to the subject according to a dosing regimen comprising a first 21-day dosing cycle and eleven subsequent 28-day dosing cycles. The subject (a) has relapsed or refractory follicular lymphoma (R / R FL) expressing CD20, and (b) has been previously treated with at least one chemoimmunotherapy regimen; and (a) The first drug cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of mosnetuzumab administered intravenously on day 1, day 8, and day 15 of the first drug cycle, wherein C1D1 is 1 mg, C1D2 is 2 mg, and C1D3 is 30 mg. (b) Each of the 2nd to 12th drug cycles contains a single dose (C2D1 to C12D1) of mosnetuzumab administered intravenously on day 1 of each drug cycle, with each single dose C2D1 to C12D1 being 30 mg. (c) Each of the second to twelfth drug cycles further comprises a daily oral administration of 20 mg of lenalidomide on days 1 to 21 of each drug cycle. The subject is a human, and the drug regimen further includes the administration of corticosteroids. Pharmaceuticals.

4. (a) At least one chemoimmunotherapy regimen comprises an anti-CD20 monoclonal antibody; (b) The subject has received only one preceding line of systemic therapy, (i) Having a Follicular Lymphoma International Prognostic Index (FLIPI) score of 2 to 5, (ii) Was the patient refractory to previous obinutuzumab treatment? (iii) Was the treatment refractory to previous rituximab treatment, or (iv) Has the disease progressed within 24 months of the start of previous treatment? It is either one of the following; (c) The subject has not been treated with obinutuzumab or rituximab for at least four weeks prior to the administration of an effective dose of mosnetuzumab and lenalidomide; and / or (d) Mosnetuzumab and lenalidomide have a synergistic effect on the R / R FL. A pharmaceutical product according to any one of claims 1 to 3.

5. The pharmaceutical product according to claim 4, wherein the synergistic effect is a partial response or a complete response as defined by the Lugano 2014 criteria (Cheson BD, et al. J Clin Oncol 2014;32:1-9).

6. The pharmaceutical product according to any one of claims 1 to 3, wherein the FL is histologically demonstrated to be of grade 1, 2, or 3a, but not 3b, according to the World Health Organization's classification of lymphoid neoplasms (referenced in Swerdlow SH, et al. Blood 2016;127:2375-90).

7. The pharmaceutical product according to any one of claims 1 to 3, wherein the incidence of adverse events in subjects administered mosnetuzumab and lenalidomide according to the aforementioned drug regimen is not significantly higher than the incidence of adverse events in subjects administered mosnetuzumab without lenalidomide.

8. (a) In subjects administered mosnetuzumab and lenalidomide in accordance with the aforementioned drug regimen, the incidence of cytokine release syndrome as defined by the American Society for Transplantation and Cell Therapy (ASTCT) Consensus Grading for Cytokine Release Syndrome ("ASTCT CRS Grading"; Lee et al., Biol Blood Marrow Transplant 2019) is less than 45%, less than 35%, or less than 25%; (b) The incidence of cytokine release syndrome of grade 3 or higher as defined by ASTCT CRS grading is less than 10%, less than 3%, or less than 1%; and / or (c) The incidence of neutropenia in subjects administered mosnetuzumab and lenalidomide according to the drug regimen is less than 40%, less than 30%, or less than 20%. A pharmaceutical product according to any one of claims 1 to 3.

9. (a) The overall response rate in subjects administered mosnetuzumab and lenalidomide according to the drug regimen is at least 80%, at least 90%, at least 95%, or at least 99%; and / or (b) The complete response rate in subjects who were administered mosnetuzumab and lenalidomide according to the drug regimen is at least 65%, at least 75%, or at least 85%. A pharmaceutical product according to any one of claims 1 to 3.

10. The pharmaceutical product according to any one of claims 1 to 3, wherein the subject exhibits a reduction in tumor burden after being administered an effective dose of mosnetuzumab and an effective dose of lenalidomide.

11. The pharmacopoeia according to claim 10, wherein the reduction in tumor load is determined by computed tomography (CT), and / or the reduction in tumor load is a reduction in the sum of product diameters (SPD) of the target lesion.

12. The pharmaceutical product according to claim 11, wherein the reduction in SPD is at least 40%, at least 60%, or at least 80%.

13. The pharmaceutical product according to any one of claims 1 to 3, wherein at least 45%, at least 60%, or at least 75% of subjects administered mosnetuzumab and lenalidomide in accordance with the aforementioned drug regimen exhibit a reduction in tumor burden after administration of an effective dose of mosnetuzumab and an effective dose of lenalidomide.

14. The pharmacopoeia according to claim 13, wherein the reduction in tumor load is determined by computed tomography (CT), and / or the reduction in tumor load is a reduction in the sum of product diameters (SPD) of the target lesion.

15. The pharmaceutical product according to claim 14, wherein the reduction in SPD is at least 40%, at least 60%, or at least 80%.

16. The pharmaceutical product according to any one of claims 1 to 3, wherein the corticosteroid is administered to the subject during the first drug administration cycle.

17. The pharmaceutical product according to claim 16, wherein the first drug administration cycle comprises a first dose (C1D1), a second dose (C1D2), and a third dose (C1D3) of the corticosteroid.

18. The pharmacopoeia according to claim 17, wherein the corticosteroids C1D1, C1D2, and C1D3 are administered to the subject on day 1, day 8, and day 15, respectively, of the first drug cycle, and / or each single dose of the corticosteroids C1D1 to C1D3 is administered to the subject before the administration of mosnetuzumab C1D1 to C1D3.

19. The pharmaceutical product according to any one of claims 1 to 3, wherein the corticosteroid is administered to the subject in the first drug administration cycle and not administered in the second drug administration cycle.

20. The pharmaceutical product according to any one of claims 1 to 3, wherein the corticosteroid is administered to the subject in the second drug administration cycle.

21. The pharmaceutical product according to claim 20, wherein the second drug administration cycle comprises a single dose (C2D1) of the corticosteroid.

22. The pharmacopoeia according to claim 21, wherein the corticosteroid of C2D1 is administered to the subject on the first day of the second drug administration cycle, and / or the corticosteroid of C2D1 is administered to the subject before the administration of mosnetuzumab of C2D1.

23. The pharmaceutical product according to any one of claims 1 to 3, wherein the corticosteroid is administered intravenously.

24. The pharmaceutical product according to claim 23, wherein the corticosteroid is dexamethasone.

25. The pharmaceutical product according to claim 24, wherein each dose of dexamethasone is 10 mg.

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