Methods of using anti-CD79B immunoconjugates to treat diffuse large B-cell lymphoma - Patents.com

Abstract

Provided herein are methods of treating a B cell proliferative disorder (e.g., diffuse large B cell lymphoma "DLBCL") using an immunoconjugate comprising an anti-CD79b antibody in combination with an immunomodulatory agent (e.g., lenalidomide) and an anti-CD20 antibody (e.g., obinutuzumab or rituximab).

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 187858, filed May 12, 2021, the entire contents of which are incorporated herein by reference.

[0002] Submitting a sequence listing as an ASCII text file

[0002] The following submission in an ASCII text file is incorporated by reference in its entirety into this specification: Sequence Listing in Computer Readable Form (CRF) (Filename: 146392054040SEQLIST.TXT, Recorded: May 4, 2021, Size: 64KB).

[0003] FIELD OF THE INVENTION

[0003] The present disclosure relates to methods of treating B-cell proliferative disorders, such as diffuse large B-cell lymphoma (DLBCL), by administering an immunoconjugate comprising an anti-CD79b antibody in combination with an immunomodulatory agent (e.g., lenalidomide) and an anti-CD20 antibody (e.g., obinutuzumab or rituximab). [Background technology]

[0004] Non-Hodgkin's lymphoma (NHL) is the most common hematologic malignancy worldwide and the 13th most common cancer overall (Bray et al., (2018) CA Cancer J Clin, 68:394-424). Diffuse large B-cell lymphoma (DLBCL) is an aggressive subtype of NHL, accounting for approximately 32.5% of all NHL cases. DLBCL originates from mature B cells, and untreated patients have a median survival of less than one year (Rovira et al., (2015) Ann Hematol, 378:1396-1407). The majority of DLBCL cells express CD20, a membrane antigen important in cell cycle initiation and differentiation (Anderson et al., (1984) Blood, 63:1424-1433).

[0005] First-line treatment for DLBCL consists of anti-CD20 monoclonal antibodies combined with multiagent chemotherapy (National Comprehensive Cancer Network 2018; Shen et al., (2018) Lancet vol 5, e264). For patients not cured by first-line therapy, high-dose chemotherapy followed by autologous stem cell transplantation offers a second chance for long-term remission. For patients with relapsed / refractory (R / R) DLBCL who are ineligible for stem cell transplantation due to age, comorbidities, or other factors, various treatment options are available, including various chemoimmunotherapies. However, these chemoimmunotherapies tend to be used with the goal of palliation rather than long-term survival. Recently approved treatments for the R / R DLBCL setting include CAR-T therapy and polatuzumab vedotin-piiq in combination with bendamustine and rituximab.

[0006] Approximately half of patients with relapsed DLBCL do not respond to second-line therapy due to refractory disease (Gisselbrecht et al., (2010) J Clin Oncol, 28:41844190). Patients who relapse after or are ineligible for stem cell transplantation due to refractory disease or frailty have poor outcomes. In addition, a significant number of relapsed / refractory patients are ineligible for aggressive therapy due to age, comorbidities, or other factors. Although salvage therapy for relapsed or refractory DLBCL has shown promising results in terms of response rate to therapy, the long-term survival of patients with relapsed or refractory DLBCL remains limited (Lopez et al., (2007) European J of Haematology 80:127-32; Gnaoui et al., (2007) Ann Oncol 18:1363-68; Mounier et al., (2013) Haematologica 98(11)1726-31).

[0007]

[0007] Therefore, there is a need in the art for new therapeutic approaches in patients with relapsed or refractory DLBCL.

[0008]

[0008] All references cited herein, including patent applications and publications, are hereby incorporated by reference in their entirety. Summary of the Invention

[0009] In some aspects, there is provided a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of: (a) a compound of the formula: (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26, wherein p is between 1 and 8; (b) an immunoconjugate having TIFF2024520901000002.tif27170, wherein the Ab is an anti-CD79b antibody comprising: (i) a hypervariable region H1 (HVR-H1) comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26, wherein p is between 1 and 8; (b) an immunomodulatory agent; and (c) an anti-CD20 antibody, wherein the human achieves at least a complete remission during or after treatment with the immunoconjugate, the immunomodulatory agent, and the anti-CD20 antibody. In some embodiments, at least about 25%, at least about 27%, at least about 29%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the treated humans achieve a complete remission during or after treatment with the immunoconjugate, immunomodulatory agent, and anti-CD20 antibody. In some embodiments, at least about 70%, at least about 74%, at least about 80%, at least about 90%, or 100% of the treated humans achieve a best overall response during or after treatment with the immunoconjugate, immunomodulatory agent, and anti-CD20 antibody. In some embodiments, of the treated humans, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% achieve a best complete remission during or after treatment with the immunoconjugate, immunomodulatory agent, and anti-CD20 antibody.In some embodiments, at least about 30%, at least about 35%, at least about 39%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the treated humans achieve an objective response during or after treatment with the immunoconjugate, immunomodulatory agent, and anti-CD20 antibody. In some embodiments, the duration of complete remission, best complete remission, objective response, or best overall response is at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, or longer, as assessed from the time of first occurrence of the complete remission, best complete remission, objective response, or best overall response. In some embodiments, the human survives for at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, or longer without disease progression, as assessed from the initiation of treatment with the immunoconjugate, immunomodulatory agent, and anti-CD20 antibody. In some embodiments, the human survives for at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or longer, as assessed from the initiation of treatment with the immunoconjugate, immunomodulatory agent, and anti-CD20 antibody.

[0010] In some embodiments, the anti-CD79b antibody comprises (i) a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 19, and (ii) a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, the anti-CD79b antibody comprises (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 36, and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 35. In some embodiments, the immunoconjugate is polatuzumab vedotin. In some embodiments, the immunomodulatory agent is lenalidomide. In some embodiments, the anti-CD20 antibody is rituximab. In some embodiments, polatuzumab vedotin is administered at a dose of about 1.8 mg / kg, lenalidomide is administered at a dose between about 10 mg and about 20 mg, and rituximab is administered at a dose of about 375 mg / kg. 2 is administered at a dose of

[0011] In some embodiments, polatuzumab vedotin, lenalidomide, and rituximab are administered in 28-day cycles during the induction phase, with polatuzumab vedotin administered intravenously at a dose of about 1.8 mg / kg on day 1 of each 28-day cycle, lenalidomide administered orally at a dose of between about 10 mg and about 20 mg on each of days 1-21 of each 28-day cycle, and rituximab administered orally at a dose of about 375 mg / m on day 1 of each 28-day cycle. 2and the induction phase comprises at least six 28-day cycles. In some embodiments, polatuzumab vedotin, lenalidomide, and rituximab are administered sequentially. In some embodiments, lenalidomide is administered prior to rituximab, and rituximab is administered prior to polatuzumab vedotin on day 1 of each 28-day cycle. In some embodiments, at least about 25%, at least about 27%, at least about 29%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the treated humans achieve a complete remission after six 28-day cycles. In some embodiments, at least about 70%, at least about 74%, at least about 80%, at least about 90%, or 100% of the treated humans achieve a best overall response after six 28-day cycles. In some embodiments, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the treated humans achieve a best complete remission after six 28-day cycles. In some embodiments, at least about 30%, at least about 35%, at least about 39%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the treated humans achieve an objective response after six 28-day cycles. In some embodiments, the duration of the complete remission, best complete remission, objective response, or best overall response is at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, or longer, as assessed from the time of first occurrence of the complete remission, best complete remission, objective response, or best overall response.In some embodiments, the human survives for at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, or longer without disease progression, as assessed from the initiation of treatment with polatuzumab vedotin, lenalidomide, and rituximab. In some embodiments, the human survives for at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or longer, as assessed from the initiation of treatment with polatuzumab vedotin, lenalidomide, and rituximab.

[0012] In some embodiments, lenalidomide and rituximab are further administered during the consolidation phase after the sixth 28-day cycle of the induction phase. In some embodiments, lenalidomide is administered orally at a dose of about 10 mg on each of days 1-21 of each month during the consolidation phase, and rituximab is administered orally at a dose of about 375 mg / m on day 1 of every other month during the consolidation phase. 2 In some embodiments, lenalidomide is administered intravenously at a dose of 0.01 mg / kg / day. In some embodiments, lenalidomide is administered for up to 6 months during the consolidation phase. In some embodiments, rituximab is administered on day 1 of each of months 1, 3, and 5 during the consolidation phase. In some embodiments, lenalidomide and rituximab are administered sequentially during the consolidation phase. In some embodiments, lenalidomide is administered prior to rituximab on day 1 of each of months 1, 3, and 5 during the consolidation phase.

[0013] In another aspect, there is provided a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of: (a) a compound of the formula: (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26, wherein p is between 1 and 8; (b) an immunoconjugate having TIFF2024520901000003.tif27170, wherein the Ab is an anti-CD79b antibody comprising: (i) a hypervariable region H1 (HVR-H1) comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26, wherein p is between 1 and 8; (b) an immunomodulatory agent; and (c) an anti-CD20 antibody, wherein the human does not exhibit disease progression during or within at least about 4 months after treatment with the immunoconjugate, the immunomodulatory agent, and the anti-CD20 antibody. In some embodiments, at least about 25%, at least about 27%, at least about 29%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the treated humans achieve a complete remission during or after treatment with the immunoconjugate, immunomodulatory agent, and anti-CD20 antibody. In some embodiments, at least about 70%, at least about 74%, at least about 80%, at least about 90%, or 100% of the treated humans achieve a best overall response during or after treatment with the immunoconjugate, immunomodulatory agent, and anti-CD20 antibody. In some embodiments, of the treated humans, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% achieve a best complete remission during or after treatment with the immunoconjugate, immunomodulatory agent, and anti-CD20 antibody.In some embodiments, at least about 30%, at least about 35%, at least about 39%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the treated humans achieve an objective response during or after treatment with the immunoconjugate, immunomodulatory agent, and anti-CD20 antibody. In some embodiments, the duration of complete remission, best complete remission, objective response, or best overall response is at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, or longer, as assessed from the time of first occurrence of the complete remission, best complete remission, objective response, or best overall response. In some embodiments, the human survives for at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, or longer without disease progression, as assessed from the initiation of treatment with the immunoconjugate, immunomodulatory agent, and anti-CD20 antibody. In some embodiments, the human survives for at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or longer, as assessed from the initiation of treatment with the immunoconjugate, immunomodulatory agent, and anti-CD20 antibody.

[0014] In some embodiments, the anti-CD79b antibody comprises (i) a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 19, and (ii) a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, the anti-CD79b antibody comprises (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 36, and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 35. In some embodiments, the immunoconjugate is polatuzumab vedotin. In some embodiments, the immunomodulatory agent is lenalidomide. In some embodiments, the anti-CD20 antibody is rituximab. In some embodiments, polatuzumab vedotin is administered at a dose of about 1.8 mg / kg, lenalidomide is administered at a dose between about 10 mg and about 20 mg, and rituximab is administered at a dose of about 375 mg / kg. 2 is administered at a dose of

[0015] In some embodiments, polatuzumab vedotin, lenalidomide, and rituximab are administered in 28-day cycles during the induction phase, with polatuzumab vedotin administered intravenously at a dose of about 1.8 mg / kg on day 1 of each 28-day cycle, lenalidomide administered orally at a dose of between about 10 mg and about 20 mg on each of days 1-21 of each 28-day cycle, and rituximab administered orally at a dose of about 375 mg / m on day 1 of each 28-day cycle. 2and the induction phase comprises at least six 28-day cycles. In some embodiments, polatuzumab vedotin, lenalidomide, and rituximab are administered sequentially. In some embodiments, lenalidomide is administered prior to rituximab, and rituximab is administered prior to polatuzumab vedotin on day 1 of each 28-day cycle. In some embodiments, at least about 25%, at least about 27%, at least about 29%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the treated humans achieve a complete remission after six 28-day cycles. In some embodiments, at least about 70%, at least about 74%, at least about 80%, at least about 90%, or 100% of the treated humans achieve a best overall response after six 28-day cycles. In some embodiments, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the treated humans achieve a best complete remission after six 28-day cycles. In some embodiments, at least about 30%, at least about 35%, at least about 39%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the treated humans achieve an objective response after six 28-day cycles. In some embodiments, the duration of the complete remission, best complete remission, objective response, or best overall response is at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, or longer, as assessed from the time of first occurrence of the complete remission, best complete remission, objective response, or best overall response.In some embodiments, the human survives for at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, or longer without disease progression, as assessed from the initiation of treatment with polatuzumab vedotin, lenalidomide, and rituximab. In some embodiments, the human survives for at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or longer, as assessed from the initiation of treatment with polatuzumab vedotin, lenalidomide, and rituximab.

[0016] In some embodiments, lenalidomide and rituximab are further administered during the consolidation phase after the sixth 28-day cycle of the induction phase. In some embodiments, lenalidomide is administered orally at a dose of about 10 mg on each of days 1-21 of each month during the consolidation phase, and rituximab is administered orally at a dose of about 375 mg / m on day 1 of every other month during the consolidation phase. 2 In some embodiments, lenalidomide is administered intravenously at a dose of 0.01 mg / kg / day. In some embodiments, lenalidomide is administered for up to 6 months during the consolidation phase. In some embodiments, rituximab is administered on day 1 of each of months 1, 3, and 5 during the consolidation phase. In some embodiments, lenalidomide and rituximab are administered sequentially during the consolidation phase. In some embodiments, lenalidomide is administered prior to rituximab on day 1 of each of months 1, 3, and 5 during the consolidation phase.

[0017] In another aspect, there is provided a method of treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human an effective amount of: (a) a compound of the formula: TIFF2024520901000004.tif28170, wherein Ab is an anti-CD79b antibody comprising (i) a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 19 and (ii) a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 20, and p is between 2 and 5; (b) lenalidomide; and (c) rituximab, wherein the immunoconjugate is administered at a dose of about 1.8 mg / kg, the lenalidomide is administered at a dose of between about 10 mg and about 20 mg, and the rituximab is administered at a dose of about 375 mg / m 2and the human achieves at least a complete remission during or after treatment with the immunoconjugate, lenalidomide, and rituximab. In some embodiments, at least about 25%, at least about 27%, at least about 29%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the treated humans achieve a complete remission during or after treatment with the immunoconjugate, lenalidomide, and rituximab. In some embodiments, at least about 70%, at least about 74%, at least about 80%, at least about 90%, or 100% of the treated humans achieve a best overall response during or after treatment with the immunoconjugate, lenalidomide, and rituximab. In some embodiments, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the treated humans achieve a best complete remission during or after treatment with the immunoconjugate, lenalidomide, and rituximab. In some embodiments, at least about 30%, at least about 35%, at least about 39%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the treated humans achieve an objective response during or after treatment with the immunoconjugate, lenalidomide, and rituximab. In some embodiments, the duration of the complete remission, best complete remission, objective response, or best overall response is at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, or longer, as assessed from the time of first occurrence of the complete remission, best complete remission, objective response, or best overall response.In some embodiments, the human survives for at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, or longer without disease progression, as assessed from the initiation of treatment with the immunoconjugate, lenalidomide, and rituximab. In some embodiments, the human survives for at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or longer, as assessed from the initiation of treatment with the immunoconjugate, lenalidomide, and rituximab.

[0018] In some embodiments, p is between 3 and 4. In some embodiments, the antibody comprises (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 35. In some embodiments, the immunoconjugate is polatuzumab vedotin.

[0019] In some embodiments, polatuzumab vedotin, lenalidomide, and rituximab are administered in 28-day cycles during the induction phase, with polatuzumab vedotin administered intravenously at a dose of about 1.8 mg / kg on day 1 of each 28-day cycle, lenalidomide administered orally at a dose of between about 10 mg and about 20 mg on each of days 1-21 of each 28-day cycle, and rituximab administered orally at a dose of about 375 mg / m on day 1 of each 28-day cycle. 2and the induction phase comprises at least six 28-day cycles. In some embodiments, polatuzumab vedotin, lenalidomide, and rituximab are administered sequentially. In some embodiments, lenalidomide is administered prior to rituximab, and rituximab is administered prior to polatuzumab vedotin on day 1 of each 28-day cycle. In some embodiments, at least about 25%, at least about 27%, at least about 29%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the treated humans achieve a complete remission after six 28-day cycles. In some embodiments, at least about 70%, at least about 74%, at least about 80%, at least about 90%, or 100% of the treated humans achieve a best overall response after six 28-day cycles. In some embodiments, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the treated humans achieve a best complete remission after six 28-day cycles. In some embodiments, at least about 30%, at least about 35%, at least about 39%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the treated humans achieve an objective response after six 28-day cycles. In some embodiments, the duration of the complete remission, best complete remission, objective response, or best overall response is at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, or longer, as assessed from the time of first occurrence of the complete remission, best complete remission, objective response, or best overall response.In some embodiments, the human survives for at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, or longer without disease progression, as assessed from the initiation of treatment with polatuzumab vedotin, lenalidomide, and rituximab. In some embodiments, the human survives for at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or longer, as assessed from the initiation of treatment with polatuzumab vedotin, lenalidomide, and rituximab.

[0020] In some embodiments, lenalidomide and rituximab are further administered during the consolidation phase after the sixth 28-day cycle of the induction phase. In some embodiments, lenalidomide is administered orally at a dose of about 10 mg on each of days 1-21 of each month during the consolidation phase, and rituximab is administered orally at a dose of about 375 mg / m on day 1 of every other month during the consolidation phase. 2 In some embodiments, lenalidomide is administered intravenously at a dose of 0.01 mg / kg / day. In some embodiments, lenalidomide is administered for up to 6 months during the consolidation phase. In some embodiments, rituximab is administered on day 1 of each of months 1, 3, and 5 during the consolidation phase. In some embodiments, lenalidomide and rituximab are administered sequentially during the consolidation phase. In some embodiments, lenalidomide is administered prior to rituximab on day 1 of each of months 1, 3, and 5 during the consolidation phase.

[0021] In another aspect, there is provided a method of treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, the method comprising administering to the human effective amounts of: (a) polatuzumab vedotin; (b) lenalidomide; and (c) rituximab in 28-day cycles during an induction phase, wherein during the induction phase, polatuzumab vedotin is administered at a dose of about 1.8 mg / kg, lenalidomide is administered at a dose of about 20 mg, and rituximab is administered at a dose of about 375 mg / m 2and the human achieves complete remission during or after the induction phase. In some embodiments, the induction phase comprises at least six 28-day cycles. In some embodiments, polatuzumab vedotin is administered intravenously at a dose of about 1.8 mg / kg on day 1 of each 28-day cycle, lenalidomide is administered orally at a dose of about 20 mg on each of days 1-21 of each 28-day cycle, and rituximab is administered orally at a dose of about 375 mg / m on day 1 of each 28-day cycle. 2In some embodiments, polatuzumab vedotin, lenalidomide, and rituximab are administered sequentially. In some embodiments, lenalidomide is administered prior to rituximab, and rituximab is administered prior to polatuzumab vedotin on day 1 of each 28-day cycle. In some embodiments, at least about 25%, at least about 27%, at least about 29%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the treated humans achieve a complete remission after six 28-day cycles. In some embodiments, at least about 70%, at least about 74%, at least about 80%, at least about 90%, or 100% of the treated humans achieve a best overall response after six 28-day cycles. In some embodiments, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the treated humans achieve a best complete remission after six 28-day cycles. In some embodiments, at least about 30%, at least about 35%, at least about 39%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the treated humans achieve an objective response after six 28-day cycles. In some embodiments, the duration of the complete remission, best complete remission, objective response, or best overall response is at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, or longer, as assessed from the time of first occurrence of the complete remission, best complete remission, objective response, or best overall response.In some embodiments, the human survives for at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, or longer without disease progression, as assessed from the initiation of treatment with polatuzumab vedotin, lenalidomide, and rituximab. In some embodiments, the human survives for at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or longer, as assessed from the initiation of treatment with polatuzumab vedotin, lenalidomide, and rituximab.

[0022] In some embodiments, the induction phase is followed by a consolidation phase, during which lenalidomide is administered at a dose of about 10 mg and rituximab is administered at a dose of about 375 mg / m 2 In some embodiments, lenalidomide is administered orally at a dose of about 10 mg on each of days 1-21 of each month during the consolidation phase, and rituximab is administered orally at a dose of about 375 mg / m on day 1 of every other month during the consolidation phase. 2 In some embodiments, lenalidomide is administered intravenously at a dose of 0.01 mg / kg / day. In some embodiments, lenalidomide is administered for up to 6 months during the consolidation phase. In some embodiments, rituximab is administered on day 1 of each of months 1, 3, and 5 during the consolidation phase. In some embodiments, lenalidomide and rituximab are administered sequentially during the consolidation phase. In some embodiments, lenalidomide is administered prior to rituximab on day 1 of each of months 1, 3, and 5 during the consolidation phase.

[0023] In another aspect, provided herein is a method of treating diffuse large B-cell lymphoma (DLBCL) in a plurality of humans in need of such treatment, the method comprising administering to the human effective amounts of: (a) polatuzumab vedotin; (b) lenalidomide; and (c) rituximab in 28-day cycles during an induction phase, wherein during the induction phase, polatuzumab vedotin is administered at a dose of about 1.8 mg / kg, lenalidomide is administered at a dose of about 20 mg, and rituximab is administered at a dose of about 375 mg / m 2 and at least about 25% of the individuals achieve a complete remission during or after the induction phase. In some embodiments, the induction phase comprises at least six 28-day cycles. In some embodiments, polatuzumab vedotin is administered intravenously at a dose of about 1.8 mg / kg on day 1 of each 28-day cycle, lenalidomide is administered orally at a dose of about 20 mg on each of days 1-21 of each 28-day cycle, and rituximab is administered at a dose of about 375 mg / m on day 1 of each 28-day cycle. 2In some embodiments, polatuzumab vedotin, lenalidomide, and rituximab are administered sequentially. In some embodiments, lenalidomide is administered prior to rituximab, and rituximab is administered prior to polatuzumab vedotin on day 1 of each 28-day cycle. In some embodiments, at least about 27%, at least about 29%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the people achieve a complete remission after six 28-day cycles. In some embodiments, at least about 70%, at least about 74%, at least about 80%, at least about 90%, or 100% of the people achieve a best overall response after six 28-day cycles. In some embodiments, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the treated humans achieve a best complete remission after six 28-day cycles. In some embodiments, at least about 30%, at least about 35%, at least about 39%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the treated humans achieve an objective response after six 28-day cycles. In some embodiments, the duration of the complete remission, best complete remission, objective response, or best overall response is at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, or longer, as assessed from the time of first occurrence of the complete remission, best complete remission, objective response, or best overall response.

[0024] In some embodiments, the induction phase is followed by a consolidation phase, during which lenalidomide is administered at a dose of about 10 mg and rituximab is administered at a dose of about 375 mg / m 2In some embodiments, lenalidomide is administered orally at a dose of about 10 mg on each of days 1-21 of each month during the consolidation phase, and rituximab is administered orally at a dose of about 375 mg / m on day 1 of every other month during the consolidation phase. 2 In some embodiments, lenalidomide is administered intravenously at a dose of 0.01 mg / kg / day. In some embodiments, lenalidomide is administered for up to 6 months during the consolidation phase. In some embodiments, rituximab is administered on day 1 of each of months 1, 3, and 5 during the consolidation phase. In some embodiments, lenalidomide and rituximab are administered sequentially during the consolidation phase. In some embodiments, lenalidomide is administered prior to rituximab on day 1 of each of months 1, 3, and 5 during the consolidation phase.

[0025] In some embodiments of any of the aspects or embodiments provided herein, the human or human of the plurality of humans has received at least one prior therapy for DLBCL. In some embodiments, the human or human of the plurality of humans has received at least two prior therapies for DLBCL. In some embodiments, the human or human of the plurality of humans has received a prior therapy for DLBCL including chemoimmunotherapy comprising an anti-CD20 antibody. In some embodiments, the human or human of the plurality of humans has received a prior bone marrow transplant for DLBCL. In some embodiments, the human or human of the plurality of humans has received a prior chimeric antigen receptor (CAR)-T cell therapy for DLBCL. In some embodiments, the human or human of the plurality of humans has DLBCL that was refractory to a first prior therapy for DLBCL administered to the human or human of the plurality of humans. In some embodiments, the human or human of the plurality of humans has DLBCL that was refractory to the most recent prior therapy for DLBCL. In some embodiments, the DLBCL is relapsed / refractory DLBCL. In some embodiments, the DLBCL is relapsed / refractory DLBCL after treatment with at least one prior chemoimmunotherapeutic regimen that included an anti-CD20 antibody. In some embodiments, the human or humans among the plurality of humans have experienced disease progression after treatment with high-dose chemotherapy and autologous hematopoietic stem cell transplantation. In some embodiments, the DLBCL is CD20-positive DLBCL. In some embodiments, the DLBCL is a positron emission tomography (PET)-positive lymphoma. In some embodiments, the human or humans among the plurality of humans are ineligible for autologous hematopoietic stem cell transplantation. In some embodiments, the human or humans among the plurality of humans do not have central nervous system (CNS) lymphoma or perichondrial invasion. In some embodiments, the human or humans among the plurality of humans have at least one bidimensionally measurable lesion.In some embodiments, at least one bidimensionally measurable lesion has a maximum dimension greater than 1.5 cm as assessed by computed tomography (CT) scan or magnetic resonance imaging (MRI). In some embodiments, the human or human among the plurality of humans has not undergone a prior allogeneic hematopoietic stem cell transplant (SCT). In some embodiments, the human or human among the plurality of humans has no history of transformation of indolent disease to DLBCL. In some embodiments, the human or human among the plurality of humans does not have neurological disease of Grade 2 or higher. In some embodiments, the human or human among the plurality of humans has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. In some embodiments, the human or human among the plurality of humans has DLBCL with Ann Arbor Stage III or IV. In some embodiments, the human or human among the plurality of humans has DLBCL with an International Prognostic Index of between 3 and 5.

[0026] In another aspect, provided herein is a compound of the formula: and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26; and p is between 1 and 8, for use in combination with an immunomodulatory agent and an anti-CD20 antibody to treat a human having diffuse large B-cell lymphoma (DLBCL) and in need thereof by any of the methods provided herein.

[0024] A kit comprising an immunoconjugate having the formula: TIFF2024520901000005.tif28170, wherein Ab is an anti-CD79b antibody comprising: (i) hypervariable region H1 (HVR-H1) comprising the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26; and p is between 1 and 8.

[0025] A kit comprising: an immunoconjugate having the formula: TIFF2024520901000005.tif28170, wherein Ab is an anti-CD79b antibody comprising: (i) hypervariable region H1 (HVR-H1) comprising the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26; and p is between In some embodiments, the anti-CD79b antibody comprises (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 35. In some embodiments, the DLBCL is relapsed / refractory DLBCL.

[0027] In another aspect, provided herein is a compound of the formula: TIFF2024520901000006.tif27170, wherein Ab is an anti-CD79b antibody comprising (i) a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 19 and (ii) a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 20, and p is between 2 and 5, for use in combination with lenalidomide and rituximab to treat a human having diffuse large B-cell lymphoma (DLBCL) and in need thereof by any of the methods provided herein. In some embodiments, p is between 3 and 4. In some embodiments, the anti-CD79b antibody comprises (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 35. In some embodiments, the DLBCL is relapsed / refractory DLBCL.

[0028] In another aspect, provided herein is a kit comprising polatuzumab vedotin in combination with lenalidomide and rituximab for treating a human having diffuse large B-cell lymphoma (DLBCL) and in need thereof by any of the methods provided herein. In some embodiments, the DLBCL is relapsed / refractory DLBCL.

[0029] In another aspect, provided herein is a compound of the formula: (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26; and p is between 1 and 8; wherein the Ab is an anti-CD79b antibody comprising (i) a hypervariable region H1 (HVR-H1) comprising the amino acid sequence of SEQ ID NO: 21, (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22, (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23, (iv) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24, (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25, and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26; and p is between 1 and 8; In some embodiments, the anti-CD79b antibody comprises (i) a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 19, and (ii) a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, p is between 3 and 4. In some embodiments, the anti-CD79b antibody comprises (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 36, and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 35. In some embodiments, the DLBCL is relapsed / refractory DLBCL.

[0030] In another aspect, provided herein is a compound of the formula: TIFF2024520901000008.tif21170, wherein Ab is an anti-CD79b antibody comprising (i) a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 19 and (ii) a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 20, and p is between 2 and 5; An immunoconjugate for use in a method of treating diffuse large B-cell lymphoma (DLBCL) by any of the methods described herein. In some embodiments, p is between 3 and 4. In some embodiments, the anti-CD79b antibody comprises (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 35. In some embodiments, the DLBCL is relapsed / refractory DLBCL.

[0031] In another aspect, provided herein is polatuzumab vedotin for use in a method of treating diffuse large B-cell lymphoma (DLBCL) by any of the methods provided herein. In some embodiments, the DLBCL is relapsed / refractory DLBCL. [Brief explanation of the drawings]

[0032] [Figure 1]

[0032] Figure 1 is a diagram of the study design for the Phase Ib / II study described in Example 1. C = cycle; CR = complete response; D = day; DLBCL = diffuse large B-cell lymphoma; EOI = end of induction; Len = lenalidomide; PO = oral; Pola = polatuzumab vedotin; PR = partial response; QD = daily; Q2M = every 2 months; R = rituximab; RP2D = recommended Phase II dose; SD = stable disease. [Figure 2]

[0033] FIG. 1 is a diagram of the 3+3 dose escalation schema used during the dose escalation phase of the Phase Ib / II study described in Example 1. [Figure 3]

[0034] FIG. 1 outlines the dosing regimen used in the Phase Ib / II study described in Example 1. [Figure 4]

[0035] 1 shows an overview of the study design for the Phase Ib / II study described in Examples 1 and 2. CR, complete response; IV, intravenous; Len, lenalidomide; PO, oral; Pola, polatuzumab vedotin; PR, partial response; R, rituximab; RP2D, recommended Phase II dose. [Figure 5]

[0036] 1 shows an overview of the study population in the primary analysis of the Phase Ib / II study described in Example 2. RP2D = recommended Phase II dose. [Figure 6]

[0037]

[0023] Figure 1 is a swimlane graph showing time to response and duration of response for patients evaluated in the primary analysis of the Phase Ib / II study described in Example 2. Intermediate response was assessed by CT according to the Lugano criteria (2014). EOI response was assessed by PET-CT according to the modified Lugano criteria (2014). [Figure 7]

[0038] Kaplan-Meier survival curves for progression-free survival (PFS) and overall survival (OS) are shown. DETAILED DESCRIPTION OF THE INVENTION

[0033]

[0039] As used herein, the term "polatuzumab vedotin" refers to the anti-CD79b immunoconjugate having IUPHAR / BPS number 8404, KEGG number D10761, or CAS registry number 1313206-42-6. Polatuzumab vedotin is also referred to interchangeably as "polatuzumab vedotin-piiq," "huMA79bv28-MC-vc-PAB-MMAE," "DCDS4501A," or "RG7596."

[0034]

[0040] Provided herein are methods for treating or delaying the progression of lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL), e.g., relapsed / refractory DLBCL) in an individual (e.g., a human), comprising administering to the individual an effective amount of an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE, also known as polatuzumab vedotin), an immunomodulatory agent (e.g., lenalidomide), and an anti-CD20 agent (e.g., an anti-CD20 antibody such as obinutuzumab or rituximab). In some embodiments, the method comprises administering to the individual: (a) an immunoconjugate of the formula: TIFF2024520901000009.tif27170 [wherein Ab is selected from the group consisting of: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26. and p is between 1 and 8 (e.g., between 2 and 5 or between 3 and 4); (b) an immunoconjugate comprising: (a) an immunomodulatory agent (e.g., lenalidomide); and (c) an anti-CD20 antibody (e.g., obinutuzumab or rituximab). In some embodiments, the immunoconjugate is administered at a dose of between about 1.4 mg / kg and about 1.8 mg / kg, the immunomodulatory agent (e.g., lenalidomide) is administered at a dose of between about 10 mg and about 20 mg, and the anti-CD20 antibody (e.g., rituximab) is administered at a dose of about 375 mg / kg. 2In some embodiments, the immunoconjugate is administered at a dose of between about 1.4 mg / kg and about 1.8 mg / kg, the immunomodulatory agent (e.g., lenalidomide) is administered at a dose of between about 10 mg and about 20 mg, and the anti-CD20 antibody (e.g., obinutuzumab) is administered at a dose of about 1000 mg. In some embodiments, the individual achieves a response of at least stable disease (SD) (e.g., at least SD, at least partial remission (PR), or complete remission / cure (CR)) during or after treatment with the immunoconjugate, immunomodulatory agent, and anti-CD20 antibody. In some embodiments, the individual achieves an objective response, best overall response, best complete remission, best partial remission, or complete remission during or after treatment with the immunoconjugate, immunomodulatory agent, and anti-CD20 antibody.

[0035] I. General Techniques

[0041] The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry, and immunology, which are within the skill of those in the art. Such techniques are described in detail in the literature, for example, in "Molecular Cloning: A Laboratory Manual", second edition (Sambrook et al., 1989); "Oligonucleotide Synthesis" (M.J. Gait, ed., 1984); "Animal Cell Culture" (R.I. Freshney, ed., 1987); "Methods in Enzymology" (Academic Press, Inc.); "Current Protocols in Molecular Biology" (F.M. Usubel et al., eds., 1987, and periodic updates); "PCR: The Polymerase Chain Reaction" (Mullis et al., ed., 1994); "A Practical Guide to Molecular Cloning" (Perbal Bernard V., 1988); "Phage Display: A Laboratory Manual" (Barbas et al., 2001).

[0036] II. Definition

[0042] Before describing the present invention in detail, it is to be understood that this invention is not limited to particular compositions or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0037]

[0043] As used in the specification and claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to a "molecule" in the singular optionally includes a combination of two or more such molecules, and the like.

[0038]

[0044] The term "about" as used herein refers to a normal error range for the respective value, which would be readily understood by one of ordinary skill in the art. Reference herein to a value or parameter preceded by "about" includes (and describes) embodiments that are directed to the value or parameter itself.

[0039]

[0045] It is to be understood that aspects and embodiments of the invention described herein include "comprising," "consisting of," and "consisting essentially of" aspects and embodiments.

[0040]

[0046] As used herein, the term "CD79b," unless otherwise indicated, refers to any native CD79b from any vertebrate source, including mammals such as primates (e.g., humans, cynomolgus monkeys (cyno)), and rodents (e.g., mice and rats). Human CD79b is also referred to herein as "Igβ," "B29," "DNA225786," ​​or "PRO36249." An exemplary CD79b sequence including the signal sequence is set forth in SEQ ID NO: 1. An exemplary CD79b sequence without the signal sequence is set forth in SEQ ID NO: 2. The term "CD79b" encompasses "full-length," unprocessed CD79b, as well as any form of CD79b resulting from processing within a cell. The term also encompasses naturally occurring variants of CD79b, such as splice variants, allelic variants, and isoforms. The CD79b polypeptides described herein can be isolated from a variety of sources, such as human tissue types or another source, or can be prepared by recombinant or synthetic methods. A "native sequence CD79b polypeptide" includes a polypeptide having the same amino acid sequence as a corresponding naturally-occurring CD79b polypeptide. Such native sequence CD79b polypeptides can be isolated from nature or can be produced by recombinant or synthetic methods. The term "native sequence CD79b polypeptide" specifically encompasses naturally occurring truncated or secreted forms of a particular CD79b polypeptide (e.g., an extracellular domain sequence), naturally occurring variant forms (e.g., alternatively spliced ​​forms), and naturally occurring allelic variants of the polypeptide.

[0041]

[0047] As used herein, "CD20" refers to the human B lymphocyte antigen CD20 (also known as CD20, B lymphocyte surface antigen B1, Leu-16, Bp35, BM5, and LF5; its sequence is characterized by SwissProt database entry P11836), a hydrophobic transmembrane protein with a molecular weight of approximately 35 kD located on pre-B lymphocytes and mature B lymphocytes. (Valentine,MA,et al.,J.Biol.Chem.264(19)(1989 11282-11287,Tedder,TF,et al,Proc.Natl.Acad.Sci.USA85(1988)208-12,Stamenkovic,I.,et al.,J.Exp.Med.167(1988)1975-80,Einfeld,DAet al.,EMBO J.7(1988)711-7,Tedder,TF,et al., J. Immunol. 142 (1989) 2560-8). The corresponding human gene is transmembrane 4 domain, subfamily A, member 1, also known as MS4A1. This gene encodes a member of the transmembrane 4A gene family. Members of this emerging protein family are characterized by common structural features and similar intron / exon splice boundaries and display unique expression patterns between hematopoietic cells and non-lymphoid tissues. This gene encodes a B lymphocyte surface molecule that plays a role in the development and differentiation of B cells into plasma cells. This family member is localized to 11q12 within a cluster of family members. Alternative splicing of this gene results in two transcript variants encoding the same protein.

[0042]

[0048] The terms "CD20" and "CD20 antigen" are used interchangeably herein and include any variant, isoform, and species homolog of human CD20 naturally expressed by cells or expressed on cells transfected with the CD20 gene. Binding of the antibodies of the invention to the CD20 antigen mediates the killing of cells expressing CD20 (e.g., tumor cells) by inactivating CD20. Killing of cells expressing CD20 can occur by one or more of the following mechanisms: cell death / apoptosis induction, ADCC, and CDC. Art-recognized synonyms for CD20 include B-lymphocyte antigen CD20, B-lymphocyte surface antigen B1, Leu-16, Bp35, BM5, and LF5.

[0043]

[0049] The term "expression of CD20" antigen is intended to refer to a significant level of expression of the CD20 antigen on a cell, e.g., a T cell or a B cell. In one embodiment, a patient treated by the methods of the present invention expresses a significant level of CD20 on a B cell tumor or cancer. Patients with "CD20-expressing cancer" can be determined by standard assays known in the art. For example, CD20 antigen expression is measured using immunohistochemistry (IHC) detection, FACS, or via PCR-based detection of the corresponding mRNA.

[0044]

[0050] "Affinity" refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, "binding affinity," as used herein, refers to the intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (Kd). Affinity can be measured by common methods known in the art, including those described herein. Certain specific and exemplary embodiments for measuring binding affinity are described below.

[0045]

[0051] An "affinity matured" antibody contains one or more alterations in one or more hypervariable regions (HVRs) relative to a parent antibody which does not possess those alterations, which alterations result in an improvement in the affinity of the antibody for antigen.

[0046]

[0052] The term "antibody" as used herein is used in the broadest sense and encompasses a variety of antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired antigen-binding activity.

[0047]

[0053] "Antibody fragment" refers to a molecule other than an intact antibody that contains a portion of an intact antibody that binds to the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab'), diabodies, linear antibodies, single-chain antibody molecules (e.g., scFv), and multispecific antibodies formed from antibody fragments.

[0048]

[0054] An "antibody that binds to the same epitope" as a reference antibody refers to an antibody that blocks the binding of the reference antibody to its antigen by 50% or more in a competition assay; conversely, the reference antibody blocks the binding of the antibody to its antigen by 50% or more in a competition assay. Exemplary competition assays are provided herein.

[0049]

[0055] The term "epitope" refers to the specific site on an antigen molecule to which an antibody binds.

[0050]

[0056] The term "chimeric" antibody refers to an antibody in which a portion of the heavy and / or light chain is derived from a particular source or species, while the remainder of the heavy and / or light chain is derived from a different source or species.

[0051]

[0057] The "class" of an antibody refers to the type of constant domain or constant region possessed 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), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy-chain constant domains that correspond to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0052]

[0058] The terms "anti-CD79b antibody" or "antibody that binds to CD79b" refer to an antibody that can bind to CD79b with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting CD79b. Preferably, the binding of an anti-CD79b antibody to an unrelated, non-CD79b protein is less than about 10% of the binding of the antibody to CD79b, as measured, for example, by radioimmunoassay (RIA). In some embodiments, the dissociation constant (Kd value) of an antibody that binds to CD79b is ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, or ≦0.1 nM. In some embodiments, the anti-CD79b antibody binds to an epitope of CD79b that is conserved among CD79b from different species.

[0053]

[0059] The term "anti-CD20 antibody" according to the present invention refers to an antibody that can bind to CD20 with sufficient affinity so that the antibody is useful as a diagnostic and / or therapeutic agent in targeting CD20. Preferably, the binding of the anti-CD20 antibody to an unrelated, non-CD20 protein is less than about 10% of the binding of the antibody to CD20, as measured, for example, by radioimmunoassay (RIA). In some embodiments, the dissociation constant (Kd value) of the antibody that binds to CD20 is ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, or ≦0.1 nM. In some embodiments, the anti-CD20 antibody binds to an epitope of CD20 that is conserved among CD20 from different species.

[0054]

[0060] An "isolated" antibody is one that has been separated from a component of its natural environment. In some embodiments, antibodies are purified to greater than 95% or 99% purity, for example, as determined by electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse-phase HPLC) methods. For a review of methods for assessing antibody purity, see, e.g., Flatman et al., J. Chromatogr. B 848:79-87 (2007). The "variable region" or "variable domain" of an antibody refers to the amino-terminal domain of the heavy or light chain of the antibody. The variable domain of a heavy chain may also be referred to as "VH." The variable domain of a light chain may also be referred to as "VL." These domains are generally the most variable parts of an antibody and contain the antigen-binding sites.

[0055]

[0061] An "isolated nucleic acid encoding an anti-CD79b antibody" refers to one or more nucleic acid molecules encoding the antibody heavy and light chains (or fragments thereof), including one or more such nucleic acid molecules in a single vector or separate vectors, and wherein such one or more nucleic acid molecules are present in one or more locations within a host cell.

[0056]

[0062] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous antibody population, i.e., the individual antibodies comprising the population are identical and / or bind to the same epitope, excluding possible variant antibodies typically present in minor amounts, including, for example, naturally occurring mutations or mutations that arise during production of the monoclonal antibody preparation. In contrast to polyclonal antibody preparations, which generally include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous antibody population and should not be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies used in accordance with the present invention can be produced by a variety of techniques, including, but not limited to, hybridoma methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci; such methods and other exemplary methods for producing monoclonal antibodies are described herein.

[0057]

[0063] A "naked antibody" refers to an antibody that is not conjugated to a heterologous moiety (e.g., a cytotoxic moiety) or radiolabel. The naked antibody may be present in a pharmaceutical formulation.

[0058]

[0064] "Native antibodies" refer to naturally occurring immunoglobulin molecules with diverse structures. For example, native IgG antibodies are heterotetrameric glycoproteins of approximately 150,000 daltons composed of two identical light chains and two identical heavy chains that are disulfide-bonded. From the N-terminus to the C-terminus, each heavy chain has a variable region (VH), also called a variable heavy domain or heavy chain variable domain, followed by three constant domains (CH1, CH2, and CH3). Similarly, from the N-terminus to the C-terminus, each light chain has a variable region (VL), also called a variable light domain or light chain variable domain, followed by one constant light (CL) domain. Based on the amino acid sequence of its constant domain, the light chain of an antibody can be assigned to one of two types, called kappa (κ) and lambda (λ).

[0059]

[0065] The term "Fc region" as used herein defines the C-terminal region of an immunoglobulin heavy chain containing at least a portion of the constant region. This term includes native-sequence Fc regions and variant Fc regions. In one embodiment, a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present. Unless otherwise indicated herein, the numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also known as the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0060]

[0066] "Framework" or "FR" refers to variable domain residues other than hypervariable region (HVR) residues. The FR of a variable domain typically consists of four FR domains: FR1, FR2, FR3, FR4, FR5, FR6, FR7, FR8, FR9, FR10, FR11, FR12, FR13, FR14, FR15, FR16, FR17, FR18, FR1 2 , F.R. 3 , and FR 4Thus, the HVR and FR sequences usually consist of the following sequence in VH (or VL): FR1-H1(L1)-FR 2 -H2(L2)-FR 3 -H3(L3)-FR 4 It appears in.

[0061]

[0067] For purposes herein, an "acceptor human framework" is a framework that comprises the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or a human consensus framework, as defined below. An acceptor human framework "derived from" a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence, or it may contain amino acid sequence changes. In some embodiments, the number of amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, the VL acceptor human framework is identical in sequence to the VL human immunoglobulin framework sequence or the human consensus framework sequence.

[0062]

[0068] The terms "full length antibody," "intact antibody," and "whole antibody" are used interchangeably herein and refer to an antibody having a heavy chain that has a structure substantially similar to a native antibody structure or that contains an Fc region as defined herein.

[0063]

[0069] The terms "host cell," "host cell line," and "host cell culture" are used interchangeably herein and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include "transformants" and "transformed cells," which include the primary transformed cell and its progeny, regardless of the number of passages. The progeny may not be completely identical in nucleic acid content to the parent cell and may contain mutations. Mutant progeny that have the same function or biological activity as screened or selected for in the originally transformed cell are included herein.

[0064]

[0070] A "human antibody" is an antibody having an amino acid sequence corresponding to an antibody produced by a human or a human cell, or an antibody derived from a non-human source that utilizes the human antibody repertoire or other human antibody-encoding sequences. This definition of human antibody specifically excludes humanized antibodies that comprise non-human antigen-binding residues.

[0065]

[0071] A "human consensus framework" is a framework that represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Typically, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Typically, the subgroup of sequences is a subgroup 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., supra. In one embodiment, for VH, the subgroup is subgroup III in Kabat et al., supra.

[0066]

[0072] A "humanized" antibody refers to a chimeric antibody comprising amino acid residues from non-human HVRs and amino acid residues from human FRs. In some embodiments, a humanized antibody comprises substantially all of at least one, and typically two, variable domains, in which all or substantially all of the HVRs (e.g., CDRs) correspond to a non-human antibody and all or substantially all of the FRs correspond to a human antibody. A humanized antibody may optionally comprise at least a portion of an antibody constant region derived from a human antibody. A "humanized form" of an antibody, e.g., a non-human antibody, refers to an antibody that has been humanized.

[0067]

[0073] As used herein, the term "hypervariable region" or "HVR" refers to each of the regions of an antibody variable domain that are hypervariable in sequence and / or form structurally defined loops ("hypervariable loops"). Typically, a naturally occurring four-chain antibody comprises six HVRs: three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3). HVRs typically comprise amino acid residues from the hypervariable loops and / or from the "complementarity-determining regions" (CDRs), the latter having the highest sequence variability and / or involved in antigen recognition. Exemplary hypervariable loops occur at (a) 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)). Exemplary CDRs (CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3) are located at positions 24-34 of L1, 50-56 of L2, 89-97 of L3, 31-35B of H1, 50-65 of H2, and 95-102 of H3 (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)). Except for CDR1 in VH, CDRs typically comprise amino acid residues that form hypervariable loops. CDRs also contain "specificity-determining regions," or "SDRs," which are residues that contact antigen. SDRs are contained within the region of CDRs referred to as abbreviated-CDRs, or a-CDRs. Exemplary a-CDRs (a-CDR-L1, a-CDR-L2, a-CDR-L3, a-CDR-H1, a-CDR-H2, and a-CDR-H3) are located at amino acid residues 31-34 of L1, 50-55 of L2, 89-96 of L3, 31-35B of H1, 50-58 of H2, and 95-102 of H3. (See Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008)).) Unless otherwise indicated, HVR residues and other residues of the variable domain (e.g., FR residues) are numbered herein according to Kabat et al., supra.

[0068]

[0074] The term "variable region" or "variable domain" refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to an antigen. The heavy and light chain variable domains (VH and VL, respectively) of natural antibodies typically have similar structures, with each domain containing four conserved framework regions (FR) and three hypervariable regions (HVR) (see, for example, Kindt et al., Kuby Immunology, 6th ed., W.H. 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 be isolated using a VH or VL domain derived from an antibody that binds to that antigen, and a library of complementary VL or VH domains, respectively, may be screened. See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

[0069]

[0075] "Effector function" refers to a biological activity attributable to the Fc region of an antibody, which varies depending on the antibody isotype. Examples of antibody effector functions include C1q binding and complement-dependent cytotoxicity (CDC), Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), phagocytosis, down-regulation of cell surface receptors (e.g., B cell receptors), and B cell activation.

[0070]

[0076] "CD79b polypeptide variant" means a CD79b polypeptide, preferably an active CD79b polypeptide, as defined herein, having at least about 80% amino acid sequence identity to a full-length native sequence CD79b polypeptide sequence disclosed herein, a CD79b polypeptide sequence lacking the signal peptide disclosed herein, the extracellular domain of a CD79b polypeptide with or without the signal peptide disclosed herein, or any other fragment of the full-length CD79b polypeptide sequence disclosed herein (such as one encoded by a nucleic acid representing only a portion of the complete coding sequence of a full-length CD79b polypeptide). Such CD79b polypeptide variants include, for example, CD79b polypeptides in which one or more amino acid residues have been added to, or deleted from, the N- or C-terminus of the full-length native amino acid sequence. Typically, a CD79b polypeptide variant will have at least about 80% amino acid sequence identity, alternatively at least about 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity to a full-length native sequence CD79b polypeptide sequence disclosed herein, a CD79b polypeptide sequence lacking the signal peptide disclosed herein, the extracellular domain of a CD79b polypeptide with or without the signal peptide disclosed herein, or any other specifically defined fragment of a full-length CD79b polypeptide sequence disclosed herein. Typically, the CD79b variant polypeptides are at least about 10 amino acids in length, alternatively at least about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1 0, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600 amino acids in length or longer.Optionally, the CD79b variant polypeptide will have no more than one conservative amino acid substitution compared to a native CD79b polypeptide sequence, alternatively no more than 2, 3, 4, 5, 6, 7, 8, 9, or 10 conservative amino acid substitutions compared to a native CD79b polypeptide sequence.

[0071]

[0077] "Percent (%) amino acid sequence identity" with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to those in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, without considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in a variety of ways within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for performing sequence alignment, including any algorithms necessary to achieve maximum alignment over the full length of the sequences being compared. However, for purposes of this specification, percent amino acid sequence identity values ​​are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was created by Genentech, Inc., and the source code, together with user documentation, has been filed with the U.S. Copyright Office, Washington, DC 20559, and is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc. (South San Francisco, California) or can be compiled from its source code. The ALIGN-2 program should be compiled for use on UNIX operating systems, including Digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.

[0072]

[0078] In situations where ALIGN-2 is used for amino acid sequence comparison, the % amino acid sequence identity of a given amino acid sequence A to, with, or in contrast to a given amino acid sequence B (which can alternatively be written as a given amino acid sequence A having or comprising a particular % amino acid sequence identity to, with, or in contrast to a given amino acid sequence B) is calculated as follows: 100 x fraction X / Y where X is the number of amino acid residues scored as identical by the sequence alignment program ALIGN-2 in a programmatic alignment of A and B, and Y is the total number of amino acid residues in B. It will be understood that if the length of amino acid sequence A is not equal to the length of amino acid sequence B, then the % amino acid sequence identity of A to B will not be equal to the % amino acid sequence identity of B to A. Unless otherwise specified, all % amino acid sequence identity values ​​used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.

[0073]

[0079] As used herein, the term "vector" refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes vectors as self-replicating nucleic acid structures and vectors that integrate into the genome of a host cell into which they are introduced. Some vectors are capable of directing the expression of nucleic acids to which they are operably linked. Such vectors are referred to herein as "expression vectors."

[0074]

[0080] An "immunoconjugate" is an antibody conjugated to one or more heterologous molecules, including, but not limited to, cytotoxic agents.

[0075]

[0081] In the context of the formulas provided herein, "p" refers to the average number of drug moieties per antibody, ranging, for example, from about 1 to about 20 drug moieties per antibody, and in some embodiments, from 1 to about 8 drug moieties per antibody. The invention includes compositions comprising mixtures of antibody-drug compounds of Formula I having an average drug loading per antibody of from about 2 to about 5, or from about 3 to about 4 (e.g., about 3.4 or about 3.5).

[0076]

[0082] The term "cytotoxic agent" as used herein refers to a substance that inhibits or prevents cellular function and / or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioisotopes (e.g., At211, I131, I125, Y90, Re186, Re188, Sm153, Bi212, P32, Pb212, and radioisotopes of Lu); chemotherapeutic agents or drugs (e.g., methotrexate, adriamycin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin, or other intercalating agents); growth inhibitory agents; enzymes and fragments thereof, e.g., nucleases; antibiotics; toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant, or animal origin (including fragments and / or variants thereof); and various antitumor or anticancer agents as disclosed below.

[0077]

[0083] The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include, but are not limited to, B-cell lymphoma (including low-grade / follicular non-Hodgkin's lymphoma (NHL), small lymphocytic (SL) NHL, intermediate-grade / follicular NHL, intermediate-grade diffuse NHL, high-grade immunoblastic NHL, high-grade lymphoblastic NHL, high-grade small non-cleaved cell NHL, bulky mass disease NHL, mantle cell lymphoma, AIDS-related lymphoma, and Waldenstrom's macroglobulinemia), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), hairy cell leukemia, chronic myeloblastic leukemia, and post-transplant lymphoproliferative disorder (PTLD), as well as phacomatosis, edema (e.g., associated with brain tumors), and abnormal blood vessel growth associated with Meigs' syndrome.More specific examples include, but are not limited to, relapsed or refractory NHL, frontline line) low-grade NHL, stage III / IV NHL, chemotherapy-resistant NHL, precursor B-lymphoblastic leukemia and / or lymphoma, small lymphocytic lymphoma, B-cell chronic lymphocytic leukemia and / or prolymphocytic leukemia and / or small lymphocytic lymphoma, B-cell prolymphocytic lymphoma, immunocytoma and / or lymphoplasmacytic lymphoma, lymphoplasmacytic lymphoma, marginal zone B-cell lymphoma, splenic marginal zone lymphoma, extranodal marginal zone-MALT lymphoma, nodal marginal zone lymphoma, hairy cell leukemia, plasmacytoma and / or plasma cell myeloma, low-grade / follicular lymphoma, intermediate-grade / follicular NHL, mantle cell lymphoma, follicle center lymphoma (follicular), follicular lymphoma (e.g., relapsed) relapsed / refractory follicular lymphoma), intermediate-grade diffuse NHL, diffuse large B-cell lymphoma (DLBCL: e.g., relapsed / refractory DLBCL), invasive NHL (including invasive first-line NHL and invasive relapsed NHL), NHL relapsed after or refractory to autologous stem cell transplant, primary mediastinal large B-cell lymphoma, primary effusion lymphoma, high-grade immunoblastic NHL, high-grade lymphoblastic NHL, high-grade small non-cleaved cell NHL, bulky mass disease NHL, Burkitt's lymphoma, precursor (peripheral) large granular lymphocytic leukemia, mycosis fungoides and / or Sézary syndrome, cutaneous (cutaneous) lymphoma, anaplastic large cell lymphoma, angiocentric lymphoma.

[0078]

[0084] An "individual" or "subject" is a mammal. Mammals include, but are not limited to, domestic animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates, such as monkeys), rabbits, and rodents (e.g., mice and rats). In some embodiments, the individual or subject is human.

[0079]

[0085] An "effective amount" of an agent, eg, a pharmaceutical formulation, refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic or prophylactic result.

[0080]

[0086] The term "pharmaceutical formulation" refers to a preparation that is in a form that allows the biological activity of the active ingredient contained therein to be effective and that does not contain other ingredients that have unacceptable toxicity to the subject to which the formulation is administered.

[0081]

[0087] A "pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, that is non-toxic to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0082]

[0088] As used herein, "treatment" (and its grammatical variations, e.g., "treat" or "treating") refers to clinical intervention in an attempt to alter the natural course of the individual being treated and can be performed for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, reduction of free light chains, prevention of disease onset or recurrence, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, slowing the rate of disease progression, amelioration or palliation of the condition, and remission or improved prognosis. In some embodiments, the methods described herein are used to delay the onset of disease or slow the progression of the disease.

[0083]

[0089] The term "CD79b-positive cancer" refers to a cancer comprising cells that express CD79b on their surface. In some embodiments, cell surface expression of CD79b is determined using an antibody to CD79b in methods such as immunohistochemistry, FACS, etc. Alternatively, expression of CD79b mRNA, which may correlate with cell surface expression of CD79b, can be determined by a method selected from in situ hybridization and RT-PCR (including quantitative RT-PCR).

[0084]

[0090] As used herein, "in conjunction with" refers to the administration of one therapeutic modality in addition to another. Thus, "in conjunction with" refers to the administration of one therapeutic modality before, during, or after the administration of another therapeutic modality to an individual.

[0085]

[0091] Chemotherapeutic agents are chemical compounds useful in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (TARCEVA®, Genentech / OSI Pharm), bortezomib (VELCADE®, Millennium), and erythropoietin (ERT). Pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG (geldanamycin), Radicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX®, AstraZeneca), sunitib (SUTENT®, Pfizer / Sugen)), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), finasteride (VATALANIB®, Novartis), oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (sirolimus, RAPAMUNE®, Wyeth), lapatinib (TYKERB®, GSK572016, GlaxoSmithKline), Kline), lonafamib (SCH 66336), sorafenib (NEXAVAR®, Bayer Labs), gefitinib (IRESSA®, AstraZeneca), AG1478, thiotepa, and CYTOXAN® cyclophosphamide; alkylating agents such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carbocuron, metoledopa, and uredopa; ethylenimines including altretamine, triethylenemelamine, triethylenephosphamide, triethylenethiophosphamide, and trimethylmelamine; Methylmelamines; acetogenins (especially bullatacin and bullatacinone); camptothecins (including topotecan and irinotecan); bryostatin; kallystatin; CC-1065 (including its synthetic analogs adozelesin, carzelesin, and bizelesin); cryptophycins (especially cryptophycin 1 and cryptophycin 8); corticosteroids (including prednisone and prednisolone); cyproterone acetate; 5a-reductase inhibitors, including finasteride and dutasteride;vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat dolastatins; aldesleukin, talczuocarmycin (including synthetic analogs, KW-2189 and CB1-TM1); eletarobin; pancratistatin; sarcodictine; spongistatin, chlorambucil, chromafazine, chlorophosphamide, estramustine, ifosfamide, mechlorestamine, mechlorestamine oxide hydrochloride, melphalan, nobembine, phenesterine, prednimustine, trophosfamide, nitrogen mustards such as uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics such as endene antibiotics (e.g., calicheamicins, particularly calicheamicin γ1I and calicheamicin ωII (Angew Chem. Inti. Ed. Engl. 1994 33:183-186); dynemicins, including dynemicin A; bisphosphonates such as clodronate; espermycin; and neocarzinostatin chromophores and related enediyne antibiotic chromophores (enediyne antibiotic chromophores), aclacinomycins, actinomycin, autramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, Adriamycin (doxorubicin), morpholinodoxorubicin, cyanomorpholinodoxorubicin, 2-pi lorino-doxorubicin and deoxydoxorubicin), mitomycins such as epirubicin, esorubicin, everolimus, sotrataurine, idarubicin, marcelomycin, and mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, chelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; metabolic antagonists such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimetrexate;Purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifuridine, enocitabine, and floxuridine; androgens such as calusterone, dromostanolone propionate, epithiostanol, mepitiosteine, and testolactone; antiadrenal agents such as aminoglutethimide, mitotane, and trilosteine; folic acid supplements such as furoic acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; Eniluracil; Amsacrine; Bestravsil; Bisantrene; Edatraxate; Defofamine; Demecolcine; Diaziquion; Elfomitin; Elliptinium acetate; Epothilone; Etoglucide; Gallium nitrate; Hydroxyurea; Lentinan; Lonidynin; Maytansinoids such as maytansine and ansamitocin; Mitoguazone; Mitoxantrone; Mopidanmol; Nitraerin; Pentostatin; Fenameth; Pirarubicin; Rosoxantrone; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; PSK® Polysaccharide Complex (JHS) Natural Products, Eugene, Oreg.); razoxane; rhizoxin; schizofuran; spirogermanium; tenuazonic acid; triaziquione; 2,2',2''-trichlorotriethylamine; trichothecenes (especially T-2 toxin, veraculin A, roridin A, and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, such as taxol (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE® (cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE® (docetaxel; Sanofi-Aventis): chlorambucil, GEMZAR® (gemcitabine), 6-thioguanine, mercaptopurine;Included are methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); nobandrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; the topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid, and pharmaceutically acceptable salts, acids, and derivatives of any of the above, and combinations of two or more of the above, such as CHOP, which is an abbreviation for combination therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone, and FOLFOX, which is an abbreviation for a treatment regimen with oxaliplatin in combination with 5-FU and leucovorin (ELOXATIN™). Additional examples of chemotherapeutic agents include bendamustine (or bendamustine-HCl) (Treanda®), ibrutinib, lenalidomide, and / or idelalisib (GS-1101);

[0086]

[0092] Additional examples of "chemotherapeutic agents" include antihormonal agents, which act to regulate, reduce, block, or inhibit the effects of hormones that can promote cancer growth, often in the form of systemic or body-wide treatment. They may be hormones themselves. Examples include antiestrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX® tamoxifen), raloxifene (EVISTA®), droloxifene, 4-hydroxytamoxifen, trioxifene, ketoxifene, LY117018, onapristone, and toremifene (FARESTON®); antiprogesterones; estrogen receptor downregulators (ERDs); estrogen receptor antagonists such as fulvestrant (FASLODEX®); agents that function to suppress or shut down the ovaries, such as leuprolide acetate (LUPRON® and ELIGARD®). (R), goserelin acetate, buserelin acetate, and tripterelin; other antiandrogens such as flutamide, nilutamide, and bicalutamide; and aromatase inhibitors, which inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as 4(5)-imidazole, aminoglutethimide, megestrol acetate (MEGASE®), exemestane (AROMASIN®), formestanie, fadrozole, vorozole (RIVISOR®), letrozole (FEMARA®), and anastrozole (ARIMIDEX®).Additionally, such definition of chemotherapeutic agent includes bisphosphonates, such as clodronate (e.g., BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid / zoledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®); and troxacitabine. (1,3-dioxolane nucleoside cytosine analogs), antisense oligonucleotides, particularly antisense oligonucleotides that inhibit the expression of genes in signal transduction pathways involved in abnormal cell proliferation (e.g., PKC-α, Raf, H-Ras, and epidermal growth factor receptor (EGF-R)); vaccines such as the THERATOPE® vaccine and gene therapy vaccines, for example, the ALLOVECTIN® vaccine, the LEUVECTIN® vaccine, and the VAXID® vaccine.

[0087]

[0093] In some embodiments, chemotherapeutic agents include topoisomerase 1 inhibitors (e.g., LURTOTECAN®); antiestrogens such as fulvestrant; Kit inhibitors such as imatinib or EXEL-0862 (tyrosine kinase inhibitors); EGFR inhibitors such as erlotinib or cetuximab; anti-VEGF inhibitors such as bevacizumab; alinotecan, rmRH (e.g., ABARELIX®); lapatinib and lapatinium ditosylate (ErbB-2 and EGFR dual tyrosine kinase small molecule inhibitor, also known as GW572016); 17AAG (a geldanamycin derivative, a heat shock protein (Hsp) 90 poison), and pharmaceutically acceptable salts, acids, or derivatives of any of the above.

[0088]

[0094] Chemotherapeutic agents also include antibodies, such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech / Biogen Idec), ublituximab, ofatumumab, ibritumomab tiuxetan, pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody-drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).Additional humanized monoclonal antibodies with therapeutic potential as drugs in combination with the compounds or drugs of the disclosure include apolizumab, acelizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, celelizumab pegol, cidofusituzumab, cidtuzumab, daclizumab, eculizumab, f alizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motavizumab, natalizumab, nimotuzumab, norobizumab, numavizumab, ocrelizumab, omalizumab , palivizumab, pascolizumab, pecfusituzumab, pexelizumab, pexelizumab, ralivizumab, ranibizumab, reslizumab, reslizumab, reslizumab, rovelizumab, lupizumab, sibrotuzumab, siplizumab, sontuzumab, tacatatuzumab tetraxetan, tadoxizumab, talizumab, tefibazumab, tocilizumab , toralizumab, tucotuzumab-sermoreukin, tuxituzumab, umavisumab, urtoxazumab, ustekinumab, visilizumab, and anti-interleukin-12 (ABT-874 / J695, Wyeth Research and Abbott Laboratories), a human-sequence only recombinant full-length IgG1λ antibody genetically modified to recognize the interleukin-12p40 protein.

[0089]

[0095] The term "package insert" is used to refer to instructions customarily included in commercial packaging of therapeutic products that contain information about the indications, usage, dosage, administration, concomitant therapy, contraindications and / or warnings for use of such therapeutic product.

[0090]

[0096] "Alkyl" means a C1-C2 alkyl group containing normal, secondary, tertiary or cyclic carbon atoms. 18It is a hydrocarbon. Examples are methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3 )CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-CCH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1- Butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-C H(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-CCH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3), C(CH3)3).

[0091]

[0097] The term "C1-C8 alkyl" as used herein refers to a straight or branched, saturated or unsaturated hydrocarbon having from 1 to 8 carbon atoms. Representative "C1-C8 alkyl" groups include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl, and -n-decyl; branched C1-C8 alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl; unsaturated C1-C8 alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl. Examples include, but are not limited to, -vinyl, -allyl, -1-butenyl, -2-butenyl, -isobutylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, 1-hexyl, 2-hexyl, 3-hexyl, -acetylenyl, -propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl, and -3-methyl-1 butynyl. The C1-C8 alkyl group can be unsubstituted or substituted with one or more groups including, but not limited to, —C1-C8 alkyl, —O—(C1-C8 alkyl), -aryl, —C(O)R′—OC(O)R′, —C(O)OR′—C(O)NH2, —C(O)NHR′, —C(O)N(R′)2-NHC(O)R′, —S3R′, —S(O)2R′, —S(O)R′, —OH, -halogen, —N3, —NH2, —NH(R′), —N(R′)2, and —CN, where each R′ is independently selected from H, —C1-C8 alkyl, and aryl.

[0092]

[0098] As used herein, "C1-C 12 The term "alkyl" refers to a straight or branched chain, saturated or unsaturated hydrocarbon having 1 to 12 carbon atoms. 12An alkyl group can be unsubstituted or substituted with one or more groups including, but not limited to, -C1-C8 alkyl, -O-(C1-C8 alkyl), -aryl, -C(O)R', -OC(O)R', -C(O)OR', -C(O)NH2, -C(O)NHR', -C(O)N(R')2-NHC(O)R', -S3R', -S(O)2R', -S(O)R', -OH, -halogen, -N3, -NH2, -NH(R'), -N(R')2 and -CN, where each R' is independently selected from H, -C1-C8 alkyl and aryl.

[0093]

[0099] The term "C1-C6 alkyl" as used herein refers to a straight-chain or branched, saturated or unsaturated hydrocarbon having 1 to 6 carbon atoms. Representative "C1-C6 alkyl" groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl; branched C1-C6 alkyls include, but are not limited to, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and 2-methylbutyl; unsaturated C1-C6 alkyls include, but are not limited to, vinyl, allyl, 1-butenyl, 2-butenyl, and isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexyl, 2-hexyl, and 3-hexyl. The C1-C6 alkyl group may be unsubstituted or substituted with one or more groups as described above for the C1-C8 alkyl group.

[0094]

[0100] The term "C1-C4 alkyl" as used herein refers to a straight-chain or branched, saturated or unsaturated hydrocarbon having from 1 to 4 carbon atoms. Representative "C1-C4 alkyl" groups include, but are not limited to, -methyl, -ethyl, -n-propyl, and -n-butyl; branched C1-C4 alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, and -tert-butyl; and unsaturated C1-C4 alkyls include, but are not limited to, -vinyl, -allyl, -1-butenyl, -2-butenyl, and -isobutylenyl. C1-C4 alkyl groups can be unsubstituted or substituted with one or more groups as described above for C1-C8 alkyl groups.

[0095]

[0101] An "alkoxy" is an alkyl group singly bonded to oxygen. Exemplary alkoxy groups include, but are not limited to, methoxy (-OCH3) and ethoxy (-OCH2CH3). A "C1-C5 alkoxy" is an alkoxy group having from 1 to 5 carbon atoms. An alkoxy group can be unsubstituted or substituted with one or more groups, as described above for alkyl groups.

[0096]

[0102] "Alkenyl" means an alkyl group having at least one site of unsaturation, i.e., a carbon-carbon sp 2 C2-C containing normal, secondary, tertiary or cyclic carbon atoms with double bonds 18 Examples include, but are not limited to: ethylene or vinyl (-CH=CH), allyl (-CHCH=CH), cyclopentenyl (-C5H7), and 5-hexenyl (-CHCHCHCHCH=CH). "C2-C8 alkenyl" refers to an alkenyl group having at least one site of unsaturation, i.e., carbon-carbon, sp 2 It is a hydrocarbon containing 2 to 8 normal, secondary, tertiary or cyclic carbon atoms with a double bond.

[0097]

[0103] "Alkynyl" refers to a C-C alkyl group containing normal, secondary, tertiary, or cyclic carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon sp triple bond. 18A "C2-C8 alkynyl" is a hydrocarbon containing from 2 to 8 normal, secondary, tertiary, or cyclic carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond.

[0098]

[0104] "Alkylene" refers to a saturated, branched or straight-chain or cyclic hydrocarbon radical of 1 to 18 carbon atoms and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. Typical alkylene radicals include, but are not limited to, methylene (-CH2-), 1,2-ethyl (-CH2CH2-), 1,3-propyl (-CH2CH2CH2-), and 1,4-butyl (-CH2CH2CH2CH2-).

[0099]

[0105] "C1-C 10 "Alkylene" is a group of the formula -(CH2) 1-10- It is a straight chain saturated hydrocarbon group of C1-C 10 Examples of alkylene include methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene, and decalene.

[0100]

[0106] "Alkenylene" refers to an unsaturated, branched or straight-chain or cyclic hydrocarbon radical of 2 to 18 carbon atoms and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene. Typical alkenylene radicals include, but are not limited to, 1,2-ethylene (-CH=CH-).

[0101]

[0107] "Alkynylene" refers to an unsaturated, branched or straight-chain or cyclic hydrocarbon radical of 2 to 18 carbon atoms and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne. Typical alkynylene radicals include, but are not limited to, acetylene (-C≡C-), propargyl (-CHC≡C-), and 4-pentynyl (-CHCHCHC≡C-).

[0102]

[0108] "Aryl" refers to a carbocyclic aromatic group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. A carbocyclic aromatic or heterocyclic aromatic group can be unsubstituted or substituted with one or more groups including, but not limited to, -C1-C8 alkyl, -O-(C1-C8 alkyl), -aryl, -C(O)R', -OC(O)R', -C(O)OR', -C(O)NH2, -C(O)NHR', -C(O)N(R')2-NHC(O)R', -S(O)2R', -S(O)R', -OH, -halogen, -N3, -NH2, -NH(R'), -N(R')2, and -CN, where each R' is independently selected from H, -C1-C8 alkyl, and aryl.

[0103]

[0109] "C5-C 20 "Aryl" is an aryl group having from 5 to 20 carbon atoms in a carbocyclic aromatic ring. C5-C 20 Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. 20 The aryl group can be substituted or unsubstituted as described above for aryl groups. 14 "Aryl" is an aryl group having from 5 to 14 carbon atoms in the carbocyclic aromatic ring. C5-C 14 Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. 14 The aryl group can be substituted or unsubstituted as described above for aryl groups.

[0104]

[0110] An "arylene" is an aryl group that has two covalent bonds and can be in the ortho, meta, or para configuration as shown in the following structures: TIFF2024520901000010.tif22170, wherein the phenyl group is unsubstituted or optionally substituted with up to four groups including, but not limited to, -C1-C8 alkyl, -O-(C1-C8 alkyl), -aryl, -C(O)R', -OC(O)R', -C(O)OR', -C(O)NH2, -C(O)NHR', -C(O)N(R')2-NHC(O)R', -S(O)2R', -S(O)R', -OH, -halogen, -N3, -NH2, -NH(R'), -N(R')2, and -CN, where each R' is independently selected from H, -C1-C8 alkyl, and aryl.

[0105]

[0111] "Arylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with an aryl radical. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethene-1-yl, naphthobenzyl, and 2-naphthophenylethan-1-yl. Arylalkyl groups contain 6 to 20 carbon atoms; for example, the alkyl portion of the arylalkyl group, including the alkanyl, alkenyl, or alkynyl group, is 1 to 6 carbon atoms, and the aryl portion is 5 to 14 carbon atoms.

[0106]

[0112] "Heteroarylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a heteroaryl radical. Typical heteroarylalkyl groups include, but are not limited to, 2-benzimidazolylmethyl and 2-furylethyl. Heteroarylalkyl groups contain 6 to 20 carbon atoms, e.g., the alkyl portion, including the alkanyl, alkenyl, or alkynyl group of the heteroarylalkyl group, is 1 to 6 carbon atoms, and the heteroaryl portion is 5 to 14 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S. The heteroaryl portion of the heteroarylalkyl group can be a monocyclic ring (2 to 6 carbon atoms) having 3 to 7 ring members or a bicyclic ring (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) having 7 to 10 ring members, e.g., bicyclo[4,5], [5,5], [5,6], or [6,6] systems.

[0107]

[0113] "Substituted alkyl," "substituted aryl," and "substituted arylalkyl" refer to alkyl, aryl, and arylalkyl, respectively, in which one or more hydrogen atoms are each independently replaced with a substituent. Exemplary substituents include, but are not limited to, -X, -R, -O-, -OR, -SR, -S-, -NR 2 , -NR 3 , =NR, -CX3, -CN, -OCN, -SCN, -N=C=O, -NCS, -NO, -NO2, =N2, -N3, NC(=O)R, -C(=O)R, -C(=O)NR 2 , -SO3-, -SO3H, -S(=O)2R, -OS(=O)2OR, -S(=O)2NR, -S(=O)R, -OP(=O)(OR)2, -P(=O)(OR)2, -PO - 3, -PO3H2, -C(=O)R, -C(=O)X, -C(=S)R, -CO2R, -CO2 - , -C(=S)OR, -C(=O)SR, -C(=S)SR, -C(=O)NR 2 , -C(=S)NR 2 , -C(=NR)NR 2wherein each X is independently a halogen: F, Cl, Br, or I; and each R is independently —H, C—C 18 Alkyl, C6-C 20 Aryl, C3-C 14 The alkylene, alkenylene and alkynylene groups mentioned above may also be similarly substituted.

[0108]

[0114] "Heteroaryl" and "heterocycle" refer to a ring system in which one or more ring atoms is a heteroatom, such as nitrogen, oxygen, and sulfur. Heterocyclyl radicals contain 3 to 20 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S. Heterocycles can be monocyclic rings having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S), or bicyclic rings having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S), such as bicyclo[4,5], [5,5], [5,6], or [6,6] systems.

[0109]

[0115] Exemplary heterocycles are described, for example, in Paquette, Leo A., "Principles of Modern Heterocyclic Chemistry" (WA Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 to present), particularly Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566.

[0110]

[0116] Examples of heterocycles include, by way of example and not limitation, pyridyl, dihydropyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur-oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidyl, and the like. nyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuran, bis-tetrahydrofuran, tetrahydropyranyl, bis-tetrahydropyranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuran nyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolidinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl nyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, and isatinoyl.

[0111]

[0117] By way of example and not limitation, carbon-bonded heterocycles are bonded at the 2-, 3-, 4-, 5-, or 6-position of pyridine, the 3-, 4-, 5-, or 6-position of pyridazine, the 2-, 4-, 5-, or 6-position of pyrimidine, the 2-, 3-, 5-, or 6-position of pyrazine, the 2-, 3-, 4-, or 5-position of furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole, the 2-, 4-, or 5-position of oxazole, imidazole, or thiazole, the 3-, 4-, or 5-position of isoxazole, pyrazole, or isothiazole, the 2- or 3-position of aziridine, the 2-, 3-, or 4-position of azetidine, the 2-, 3-, 4-, 5-, 6-, 7-, or 8-position of quinoline, or the 1-, 3-, 4-, 5-, 6-, 7-, or 8-position of isoquinoline. Even more typically, the carbon-linked heterocycle includes 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl.

[0112]

[0118] By way of example and not limitation, nitrogen-linked heterocycles are linked at the 1-position of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, 2-position of isoindole or isoindoline, 4-position of morpholine, and 9-position of carbazole or β-carboline. Even more typically, nitrogen-linked heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

[0113]

[0119] A "C3-C8 heterocycle" refers to an aromatic or non-aromatic C3-C8 carbocycle in which one to four of the ring carbon atoms are independently replaced with a heteroatom selected from the group consisting of O, S, and N. Representative examples of C3-C8 heterocycles include, but are not limited to, benzofuranyl, benzothiophene, indolyl, benzopyrazolyl, coumarinyl, isoquinolinyl, pyrrolyl, thiophenyl, furanyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, quinolinyl, pyrimidinyl, pyridinyl, pyridonyl, pyrazinyl, pyridazinyl, isothiazolyl, isoxazolyl, and tetrazolyl. A C3-C8 heterocycle can be unsubstituted or substituted with up to seven groups including, but not limited to, -C1-C8 alkyl, -O-(C1-C8 alkyl), -aryl, -C(O)R', -OC(O)R', -C(O)OR', -C(O)NH2, -C(O)NHR', -C(O)N(R')2-NHC(O)R', -S(O)2R', -S(O)R', -OH, -halogen, -N3, -NH2, -NH(R'), -N(R')2 and -CN, where each R' is independently selected from H, -C1-C8 alkyl and aryl.

[0114]

[0120] "C3-C8 heterocyclo" refers to a C3-C8 heterocyclic group, as defined above, in which one of the heterocyclic group's hydrogen atoms is replaced with a single bond. The C3-C8 heterocyclyl can be unsubstituted or substituted with up to seven groups, including, but not limited to, -C1-C8 alkyl, -O-(C1-C8 alkyl), -aryl, -C(O)R', -OC(O)R', -C(O)OR', -C(O)NH2, -C(O)NHR', -C(O)N(R')2-NHC(O)R', -S(O)2R', -S(O)R', -OH, -halogen, -N3, -NH2, -NH(R'), -N(R')2, and -CN, where each R' is independently selected from H, -C1-C8 alkyl, and aryl.

[0115]

[0121] "C3-C 20"Heterocycle" refers to an aromatic or non-aromatic C3-C8 carbocyclic ring in which one to four of the ring carbon atoms are independently replaced with a heteroatom from the group consisting of O, S, and N. 20 Heterocycles can be unsubstituted or substituted with up to seven groups including, but not limited to, -C1-C8 alkyl, -O-(C1-C8 alkyl), -aryl, -C(O)R', -OC(O)R', -C(O)OR', -C(O)NH2, -C(O)NHR', -C(O)N(R')2-NHC(O)R', -S(O)2R', -S(O)R', -OH, -halogen, -N3, -NH2, -NH(R'), -N(R')2 and -CN, where each R' is independently selected from H, -C1-C8 alkyl and aryl.

[0116]

[0122] "C3-C 20 "Heterocyclo" refers to a C-C heterocyclic ring, as defined above, in which one of the hydrogen atoms of the heterocyclic ring is replaced by a single bond. 20 It refers to a heterocyclic group.

[0117]

[0123] "Carbocycle" means a saturated or unsaturated ring having 3 to 7 carbon atoms as a monocycle or 7 to 12 carbon atoms as a bicycle. Monocyclic carbocycles have 3 to 6 ring atoms, and even more typically 5 or 6 ring atoms. Bicyclic carbocycles have, for example, 7 to 12 ring atoms arranged as a bicyclo[4,5], [5,5], [5,6], or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo[5,6] or [6,6] system. Examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cycloheptyl, and cyclooctyl.

[0118]

[0124] A "C3-C8 carbocycle" is a 3-, 4-, 5-, 6-, 7-, or 8-membered saturated or unsaturated non-aromatic carbocyclic ring. Representative C3-C8 carbocycles include, but are not limited to, -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclopentadienyl, -cyclohexyl, -cyclohexenyl, -1,3-cyclohexadienyl, -1,4-cyclohexadienyl, -cycloheptyl, -1,3-cycloheptadienyl, -1,3,5-cycloheptatrienyl, -cyclooctyl, and -cyclooctadienyl. A C3-C8 carbocyclic group can be unsubstituted or substituted with one or more groups including, but not limited to, -C1-C8 alkyl, -O-(C1-C8 alkyl), -aryl, -C(O)R', -OC(O)R', -C(O)OR', -C(O)NH2, -C(O)NHR', -C(O)N(R')2-NHC(O)R', -S(O)2R', -S(O)R', -OH, -halogen, -N3, -NH2, -NH(R'), -N(R')2 and -CN, where each R' is independently selected from H, -C1-C8 alkyl and aryl.

[0119]

[0125] "C3-C8 carbocyclo" refers to a C3-C8 carbocyclic group, as defined above, in which one of the carbocyclic group's hydrogen atoms is replaced with a single bond.

[0120]

[0126] "Linker" refers to a chemical moiety comprising a covalent bond or a chain of atoms that covalently attaches an antibody to a drug moiety. In various embodiments, the linker is a divalent radical such as alkyldiyl, aryldiyl, heteroaryldiyl, -(CR 2 )nO(CR 2 )n-, repeating units of alkyloxy (e.g., polyethyleneoxy, PEG, polymethyleneoxy) and alkylamino (e.g., polyethyleneamino, Jeffamine™); and diacid esters and amides, including succinate, succinamide, diglycolate, malonate, and caproamide. In various embodiments, the linker can include one or more amino acid residues, such as valine, phenylalanine, lysine, and homolysine.

[0121]

[0127] The term "chiral" refers to molecules that have the property of not being superimposable on their mirror image partners, while the term "achiral" refers to molecules that are superimposable on their mirror image partners.

[0122]

[0128] The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0123]

[0129] "Diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can separate under high-resolution analytical procedures such as electrophoresis and chromatography.

[0124]

[0130] "Enantiomers" refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0125]

[0131] Stereochemical definitions and conventions used herein generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994), John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its one or more chiral centers. The prefixes d and l, or (+) and (-), are used to denote the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0126]

[0132] A "leaving group" refers to a functional group that can be displaced by another functional group. Certain leaving groups are well known in the art, and examples include, but are not limited to, halides (e.g., chloride, bromide, iodide), methanesulfonyl (mesyl), p-toluenesulfonyl (tosyl), trifluoromethylsulfonyl (triflate), and trifluoromethylsulfonate.

[0127]

[0133] The term "protecting group" refers to a substituent that is commonly used to block or protect a particular functionality while reacting with other functional groups on a compound. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality of the compound. Suitable amino-protecting groups include, but are not limited to, acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenylmethylenoxycarbonyl (Fmoc). For a general description of protecting groups and their uses, see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991, or subsequent editions.

[0128] III. Method

[0134] Provided herein are methods of treating a B cell proliferative disorder (e.g., diffuse large B cell lymphoma (DLBCL), e.g., relapsed / refractory DLBCL) in an individual (human individual) in need thereof, the method comprising administering to the individual an effective amount of: (a) an immunoconjugate comprising an antibody that binds CD79b linked to a cytotoxic agent, and (b) at least one additional therapeutic agent. In some embodiments, the at least one additional therapeutic agent is a chemotherapeutic agent. In some embodiments, the at least one additional therapeutic agent is a cytotoxic agent. In some embodiments, the at least one additional therapeutic agent is an immunomodulatory agent. In some embodiments, the at least one additional therapeutic agent is an anti-CD20 agent, e.g., an anti-CD20 antibody.

[0129]

[0135] In some embodiments, the methods comprise administering to the individual effective amounts of: (a) an immunoconjugate comprising an anti-CD79b antibody linked to a cytotoxic agent (i.e., an anti-CD79b immunoconjugate), (b) an immunomodulatory agent, and (c) an anti-CD20 antibody.

[0130]

[0136] Also provided herein is a method of treating diffuse large B-cell lymphoma (DLBCL, e.g., relapsed / refractory DLBCL) in an individual (human individual) in need thereof, the method comprising administering to a subject an effective amount of: (a) a compound of the formula: TIFF2024520901000011.tif28170 (wherein Ab is an anti-CD79b antibody comprising (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26, and p is between 1 and 8), (b) an immunomodulatory agent, and (c) an anti-CD20 antibody.

[0131]

[0137] In some embodiments, an immunoconjugate comprises an anti-CD79b antibody comprising a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 19 and a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, an immunoconjugate comprises an anti-CD79b antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 37 and a light chain comprising the amino acid sequence of SEQ ID NO: 35. In some embodiments, an immunoconjugate comprises an anti-CD79b antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 36 and a light chain comprising the amino acid sequence of SEQ ID NO: 38. In some embodiments, an immunoconjugate comprises an anti-CD79b antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 36 and a light chain comprising the amino acid sequence of SEQ ID NO: 35. In some embodiments, p is between 2 and 7, between 2 and 6, between 2 and 5, between 3 and 5, or between 3 and 4. In some embodiments, p is 3.4. In some embodiments, p is 3.5. In some embodiments, the anti-CD79b immunoconjugate is huMA79bv28-MC-vc-PAB-MMAE. In some embodiments, the immunoconjugate is polatuzumab vedotin (CAS Registry Number 1313206426).

[0132]

[0138] In some embodiments, the immunomodulatory agent is lenalidomide.

[0133]

[0139] In some embodiments, the anti-CD20 antibody is a humanized B-Ly1 antibody. In some embodiments, the humanized B-Ly1 antibody is obinutuzumab. In some embodiments, the anti-CD20 antibody is rituximab. In some embodiments, the anti-CD20 antibody is ofatumumab, ublituximab, and / or ibritumomab tiuxetan.

[0134]

[0140] In some embodiments, treatment of an individual, e.g., a human, with any of the methods of the present disclosure results in a response of at least stable disease (SD) (e.g., at least SD, at least partial remission (PR), or complete response / cure (CR)) during or after treatment (e.g., during or after a therapeutic regimen described herein). In some embodiments, treatment of an individual, e.g., a human, with any of the methods of the present disclosure results in an objective response, best overall response, best complete remission, best partial remission, or complete remission during or after treatment (e.g., during or after a therapeutic regimen described herein). Additional details regarding objective response, best overall response, best complete remission, best partial remission, complete remission, and other therapeutic responses are provided herein below.

[0135] A. Medication and Administration

[0141] The anti-CD79b immunoconjugates and additional therapeutic agents (e.g., immunomodulatory agents and anti-CD20 agents) provided herein for use in any of the therapeutic methods described herein are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this regard include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the dosing schedule, and other factors known to the medical profession. The immunoconjugates are optionally, but not necessarily, formulated with one or more agents currently used to prevent or treat the disorder in question. The amounts of anti-CD79b immunoconjugates and additional therapeutic agents (e.g., immunomodulatory agents and anti-CD20 agents), as well as the timing of co-administration, will depend on the type (species, sex, age, weight, etc.) and condition of the patient being treated and the severity of the disease or condition being treated. The anti-CD79b immunoconjugate and additional therapeutic agent (e.g., an immunomodulatory agent and an anti-CD20 agent) are suitably co-administered to the patient at one time or over a series of treatments, e.g., according to any of the treatment regimens described below.

[0136]

[0142] In some embodiments, the dosage of the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is about 1.4-5 mg / kg, 1.4-4 mg / kg, 1.4-3.2 mg / kg, 1.4-2.4 mg / kg, or 1.4-1.8 mg / kg. In some embodiments of any of the methods, the dosage of the anti-CD79 immunoconjugate is about 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, 3.4, 3.6, 3.8, 4.0, 4.2, 4.4, 4.6, and / or 4.8 mg / kg. In some embodiments, the dosage of the anti-CD79b immunoconjugate is about 1.4 mg / kg. In some embodiments, the dosage of the anti-CD79b immunoconjugate is about 1.8 mg / kg. In some embodiments, the dosage of the anti-CD79b immunoconjugate is about 2.4 mg / kg. In some embodiments, the dosage of the anti-CD79b immunoconjugate is about 3.2 mg / kg. In some embodiments, the dosage of the anti-CD79b immunoconjugate is about 3.6 mg / kg. In some embodiments of any of the methods, the anti-CD79b immunoconjugate is administered q3w (i.e., once every three weeks). In some embodiments of any of the methods, the anti-CD79b immunoconjugate is administered q4w (i.e., once every four weeks). In some embodiments of any of the methods, the anti-CD79b immunoconjugate is administered once a month. In some embodiments of any of the methods, a month is 28 days. In some embodiments of any of the methods, the anti-CD79b immunoconjugate is administered once every 28 days. In some embodiments, the anti-CD79b immunoconjugate is administered via intravenous infusion. In some embodiments, the dosage administered via infusion ranges from about 1 mg to about 1,500 mg per dose.Alternatively, dosage ranges are about 1 mg to about 1,500 mg, about 1 mg to about 1,000 mg, about 400 mg to about 1,200 mg, about 600 mg to about 1,000 mg, about 10 mg to about 500 mg, about 10 mg to about 300 mg, about 10 mg to about 200 mg, and about 1 mg to about 200 mg. In some embodiments, the dosage administered via infusion is about 1 μg / m per dose. 2 to approximately 10,000 μg / m 2 Alternatively, the dosage range is about 1 μg / m 2 to approximately 1000 μg / m 2 , about 1μg / m 2 to approximately 800 μg / m 2 , about 1μg / m 2 to approximately 600 μg / m 2 , about 1μg / m 2 to approximately 400 μg / m 2 , about 10μg / m 2 to approximately 500 μg / m 2 , about 10μg / m 2 to approximately 300 μg / m 2 , about 10μg / m 2 to approximately 200 μg / m 2 , and approximately 1 μg / m 2 to approximately 200 μg / m 2 The dose may be administered once daily, once weekly, multiple times per week but less than once daily, multiple times per month but less than once daily, multiple times per month but less than once per week, monthly, once every 28 days, or intermittently to relieve or alleviate the symptoms of the disease. In some embodiments, the dosage of the immunoconjugate is 1.8 mg / kg and is administered on day 1 of each 28-day cycle or on day 1 of each month, where a month has 28 days. Administration may continue at any of the disclosed intervals until remission of the tumor or symptoms of the B-cell proliferative disorder being treated. Administration may continue after remission or alleviation of symptoms is achieved, if such remission or alleviation is prolonged by such continued administration.

[0137]

[0143] In some embodiments, the dosage of the anti-CD20 agent (e.g., an anti-CD20 antibody, e.g., rituximab or obinutuzumab) is about 300 to 1600 mg / m 2 and / or 300-2000 mg. In some embodiments, the dosage of the anti-CD20 antibody is about 300, 375, 600, 1000, or 1250 mg / m 2 and / or 300, 1000, or 2000 mg. In some embodiments, the anti-CD20 antibody is rituximab and the administered dosage is 375 mg / m 2 In some embodiments, the anti-CD20 antibody is obinutuzumab and the administered dosage is 1000 mg. In some embodiments, the anti-CD20 antibody is administered q3w (i.e., every 3 weeks). In some embodiments, the anti-CD20 antibody is administered q4w (i.e., once every 4 weeks). In some embodiments, the anti-CD20 antibody is administered once a month. In some embodiments, a month is 28 days. In some embodiments, the anti-CD20 antibody is administered once every 28 days. In some embodiments, the dosage of the afucosylated anti-CD20 antibody (preferably, an afucosylated humanized B-LyI antibody) can be 800 to 1600 mg (in one embodiment, 800 to 1200 mg, e.g., 1000 mg) on ​​days 1, 8, and 15 of a 3- to 6-week dosing cycle, followed by 400 to 1200 mg (in one embodiment, 800 to 1200 mg) on ​​day 1 of up to nine 3- to 4-week dosing cycles. In some embodiments, the dose is a flat 1000 mg dose on a 3-week dosing schedule, optionally with an additional cycle of a flat 1000 mg dose in week 2. In some embodiments, the dosage of rituximab is 375 mg / m 2 and is administered on the first day of each month or on the first day of every two months. In some embodiments, the dosage of rituximab is 375 mg / m 2 and is administered on day 1 of each 28-day cycle or on day 1 of every two months, where a month has 28 days. In some embodiments, the anti-CD20 antibody is administered by intravenous infusion.

[0138]

[0144] In some embodiments, the dosage of the immunomodulatory agent, e.g., lenalidomide, is between about 5 mg and about 10 mg, between about 10 mg and about 15 mg, or between about 15 mg and about 20 mg. In some embodiments, the dosage of the immunomodulatory agent, e.g., lenalidomide, is between about 10 mg and about 20 mg. In some embodiments, the dosage of the immunomodulatory agent, e.g., lenalidomide, is about 5 mg, about 10 mg, about 15 mg, or about 20 mg. In some embodiments, the dosage of the immunomodulatory agent, e.g., lenalidomide, is about 5 mg. In some embodiments, the dosage of the immunomodulatory agent, e.g., lenalidomide, is about 10 mg. In some embodiments, the dosage of the immunomodulatory agent, e.g., lenalidomide, is about 15 mg. In some embodiments, the dosage of the immunomodulatory agent, e.g., lenalidomide, is about 20 mg. In some embodiments, the immunomodulatory agent, e.g., lenalidomide, is administered orally, e.g., in the form of a capsule (e.g., a capsule containing 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, or 25 mg of immunomodulatory agent). In some embodiments, the immunomodulatory agent, e.g., lenalidomide, is administered daily (e.g., once daily). In some embodiments, the immunomodulatory agent, e.g., lenalidomide, may be administered daily (e.g., once daily) at a dose of about 5 mg, about 10 mg, about 15 mg, or about 20 mg on days 1-21 of each 28-day cycle of a treatment regimen, e.g., a treatment regimen described herein. In some embodiments, the immunomodulatory agent, e.g., lenalidomide, may be administered daily (e.g., once daily) at a dose of about 5 mg, about 10 mg, about 15 mg, or about 20 mg on days 1-21 of each month during a treatment regimen, e.g., a treatment regimen described herein.

[0139]

[0145] An exemplary dosing regimen for combination therapy of an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) with one or more additional therapeutic agents is an anti-CD79 immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) administered q4w at a dose of about 1.4-5 mg / kg and an additional therapeutic agent (e.g., 375 mg / m2 and an immunomodulatory agent (e.g., lenalidomide) administered at a dose of about 10-20 mg q4w on days 1-21 of each 28-day cycle (e.g., on each of days 1-21 q4w). Another exemplary dosing regimen for combination therapy of an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) and one or more additional therapeutic agents includes an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) administered once every 28 days (e.g., on day 1 of each 28-day cycle) at a dose of about 1.4-5 mg / kg and an immunomodulatory agent (e.g., lenalidomide) administered at a dose of about 375 mg / m 2 and an immunomodulatory agent (e.g., lenalidomide) administered at a dose of about 10-20 mg once every 28 days (e.g., on day 1 of each 28-day cycle). In some embodiments, the anti-CD79b immunoconjugate is administered at a dose of about 1.4 mg / kg, 1.8 mg / kg, 2.0 mg / kg, 2.2 mg / kg, 2.4 mg / kg, 3.2 mg / kg, or 4.0 mg / kg. In some embodiments, the anti-CD79b immunoconjugate is administered at a dose of about 1.4 mg / kg. In some embodiments, the anti-CD79b immunoconjugate is administered at a dose of about 1.8 mg / kg. In some embodiments, the anti-CD79b immunoconjugate is administered at a dose of about 2.4 mg / kg. In some embodiments, the immunomodulatory agent (e.g., lenalidomide) is administered at a dose of about 10 mg. In some embodiments, the immunomodulatory agent (e.g., lenalidomide) is administered at a dose of about 15 mg. In some embodiments, the immunomodulatory agent (e.g., lenalidomide) is administered at a dose of about 20 mg.

[0140]

[0146] An exemplary dosing regimen for combination therapy of an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) with one or more additional therapeutic agents is an anti-CD79 immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) administered q4w at a dose of about 1.4-5 mg / kg and an additional therapeutic agent (e.g., polatuzumab vedotin) administered q4w at a dose of about 1000 mg / m 2and an immunomodulatory agent (e.g., lenalidomide) administered on days 1-21 of each 28-day cycle (e.g., on each of days 1-21 q4w) at a dose of about 10-20 mg. Another exemplary dosing regimen for combination therapy of an anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) and one or more additional therapeutic agents includes an anti-CD79 immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) administered once every 28 days (e.g., on day 1 of each 28-day cycle) at a dose of about 1.4-5 mg / kg; obinutuzumab administered once every 28 days (e.g., on day 1 of each 28-day cycle) at a dose of about 1000 mg or on days 1, 8, and 15 of each 28-day cycle; and an immunomodulatory agent (e.g., lenalidomide) administered at a dose of about 10-20 mg on days 1-21 of each 28-day cycle. In some embodiments, the anti-CD79 immunoconjugate is administered at a dose of about 1.4 mg / kg, 1.8 mg / kg, 2.0 mg / kg, 2.2 mg / kg, 2.4 mg / kg, 3.2 mg / kg, or 4.0 mg / kg. In some embodiments, the anti-CD79b immunoconjugate is administered at a dose of about 1.4 mg / kg. In some embodiments, the anti-CD79b immunoconjugate is administered at a dose of about 1.8 mg / kg. In some embodiments, the anti-CD79b immunoconjugate is administered at a dose of about 2.4 mg / kg. In some embodiments, the immunomodulatory agent (e.g., lenalidomide) is administered at a dose of about 10 mg. In some embodiments, the immunomodulatory agent (e.g., lenalidomide) is administered at a dose of about 15 mg. In some embodiments, the immunomodulatory agent (e.g., lenalidomide) is administered at a dose of about 20 mg.

[0141]

[0147] The terms "co-administration," "co-administering," "combination," or "in combination," with respect to administration of two or more therapeutic agents, e.g., an anti-CD79b immunoconjugate and at least one additional therapeutic agent (e.g., an immunomodulatory agent and an anti-CD20 agent), refer to the administration of the two or more therapeutic agents as two (or more) separate formulations or as a single formulation containing the two or more therapeutic agents. When separate formulations are used, the co-administration can occur simultaneously (i.e., at the same time) or sequentially in any order, preferably with a period of time during which all active agents simultaneously exert their biological activities. In some embodiments, the two or more therapeutic agents are co-administered simultaneously or sequentially. In some embodiments, when all therapeutic agents are co-administered sequentially, e.g., according to any of the treatment regimens described herein, doses of each agent are administered on the same day in two or more separate administrations, or one of the agents is administered on day 1 and one or more other agents are co-administered the following day.

[0142]

[0148] The immunoconjugates provided herein (and any additional therapeutic agents, e.g., immunomodulatory agents and anti-CD20 agents) for use in any of the methods of treatment described herein can be administered by any suitable means, including parenteral, intrapulmonary, and intranasal, as well as intralesional administration if desired for localized treatment. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. Dosing can be by any suitable route, e.g., injections, such as intravenous or subcutaneous injections, depending in part on whether administration is brief or chronic. Various dosing schedules are contemplated herein, including, but not limited to, single or multiple doses at various time points, bolus administration, and pulse infusion. The anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), immunomodulatory agent (e.g., lenalidomide), and anti-CD20 antibody (e.g., obinutuzumab or rituximab) may be administered by the same route of administration or by different routes of administration. In some embodiments, the anti-CD79b immunoconjugate is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intracerebroventricularly, or intranasally. In some embodiments, the immunomodulatory agent (e.g., lenalidomide) is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intracerebroventricularly, or intranasally. In some embodiments, the anti-CD20 antibody (e.g., obinutuzumab or rituximab) is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intracerebroventricularly, or intranasally. In some embodiments, the anti-CD79b immunoconjugate and the anti-CD20 antibody (e.g., obinutuzumab or rituximab) are each administered via intravenous infusion, and the immunomodulatory agent (e.g., lenalidomide) is administered orally. Effective amounts of the anti-CD79b immunoconjugate, immunomodulatory agent (e.g., lenalidomide), and anti-CD20 antibody (e.g., obinutuzumab or rituximab) can be administered to prevent or treat a disease, e.g., R / R DLBCL.

[0143] (i) Induction period

[0149] In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), immunomodulatory agent (e.g., lenalidomide), and anti-CD20 antibody (e.g., obinutuzumab or rituximab) are administered during an induction phase. "Induction phase" refers to the period of treatment during which the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered to an individual, e.g., a human.

[0144]

[0150] In some embodiments, during the induction phase, the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), immunomodulatory agent (e.g., lenalidomide), and anti-CD20 antibody (e.g., obinutuzumab or rituximab) are administered in 28-day cycles. In some embodiments, the induction phase comprises less than one complete 28-day cycle. In some embodiments, the induction phase comprises between one and six (e.g., 1, 2, 3, 4, 5, or 6) 28-day cycles. In some embodiments, the induction phase comprises at least six 28-day cycles.

[0145]

[0151] In some embodiments, during the induction phase, the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.4 mg / kg on day 1 of an initial 28-day cycle, the immunomodulatory agent (e.g., lenalidomide) is administered orally at a dose of about 10 mg on each of days 1-21 of an initial 28-day cycle, and the anti-CD20 antibody is obinutuzumab, which is administered intravenously at a dose of about 1000 mg on each of days 1, 8, and 15 of an initial 28-day cycle; (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.4 mg / kg on day 1 of each of the second, third, fourth, fifth, and sixth 28-day cycles, an immunomodulatory agent (e.g., lenalidomide) is administered orally at a dose of about 10 mg on each of days 1-21 of each of the second, third, fourth, fifth, and sixth 28-day cycles, and obinutuzumab is administered intravenously at a dose of about 1000 mg on day 1 of each of the second, third, fourth, fifth, and sixth 28-day cycles.

[0146]

[0152] In some embodiments, during the induction phase, the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.4 mg / kg on day 1 of an initial 28-day cycle, the immunomodulatory agent (e.g., lenalidomide) is administered orally at a dose of about 15 mg on each of days 1-21 of an initial 28-day cycle, and the anti-CD20 antibody is obinutuzumab, which is administered intravenously at a dose of about 1000 mg on each of days 1, 8, and 15 of an initial 28-day cycle; (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.4 mg / kg on day 1 of each of the second, third, fourth, fifth, and sixth 28-day cycles, an immunomodulatory agent (e.g., lenalidomide) is administered orally at a dose of about 15 mg on each of days 1-21 of each of the second, third, fourth, fifth, and sixth 28-day cycles, and obinutuzumab is administered intravenously at a dose of about 1000 mg on day 1 of each of the second, third, fourth, fifth, and sixth 28-day cycles.

[0147]

[0153] In some embodiments, during the induction phase, the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.4 mg / kg on day 1 of an initial 28-day cycle, the immunomodulatory agent (e.g., lenalidomide) is administered orally at a dose of about 20 mg on each of days 1-21 of an initial 28-day cycle, and the anti-CD20 antibody is obinutuzumab, which is administered intravenously at a dose of about 1000 mg on each of days 1, 8, and 15 of an initial 28-day cycle; (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.4 mg / kg on day 1 of each of the second, third, fourth, fifth, and sixth 28-day cycles, an immunomodulatory agent (e.g., lenalidomide) is administered orally at a dose of about 20 mg on each of days 1-21 of each of the second, third, fourth, fifth, and sixth 28-day cycles, and obinutuzumab is administered intravenously at a dose of about 1000 mg on day 1 of each of the second, third, fourth, fifth, and sixth 28-day cycles.

[0148]

[0154] In some embodiments, during the induction phase, the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.8 mg / kg on day 1 of an initial 28-day cycle, the immunomodulatory agent (e.g., lenalidomide) is administered orally at a dose of about 10 mg on each of days 1-21 of an initial 28-day cycle, and the anti-CD20 antibody is obinutuzumab, which is administered intravenously at a dose of about 1000 mg on each of days 1, 8, and 15 of an initial 28-day cycle; (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.8 mg / kg on day 1 of each of the second, third, fourth, fifth, and sixth 28-day cycles, an immunomodulatory agent (e.g., lenalidomide) is administered orally at a dose of about 10 mg on each of days 1-21 of each of the second, third, fourth, fifth, and sixth 28-day cycles, and obinutuzumab is administered intravenously at a dose of about 1000 mg on day 1 of each of the second, third, fourth, fifth, and sixth 28-day cycles.

[0149]

[0155] In some embodiments, during the induction phase, the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.8 mg / kg on day 1 of an initial 28-day cycle, the immunomodulatory agent (e.g., lenalidomide) is administered orally at a dose of about 15 mg on each of days 1-21 of an initial 28-day cycle, and the anti-CD20 antibody is obinutuzumab, which is administered intravenously at a dose of about 1000 mg on each of days 1, 8, and 15 of an initial 28-day cycle; (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.8 mg / kg on day 1 of each of the second, third, fourth, fifth, and sixth 28-day cycles, an immunomodulatory agent (e.g., lenalidomide) is administered orally at a dose of about 15 mg on each of days 1-21 of each of the second, third, fourth, fifth, and sixth 28-day cycles, and obinutuzumab is administered intravenously at a dose of about 1000 mg on day 1 of each of the second, third, fourth, fifth, and sixth 28-day cycles.

[0150]

[0156] In some embodiments, during the induction phase, the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.8 mg / kg on day 1 of an initial 28-day cycle, the immunomodulatory agent (e.g., lenalidomide) is administered orally at a dose of about 20 mg on each of days 1-21 of an initial 28-day cycle, and the anti-CD20 antibody is obinutuzumab, which is administered intravenously at a dose of about 1000 mg on each of days 1, 8, and 15 of an initial 28-day cycle; (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.8 mg / kg on day 1 of each of the second, third, fourth, fifth, and sixth 28-day cycles, an immunomodulatory agent (e.g., lenalidomide) is administered orally at a dose of about 20 mg on each of days 1-21 of each of the second, third, fourth, fifth, and sixth 28-day cycles, and obinutuzumab is administered intravenously at a dose of about 1000 mg on day 1 of each of the second, third, fourth, fifth, and sixth 28-day cycles.

[0151]

[0157] In some embodiments, during the induction phase, the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.4 mg / kg on day 1 of each 28-day cycle, the immunomodulatory agent (e.g., lenalidomide) is administered orally at a dose of about 10 mg on each of days 1-21 of each 28-day cycle, and the anti-CD20 antibody is rituximab, and the rituximab is administered orally at a dose of about 375 mg / m 2 It will be administered intravenously on day 1 of each 28-day cycle at a dose of

[0152]

[0158] In some embodiments, during the induction phase, the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.4 mg / kg on day 1 of each 28-day cycle, the immunomodulatory agent (e.g., lenalidomide) is administered orally at a dose of about 15 mg on each of days 1-21 of each 28-day cycle, and the anti-CD20 antibody is rituximab, and the rituximab is administered orally at a dose of about 375 mg / m 2 It will be administered intravenously on day 1 of each 28-day cycle at a dose of

[0153]

[0159] In some embodiments, during the induction phase, the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.4 mg / kg on day 1 of each 28-day cycle, the immunomodulatory agent (e.g., lenalidomide) is administered orally at a dose of about 20 mg on each of days 1-21 of each 28-day cycle, and the anti-CD20 antibody is rituximab, and the rituximab is administered orally at a dose of about 375 mg / m 2 It will be administered intravenously on day 1 of each 28-day cycle at a dose of

[0154]

[0160] In some embodiments, during the induction phase, the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.8 mg / kg on day 1 of each 28-day cycle, the immunomodulatory agent (e.g., lenalidomide) is administered orally at a dose of about 10 mg on each of days 1-21 of each 28-day cycle, and the anti-CD20 antibody is rituximab, and the rituximab is administered orally at a dose of about 375 mg / m 2 It will be administered intravenously on day 1 of each 28-day cycle at a dose of

[0155]

[0161] In some embodiments, during the induction phase, the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.8 mg / kg on day 1 of each 28-day cycle, the immunomodulatory agent (e.g., lenalidomide) is administered orally at a dose of about 15 mg on each of days 1-21 of each 28-day cycle, and the anti-CD20 antibody is rituximab, and the rituximab is administered orally at a dose of about 375 mg / m 2 It will be administered intravenously on day 1 of each 28-day cycle at a dose of

[0156]

[0162] In some embodiments, during the induction phase, the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.8 mg / kg on day 1 of each 28-day cycle, the immunomodulatory agent (e.g., lenalidomide) is administered orally at a dose of about 20 mg on each of days 1-21 of each 28-day cycle, and the anti-CD20 antibody is rituximab, and the rituximab is administered orally at a dose of about 375 mg / m 2 It will be administered intravenously on day 1 of each 28-day cycle at a dose of

[0157]

[0163] In some embodiments, the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), immunomodulatory agent (e.g., lenalidomide), and anti-CD20 antibody (e.g., obinutuzumab or rituximab) are administered for at least one 28-day cycle. In some embodiments, the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), immunomodulatory agent (e.g., lenalidomide), and anti-CD20 antibody (e.g., obinutuzumab or rituximab) are administered for one, two, three, four, five, six, or more 28-day cycles. In some embodiments, the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), immunomodulatory agent (e.g., lenalidomide), and anti-CD20 antibody (e.g., obinutuzumab or rituximab) are administered for up to six 28-day cycles. In some embodiments, the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), immunomodulatory agent (e.g., lenalidomide), and anti-CD20 antibody (e.g., obinutuzumab or rituximab) are administered for six 28-day cycles.

[0158]

[0164] In some embodiments, during the induction phase, the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.4 mg / kg on day 1 of each of the first, second, third, fourth, fifth, and sixth 28-day cycles, the immunomodulatory agent (e.g., lenalidomide) is administered orally at a dose of about 10 mg on each of days 1-21 of each of the first, second, third, fourth, fifth, and sixth 28-day cycles, and the anti-CD20 antibody is rituximab, and the rituximab is administered at a dose of about 375 mg / m 2 is administered intravenously on day 1 of each of the first, second, third, fourth, fifth, and sixth 28-day cycles at a dose of

[0159]

[0165] In some embodiments, during the induction phase, the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.4 mg / kg on day 1 of each of the first, second, third, fourth, fifth, and sixth 28-day cycles, the immunomodulatory agent (e.g., lenalidomide) is administered orally at a dose of about 15 mg on each of days 1-21 of each of the first, second, third, fourth, fifth, and sixth 28-day cycles, and the anti-CD20 antibody is rituximab, and the rituximab is administered orally at a dose of about 375 mg / m 2 is administered intravenously on day 1 of each of the first, second, third, fourth, fifth, and sixth 28-day cycles at a dose of

[0160]

[0166] In some embodiments, during the induction phase, the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.4 mg / kg on day 1 of each of the first, second, third, fourth, fifth, and sixth 28-day cycles, the immunomodulatory agent (e.g., lenalidomide) is administered orally at a dose of about 20 mg on each of days 1-21 of each of the first, second, third, fourth, fifth, and sixth 28-day cycles, and the anti-CD20 antibody is rituximab, and the rituximab is administered orally at a dose of about 375 mg / m 2 is administered intravenously on day 1 of each of the first, second, third, fourth, fifth, and sixth 28-day cycles at a dose of

[0161]

[0167] In some embodiments, during the induction phase, the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.8 mg / kg on day 1 of each of the first, second, third, fourth, fifth, and sixth 28-day cycles, the immunomodulatory agent (e.g., lenalidomide) is administered orally at a dose of about 10 mg on each of days 1-21 of each of the first, second, third, fourth, fifth, and sixth 28-day cycles, and the anti-CD20 antibody is rituximab, and the rituximab is administered orally at a dose of about 375 mg / m 2is administered intravenously on day 1 of each of the first, second, third, fourth, fifth, and sixth 28-day cycles at a dose of

[0162]

[0168] In some embodiments, during the induction phase, the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.8 mg / kg on day 1 of each of the first, second, third, fourth, fifth, and sixth 28-day cycles, the immunomodulatory agent (e.g., lenalidomide) is administered orally at a dose of about 15 mg on each of days 1-21 of each of the first, second, third, fourth, fifth, and sixth 28-day cycles, and the anti-CD20 antibody is rituximab, and the rituximab is administered orally at a dose of about 375 mg / m 2 is administered intravenously on day 1 of each of the first, second, third, fourth, fifth, and sixth 28-day cycles at a dose of

[0163]

[0169] In some embodiments, during the induction phase, the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) is administered intravenously at a dose of about 1.8 mg / kg on day 1 of each of the first, second, third, fourth, fifth, and sixth 28-day cycles, the immunomodulatory agent (e.g., lenalidomide) is administered orally at a dose of about 20 mg on each of days 1-21 of each of the first, second, third, fourth, fifth, and sixth 28-day cycles, and the anti-CD20 antibody is rituximab, and the rituximab is administered orally at a dose of about 375 mg / m 2 is administered intravenously on day 1 of each of the first, second, third, fourth, fifth, and sixth 28-day cycles at a dose of

[0164]

[0170] Exemplary induction phase dosing and administration schedules are shown in Tables A-L below. Tables A-L: Exemplary induction phase dosing and administration schedules TIFF2024520901000012.tif72170TIFF2024520901000013.tif71170TIFF2024520901000014.tif71170 TIFF2024520901000015.tif71170TIFF2024520901000016.tif71170TIFF2024520901000017.tif71170 TIFF2024520901000018.tif64170TIFF2024520901000019.tif64170TIFF2024520901000020.tif64170 TIFF2024520901000021.tif64170TIFF2024520901000022.tif64170TIFF2024520901000023.tif64170

[0165]

[0171] In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), immunomodulatory agent (e.g., lenalidomide), and anti-CD20 antibody (e.g., obinutuzumab or rituximab) are administered sequentially during the induction phase, e.g., in the first, second, third, fourth, fifth, and sixth 28-day cycles. In some embodiments, the immunomodulatory agent (e.g., lenalidomide) is administered prior to the anti-CD20 antibody (e.g., obinutuzumab or rituximab), and the anti-CD20 antibody (e.g., obinutuzumab or rituximab) is administered prior to the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin). In some embodiments, the immunomodulatory agent (e.g., lenalidomide) is administered on day 1 of each 28-day cycle prior to the anti-CD20 antibody (e.g., obinutuzumab or rituximab), which is administered prior to the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin).

[0166] (ii) Consolidation phase

[0172] In some embodiments, the immunomodulatory agent (e.g., lenalidomide) and the anti-CD20 antibody (e.g., obinutuzumab or rituximab) are further administered during a consolidation phase after the induction phase described herein, e.g., after the last 28-day cycle of the induction phase described herein, e.g., after the sixth 28-day cycle of the induction phase described herein. "Consolidation phase" refers to the treatment period following the induction phase. In some embodiments, the consolidation phase begins immediately after the end of the induction phase. In some embodiments, the induction phase and the consolidation phase are separated by a time interval. In some embodiments, the consolidation phase begins at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks after the end of the induction phase. In some embodiments, the consolidation phase begins about 7, about 8, or about 9 weeks after day 1 of the last cycle of the induction phase. In some embodiments, the consolidation phase begins about 8 weeks after day 1 of the last cycle of the induction phase. In some embodiments, the consolidation phase begins about 7, about 8, or about 9 weeks after day 1 of the sixth 28-day cycle of the induction phase. In some embodiments, the consolidation phase begins about 8 weeks after day 1 of the sixth 28-day cycle of the induction phase.

[0167]

[0173] In some embodiments, the immunomodulatory agent (e.g., lenalidomide) is administered orally at a dose of between about 10 mg and about 20 mg on each of days 1-21 of each month during the consolidation phase, and the anti-CD20 antibody is obinutuzumab, which is administered intravenously at a dose of about 1000 mg on day 1 of every other month during the consolidation phase. In some embodiments, the immunomodulatory agent (e.g., lenalidomide) is administered orally at a dose of about 10 mg on each of days 1-21 of each month during the consolidation phase, and the anti-CD20 antibody is obinutuzumab, which is administered intravenously at a dose of about 1000 mg on day 1 of every other month during the consolidation phase. In some embodiments, the immunomodulatory agent (e.g., lenalidomide) is administered orally at a dose of about 15 mg on each of days 1-21 of each month during the consolidation phase, and the anti-CD20 antibody is obinutuzumab, which is administered intravenously at a dose of about 1000 mg on day 1 of every other month during the consolidation phase. In some embodiments, the immunomodulatory agent (e.g., lenalidomide) is administered orally at a dose of about 20 mg on each of days 1-21 of each month during the consolidation phase, and the anti-CD20 antibody is obinutuzumab, which is administered intravenously at a dose of about 1000 mg on day 1 of every other month during the consolidation phase. In some embodiments, a month comprises 28 days. In some embodiments, the immunomodulatory agent (e.g., lenalidomide) is administered for any of 1, 2, 3, 4, 5, 6, or longer months during the consolidation phase. In some embodiments, the immunomodulatory agent (e.g., lenalidomide) is administered for up to 6 months during the consolidation phase. In some embodiments, the anti-CD20 antibody (e.g., obinutuzumab) is administered beginning in month 1 of the consolidation phase. In some embodiments, the anti-CD20 antibody (e.g., obinutuzumab) is administered on day 1 of each of months 1, 3, and 5 of the consolidation phase.

[0168]

[0174] In some embodiments, the immunomodulatory agent (e.g., lenalidomide) is administered orally at a dose of between about 10 mg and about 20 mg on each of days 1-21 of each month during the consolidation phase, and the anti-CD20 antibody is rituximab, which is administered intravenously at a dose of about 375 mg on day 1 of every other month during the consolidation phase. In some embodiments, the immunomodulatory agent (e.g., lenalidomide) is administered orally at a dose of about 10 mg on each of days 1-21 of each month during the consolidation phase, and the anti-CD20 antibody is rituximab, which is administered intravenously at a dose of about 375 mg on day 1 of every other month during the consolidation phase. In some embodiments, the immunomodulatory agent (e.g., lenalidomide) is administered orally at a dose of about 15 mg on each of days 1-21 of each month during the consolidation phase, and the anti-CD20 antibody is rituximab, which is administered intravenously at a dose of about 375 mg on day 1 of every other month during the consolidation phase. In some embodiments, the immunomodulatory agent (e.g., lenalidomide) is administered orally at a dose of about 20 mg on each of days 1-21 of each month during the consolidation phase, and the anti-CD20 antibody is rituximab, which is administered intravenously at a dose of about 375 mg / m 2 on day 1 of every other month during the consolidation phase. In some embodiments, a month comprises 28 days. In some embodiments, the immunomodulatory agent (e.g., lenalidomide) is administered for any of 1, 2, 3, 4, 5, 6, or longer months during the consolidation phase. In some embodiments, the immunomodulatory agent (e.g., lenalidomide) is administered for up to 6 months during the consolidation phase. In some embodiments, the anti-CD20 antibody (e.g., rituximab) is administered beginning in month 1 of the consolidation phase. In some embodiments, the anti-CD20 antibody (e.g., rituximab) is administered on day 1 of each of months 1, 3, and 5 of the consolidation phase.

[0169]

[0175] In some embodiments, the immunomodulatory agent (e.g., lenalidomide) and the anti-CD20 antibody (e.g., obinutuzumab or rituximab) are administered sequentially during the consolidation phase. In some embodiments, the immunomodulatory agent (e.g., lenalidomide) is administered prior to the anti-CD20 antibody (e.g., obinutuzumab or rituximab) during the consolidation phase. In some embodiments, the immunomodulatory agent (e.g., lenalidomide) is administered prior to the anti-CD20 antibody (e.g., obinutuzumab or rituximab) on day 1 of each of months 1, 3, and 5 during the consolidation phase.

[0170]

[0176] Exemplary consolidation phase dosing and administration schedules are shown in Tables M-R below. Tables M-R: Exemplary Consolidation Phase Dosage and Administration Schedules TIFF2024520901000024.tif49170TIFF2024520901000025.tif49170TIFF2024520901000026.tif49170 TIFF2024520901000027.tif49170TIFF2024520901000028.tif49170TIFF2024520901000029.tif49170

[0171] B. Exemplary Treatment Regimens

[0177] Any one of the exemplary induction periods described herein or shown in Tables A-L can be followed by any one of the exemplary potentiation periods described herein or shown in Tables M-R.

[0172]

[0178] In some embodiments, the methods provided herein for treating diffuse large B-cell lymphoma (DLBCL) in an individual, e.g., a human, in need of such treatment include administering to the individual a compound of formula (a) of the formula: TIFF2024520901000030.tif28170 (wherein Ab is an anti-CD79b antibody comprising (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26, and p is between 1 and 8), (b) an immunomodulatory agent, and (c) an anti-CD20 antibody.

[0173]

[0179] In some embodiments, the method for treating diffuse large B-cell lymphoma (DLBCL) in an individual in need thereof, e.g., a human, comprises administering to the individual an effective amount of: (a) Formula: TIFF2024520901000031.tif27170, wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26, and p is between 1 and 8; (b) an immunomodulatory agent; and (c) an anti-CD20 antibody. In some embodiments, p is between 2 and 5. In some embodiments, p is between 3 and 4. In some embodiments, p is 3.4. In some embodiments, p is 3.5. In some embodiments, the anti-CD79b antibody comprises (i) a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 19, and (ii) a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, the anti-CD79b antibody comprises (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 36, and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 35.

[0174]

[0180] In some embodiments, the method for treating diffuse large B-cell lymphoma (DLBCL) in an individual in need thereof, e.g., a human, comprises administering to the individual an effective amount of: (a) a compound of the formula: TIFF2024520901000032.tif27170, (wherein Ab is an anti-CD79b antibody comprising (i) a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 19 and (ii) a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 20, and p is between 2 and 5; (b) an immunomodulatory agent; and (c) an anti-CD20 antibody. In some embodiments, p is between 3 and 4. In some embodiments, p is 3.4. In some embodiments, p is 3.5. In some embodiments, the anti-CD79b antibody comprises (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 36 and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 35.

[0175]

[0181] In some embodiments, the immunoconjugate is administered at a dose of about 1.8 mg / kg, the immunomodulatory agent is administered at a dose between about 10 mg and about 20 mg, and the anti-CD20 antibody is administered at a dose of about 375 mg / m 2 In some embodiments, the immunoconjugate, immunomodulatory agent, and rituximab are administered in 28-day cycles during the induction phase, wherein: the immunoconjugate is administered intravenously on day 1 of each 28-day cycle at a dose of about 1.8 mg / kg, the immunomodulatory agent is administered orally on each of days 1-21 of each 28-day cycle at a dose between about 10 mg and about 20 mg, and the rituximab is administered at a dose of about 375 mg / m 2In some embodiments, the immunomodulatory agent is administered intravenously on day 1 of each 28-day cycle at a dose of about 20 mg. In some embodiments, the induction phase comprises less than one complete 28-day cycle. In some embodiments, the induction phase comprises between one and six (e.g., 1, 2, 3, 4, 5, or 6) 28-day cycles. In some embodiments, the induction phase comprises at least six 28-day cycles. In some embodiments, the induction phase comprises six 28-day cycles. In some embodiments, the immunoconjugate, immunomodulatory agent, and rituximab are administered sequentially. In some embodiments, on day 1 of each 28-day cycle, the immunomodulatory agent is administered prior to rituximab, which is administered prior to the immunoconjugate. In some embodiments, the immunomodulatory agent and rituximab are further administered during the consolidation phase after the sixth 28-day cycle of the induction phase. In some embodiments, the immunomodulatory agent is administered orally at a dose of about 10 mg on each of days 1-21 of each month during the consolidation phase, and rituximab is administered orally at a dose of about 375 mg / m 2on day 1 of every other month during the intensification phase. In some embodiments, the immunomodulatory agent is administered intravenously during the intensification phase for up to 6 months. In some embodiments, rituximab is administered on day 1 of each of months 1, 3, and 5 during the intensification phase. In some embodiments, the immunomodulatory agent and rituximab are administered sequentially during the intensification phase. In some embodiments, the immunomodulatory agent is administered prior to rituximab on day 1 of each of months 1, 3, and 5 during the intensification phase. In some embodiments, a month during the intensification phase comprises 28 days. In some embodiments, the intensification phase begins immediately after the end of the induction phase. In some embodiments, the induction and intensification phases are separated by a time interval. In some embodiments, the intensification phase begins at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks after the end of the induction phase. In some embodiments, the intensification phase begins about 7, about 8, or about 9 weeks after day 1 of the last cycle of the induction phase. In some embodiments, the consolidation phase begins about 8 weeks after day 1 of the last cycle of the induction phase. In some embodiments, the consolidation phase begins about 7, about 8, or about 9 weeks after day 1 of the sixth 28-day cycle of the induction phase. In some embodiments, the consolidation phase begins about 8 weeks after day 1 of the sixth 28-day cycle of the induction phase.

[0176]

[0182] In some embodiments, the immunoconjugate is polatuzumab vedotin. In some embodiments, the immunomodulatory agent is lenalidomide. In some embodiments, the anti-CD20 antibody is rituximab. In some embodiments, polatuzumab vedotin is administered at a dose of about 1.8 mg / kg, lenalidomide is administered at a dose between about 10 mg and about 20 mg, and rituximab is administered at a dose of about 375 mg / m 2In some embodiments, polatuzumab vedotin is administered at a dose of about 1.8 mg / kg intravenously on day 1 of each 28-day cycle, lenalidomide is administered at a dose of between about 10 mg and about 20 mg orally on each of days 1-21 of each 28-day cycle, and rituximab is administered at a dose of about 375 mg / m 2 In some embodiments, polatuzumab vedotin, lenalidomide, and rituximab are administered sequentially. In some embodiments, lenalidomide is administered prior to rituximab, and rituximab is administered prior to polatuzumab vedotin on day 1 of each 28-day cycle. In some embodiments, lenalidomide is administered at a dose of about 20 mg. In some embodiments, the induction phase comprises less than one complete 28-day cycle. In some embodiments, the induction phase comprises between one and six (e.g., 1, 2, 3, 4, 5, or 6) 28-day cycles. In some embodiments, the induction phase comprises at least six 28-day cycles. In some embodiments, the induction phase comprises six 28-day cycles. In some embodiments, polatuzumab vedotin, lenalidomide, and rituximab are administered sequentially. In some embodiments, lenalidomide is administered prior to rituximab, and rituximab is administered prior to polatuzumab vedotin on day 1 of each 28-day cycle. In some embodiments, lenalidomide and rituximab are further administered during the consolidation phase after the sixth 28-day cycle of the induction phase. In some embodiments, lenalidomide is administered orally at a dose of about 10 mg on each of days 1-21 of each month during the consolidation phase, and rituximab is administered orally at a dose of about 375 mg / m on day 1 of every other month during the consolidation phase. 2In some embodiments, lenalidomide is administered intravenously at a dose of 0.01 mg / kg / day. In some embodiments, lenalidomide is administered for up to 6 months during the intensification phase. In some embodiments, rituximab is administered on day 1 of each of months 1, 3, and 5 during the intensification phase. In some embodiments, lenalidomide and rituximab are administered sequentially during the intensification phase. In some embodiments, lenalidomide is administered prior to rituximab on day 1 of each of months 1, 3, and 5 during the intensification phase. In some embodiments, one month during the intensification phase comprises 28 days. In some embodiments, the intensification phase begins immediately after the end of the induction phase. In some embodiments, the induction and intensification phases are separated by a time interval. In some embodiments, the intensification phase begins at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks after the end of the induction phase. In some embodiments, the intensification phase begins about 7, about 8, or about 9 weeks after day 1 of the last cycle of the induction phase. In some embodiments, the consolidation phase begins about 8 weeks after day 1 of the last cycle of the induction phase. In some embodiments, the consolidation phase begins about 7, about 8, or about 9 weeks after day 1 of the sixth 28-day cycle of the induction phase. In some embodiments, the consolidation phase begins about 8 weeks after day 1 of the sixth 28-day cycle of the induction phase.

[0177]

[0183] In some embodiments, a method for treating diffuse large B-cell lymphoma (DLBCL) in an individual in need thereof, e.g., a human, comprises administering to the individual effective amounts of: (a) polatuzumab vedotin, (b) lenalidomide, and (c) rituximab. In some embodiments, polatuzumab vedotin, lenalidomide, and rituximab are administered in 28-day cycles during an induction phase, e.g., an induction phase described herein. In some embodiments, the induction phase comprises less than one complete 28-day cycle. In some embodiments, the induction phase comprises between one and six (e.g., 1, 2, 3, 4, 5, or 6) 28-day cycles. In some embodiments, the induction phase comprises at least six 28-day cycles. In some embodiments, the induction phase comprises six 28-day cycles. In some embodiments, polatuzumab vedotin is administered intravenously at a dose of about 1.8 mg / kg on day 1 of each 28-day cycle, lenalidomide is administered orally at a dose between about 10 mg and about 20 mg on each of days 1-21 of each 28-day cycle, and rituximab is administered orally at a dose of about 375 mg / m 2 In some embodiments, polatuzumab vedotin is administered intravenously at a dose of about 10 mg on day 1 of each 28-day cycle. In some embodiments, lenalidomide is administered at a dose of about 20 mg. In some embodiments, polatuzumab vedotin, lenalidomide, and rituximab are administered sequentially. In some embodiments, lenalidomide precedes rituximab, and rituximab precedes polatuzumab vedotin on day 1 of each 28-day cycle. In some embodiments, the induction phase is followed by a consolidation phase, during which lenalidomide is administered at a dose of about 10 mg and rituximab is administered at a dose of about 375 mg / m 2 In some embodiments, lenalidomide is administered orally at a dose of about 10 mg on each of days 1-21 of each month during the consolidation phase, and rituximab is administered orally at a dose of about 375 mg / m on day 1 of every other month during the consolidation phase. 2In some embodiments, lenalidomide is administered intravenously at a dose of 0.01 mg / kg / day. In some embodiments, lenalidomide is administered for up to 6 months during the intensification phase. In some embodiments, rituximab is administered on day 1 of each of months 1, 3, and 5 during the intensification phase. In some embodiments, lenalidomide and rituximab are administered sequentially during the intensification phase. In some embodiments, lenalidomide is administered prior to rituximab on day 1 of each of months 1, 3, and 5 during the intensification phase. In some embodiments, one month during the intensification phase comprises 28 days. In some embodiments, the intensification phase begins immediately after the end of the induction phase. In some embodiments, the induction and intensification phases are separated by a time interval. In some embodiments, the intensification phase begins at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks after the end of the induction phase. In some embodiments, the intensification phase begins about 7, about 8, or about 9 weeks after day 1 of the last cycle of the induction phase. In some embodiments, the consolidation phase begins about 8 weeks after day 1 of the last cycle of the induction phase. In some embodiments, the consolidation phase begins about 7, about 8, or about 9 weeks after day 1 of the sixth 28-day cycle of the induction phase. In some embodiments, the consolidation phase begins about 8 weeks after day 1 of the sixth 28-day cycle of the induction phase.

[0178] C. Response

[0184] In some embodiments, a human being treated by any of the methods described herein achieves at least stable disease (SD) (e.g., at least SD, at least partial remission (PR), or complete remission (CR)) during or after treatment with the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an immunomodulatory agent (e.g., lenalidomide), and an anti-CD20 antibody (e.g., obinutuzumab or rituximab). In some embodiments, a human being treated by any of the methods described herein achieves at least partial remission (PR) (e.g., at least PR or complete remission (CR)) during or after treatment with the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an immunomodulatory agent (e.g., lenalidomide), and an anti-CD20 antibody (e.g., obinutuzumab or rituximab). In some embodiments, a human treated by any of the methods described herein achieves a complete remission (CR) during or after treatment with the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an immunomodulatory agent (e.g., lenalidomide), and an anti-CD20 antibody (e.g., obinutuzumab or rituximab). In some embodiments, a human treated by any of the methods described herein does not exhibit disease progression within at least about 4 months after initiation of treatment with the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an immunomodulatory agent (e.g., lenalidomide), and an anti-CD20 antibody (e.g., obinutuzumab or rituximab). In some embodiments, humans treated with any of the methods described herein achieve an improved response compared to humans treated with a treatment comprising a single agent, e.g., treatment with only an immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), treatment with only an immunomodulatory agent (e.g., lenalidomide), or treatment with only an anti-CD20 antibody (e.g., obinutuzumab or rituximab).In some embodiments, humans treated with any of the methods described herein achieve an improved response compared to humans treated with a therapy comprising a combination of two immunoconjugates (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) and an immunomodulatory agent (e.g., lenalidomide). In some embodiments, humans treated with any of the methods described herein achieve an improved response compared to humans treated with a therapy comprising a combination of two immunoconjugates (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) and an anti-CD20 antibody (e.g., obinutuzumab or rituximab). In some embodiments, humans treated with any of the methods described herein achieve an improved response compared to humans treated with a therapy comprising a combination of two immunomodulators (e.g., lenalidomide) and an anti-CD20 antibody (e.g., obinutuzumab or rituximab).

[0179]

[0185] In some embodiments, of a plurality of humans treated with any of the methods described herein, at least about 25%, at least about 27%, at least about 29%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the humans achieve stable disease during or after treatment with the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), immunomodulatory agent (e.g., lenalidomide), and anti-CD20 antibody (e.g., obinutuzumab or rituximab).

[0180]

[0186] In some embodiments, of a plurality of humans treated with any of the methods described herein, at least about 25%, at least about 27%, at least about 29%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the humans achieve a partial remission during or after treatment with the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an immunomodulatory agent (e.g., lenalidomide), and an anti-CD20 antibody (e.g., obinutuzumab or rituximab).

[0181]

[0187] In some embodiments, of a plurality of humans treated with any of the methods described herein, at least about 25%, at least about 27%, at least about 29%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the humans achieve a complete remission during or after treatment with the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an immunomodulatory agent (e.g., lenalidomide), and an anti-CD20 antibody (e.g., obinutuzumab or rituximab).

[0182]

[0188] In some embodiments, of a plurality of humans treated with any of the methods described herein, at least about 70%, at least about 74%, at least about 80%, at least about 90%, or 100% of the humans achieve a best overall response during or after treatment with the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an immunomodulatory agent (e.g., lenalidomide), and an anti-CD20 antibody (e.g., obinutuzumab or rituximab).

[0183]

[0189] In some embodiments, of a plurality of humans treated with any of the methods described herein, at least about 30%, at least about 35%, at least about 39%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the humans achieve an objective response during or after treatment with the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an immunomodulatory agent (e.g., lenalidomide), and an anti-CD20 antibody (e.g., obinutuzumab or rituximab).

[0184]

[0190] In some embodiments, of a plurality of humans treated with any of the methods described herein, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the humans achieve a best partial remission during or after treatment with the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an immunomodulatory agent (e.g., lenalidomide), and an anti-CD20 antibody (e.g., obinutuzumab or rituximab).

[0185]

[0191] In some embodiments, of a plurality of humans treated with any of the methods described herein, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the humans achieve a best complete remission during or after treatment with the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an immunomodulatory agent (e.g., lenalidomide), and an anti-CD20 antibody (e.g., obinutuzumab or rituximab).

[0186]

[0192] In some embodiments, the duration of the response (i.e., stable disease response, partial response, complete response, objective response, best overall response, best complete response, or best partial response) is at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, or longer.

[0187]

[0193] In some embodiments, humans treated by any of the methods described herein survive without disease progression for at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, or longer, as assessed from the start of treatment with the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), immunomodulatory agent (e.g., lenalidomide), and anti-CD20 antibody (e.g., obinutuzumab or rituximab).

[0188]

[0194] In some embodiments, among humans treated with any of the methods described herein, the median progression-free survival (PFS) is at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, or longer.

[0189]

[0195] In some embodiments, humans treated by any of the methods described herein survive for at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or longer, as assessed from the start of treatment with the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), immunomodulatory agent (e.g., lenalidomide), and anti-CD20 antibody (e.g., obinutuzumab or rituximab).

[0190]

[0196] In some embodiments, among humans treated with any of the methods described herein, the median overall survival, assessed from the start of treatment with the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), immunomodulatory agent (e.g., lenalidomide), and anti-CD20 antibody (e.g., obinutuzumab or rituximab), is at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or longer.

[0191]

[0197] In some embodiments, treatment with an immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an immunomodulatory agent (e.g., lenalidomide), and an anti-CD20 antibody (e.g., obinutuzumab or rituximab) by any of the methods described herein does not cause tumor lysis syndrome in humans.

[0192]

[0198] In some embodiments, treatment with an immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an immunomodulator (e.g., lenalidomide), and an anti-CD20 antibody (e.g., obinutuzumab or rituximab) by any of the methods described herein does not cause secondary cancers in humans.

[0193]

[0199] In some embodiments, a human treated with an induction phase described herein achieves at least stable disease (SD) (e.g., at least SD, at least partial remission (PR), or complete remission (CR)) during or after treatment with the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), immunomodulator (e.g., lenalidomide), and anti-CD20 antibody (e.g., obinutuzumab or rituximab), e.g., during or after the induction phase, e.g., after less than one 28-day cycle, or after at least one, two, three, four, five, six, or more 28-day cycles. In some embodiments, a human treated with an induction phase described herein achieves at least stable disease (SD) (e.g., at least SD, at least partial remission (PR), or complete remission (CR)) after six 28-day cycles. In some embodiments, a human treated with an induction phase described herein achieves at least a partial response (PR) during or after treatment with an immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an immunomodulator (e.g., lenalidomide), and an anti-CD20 antibody (e.g., obinutuzumab or rituximab), e.g., during or after the induction phase, e.g., after less than one 28-day cycle, or after one, two, three, four, five, six, or more 28-day cycles. In some embodiments, a human treated with an induction phase described herein achieves at least a partial response (PR) after six 28-day cycles. In some embodiments, a human treated with an induction phase described herein achieves a complete remission (CR) during or after treatment with the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an immunomodulator (e.g., lenalidomide), and an anti-CD20 antibody (e.g., obinutuzumab or rituximab), e.g., during or after the induction phase, e.g., after less than one 28-day cycle, or after at least one, two, three, four, five, six, or more 28-day cycles.In some embodiments, humans treated with the induction phases described herein achieve at least a complete remission (CR) after six 28-day cycles. In some embodiments, humans treated with any of the induction phases described herein do not exhibit disease progression within at least about four months after initiation of treatment with the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), immunomodulator (e.g., lenalidomide), and anti-CD20 antibody (e.g., obinutuzumab or rituximab). In some embodiments, humans treated with any of the induction phases described herein achieve an improved response compared to humans treated with a treatment comprising a single agent, e.g., treatment with only an immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), treatment with only an immunomodulatory agent (e.g., lenalidomide), or treatment with only an anti-CD20 antibody (e.g., obinutuzumab or rituximab). In some embodiments, humans treated with any of the induction phases described herein achieve an improved response compared to humans treated with a treatment comprising a combination of two immunoconjugates (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) and an immunomodulatory agent (e.g., lenalidomide). In some embodiments, humans treated with any of the induction phases described herein achieve an improved response compared to humans treated with a therapy comprising a dual combination of an immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin) and an anti-CD20 antibody (e.g., obinutuzumab or rituximab). In some embodiments, humans treated with any of the induction phases described herein achieve an improved response compared to humans treated with a therapy comprising a dual combination of an immunomodulatory agent (e.g., lenalidomide) and an anti-CD20 antibody (e.g., obinutuzumab or rituximab).

[0194]

[0200] In some embodiments, of a plurality of humans treated with any induction phase described herein, at least about 25%, at least about 27%, at least about 29%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the humans achieve stable disease during or after treatment with the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), immunomodulatory agent (e.g., lenalidomide), and anti-CD20 antibody (e.g., obinutuzumab or rituximab), e.g., during or after the induction phase, e.g., after less than one 28-day cycle, or after at least any of one, two, three, four, five, six, or more 28-day cycles. In some embodiments, of humans treated with any of the induction phases described herein, at least about 25%, at least about 27%, at least about 29%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of humans achieve stable disease after six 28-day cycles of treatment with the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), immunomodulatory agent (e.g., lenalidomide), and anti-CD20 antibody (e.g., obinutuzumab or rituximab).

[0195]

[0201] In some embodiments, of a plurality of humans treated with any induction phase described herein, at least about 25%, at least about 27%, at least about 29%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the humans achieve a partial remission during or after treatment with the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), immunomodulatory agent (e.g., lenalidomide), and anti-CD20 antibody (e.g., obinutuzumab or rituximab), e.g., during or after the induction phase, e.g., after less than one 28-day cycle, or after at least any of one, two, three, four, five, six, or more 28-day cycles. In some embodiments, of humans treated with any of the induction phases described herein, at least about 25%, at least about 27%, at least about 29%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of humans achieve a partial remission after six 28-day cycles of treatment with the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an immunomodulatory agent (e.g., lenalidomide), and an anti-CD20 antibody (e.g., obinutuzumab or rituximab).

[0196]

[0202] In some embodiments, of humans treated with any induction phase described herein, at least about 25%, at least about 27%, at least about 29%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of humans achieve a complete remission during or after treatment with the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), immunomodulatory agent (e.g., lenalidomide), and anti-CD20 antibody (e.g., obinutuzumab or rituximab), e.g., during or after the induction phase, e.g., after less than one 28-day cycle, or after at least any of one, two, three, four, five, six, or more 28-day cycles. In some embodiments, of humans treated with any of the induction phases described herein, at least about 25%, at least about 27%, at least about 29%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of humans achieve a complete remission after six 28-day cycles of treatment with the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an immunomodulatory agent (e.g., lenalidomide), and an anti-CD20 antibody (e.g., obinutuzumab or rituximab).

[0197]

[0203] In some embodiments, of a plurality of humans treated with any induction phase described herein, at least about 70%, at least about 74%, at least about 80%, at least about 90%, or 100% of the humans achieve a best overall response during or after treatment with the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), immunomodulatory agent (e.g., lenalidomide), and anti-CD20 antibody (e.g., obinutuzumab or rituximab), e.g., during or after the induction phase, e.g., after less than one 28-day cycle, or after at least any of one, two, three, four, five, six, or more 28-day cycles. In some embodiments, of a plurality of humans treated with any of the induction phases described herein, at least about 70%, at least about 74%, at least about 80%, at least about 90%, or 100% of the humans achieve a best overall response after six 28-day cycles of treatment with the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an immunomodulatory agent (e.g., lenalidomide), and an anti-CD20 antibody (e.g., obinutuzumab or rituximab).

[0198]

[0204] In some embodiments, of a plurality of humans treated with any induction phase described herein, at least about 30%, at least about 35%, at least about 39%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the humans achieve an objective response during or after treatment with the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), immunomodulatory agent (e.g., lenalidomide), and anti-CD20 antibody (e.g., obinutuzumab or rituximab), e.g., during or after the induction phase, e.g., after less than one 28-day cycle, or after at least any of one, two, three, four, five, six, or more 28-day cycles. In some embodiments, of a plurality of humans treated with any of the induction phases described herein, at least about 30%, at least about 35%, at least about 39%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the humans achieve an objective response after six 28-day cycles of treatment with the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an immunomodulatory agent (e.g., lenalidomide), and an anti-CD20 antibody (e.g., obinutuzumab or rituximab).

[0199]

[0205] In some embodiments, of a plurality of humans treated with any induction phase described herein, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the humans achieve a best partial remission during or after treatment with the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), immunomodulatory agent (e.g., lenalidomide), and anti-CD20 antibody (e.g., obinutuzumab or rituximab), e.g., during or after the induction phase, e.g., after less than one 28-day cycle, or after at least any of one, two, three, four, five, six, or more 28-day cycles. In some embodiments, of a plurality of humans treated with any of the induction phases described herein, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the humans achieve a best partial remission after six 28-day cycles of treatment with the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an immunomodulatory agent (e.g., lenalidomide), and an anti-CD20 antibody (e.g., obinutuzumab or rituximab).

[0200]

[0206] In some embodiments, of a plurality of humans treated with any induction phase described herein, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the humans achieve a best complete remission during or after treatment with the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), immunomodulatory agent (e.g., lenalidomide), and anti-CD20 antibody (e.g., obinutuzumab or rituximab), e.g., during or after the induction phase, e.g., after less than one 28-day cycle, or after at least any of one, two, three, four, five, six, or more 28-day cycles. In some embodiments, of humans treated with any of the induction phases described herein, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of humans achieve a best complete remission after six 28-day cycles of treatment with the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an immunomodulatory agent (e.g., lenalidomide), and an anti-CD20 antibody (e.g., obinutuzumab or rituximab).

[0201]

[0207] In some embodiments, the duration of the response (i.e., stable disease response, partial response, complete response, objective response, best overall response, best complete response, or best partial response) is at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, or longer.

[0202]

[0208] In some embodiments, humans treated with any of the induction phases described herein survive without disease progression for at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, or longer, as assessed from the start of treatment with the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), immunomodulatory agent (e.g., lenalidomide), and anti-CD20 antibody (e.g., obinutuzumab or rituximab).

[0203]

[0209] In some embodiments, the median progression-free survival (PFS) among humans treated with any of the induction phases described herein is at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, or longer.

[0204]

[0210] In some embodiments, humans treated with any of the induction phases described herein survive for at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or longer, as assessed from the start of treatment with the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), immunomodulatory agent (e.g., lenalidomide), and anti-CD20 antibody (e.g., obinutuzumab or rituximab).

[0205]

[0211] In some embodiments, among humans treated with any of the induction phases described herein, the median overall survival, assessed from the start of treatment with the immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), immunomodulatory agent (e.g., lenalidomide), and anti-CD20 antibody (e.g., obinutuzumab or rituximab), is at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or longer.

[0206]

[0212] In some embodiments, treatment with an immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an immunomodulator (e.g., lenalidomide), and an anti-CD20 antibody (e.g., obinutuzumab or rituximab) following any of the induction phases described herein does not cause tumor lysis syndrome in humans.

[0207]

[0213] In some embodiments, treatment with an immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin), an immunomodulator (e.g., lenalidomide), and an anti-CD20 antibody (e.g., obinutuzumab or rituximab) following any of the induction phases described herein does not cause secondary cancers in humans.

[0208]

[0214] In some embodiments, response (i.e., stable disease response, partial response, complete response, objective response, best overall response, best complete response, best partial response, survival, progression-free survival, or overall survival) is determined according to the Modified Lugano Response Criteria for Malignant Lymphoma (Cheson et al. (2014) "Recommendations for Initial Evaluation, Staging and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification." J. Clin. Oncol. 32:1-9). In some embodiments, the revised Lugano response criteria include that designation of complete remission (CR) using positron emission tomography and computed tomography (PET-CT) requires morphologically normal bone marrow (if morphology is indeterminate, immunohistochemistry [IHC] must be negative) in humans with bone marrow disorders prior to initiation of treatment with any of the methods described herein. In some embodiments, the revised Lugano response criteria include that designation of partial remission (PR) based on PET-CT requires that CT-based response criteria for CR or PR be met in addition to PET-CT-based response criteria for PR. In some embodiments, therapeutic response is assessed according to the revised Lugano response criteria for malignant lymphoma (Cheson et al. 2014), as described in Example 1 herein.

[0209]

[0215] In some embodiments, complete response according to the revised Lugano response criteria for malignant lymphoma based on positron emission tomography-computed tomography (PET-CT) (Cheson et al. 2014) includes one or all of the following: (i) a score of 1, 2, or 3 on a 5-point scale (5PS) in lymph nodes and extranodal sites, with or without residual masses. In many patients, a score of 3 indicates a favorable prognosis with standard treatment, especially if present at interim scans (e.g., during treatment). However, in clinical trials involving PET that investigate attenuation, it may be preferable to consider a score of 3 as an inadequate response (to avoid undertreatment). Measured major lesions: up to six largest major nodules, nodal masses, and extranodal lesions, selected so that two diameters are clearly measurable. Nodes should preferably be from distinct regions of the body, including the mediastinal and retroperitoneal regions, as appropriate. Nonnodal lesions include solid organs (e.g., liver, spleen, kidneys, and lungs), GI disorders, skin lesions, or those detected by palpation. Nonmeasurable lesions: Any disease not selected as measured; major and truly evaluable disease should be considered unmeasured. These sites include any lymph nodes, nodal masses, and extranodal sites not selected as major or measurable or that do not meet the requirements for measurability but are still considered abnormal, as well as truly evaluable disease (any site of suspected disease that is difficult to quantitatively track by measurement, including pleural effusion, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be confirmed and subsequently imaged). In Waldeyer's ring or extranodal sites (e.g., GI tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum with a complete metabolic response, but should not be higher than the surrounding normal physiologic uptake (e.g., with bone marrow activation as a result of chemotherapy or myeloid growth factors). It is recognized that in Waldeyer's ring or extranodal sites where physiological uptake is high or with activation within the spleen or bone marrow, e.g., by chemotherapy or myeloid colony-stimulating factors, uptake may be greater than in normal mediastinum and / or liver.In such situations, a complete metabolic response can be inferred if uptake at the initial lesion site is no greater than that of surrounding normal tissue, even if the tissue has high physiological uptake; PET 5PS: 1 = no uptake above background; 2 = uptake ≤ mediastinum; 3 = uptake > mediastinum but ≤ liver; 4 = moderate uptake > liver; 5 = uptake significantly higher than liver and / or new lesions; X = new area of ​​uptake unlikely to be related to lymphoma; (ii) no new lesions; and (iii) no evidence of bone marrow FDG-affinity disease. In some embodiments, a complete remission according to the revised Lugano response criteria for malignant lymphoma (Cheson et al. 2014) based on PET-CT is referred to as a complete metabolic response. In some embodiments, a complete response according to the revised Lugano response criteria for malignant lymphoma (Cheson et al. 2014) based on computed tomography (CT) includes all of the following: (i) in lymph nodes and extranodal sites, target nodes / nodal masses must regress to a longest diameter of the lesion (LDi) of ≦1.5 cm; (ii) in lymph nodes and extranodal sites, there is no extranodal site of disease; (iii) there is no non-measurable disease; (iv) organomegaly regresses to normal; (v) there is no new disease; and (vi) there is morphologically normal bone marrow; if indeterminate, there is negative IHC. In some embodiments, a complete response according to the revised Lugano response criteria for malignant lymphoma (Cheson et al. 2014) based on CT is referred to as a radiological complete response. In some embodiments, designation of complete remission using positron emission tomography and computed tomography (PET-CT) requires morphologically normal bone marrow in patients with bone marrow involvement at baseline (if morphology is indeterminate, immunohistochemistry must be negative).

[0210]

[0216] In some embodiments, a stable disease response according to the revised Lugano response criteria for malignant lymphoma (Cheson et al. 2014) based on positron emission tomography-computed tomography (PET-CT) includes one or all of the following: (i) a score of 4 or 5, with no significant change in fluorodeoxyglucose (FDG) uptake from before the start of treatment in the target node / nodal mass, or extranodal lesions; a PET 5-point scale (5PS): 1 = no uptake above background; 2 = uptake ≦ mediastinum; 3 = uptake > mediastinum but ≦ liver; 4 = moderate uptake > liver; 5 = uptake significantly higher than liver and / or new lesions; X = new areas of uptake unlikely to be related to lymphoma; (ii) no new lesions; and (iii) no change from baseline in bone marrow. In some embodiments, a stable disease response according to the revised Lugano response criteria for malignant lymphoma (Cheson et al. 2014) based on PET-CT is referred to as no metabolic response. In some embodiments, a stable disease response according to the revised Lugano CT-based response criteria for malignant lymphoma (Cheson et al. 2014) includes one or all of the following: (i) a <50% reduction from baseline in the sum of the product of the perpendicular diameters (SPD) for up to six major measurable nodal and extranodal sites, with no target nodal / nodal mass or extranodal disease meeting criteria for progressive disease; (ii) no increase consistent with progression in non-measurable disease; (iii) no increase consistent with organomegaly progression; and (iv) no new lesions. In some embodiments, a stable disease response according to the revised Lugano CT-based response criteria for malignant lymphoma (Cheson et al. 2014) is referred to as stable disease.

[0211]

[0217] In some embodiments, partial response according to the modified Lugano response criteria for malignant lymphoma (Cheson et al. 2014) based on positron emission tomography-computed tomography (PET-CT) includes one or all of the following: (i) a score of 4 or 5 with decreased uptake compared to one or more masses of any size or residual masses in lymph nodes and extra-lymph node sites before treatment (during treatment, these findings suggest the disease is responding; at the end of treatment, these findings suggest residual disease); PET 5PS: 1 = no uptake above background; 2 = uptake ≦ mediastinum; 3 = uptake > mediastinum but ≦ liver; 4 = moderate uptake > liver; 5 = uptake significantly higher than liver and / or new lesions; X = new areas of uptake unlikely to be related to lymphoma; (ii) no new lesions; and (iii) in the bone marrow, residual uptake higher than that in normal bone marrow but decreased compared to before treatment (diffuse uptake compatible with responsive changes from chemotherapy is allowed). If persistent focal changes in the bone marrow are present in the setting of a nodal response, further evaluation with MRI or biopsy or interval scans is considered. In some embodiments, a partial response according to the revised Lugano response criteria for malignant lymphoma (Cheson et al. 2014) based on PET-CT is referred to as a metabolic partial response. In some embodiments, partial response according to the revised Lugano response criteria for malignant lymphoma (Cheson et al. 2014) based on computed tomography (CT) includes all of the following: (i) a ≥ 50% reduction in the SPD of up to six measurable target nodes and extranodal sites (when lesions are too small to measure by CT, 5mm x 5mm is assigned as the default value; when lesions are no longer visible, 0 x 0mm is assigned; for nodes > 5mm x 5mm but smaller than normal, the actual measurement is used for calculation); (ii) non-measurable lesions are absent / normal or regressing, but without an increase in non-measurable lesions; (iii) the spleen length must have regressed > 50% beyond normal; and (iv) no new lesions.In some embodiments, a CT-based partial response according to the revised Lugano response criteria for malignant lymphoma (Cheson et al. 2014) is referred to as a partial remission. In some embodiments, a designation of PET-CT-based partial response requires that the CT-based response criteria for complete or partial response be met in addition to the PET-CT-based response criteria for partial response.

[0212]

[0218] In some embodiments, disease progression according to the revised Lugano response criteria for malignant lymphoma (Cheson et al. 2014) based on positron emission tomography-computed tomography (PET-CT) includes one or all of the following: (i) a score of 4 or 5 with increased uptake intensity from pretreatment in individual target nodes / nodal masses and / or new FDG-affinity lesions consistent with lymphoma during or at the end of treatment in extranodal disease; 5PS: 1 = no uptake above background; 2 = uptake ≤ mediastinum; 3 = uptake > mediastinum but ≤ liver; 4 = moderate uptake > liver; 5 = uptake significantly higher than liver and / or new lesions; X = new area of ​​uptake unlikely to be related to lymphoma; (ii) new FDG-affinity foci consistent with lymphoma rather than alternative etiology (e.g., infection, inflammation) when uncertainty regarding the etiology of new lesions, biopsies, or interval scans can be considered; (iii) new or recurrent FDG-affinity foci in the bone marrow. In some embodiments, disease progression according to the revised Lugano response criteria for malignant lymphoma (Cheson et al. 2014) based on PET-CT is referred to as progressive metabolic disease. In some embodiments, disease progression according to the revised Lugano response criteria for malignant lymphoma (Cheson et al. 2014) based on computed tomography (CT) includes at least one of the following: (i) for individual target nodules / nodal masses, the cross-product of LDi and perpendicular diameter (PPD) progression; (ii) for extranodal disease, the individual nodule / lesion is abnormal: LDi > 1.5 cm, and a ≥ 50% increase from the PPD nadir, and an increase in the shortest axis perpendicular to LDi or LDi (SDi) from the nadir, 0.5 cm for lesions ≤ 2 cm, and 1.0 cm for lesions > 2 cm; (iii) in the setting of splenomegaly, the spleen length must have increased > 50% of the range of its preceding increase above baseline (e.g., a 15-cm spleen increases to > 16 cm).(iv) an increase of at least 2 cm from baseline in the absence of preceding splenomegaly; (v) new or recurrent splenomegaly; (vi) new or definite progression of an existing non-measurable lesion; (vi) regrowth of a previously resolved lesion; (vii) a new nodule >1.5 cm in any axis; (viii) a new extranodal site >1.0 cm in any axis; if <1.0 cm in any axis, its presence must be definite and attributable to lymphoma; (ix) a new lesion of evaluable disease of any size definite attributable to lymphoma; (x) a new or recurrent lesion in the bone marrow. In some embodiments, disease progression according to the revised Lugano response criteria for malignant lymphoma based on CT (Cheson et al. 2014) is referred to as progressive disease. In some embodiments, disease progression is determined based on CT scans alone or death from any cause.

[0213]

[0219] In some embodiments, best overall response refers to the best response of complete or partial remission during or after treatment with any of the methods described herein. Thus, a person who achieves best overall response achieved a best response of complete remission (i.e., best complete remission) or partial remission (i.e., best partial remission) during or after treatment with any of the methods described herein. In some embodiments, best complete remission is assessed by the criteria described herein for assessing complete remission. In some embodiments, best partial remission is assessed by the criteria described herein for assessing partial remission.

[0214]

[0220] In some embodiments, an objective response refers to a complete or partial response during or after treatment with any of the methods described herein. Thus, a person who achieves an objective response has achieved a complete or partial response during or after treatment with any of the methods described herein. In some embodiments, an objective response is assessed by the criteria described herein for assessing a complete or partial response.

[0215]

[0221] In some embodiments, the duration of response (i.e., stable disease response, partial response, complete response, objective response, best overall response, best complete response, or best partial response) is assessed from the time of first occurrence of the response (i.e., stable disease response, partial response, complete response, objective response, best overall response, best complete response, or best partial response) to the time of one or all (whichever occurs first) of disease progression or recurrence, initiation of new anti-lymphoma therapy, and / or treatment failure, including death from any cause.

[0216]

[0222] In some embodiments, progression-free survival (PFS) or absence of disease progression is assessed as the time from initiation of treatment with the methods provided herein to the first occurrence of disease progression or recurrence, or death from any cause.

[0217]

[0223] In some embodiments, survival is assessed as the time from initiation of treatment with the methods provided herein to death from any cause, hi some embodiments, overall survival is assessed as the time from initiation of treatment with the methods provided herein to death from any cause.

[0218]

[0224] Further details regarding clinical stages and response criteria for lymphomas, such as DLBCL, can be found in, for example, Van Heertum et al. (2017) Drug Des. Devel. Ther. 11:1719-1728, Cheson et al. (2016) Blood. 128:2489-2496, Cheson et al. (2014) J. Clin. Oncol. 32(27):3059-3067, Barrington et al. (2017) J. Clin. Oncol. 32(27):3048-3058, Gallamini et al. (2014) Haematologica. 99(6):1107-1113, Barrinton et al. al. (2010) Eur. J. Nucl. Med. Mol. Imaging. 37(10):1824-33, Moskwitz (2012) Hematology Am Soc. Hematol. Educ. Program 2012:397-401; and Follows et al. (2014) Br. J. Haematology 166:34-49. The progress of any one of the therapeutic methods provided herein can be monitored by techniques known in the art.

[0219]

[0225] In some embodiments, the human is an adult. In some embodiments, the human has received one therapy for DLBCL prior to initiating treatment with any of the methods described herein. In some embodiments, the human has received at least one therapy for DLBCL prior to initiating treatment with any of the methods described herein. In some embodiments, the human has received at least two therapies for DLBCL prior to initiating treatment with any of the methods described herein. In some embodiments, the human has received a therapy for DLBCL including chemoimmunotherapy including an anti-CD20 antibody prior to initiating treatment with any of the methods described herein. In some embodiments, the human has received a prior bone marrow transplant for DLBCL prior to initiating treatment with any of the methods described herein. In some embodiments, the human has received chimeric antigen receptor (CAR)-T cell therapy for DLBCL prior to initiating treatment with any of the methods described herein. In some embodiments, the human has DLBCL that was refractory to an initial therapy for DLBCL administered to the human prior to initiating treatment with any of the methods described herein. In some embodiments, the human has DLBCL that was refractory to a most recent prior therapy for DLBCL prior to initiation of treatment with any of the methods described herein. In some embodiments, the human has DLBCL that was not refractory to a most recent prior therapy for DLBCL prior to initiation of treatment with any of the methods described herein. In some embodiments, the human has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 prior to initiation of treatment with any of the methods described herein. In some embodiments, the human has Ann Arbor Stage III or IV DLBCL prior to initiation of treatment with any of the methods described herein.In some embodiments, the human has DLBCL with an International Prognostic Index of between 3 and 5 prior to initiation of treatment with any of the methods described herein. In some embodiments, the human has relapsed or refractory DLBCL (R / R DLBCL) prior to initiation of treatment with any of the methods described herein. In some embodiments, the human has bulky mass lesions (e.g., ≥ 7 cm). In some embodiments, the human has DLBCL comprising germinal center B cell (GCB) cells of origin (COO). In some embodiments, the human has DLBCL comprising activated B cell (ABC) cells of origin (COO). In some embodiments, COO is assessed using any suitable method known in the art, such as gene expression profiling (e.g., using microarrays), immunohistochemistry, or digital gene expression profiling (e.g., NanoString). In some embodiments, the human has DLBCL that overexpresses B cell lymphoma 2 (BCL-2). In some embodiments, the human has DLBCL that overexpresses MYC. In some embodiments, the human has a DLBCL that overexpresses MYC and BCL-2 (i.e., a double expressor or DEL). In some embodiments, the human does not have a double expressor DLBCL. In some embodiments, MYC and / or BCL-2 expression is assessed using any suitable method known in the art, such as ELISA, immunoblot, flow cytometry, mass spectrometry, or immunohistochemistry. In some embodiments, the human has an R / R DLBCL after treatment with at least one prior chemoimmunotherapeutic regimen comprising an anti-CD20 antibody (e.g., a monoclonal anti-CD20 antibody) prior to initiation of treatment with any of the methods described herein. In some embodiments, the human has an R / R DLBCL and is not eligible for autologous hematopoietic stem cell transplantation prior to initiation of treatment with any of the methods described herein. In some embodiments, the human has an R / R DLBCL and has experienced disease progression after treatment with high-dose chemotherapy plus autologous hematopoietic stem cell transplantation prior to initiation of treatment with any of the methods described herein.In some embodiments, the human has histologically confirmed CD20-positive B-cell lymphoma prior to initiation of treatment with any of the methods described herein. In some embodiments, the human has fluorodeoxyglucose (FDG)-affinity lymphoma (i.e., PET-positive lymphoma) prior to initiation of treatment with any of the methods described herein. In some embodiments, the human has at least one bidimensionally measurable lesion (e.g., greater than 1.5 cm in its greatest dimension by computed tomography [CT] scan or magnetic resonance imaging [MRI]) prior to initiation of treatment with any of the methods described herein. In some embodiments, the human does not have grade 3b follicular lymphoma prior to initiation of treatment with any of the methods described herein. In some embodiments, the human does not have a history of transformation of indolent disease to DLBCL prior to initiation of treatment with any of the methods described herein. In some embodiments, the human does not have a known CD20-negative status at relapse or progression prior to initiation of treatment with any of the methods described herein. In some embodiments, the human does not have central nervous system lymphoma or leptomeningeal infiltration. In some embodiments, the human has not undergone an allogeneic stem cell transplant (SCT) prior to initiation of treatment with any of the methods described herein. In some embodiments, the human has not completed an autologous SCT within 100 days prior to initiation of treatment with any of the methods described herein. In some embodiments, the human has not had a history of resistance to lenalidomide prior to initiation of treatment with any of the methods described herein. In some embodiments, the human has not had a history of response to lenalidomide treatment for less than 1 year in duration prior to initiation of treatment with any of the methods described herein. In some embodiments, the human has not taken or been administered lenalidomide, fludarabine, or alemtuzumab within 12 months prior to initiation of treatment with any of the methods described herein.In some embodiments, the human has not received or been administered a radioimmunoconjugate within 12 weeks prior to initiating treatment with any of the methods described herein. In some embodiments, the human has not received or been administered a monoclonal antibody or antibody-drug conjugate (ADC) therapy within 5 half-lives or 4 weeks prior to initiating treatment with any of the methods described herein. In some embodiments, the human has not received or has not received radiation therapy, chemotherapy, hormone therapy, or targeted small molecule therapy within 2 weeks prior to initiating treatment with any of the methods described herein. In some embodiments, the human has no clinically significant toxicity (other than alopecia) from a prior therapy that has not resolved to Grade ≦2 (per NCI CTCAE, Version 4.0) prior to initiating treatment with any of the methods described herein. In some embodiments, the human has not taken or been administered a systemic immunosuppressive medication, such as prednisone, azathioprine, methotrexate, thalidomide, or an anti-tumor necrosis factor agent, within two weeks prior to initiating treatment with any of the methods described herein. In some embodiments, the human has no history of a severe allergic or anaphylactic reaction to a humanized or murine monoclonal antibody prior to initiating treatment with any of the methods described herein. In some embodiments, the human has no known sensitivity or allergy to any murine product or component of a rituximab, polatuzumab vedotin, or lenalidomide formulation prior to initiating treatment with any of the methods described herein. In some embodiments, the human has no history of erythema multiforme, a grade ≥ 3 rash, or peeling (blistering) after prior treatment with an immunomodulatory derivative, such as thalidomide or lenalidomide, prior to initiating treatment with any of the methods described herein. In some embodiments, the human does not have an active bacterial, viral, fungal, or other infection prior to the initiation of treatment with any of the methods described herein.In some embodiments, the human is not positive for hepatitis B surface antigen (HBsAg), total hepatitis B core antibody (HBcAb), or hepatitis C virus (HCV) antibody prior to initiation of treatment with any of the methods described herein. In some embodiments, the human has no known history of HIV-positive status prior to initiation of treatment with any of the methods described herein. In some embodiments, the human has not received a vaccination, including a live virus vaccine, prior to initiation of treatment with any of the methods described herein. In some embodiments, the human has no history of progressive multifocal leukoencephalopathy prior to initiation of treatment with any of the methods described herein. In some embodiments, the human has no contraindications to treatment for thromboembolic event (TE) prophylaxis prior to initiation of treatment with any of the methods described herein. In some embodiments, the human does not have grade ≧2 neurological disease prior to initiation of treatment with any of the methods described herein. In some embodiments, the human does not have inadequate hematological function (e.g., hemoglobin <9 g / dL, absolute neutrophil count (ANC) <1.5 x 10 / L, and / or platelet count <75 x 10 / L) prior to initiation of treatment with any of the methods described herein, unless due to an underlying lymphoma. In some embodiments, the human does not have a calculated creatinine clearance (Cockcroft's standard deviation) <50 mL / min prior to initiation of treatment with any of the methods described herein, unless due to an underlying lymphoma. In some embodiments, the human does not have an aspartate aminotransferase (AST) or alanine transaminase (ALT) >2.5× the upper limit of normal (ULN) prior to initiation of treatment with any of the methods described herein, unless the treatment is due to an underlying lymphoma. In some embodiments, the human does not have a serum total bilirubin >1.5× the ULN (or >3× the ULN for humans with Gilbert's disease) prior to initiation of treatment with any of the methods described herein, unless the treatment is due to an underlying lymphoma. In some embodiments, the human does not have an international normalized ratio (INR) or prothrombin time (PT) >1.5× the ULN in the absence of therapeutic anticoagulation therapy prior to initiation of treatment with any of the methods described herein, unless the treatment is due to an underlying lymphoma. In some embodiments, the human has no evidence of significant uncontrolled concomitant illness, including significant cardiovascular disease (e.g., New York Heart Association grade III or IV heart disease, myocardial infarction within the previous 6 months, unstable arrhythmia, or unstable angina), or significant pulmonary disease (e.g., a history of obstructive pulmonary disease or bronchospasm), prior to initiation of treatment with any of the methods described herein. In some embodiments, the human has no other malignancy, except for curatively treated cervical intraepithelial carcinoma, favorable prognosis ductal carcinoma in situ of the breast, basal cell skin cancer or squamous cell skin cancer, stage I melanoma, low-grade and early localized prostate cancer, or a previously treated malignancy that has been in remission without treatment for ≥ 2 years, prior to initiation of treatment with any of the methods described herein. In some embodiments, the human does not have a partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) of >1.5×ULN in the absence of a lupus anticoagulant prior to initiation of treatment with any of the methods described herein, unless due to an underlying lymphoma.

[0220] IV. Immunoconjugates Comprising an Anti-CD79b Antibody and a Drug / Cytotoxic Agent ("Anti-CD79b Immunoconjugates")

[0226] In some embodiments, an anti-CD79b immunoconjugate comprises an anti-CD79b antibody (Ab) that targets a cancer cell (e.g., a diffuse large B-cell lymphoma (DLBCL) cell), a drug moiety (D), and a linker moiety (L) that connects the Ab to D. In some embodiments, the anti-CD79b antibody is linked to the linker moiety (L) through one or more amino acid residues, e.g., lysine and / or cysteine. Some immunoconjugates have the formula Ab-(LD)p, where: (a) Ab is an anti-CD79b antibody that binds to CD79b on the surface of a cancer cell (e.g., a DLBCL cell); (b) L is a linker; (c) D is a cytotoxic agent; and (d) p ranges from 1 to 8.

[0221]

[0227] An exemplary anti-CD79b immunoconjugate has Formula I: (I) Ab-(LD)p wherein p is 1 to about 20 (e.g., 1 to 15, 1 to 10, 1 to 8, 2 to 5, or 3 to 4). In some embodiments, the number of drug moieties that can be conjugated to an anti-CD79b antibody is limited by the number of free cysteine ​​residues. In some embodiments, free cysteine ​​residues are introduced into the antibody amino acid sequence by methods described elsewhere herein. Exemplary anti-CD79b immunoconjugates of Formula I include, but are not limited to, anti-CD79b antibodies containing one, two, three, or four engineered cysteine ​​amino acids (Lyon, R. et al. (2012) Methods in Enzym. 502:123-138). In some embodiments, one or more free cysteine ​​residues are already present in the anti-CD79b antibody without engineering, in which case the existing free cysteine ​​residues can be used to conjugate the anti-CD79b antibody to a drug / cytotoxic agent. In some embodiments, the anti-CD79b antibody is exposed to reducing conditions prior to conjugation of the antibody to a drug / cytotoxic agent to generate one or more free cysteine ​​residues.

[0222] A. Exemplary Linkers

[0228] A "linker" (L) is a bifunctional or multifunctional moiety that can be used to attach one or more drug moieties (D) to an anti-CD79b antibody (Ab) to form an anti-CD79b immunoconjugate of Formula I. In some embodiments, anti-CD79b immunoconjugates can be prepared using a linker with reactive functional groups for covalently binding to a drug and an anti-CD79b antibody. For example, in some embodiments, a cysteine ​​thiol of an anti-CD79b antibody (Ab) can form a bond with a reactive functional group of a linker or a drug-linker intermediate to create an anti-CD79b immunoconjugate.

[0223]

[0229] In one embodiment, the linker has a functionality that can react with a free cysteine ​​present on the anti-CD79b antibody to form a covalent bond. Exemplary reactive functional groups include, but are not limited to, maleimides, haloacetamides, α-haloacetyls, activated esters such as succinimide esters, 4-nitrophenyl esters, pentafluorophenyl esters, tetrafluorophenyl esters, anhydrides, acid chlorides, sulfonyl chlorides, isocyanates, and isothiocyanates. See, for example, Klussman, et al. (2004) Bioconjugate Chemistry 15(4):765-773, page 766 for conjugation methods, and the Examples herein.

[0224]

[0230] In some embodiments, the linker has a functionality that can react with an electrophilic group present on an anti-CD79b antibody. Exemplary electrophilic groups include, but are not limited to, aldehyde and ketone carbonyl groups. In some embodiments, the heteroatom of the reactive functional group of the linker can react with an electrophilic group on an antibody to form a covalent bond to an antibody unit. Exemplary reactive functional groups include, but are not limited to, hydrazine, oxime, amino, hydrazine, thiosemicarbazone, hydrazine carboxylate, and arylhydrazide.

[0225]

[0231] In some embodiments, the linker comprises one or more linker components. Exemplary linker components include, for example, 6-maleimidocaproyl ("MC"), maleimidopropanoyl ("MP"), valine-citrulline ("val-cit" or "vc"), alanine-phenylalanine ("ala-phe"), p-aminobenzyloxycarbonyl ("PAB"), N-succinimidyl 4-(2-pyridylthio)pentanoate ("SPP"), and 4-(maleimidomethyl)cyclohexane-1-carboxylate ("MCC"). A variety of linker components are known in the art, some of which are described below.

[0226]

[0232] In some embodiments, the linker is a "cleavable linker" that facilitates release of the drug. Non-limiting exemplary cleavable linkers include acid-labile linkers (e.g., containing hydrazones), protease-sensitive (e.g., peptidase-sensitive) linkers, photolabile linkers, or disulfide-containing linkers (Chari et al., Cancer Research 52:127-131 (1992); U.S. Pat. No. 5,208,020).

[0227]

[0233] In some embodiments, the linker (L) has the following formula II: TIFF2024520901000033.tif8170, where A is a "stretcher unit" and a is an integer from 0 to 1; W is an "amino acid unit" and w is an integer from 0 to 12; Y is a "spacer unit" and y is 0, 1, or 2; and Ab, D, and p are defined as above for Formula I. Exemplary embodiments of such linkers are described in U.S. Pat. No. 7,498,298, which is expressly incorporated herein by reference.

[0228]

[0234] In some embodiments, a linker component comprises a "stretcher unit" that links the antibody to another linker component or to a drug moiety. Exemplary stretcher units are shown below (the wavy line indicates the site of covalent attachment to an antibody, drug, or additional linker component): TIFF2024520901000034.tif89170

[0229]

[0235] In some embodiments, the linker component comprises an "amino acid unit." In some such embodiments, the amino acid unit allows for cleavage of the linker by a protease, thereby facilitating release of the drug / cytotoxic agent from the anti-CD79b immunoconjugate upon exposure to an intracellular protease, such as a lysosomal enzyme (Doronina et al. (2003) Nat. Biotechnol. 21:778784). Exemplary amino acid units include, but are not limited to, dipeptides, tripeptides, tetrapeptides, and pentapeptides. Exemplary dipeptides include, but are not limited to, valine-citrulline (vc or val-cit), alanine-phenylalanine (af or ala-phe); phenylalanine-lysine (fk or phe-lys); phenylalanine-homolysine (phe-homolys); and N-methyl-valine-citrulline (Me-val-cit). Exemplary tripeptides include, but are not limited to, glycine-valine-citrulline (gly-val-cit) and glycine-glycine-glycine (gly-gly-gly). The amino acid unit may include naturally occurring amino acid residues and / or minor amino acids and / or non-naturally occurring amino acid analogs such as citrulline. The amino acid unit can be designed and optimized for enzymatic cleavage by specific enzymes, such as tumor-associated proteases, cathepsins B, C, and D, or plasmin proteases.

[0230]

[0236] In some embodiments, the linker component comprises a "spacer" unit that links the antibody to the drug moiety directly or through a stretcher unit and / or an amino acid unit. The spacer unit can be "self-immolative" or "non-self-immolative." A "non-self-immolative" spacer unit is one in which some or all of the spacer unit remains attached to the drug moiety upon cleavage of the ADC. Examples of non-self-immolative spacer units include, but are not limited to, a glycine spacer unit and a glycine-glycine spacer unit. In some embodiments, enzymatic cleavage of an ADC containing a glycine-glycine spacer unit by a tumor-cell-associated protease releases the glycine-glycine-drug moiety from the remainder of the ADC. In some such embodiments, the glycine-glycine-drug moiety is subjected to a hydrolysis process in the tumor cell, thus cleaving the glycine-glycine spacer unit from the drug moiety.

[0231]

[0237] A "self-immolative" spacer unit allows for release of the drug moiety. In some embodiments, the spacer unit of the linker comprises a p-aminobenzyl unit. In some such embodiments, p-aminobenzyl alcohol is attached to the amino acid unit via an amide bond, and a carbamate, methylcarbamate, or carbonate is created between the benzyl alcohol and the drug (Hamann et al. (2005) Expert Opin. Ther. Patents (2005) 15:1087-1103). In some embodiments, the spacer unit is p-aminobenzyloxycarbonyl (PAB). In some embodiments, the anti-CD79b immunoconjugate has the following structure: TIFF2024520901000035.tif28170, where Q is -C1-C8 alkyl, -O-(C1-C8 alkyl), -halogen, -nitro, or -cyno; m is an integer ranging from 0 to 4; and p ranges from 1 to about 20. In some embodiments, p ranges from 1 to 10, 1 to 7, 1 to 5, or 1 to 4.

[0232]

[0238] Other examples of self-immolative spacers include, but are not limited to, aromatic compounds electronically similar to the PAB group, such as 2-aminoimidazole-5-methanol derivatives (U.S. Pat. No. 7,375,078; Hay et al. (1999) Bioorg. Med. Chem. Lett. 9:2237) and ortho- or para-aminobenzyl acetals. In some embodiments, spacers that undergo cyclization upon amide bond hydrolysis can be used, such as substituted and unsubstituted 4-aminobutyric acid amides (Rodrigues et al. (1995) Chemistry Biology 2:223), appropriately substituted bicyclo[2.2.1] and bicyclo[2.2.2] ring systems (Storm et al. (1972) J. Amer. Chem. Soc. 94:5815), and 2-aminophenylpropionic acid amides (Amsberry, et al. (1990) J. Org. Chem. 55:5867). Linking a drug to the alpha carbon of a glycine residue is another example of a self-immolative spacer that may be useful in ADCs (Kingsbury et al (1984) J. Med. Chem. 27:1447).

[0233]

[0239] In some embodiments, the linker L can be a dendritic-type linker for covalently attaching more than one drug moiety to an antibody through a branched, multifunctional linker moiety (Sun et al. (2002) Bioorganic & Medicinal Chemistry Letters 12:2213-2215; Sun et al. (2003) Bioorganic & Medicinal Chemistry 11:1761-1768). Dendritic linkers can increase the drug-to-antibody molar ratio, i.e., the loading associated with the potency of the ADC. Thus, even if an antibody possesses only one reactive cysteine ​​thiol group, multiple drug moieties can be attached through the dendritic linker.

[0234]

[0240] Non-limiting exemplary linkers include those represented by Formulae III, IV, V TIFF2024520901000036.tif161170, where (Ab) is an anti-CD79b antibody, (D) is a drug / cytotoxic agent, "Val-Cit" is a valine-citrulline dipeptide, MC is 6-maleimidocaproyl, PAB is p-aminobenzyloxycarbonyl, and p is 1 to about 20 (e.g., 1 to 15, 1 to 10, 1 to 8, 2 to 5, or 3 to 4).

[0235]

[0241] In some embodiments, the anti-CD79b immunoconjugate has the following formulae VI-V: TIFF2024520901000037.tif131170 [wherein X is: TIFF2024520901000038.tif57170, Y is: TIFF2024520901000039.tif16170; each R is independently H or C1-C6 alkyl; and n is 1 to 12.

[0236]

[0242] Typically, peptide-type linkers can be prepared by forming a peptide bond between two or more amino acids and / or peptide fragments. Such peptide bonds can be prepared, for example, by liquid phase synthesis (e.g., E. Schroder and K. Lubke (1965) "The Peptides", volume 1, pp. 76-136, Academic Press).

[0237]

[0243] In some embodiments, the linker is substituted with a group that modulates solubility and / or reactivity. As a non-limiting example, a charged substituent such as sulfonate (—SO 3 —) or ammonium may increase the water solubility of the linker reagent and facilitate the coupling reaction of the linker reagent with an antibody and / or drug moiety, or may facilitate the coupling reaction of an Ab-L (anti-CD79b antibody-linker intermediate) with D, or a DL (drug / cytotoxic agent-linker intermediate) with Ab, depending on the synthetic route used to prepare the anti-CD79b immunoconjugate. In some embodiments, one portion of the linker is attached to the antibody, one portion of the linker is attached to the drug, and then the anti-CD79 Ab-(linker moiety) a is attached to the drug / cytotoxic agent-(linker moiety) b to form the anti-CD79b immunoconjugate of Formula I. In some such embodiments, the anti-CD79b antibody comprises more than one (linker moiety) a substituent such that more than one drug / cytotoxic agent is attached to the anti-CD79b antibody in the anti-CD79b immunoconjugate of Formula I.

[0238]

[0244] The anti-CD79b immunoconjugates provided herein expressly contemplate anti-CD79b immunoconjugates prepared using, but not limited to, the following linker reagents: bis-maleimido-trioxyethylene glycol (BMPEO), N-(β-maleimidopropyloxy)-N-hydroxysuccinimide ester (BMPS), N-(ε-maleimidocaproyloxy)succinimide ester (EMCS), N-[γ-maleimidobutyryloxy]succinimide ester (GMBS), 1,6-hexanediol, ... -bis-vinyl sulfone (HBVS), succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxy-(6-amidocaproate) (LC-SMCC), m-maleimidobenzoyl-N-hydroxysuccinimide ester (MBS), 4-(4-N-maleimidophenyl)butyric acid hydrazide (MPBH), succinimidyl 3-(bromoacetamido)propionate (SBAP), succinimidyl iodoacetate (SIA), succinimidyl (4-iodoacetyl)aminobenzoate (SIA B), N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), N-succinimidyl-4-(2-pyridylthio)pentanoate (SPP), succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), succinimidyl 4-(p-maleimidophenyl)butyrate (SMPB), succinimidyl 6-[(beta-maleimidopropionamido)hexanoate] (SMPH), iminothiolane (IT), sulfo-EMCS, sulfo-GMBS, sulfo- Ho-KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC, and sulfo-SMPB, and succinimidyl-(4-vinylsulfone)benzoate (SVSB), including bismaleimide reagents: dithiobismaleimidoethane (DTME), 1,4-bismaleimidobutane (BMB), 1,4-bismaleimidyl-2,3-dihydroxybutane (BMDB), bismaleimidohexane (BMH), bismaleimidoethane (BMOE), BM(PEG)2 (shown below), and BM(PEG)3 (shown below);Bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCl), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bisazide compounds (such as bis(p-azidobenzoyl)hexanediamine), bisdiazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). In some embodiments, bismaleimide reagents enable attachment of the thiol group of a cysteine ​​in an antibody to a thiol-containing drug moiety, linker, or linker-drug intermediate. Other functional groups reactive with thiol groups include, but are not limited to, iodoacetamide, bromoacetamide, vinylpyridine, disulfide, pyridyl disulfide, isocyanate, and isothiocyanate. TIFF2024520901000040.tif31170

[0239]

[0245] Certain useful linker reagents can be obtained from a variety of commercial sources, e.g., Pierce Biotechnology, Inc. (Rockford, IL), Molecular Biosciences Inc. (Boulder, CO), or can be found in the art; e.g., Toki et al. (2002) J. Org. Chem. 67:1866-1872; Dubowchik, et al. (1997) Tetrahedron Letters, 38:5257-60; Walker, MA (1995) J. Org. Chem. 60:5352-5355; Frisch et al. (1996) Bioconjugate Chem. 7:180-186; U.S. Patent No. 6,214,345; WO 02 / 088172; U.S. Patent Application Publication Nos. 2003130189; 2003096743; WO 03 / 026577; WO 03 / 043583; and WO 04 / 032828.

[0240]

[0246] Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylenetriaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionuclides to antibodies. See, e.g., WO 94 / 11026.

[0241] B. Anti-CD79b antibody

[0247] In some embodiments, an immunoconjugate comprises an anti-CD79b antibody comprising at least one, two, three, four, five, or six HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26. In some such embodiments, the immunoconjugate comprises an anti-CD79b antibody comprising at least one of: (i) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23, and / or (ii) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24. In some embodiments, an immunoconjugate comprises an anti-CD79 antibody comprising at least one of: (i) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23, and / or (ii) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24. In some embodiments, an immunoconjugate comprises an anti-CD79b antibody comprising at least one, at least two, or all three VH HVR sequences selected from: (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; and (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23. In some embodiments, an immunoconjugate comprises an anti-CD79b antibody comprising an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23 and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody comprising an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23, an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26, and an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody comprising: (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; and (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23.

[0242]

[0248] In some embodiments, an immunoconjugate comprises an anti-CD79b antibody comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26. In some embodiments, an immunoconjugate comprises an anti-CD79b antibody comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26. In some embodiments, an immunoconjugate comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody comprising an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody comprising: (a) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24; (b) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (c) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26.

[0243]

[0249] In some embodiments, an immunoconjugate comprises an anti-CD79b antibody comprising: (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22, and (iii) HVR-H3 comprising an amino acid sequence selected from SEQ ID NO: 23, and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25, and (iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26. In some embodiments, an immunoconjugate comprises an anti-CD79b antibody comprising at least one of: (i) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23, and / or (ii) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24.

[0244]

[0250] In some embodiments, the immunoconjugate comprises anti-CD79b comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26. In some embodiments, the immunoconjugate comprises at least one of: HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23, and / or HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24. In some embodiments, the immunoconjugate comprises anti-CD79b comprising: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26.

[0245]

[0251] In some embodiments, the anti-CD79b immunoconjugate comprises a humanized anti-CD79b antibody. In some embodiments, the anti-CD79b antibody comprises an HVR according to any of the embodiments provided herein and further comprises a human acceptor framework, e.g., a human immunoglobulin framework or a human consensus framework. In some embodiments, the human acceptor framework is a human VLkappa 1 (VLKI) framework and / or a VH framework VHIII. In some embodiments, the humanized anti-CD79b antibody comprises (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26. In some embodiments, the humanized anti-CD79b antibody comprises: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26.

[0246]

[0252] In some embodiments, an immunoconjugate (e.g., an anti-CD79b immunoconjugate) comprises an anti-CD79 antibody comprising a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 19. In some embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of SEQ ID NO: 19 contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, yet an anti-CD79b immunoconjugate comprising that sequence retains the ability to bind to CD79b. In some embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 19 have been substituted, inserted, and / or deleted. In some embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 19 have been substituted, inserted, and / or deleted. In some embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., within the FRs). In some embodiments, an immunoconjugate (e.g., an anti-CD79b immunoconjugate) comprises the VH sequence of SEQ ID NO: 19, including post-translational modifications of the sequence. In some embodiments, the VH comprises one, two, or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23.

[0247]

[0253] In some embodiments, an immunoconjugate (e.g., an anti-CD79b immunoconjugate) comprises an anti-CD79b antibody comprising a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 20. In some embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of SEQ ID NO: 20 contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, although an anti-CD79b immunoconjugate comprising that sequence retains the ability to bind to CD79b. In some embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 20. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in SEQ ID NO: 20. In some embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., within the FRs). In some embodiments, an anti-CD79b immunoconjugate comprises an anti-CD79b antibody comprising the VL sequence of SEQ ID NO: 20, including post-translational modifications of that sequence. In some embodiments, the VL comprises one, two, or three HVRs selected from: (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26. In some embodiments, the VL comprises one, two, or three HVRs selected from: (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26.

[0248]

[0254] In some embodiments, an immunoconjugate (e.g., an anti-CD79b immunoconjugate) comprises an anti-CD79b antibody comprising a VH as in any of the embodiments provided herein and a VL as in any of the embodiments provided herein. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody comprising the VH and VL sequences of SEQ ID NO: 19 and SEQ ID NO: 20, respectively, including post-translational modifications of these sequences.

[0249]

[0255] In some embodiments, an immunoconjugate (e.g., an anti-CD79b immunoconjugate) comprises an anti-CD79b antibody that binds to the same epitope as an anti-CD79b antibody described herein. For example, in some embodiments, an immunoconjugate (e.g., an anti-CD79b immunoconjugate) comprises an anti-CD79b antibody that binds to the same epitope as an anti-CD79b antibody comprising the VH sequence of SEQ ID NO: 19 and the VL sequence of SEQ ID NO: 20.

[0250]

[0256] In some embodiments, the immunoconjugate comprises an anti-CD79b antibody that is a monoclonal antibody, a chimeric antibody, a humanized antibody, or a human antibody. In some embodiments, the immunoconjugate comprises an antigen-binding fragment of an anti-CD79b antibody described herein, e.g., an Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment. In some embodiments, the immunoconjugate comprises a substantially full-length anti-CD79b antibody, e.g., an IgG1 antibody or other antibody class or isotype described elsewhere herein.

[0251]

[0257] In some embodiments, an immunoconjugate comprises an anti-CD79b antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 36, and a light chain comprising the amino acid sequence of SEQ ID NO: 35. In some embodiments, an immunoconjugate comprises an anti-CD79 antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 37 and a light chain comprising the amino acid sequence of SEQ ID NO: 35. In some embodiments, an immunoconjugate comprises an anti-CD79 antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 36 and a light chain comprising the amino acid sequence of SEQ ID NO: 38.

[0252]

[0258] In some embodiments, the immunoconjugate is polatuzumab vedotin, as described in WHO Drug Information, Vol. 26, No. 4, 2012 (Proposed INN: List 108), which is incorporated herein by reference in its entirety. As shown in WHO Drug Information, Vol. 26, No. 4, 2012, polatuzumab vedotin has the following structure: immunoglobulin G1-kappa auristatin E conjugate, anti-[Homo sapiens CD79B (immunoglobulin-related CD79 beta)], a humanized monoclonal antibody conjugated to auristatin E; gamma 1 heavy chain (1-447) [humanized VH(Homo sapiens IGHV3-66*01 (79.60%)-(IGHD)-IGHJ4*01) [8.8.13] (1-120)-Homo sapiens IGH1*03 (CH1R 120>K(214)(121-218), hinge(219-233), CH2(234-343), CH3(344-448), CHS(449-450))(121-450)], (220-218')-disulfide (when unconjugated) and kappa light chain (1'-218') [humanized V-KAPPA (Homo sapiens IGKV1-39*01(80.00%)-IGKJ1*01] (1'-112')-homo sapiens IGKC*01(113'-218')], dimeric (226-226":229-229")-bisdisulfide; with an average of 3 to 4 cysteinyls conjugated to monomethyl auristatin E (MMAE) via a cleavable maleimidocaproyl-valyl-citrullinyl-p-aminobenzylcarbamate (mc-val-cit-PABC) linker; the heavy chain of polatuzumab vedotin has the following sequence: EVQLVESGGG LVQPGGSLRL SCAASGYTFS SYWIEWVRQA PGKGLEWIGE 50 ILPGGGDTNY NEIFKGRATF SADTSKNTAY LQMNSLRAED TAVYYCTRRV 100 PIRLDYWGQG TLVTVSSAST KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF 150 PEPVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSVVTVPS SSLGTQTYIC 200 NVNHKPSNTK VDKKVEPKSC DKTHTCPPCP APELLGGPSV FLFPPKPKDT 250 LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYNSTY 300 RVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK GQPREPQVYT 350 LPPSREEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS 400 DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPGK 447 (SEQ ID NO: 56); The light chain of polatuzumab vedotin has the following sequence: DIQLTQSPSS LSASVGDRVT ITCKASQSVD YEGDSFLNWY QQKPGKAPKL 50 LIYAASNLES GVPSRFSGSG SGTDFTLTIS SLQPEDFATY YCQQSNEDPL 100 TFGQGTKVEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKV 150 QWKVDNALQS GNSQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEV 200 THQGLSSPVT KSFNRGEC 218 (SEQ ID NO: 35); The disulfide bridge positions are: Intra-H 22-96 144-200 261-321 367-425 22''-96'' 147''-203'' 261''-321'' 367''-425'' Intra-L 23'-92' 138'-198' 23'''-92''' 138'''-198''' Inter-HL* 220-218' 220''-218''' Inter-HH* 226-226'' 229-229'' *Two or three of the interchain disulfide bridges are absent and the antibody is each conjugated to an average of 3 to 4 drug linkers via thioether bonds; The N-glycosylation site is H CH2N84.4:297, 297″ but lacks carbohydrate; Other post-translational modifications include: lacking the C-terminal lysine of the heavy chain. Thus, in some embodiments, the heavy chain of polatuzumab vedotin has the sequence of SEQ ID NO:36.

[0253] C. Drugs / Cytotoxic Agents

[0259] Anti-CD79 immunoconjugates comprise an anti-CD79b antibody (e.g., an anti-CD79b antibody described herein) conjugated to one or more drugs / cytotoxic agents, such as chemotherapeutic agents or drugs, growth inhibitory agents, toxins (e.g., protein toxins, enzymatically active toxins of bacterial, fungal, plant, or animal origin, or fragments thereof), or radioactive isotopes (i.e., radioconjugates). Such immunoconjugates combine the properties of both antibodies and cytotoxic drugs by targeting potent cytotoxic drugs to antigen-expressing cancer cells (e.g., tumor cells) (Teicher, BA (2009) Current Cancer Drug Targets 9:982-1004), thereby enhancing the therapeutic index by maximizing efficacy and minimizing off-target toxicity (Carter, PJ and Senter PD (2008) The Cancer Jour. 14(3):154-169; Chari, RV (2008) Acc. Chem. Res. 41:98-107). That is, anti-CD79 immunoconjugates are targeted chemotherapeutic molecules that selectively deliver an effective dose of drug to cancerous cells / tissues, thereby achieving greater selectivity, i.e., lower effective doses, while increasing the therapeutic index ("therapeutic window") (Polakis P. (2005) Current Opinion in Pharmacology 5:382-387).

[0254]

[0260] Anti-CD79 immunoconjugates used in the methods provided herein include those with anti-cancer activity. In some embodiments, an anti-CD79 immunoconjugate comprises an anti-CD79b antibody conjugated, i.e., covalently attached, to a drug moiety. In some embodiments, the anti-CD79b antibody is covalently attached to the drug moiety via a linker. The drug moiety (D) of an anti-CD79 immunoconjugate may comprise any compound, moiety, or group having cytotoxic or cytostatic activity. Drug moieties may impart their cytotoxic and cytostatic effects by mechanisms including, but not limited to, tubulin binding, DNA binding or intercalation, and inhibition of RNA polymerase, protein synthesis, and / or topoisomerase. Exemplary drug moieties include, but are not limited to, maytansinoids, dolastatins, auristatins, calicheamicins, anthracyclines, duocarmycins, vinca alkaloids, taxanes, trichothecenes, CC1065, camptothecin, elinafide, and stereoisomers, isosteres, analogs, and derivatives thereof that have cytotoxic activity.

[0255] (i) Maytansine and maytansinoids

[0261] In some embodiments, an anti-CD79b immunoconjugate comprises an anti-CD79b antibody conjugated to one or more maytansinoid molecules. Maytansinoids are derivatives of maytansine, which are mitotic inhibitors that act by inhibiting tubulin polymerization. Maytansine was first isolated from the East African shrub Maytenus serrata (U.S. Pat. No. 3,896,111). Subsequently, it was discovered that certain microorganisms also produce maytansinoids, such as maytansinol and C-3 maytansinol esters (U.S. Pat. No. 4,151,042). Synthetic maytansinoids are described, for example, in U.S. Patent Nos. 4,137,230; 4,248,870; 4,256,746; 4,260,608; 4,265,814; 4,294,757; 4,307,016; 4,308,268; 4,308,269; 4,309,428; and 4,371,533.

[0256]

[0262] Maytansinoid drug moieties are attractive drug moieties in antibody-drug conjugates because they are: (i) relatively easy to prepare by fermentation or chemical modification, or derivatization of fermentation products; (ii) amenable to derivatization with functional groups suitable for conjugation to antibodies through non-disulfide linkers; (iii) stable in plasma; and (iv) effective against a variety of tumor cell lines.

[0257]

[0263] Certain maytansinoids suitable for use as maytansinoid drug moieties are known in the art and can be isolated from natural sources according to known methods or produced using genetic engineering techniques (see, e.g., Yu et al (2002) PNAS 99:7968-7973). Maytansinoids can also be prepared synthetically according to known methods.

[0258]

[0264] Exemplary maytansinoid drug moieties include, but are not limited to, those with modified aromatic rings, such as C-19-dechloro (U.S. Pat. No. 4,256,746) (e.g., prepared by lithium aluminum hydride reduction of ansamytocin P2); C-20-hydroxy (or C-20-demethyl) + / -C-19 dechloro (U.S. Pat. Nos. 4,361,650 and 4,307,016) (e.g., prepared by demethylation using Streptomyces or Actinomyces or dechlorination using LAH); and C-20-demethoxy, C-20-acyloxy (-OCOR), + / -dechloro (U.S. Pat. No. 4,294,757) (e.g., prepared by acylation using acyl chloride), as well as those with modifications at other positions on the aromatic ring.

[0259]

[0265] Representative maytansinoid drug moieties include modifications such as: C-9-SH (U.S. Pat. No. 4,424,219) (prepared, for example, by reaction of maytansinol with H2S or P2S5); C-14-alkoxymethyl (demethoxy / CH2OR) (U.S. Pat. No. 4,331,598); C-14-hydroxymethyl or acyloxymethyl (CH2OH or CHOAc) (U.S. Pat. No. 4,450,254) (prepared, for example, from Nocardia); C-15-hydroxy / acyloxy (U.S. Pat. No. 4,364,866) (prepared, for example, by conversion of maytansinol by Streptomyces); C-15-methoxy (U.S. Pat. Nos. 4,313,946 and 4,315,929) (prepared, for example, from Trewia nudlflora); C-18-N-demethyl (U.S. Pat. Nos. 4,362,663 and 4,322,348) (prepared, for example, by demethylation of maytansinol with Streptomyces); and 4,5-deoxy (U.S. Pat. No. 4,371,533) (prepared, for example, by titanium trichloride / LAH reduction of maytansinol).

[0260]

[0266] Many positions on a maytansinoid compound are useful as attachment positions. For example, an ester bond can be formed by reaction with a hydroxyl group using conventional coupling techniques. In some embodiments, this reaction can occur at the C-3 position, which bears a hydroxyl group, the C-14 position, which is modified with a hydroxymethyl, the C-15 position, which is modified with a hydroxyl group, and the C-20 position, which bears a hydroxyl group. In some embodiments, the bond is formed at the C-3 position of maytansinol or a maytansinol analog.

[0261]

[0267] Maytansinoid drug moieties include those having the following structure: TIFF2024520901000041.tif55170, where the wavy line indicates the covalent attachment of the sulfur atom of the maytansinoid drug moiety to the linker of the anti-CD79b immunoconjugate. Each R can independently be H or C1-C6 alkyl. The alkylene chain connecting the amide group to the sulfur atom can be methanyl, ethanyl, or propyl, i.e., m is 1, 2, or 3 (U.S. Patent Nos. 633,410, 5,208,020; Chari et al. (1992) Cancer Res. 52:127-131; Liu et al. (1996) Proc. Natl. Acad. Sci USA 93:8618-8623).

[0262]

[0268] All stereoisomers of the maytansinoid drug moiety are contemplated for the anti-CD79b immunoconjugates used in the methods provided herein, i.e., any combination of R and S configurations at the chiral carbon (U.S. Pat. Nos. 7,276,497; 6,913,748; 6,441,163; 633,410 (RE39151); 5,208,020; Widdison et al. (2006) J. Med. Chem. 49:4392-4408, which are incorporated by reference in their entireties). In some embodiments, the maytansinoid drug moiety has the following stereochemistry: TIFF2024520901000042.tif48170

[0263]

[0269] Representative embodiments of maytansinoid drug moieties include, but are not limited to, those having the structure: DM1; DM3; and DM4, each having TIFF2024520901000043.tif178170 (where the wavy line indicates the covalent attachment of the sulfur atom of the drug to the linker (L) of the anti-CD79b immunoconjugate).

[0264]

[0270] Other exemplary maytansinoid anti-CD79b immunoconjugates have the following structures and abbreviations, where Ab is an anti-CD79b antibody and p is 1 to about 20. In some embodiments, p is 1 to 10, or p is 1 to 7, or p is 1 to 5, or p is 1 to 4): TIFF2024520901000044.tif156170

[0265]

[0271] An exemplary antibody-drug conjugate in which DM1 is linked to a thiol group of an antibody through a BMPEO linker has the following structure and abbreviation: TIFF2024520901000045.tif60170, where Ab is an anti-CD79b antibody; n is 0, 1, or 2; and p is 1 to about 20. In some embodiments, p is 1 to 10, or p is 1 to 7, or p is 1 to 5, or p is 1 to 4.

[0266]

[0272] Immunoconjugates containing maytansinoids, methods for their preparation, and therapeutic uses are disclosed, for example, in U.S. Patent Nos. 5,208,020 and 5,416,064; U.S. Patent Application Publication No. 2005 / 0276812; and EP 0 425 235 B1, the disclosures of which are expressly incorporated herein by reference. See also Liu et al., Liu et al., Proc. Natl. Acad. Sci. USA 93:8618-8623 (1996); and Chari et al., Cancer Research 52:127-131 (1992).

[0267]

[0273] In some embodiments, anti-CD79b antibody-maytansinoid conjugates can be prepared by chemically linking an anti-CD79b antibody to a maytansinoid molecule without significantly diminishing the biological activity of either the antibody or the maytansinoid molecule. See, e.g., U.S. Pat. No. 5,208,020, the disclosure of which is expressly incorporated herein by reference. In some embodiments, anti-CD79b immunoconjugates conjugated with an average of 3-4 maytansinoid molecules per antibody molecule have demonstrated efficacy in enhancing target cell cytotoxicity without adversely affecting antibody function or solubility. In some cases, even a single molecule of toxin / antibody is expected to enhance cytotoxicity over the use of naked anti-CD79b antibodies.

[0268]

[0274] Exemplary linking groups for producing antibody-maytansinoid conjugates include, for example, those described herein and those disclosed in U.S. Pat. No. 5,208,020; EP 0 425 235 B1; Chari et al. Cancer Research 52:127-131 (1992); U.S. Patent Application Publication Nos. 2005 / 0276812 and 2005 / 016993, the disclosures of which are expressly incorporated herein by reference.

[0269] (2) Auristatins and dolastatins

[0275] Drug moieties include dolastatins, auristatins, and their analogs and derivatives (U.S. Patent Nos. 5,635,483; 5,780,588; 5,767,237; 6,124,431). Auristatins are derivatives of the marine mollusk compound dolastatin-10. Without intending to be bound by any particular theory, dolastatins and auristatins have been shown to interfere with microtubule dynamics, GTP hydrolysis, and nuclear and cellular division (Woyke et al. (2001) Antimicrob. Agents and Chemother. 45(12):3580-3584), and to have anticancer activity (U.S. Patent No. 5,663,149) and antifungal activity (Pettit et al. (1998) Antimicrob. Agents Chemother. 42:2961-2965). Dolastatin / auristatin drug moieties can be attached to antibodies through the N (amino) terminus or the C (carboxyl) terminus of the peptide drug moiety (WO 02 / 088172; Doronina et al (2003) Nature Biotechnology 21(7):778-784; Francisco et al (2003) Blood 102(4):1458-1465).

[0270]

[0276] Representative auristatin embodiments include N-terminally linked monomethyl auristatin drug moieties DE and DF, as disclosed in U.S. Pat. Nos. 7,498,298 and 7,659,241, the disclosures of which are expressly incorporated by reference in their entireties: TIFF2024520901000046.tif62170 [wherein the DE and DF wavy lines indicate the sites of covalent attachment to the antibody or antibody linker moiety, and independently at each position: R 2 is selected from H and C1-C8 alkyl; R 3 is selected from H, C1-C8 alkyl, C3-C8 carbocycle, aryl, C1-C8 alkyl-aryl, C1-C8 alkyl-(C3-C8 carbocycle), C3-C8 heterocycle and C1-C8 alkyl-(C3-C8 heterocycle); R 4is selected from H, C1-C8 alkyl, C3-C8 carbocycle, aryl, C1-C8 alkyl-aryl, C1-C8 alkyl-(C1-C8 carbocycle), C3-C8 heterocycle and C1-C8 alkyl-(C3-C8 heterocycle); R 5 is selected from H and methyl; Or R 4 and R 5 taken together form a carbocycle and have the formula -(CRaRb)n-, where Ra and Rb are independently selected from H, C1-C8 alkyl and C3-C8 carbocycle, and n is selected from 2, 3, 4, 5, and 6; R 6 is selected from H and C1-C8 alkyl; R 7 is selected from H, C1-C8 alkyl, C3-C8 carbocycle, aryl, C1-C8 alkyl-aryl, C1-C8 alkyl-(C3-C8 carbocycle), C3-C8 heterocycle and C1-C8 alkyl-(C3-C8 heterocycle); Each R 8 is independently selected from H, OH, C1-C8 alkyl, C3-C8 carbocycle, and O—(C1-C8 alkyl); R 9 is selected from H and C1-C8 alkyl; R 10 is selected from aryl or a C3-C8 heterocycle; Z is O, S, NH or NR 12 where R 12 is C1-C8 alkyl; R 11 is H, C1-C 20 Alkyl, aryl, C3-C8 heterocycle, -(R 13 O) m -R 14 , or -(R 13 O) m -CH(R 15 )2 is selected; m is an integer ranging from 1 to 1000; R 13 is C2-C8 alkyl; R 14is H or C1-C8 alkyl; R 15 Each occurrence of may independently be H, COOH, -(CH)N(R 16 )2, —(CH2)n—SO3H, or —(CH2)n—SO3—C1-C8 alkyl; R 16 each occurrence is independently H, C-C alkyl, or —(CH)—COOH; R 18 is -C(R 8 )2-C(R 8 )2-aryl, -C(R 8 )2-C(R 8 )2-(C3-C8 heterocycle), and -C(R 8 )2-C(R 8 )2-(C3-C8 carbocyclic ring); and n is an integer ranging from 0 to 6].

[0271]

[0277] In one embodiment, R 3 , R 4 and R 7 are independently isopropyl or sec-butyl, and R 5 is —H or methyl. In an exemplary embodiment, R 3 and R 4 are each isopropyl, and R 5 is -H, and R 7 is sec-butyl.

[0272]

[0278] In yet another embodiment, R 2 and R 6 are each methyl, and R 9 is -H.

[0273]

[0279] In yet another embodiment, R 8 Each occurrence of is -OCH3.

[0274]

[0280] In an exemplary embodiment, R 3 and R 4 are each isopropyl, and R 2 and R6 are each methyl, and R 5 is -H, and R 7 is sec-butyl, and R 8 Each occurrence of is -OCH3 and R 9 is -H.

[0275]

[0281] In one embodiment, Z is —O— or —NH—.

[0276]

[0282] In one embodiment, R 10 is aryl.

[0277]

[0283] In an exemplary embodiment, R 10 is -phenyl.

[0278]

[0284] In an exemplary embodiment, when Z is —O—, R 11 is —H, methyl or t-butyl.

[0279]

[0285] In one embodiment, when Z is —NH, R 11 is -CH(R 15 )2, where R 15 is -(CH2)nN(R 16 )2 and R 16 is -C1-C8 alkyl or -(CH2) n -COOH.

[0280]

[0286] In another embodiment, when Z is -NH, R 11 is -CH(R 15 )2, where R 15 is -(CH2)n-SO3H.

[0281]

[0287] An exemplary auristatin embodiment of formula DE is MMAE, where the wavy line indicates the covalent attachment of the anti-CD79b immunoconjugate to the linker (L): TIFF2024520901000047.tif23170

[0282]

[0288] An exemplary auristatin embodiment of formula DF is MMAF, where the wavy line indicates the covalent attachment of the anti-CD79b immunoconjugate to the linker (L): TIFF2024520901000048.tif23170

[0283]

[0289] Other exemplary embodiments include monomethylvaline compounds with a phenylalanine carboxy modification at the C-terminus of the pentapeptide auristatin drug moiety (WO 2007 / 008848) and monomethylvaline compounds with a phenylalanine side chain modification at the C-terminus of the pentapeptide auristatin drug moiety (WO 2007 / 008603).

[0284]

[0290] Non-limiting exemplary embodiments of anti-CD79b immunoconjugates of Formula I comprising MMAE or MMAF and various linker moieties have the following structures and abbreviations, where "Ab" is an anti-CD79b antibody; p is 1 to about 8; "Val-Cit" is a valine-citrulline dipeptide; and "S" is a sulfur atom: In some embodiments, the anti-CD79b immunoconjugate comprises the structure Ab-MC-vc-PAB-MMAE, where p is, for example, about 1 to about 8; about 2 to about 7; about 3 to about 5; about 3 to about 4; or about 3.5. In some embodiments, the anti-CD79b immunoconjugate is huMA79bv28-MC-vc-PAB-MMAE, e.g., an anti-CD79b immunoconjugate comprising the structure MC-vc-PAB-MMAE, where p is, for example, about 1 to about 8; about 2 to about 7; about 3 to about 5; about 3 to about 4; or about 3.5, and the anti-CD79 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:36 and a light chain comprising the amino acid sequence of SEQ ID NO:35. In some embodiments, the anti-CD79b immunoconjugate is polatuzumab vedotin (CAS number 1313206-42-6), which has IUPHAR / BPS number 8404, KEGG number D10761, INN number 9714, and can also be referred to as "DCDS4501A" or "RG7596."

[0285]

[0291] Non-limiting exemplary embodiments of anti-CD79b immunoconjugates of Formula I comprising MMAF and various linker components further include Ab-MC-PAB-MMAF and Ab-PAB-MMAF. Immunoconjugates having MMAF attached to an antibody by a non-proteolytically cleavable linker have been shown to retain activity comparable to immunoconjugates having MMAF attached to an antibody by a proteolytically cleavable linker (Doronina et al. (2006) Bioconjugate Chem. 17:114-124). In some such embodiments, drug release is believed to result from antibody degradation in cells.

[0286]

[0292] Typically, peptide-based drug moieties can be prepared by forming a peptide bond between two or more amino acids and / or peptide fragments. Such peptide bonds can be prepared, for example, by solution-phase synthesis (see, for example, E. Schroder and K. Lubke, "The Peptides," volume 1, pp. 76-136, 1965, Academic Press). Auristatin / dolastatin drug moieties, in some embodiments, are prepared according to the methods of U.S. Pat. Nos. 7,498,298; 5,635,483; 5,780,588; Pettit et al (1989) J. Am. Chem. Soc. 111:5463-5465; Pettit et al (1998) Anti-Cancer Drug Design 13:243-277; Pettit, G.R., et al. Synthesis, 1996, 719-725; Pettit et al (1996) J. Chem. Soc. Perkin Trans. 1 5:859-863; and Doronina (2003) Nat Biotechnol 21(7):778-784.

[0287]

[0293] In some embodiments, auristatin / dolastatin drug moieties of formula DE, such as MMAE, and formula DF, such as MMAF, and drug-linker intermediates and derivatives thereof, such as MC-MMAF, MC-MMAE, MC-vc-PAB-MMAF, and MC-vc-PAB-MMAE, can be prepared and then conjugated to an antibody of interest using methods described in U.S. Pat. No. 7,498,298; Doronina et al. (2006) Bioconjugate Chem. 17:114124; and Doronina et al. (2003) Nat. Biotech. 21:778-784.

[0288] (3) Calicheamicin

[0294] In some embodiments, an anti-CD79b immunoconjugate comprises an anti-CD79b antibody conjugated to one or more calicheamicin molecules. The calicheamicin family of antibiotics and their analogs can generate double-stranded DNA breaks at sub-picomolar concentrations (Hinman et al., (1993) Cancer Research 53:3336-3342; Lode et al., (1998) Cancer Research 58:2925-2928). Although calicheamicin has an intracellular site of action, in some cases it does not readily cross the plasma membrane. Thus, in some embodiments, cellular uptake of these agents through antibody-mediated internalization can greatly enhance their cytotoxic effects. Non-limiting exemplary methods for preparing anti-CD79b antibody immunoconjugates bearing a calicheamicin drug moiety are described, for example, in U.S. Pat. Nos. 5,712,374; 5,714,586; 5,739,116; and 5,767,285.

[0289] (4) Other drug moieties

[0295] In some embodiments, the anti-CD79b immunoconjugate is geldanamycin (Mandler et al (2000) J. Nat. Cancer Inst. 92(19):1573-1581; Mandler et al (2000) Bioorganic & Med. Chem. Letters 10:1025-1028; Mandler et al (2002) Bioconjugate Chem. 13:786-791); and / or enzymatically active toxins and fragments thereof, including, but not limited to, diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Jatropha curcas proteins, dianthin proteins, pokeweed proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the trichothecenes. See, e.g., WO 93 / 21232.

[0290]

[0296] Drug moieties also include compounds with nucleolytic activity (eg, ribonucleases or DNA endonucleases).

[0291]

[0297] In some embodiments, anti-CD79b immunoconjugates comprise highly radioactive atoms. A variety of radioisotopes are available for the generation of radioconjugated antibodies. Examples include At211, I131, I125, Y90, Re186, Re188, Sm153, Bi212, P32, Pb212, and radioactive isotopes of Lu. In some embodiments, anti-CD79b immunoconjugates, when used for detection, may comprise radioactive atoms for scintigraphic studies, such as Tc99 or I123, or spin labels for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, MRI), such as zirconium-89, iodine-123, iodine-131, indium-111, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese, or iron. Zirconium-89 can be complexed with various metal chelators and conjugated to antibodies, for example for PET imaging (WO 2011 / 056983).

[0292]

[0298] Radiolabels or other labels can be incorporated into anti-CD79b immunoconjugates using known methods. For example, peptides can be biosynthesized or chemically synthesized using appropriate amino acid precursors, e.g., containing one or more fluorine-19 atoms in place of one or more hydrogen atoms. In some embodiments, labels such as Tc99, I123, Re186, Re188, and In111 can be attached via a cysteine ​​residue in an anti-CD79b antibody. In some embodiments, yttrium-90 can be attached via a lysine residue in an anti-CD79b antibody. In some embodiments, iodine-123 can be incorporated using the IODOGEN method (Fraker et al. (1978) Biochem. Biophys. Res. Commun. 80:49-57). "Monoclonal Antibodies in Immunoscintigraphy" (Chatal, CRC Press 1989) describes certain other methods.

[0293]

[0299] In some embodiments, an anti-CD79b immunoconjugate may comprise an anti-CD79b antibody conjugated to a prodrug-activating enzyme. In some such embodiments, the prodrug-activating enzyme converts a prodrug (e.g., a peptidyl chemotherapeutic agent, see WO 81 / 01145) to an active drug, such as an anti-cancer drug. Such immunoconjugates are, in some embodiments, useful in antibody-dependent enzyme-mediated prodrug therapy ("ADEPT"). Enzymes that can be conjugated to an anti-CD79b antibody include, but are not limited to, alkaline phosphatase, useful for converting phosphate-containing prodrugs to free drugs; arylsulfatases, useful for converting sulfate-containing prodrugs to free drugs; cytosine deaminases, useful for converting the non-toxic 5-fluorocytosine to the anti-cancer drug, 5-fluorouracil; and proteases such as Serratia protease, thermolysin, subtilisin, carboxypeptidase, and cathepsins (e.g., cathepsins B and L), useful for converting peptide-containing prodrugs to free drugs. Examples of suitable enzymes include: D-alanylcarboxypeptidases, useful for converting prodrugs containing D-amino acid substituents; carbohydrate-cleaving enzymes such as β-galactosidase and neuraminidase, useful for converting glycosylated prodrugs to free drugs; β-lactamases, useful for converting β-lactam-derivatized drugs to free drugs; and penicillin amidases, such as penicillin V amidase or penicillin G amidase, useful for converting drugs derivatized with a phenoxyacetyl or phenylacetyl group at the amine nitrogen to free drugs, respectively. In some embodiments, enzymes can be covalently attached to the antibody by recombinant DNA techniques well known in the art. See, e.g., Neuberger et al., Nature 312:604-608 (1984).

[0294] D. Drug Load

[0300] Drug loading is represented by p, the average number of drug moieties per anti-CD79b antibody molecule of Formula I. Drug loading can range from 1 to 20 drug moieties (D) per antibody. Anti-CD79b immunoconjugates of Formula I comprise a population of anti-CD79b antibodies conjugated to a range of 1 to 20 drug moieties. The average number of drug moieties per anti-CD79b antibody in preparations of anti-CD79b immunoconjugates from conjugation reactions can be characterized by conventional means, such as mass spectrometry, ELISA assays, and HPLC. The quantitative distribution of anti-CD79b immunoconjugates can also be determined in terms of p. In some cases, separation, purification, and characterization of homogeneous anti-CD79b immunoconjugates with a particular p value from anti-CD79b immunoconjugates with other drug loads can be achieved by reverse-phase HPLC, electrophoresis, or the like.

[0295]

[0301] For some anti-CD79b immunoconjugates, p may be limited by the number of binding sites on the anti-CD79b antibody. For example, when the bond is a cysteine ​​thiol, as in some exemplary embodiments described above, the anti-CD79b antibody can have only one or more cysteine ​​thiol groups or only one or more sufficiently reactive thiol groups through which a linker can be attached. In some embodiments, higher drug loading, e.g., p greater than 5, can cause aggregation, insolubility, toxicity, or loss of cell permeability of certain anti-CD79b immunoconjugates. In some embodiments, the average drug loading of an anti-CD79b immunoconjugate ranges from 1 to about 8; from about 2 to about 6; from about 3 to about 5; or from about 3 to about 4. Indeed, it has been shown that for some antibody-drug conjugates, the optimal ratio of drug moieties per antibody may be less than 8, from about 2 to about 5 (U.S. Patent No. 7,498,298). In some embodiments, the optimal ratio of drug moieties per antibody is about 3 to about 4. In some embodiments, the optimal ratio of drug moieties per antibody is about 3.5.

[0296]

[0302] In some embodiments, fewer than the theoretical maximum number of drug moieties are conjugated to an anti-CD79b antibody during the conjugation reaction. The antibody may contain lysine residues that do not react with, for example, a drug-linker intermediate or linker reagent, as described below. Generally, antibodies do not contain many free and reactive cysteine ​​thiol groups that can be linked to a drug moiety; in fact, most cysteine ​​thiol residues in antibodies exist as disulfide bridges. In some embodiments, an anti-CD79b antibody may be reduced under partial or complete reducing conditions with a reducing agent, such as dithiothreitol (DTT) or tricarbonylethylphosphine (TCEP), to generate reactive cysteine ​​thiol groups. In some embodiments, an anti-CD79b antibody is subjected to denaturing conditions to reveal reactive nucleophilic groups, such as lysine or cysteine.

[0297]

[0303] The loading (drug / antibody ratio) of anti-CD79b immunoconjugates can be controlled in various ways, for example: (i) limiting the molar excess of drug-linker intermediate or linker reagent compared to antibody, (ii) limiting the conjugation reaction time or temperature, and (iii) partial or limited reducing conditions for cysteine ​​thiol modification.

[0298]

[0304] It should be understood that if more than one nucleophilic group reacts with a drug-linker intermediate or linker reagent, the resulting product will be a mixture of anti-CD79b immunoconjugate compounds having a distribution of one or more drug moieties attached to the anti-CD79b antibody. The average number of drugs per antibody can be calculated from the mixture by a double ELISA antibody assay that is specific for the antibody and the drug. Individual anti-CD79b immunoconjugate molecules can be identified in a mixture by mass spectrometry and separated by HPLC, e.g., hydrophobic interaction chromatography (see, e.g., McDonagh et al. (2006) Prot. Engr. Design & Selection 19(7):299-307; Hamblett et al. (2004) Clin. Cancer Res. 10:7063-7070; Hamblett, KJ, et al. “Effect of drug loading on the pharmacology, pharmacokinetics, and toxicity of an anti-CD30 antibody-drug conjugate,” Abstract No. 624, American Association for Cancer Research, 2004 Annual Meeting, March 27-31, 2004, Proceedings of the AACR, Volume 45, March 2004; Alley, SC, et al. “Controlling the location of drug attachment in antibody-drug conjugates,” Abstract No. 627, American Association for Cancer Research, 2004 Annual Meeting, March 27-31, 2004, Proceedings of the AACR, Volume 45, March 2004. In some embodiments, homogenous anti-CD79b immunoconjugates having a single loading value can be isolated from the conjugation mixture by electrophoresis or chromatography.

[0299] E. Method for preparing anti-CD79b immunoconjugates

[0305] Anti-CD79b immunoconjugates of Formula I can be prepared by several routes using organic chemistry reactions, conditions, and reagents known to those skilled in the art, including, but not limited to, (1) reacting a nucleophilic group of an anti-CD79b antibody with a bivalent linker reagent to form Ab-L via a covalent bond, followed by reaction with a drug moiety, D, and (2) reacting a nucleophilic group of a drug moiety with a bivalent linker reagent to form DL via a covalent bond, followed by reaction with a nucleophilic group of an anti-CD79b antibody. An exemplary method for preparing anti-CD79b immunoconjugates of Formula I via the latter route is described in U.S. Patent No. 7,498,298, which is expressly incorporated herein by reference.

[0300]

[0306] Nucleophilic groups on antibodies include, but are not limited to: (i) N-terminal amine groups, (ii) side-chain amine groups, e.g., lysine, (iii) side-chain thiol groups, e.g., cysteine, and (iv) sugar hydroxyl or amino groups on which the antibody is glycosylated. Amine, thiol, and hydroxyl groups are nucleophilic and can react to form covalent bonds with electrophilic groups on linker moieties and linker reagents, including (i) active esters, e.g., NHS esters, HOBt esters, haloformates, and acid halides; (ii) alkyl and benzyl halides, e.g., haloacetamides; and (iii) aldehyde, ketone, carboxyl, and maleimide groups. Some antibodies have reducible interchain disulfides, i.e., cysteine ​​bridges. Anti-CD79b antibodies can be made reactive for conjugation with linker reagents by treatment with a reducing agent, such as DTT (dithiothreitol) or tricarbonylethylphosphine (TCEP), such that the anti-CD79b antibody is fully or partially reduced. Thus, each cysteine ​​bridge would theoretically form two reactive thiol nucleophiles. Additional nucleophilic groups can be introduced into anti-CD79b antibodies through modification of lysine residues, for example, by reacting the lysine residue with 2-iminothiolane (Traut's reagent) to convert the amine to a thiol. Reactive thiol groups can also be introduced into anti-CD79b antibodies by introducing one, two, three, four, or more cysteine ​​residues (e.g., by preparing a mutant antibody containing one or more non-native cysteine ​​amino acid residues).

[0301]

[0307] The anti-CD79b immunoconjugates described herein can also be generated by the reaction between an electrophilic group on an anti-CD79b antibody, such as an aldehyde or ketone carbonyl group, and a nucleophilic group on a linker reagent or drug. Useful nucleophilic groups on a linker reagent include, but are not limited to, hydrazide, oxime, amino, hydrazine, thiosemicarbazone, hydrazine carboxylate, and arylhydrazide. In one embodiment, an anti-CD79b antibody is modified to introduce an electrophilic moiety capable of reacting with a nucleophilic substituent on a linker reagent or drug. In another embodiment, the sugars of a glycosylated anti-CD79b antibody may be oxidized, for example, with a periodate oxidation reagent, to form an aldehyde or ketone group that can react with an amine group on a linker reagent or drug moiety. The resulting imine Schiff base can form a stable bond or can be reduced, for example, with a boron hydroxide reagent, to form a stable amine bond. In one embodiment, reaction of the carbohydrate moiety of a glycosylated anti-CD79b antibody with galactose oxidase or sodium metaperiodate yields carbonyl (aldehyde and ketone) groups on the anti-CD79b antibody that can react with appropriate groups on a drug (Hermanson, Bioconjugate Techniques). In another embodiment, an anti-CD79b antibody containing an N-terminal serine or threonine residue can be reacted with sodium metaperiodate, thereby generating an aldehyde in place of the first amino acid (Geoghegan & Stroh, (1992) Bioconjugate Chem. 3:138-146; U.S. Pat. No. 5,362,852). Such aldehydes can react with a drug moiety or a linker nucleophile.

[0302]

[0308] Exemplary nucleophilic groups on a drug moiety include, but are not limited to, (i) active esters, such as NHS esters, HOBt esters, haloformates, and acid halides; (ii) alkyl and benzyl halides, such as haloacetamides; and (iii) amine, thiol, hydroxyl, hydrazide, oxime, hydrazine, thiosemicarbazone, hydrazine carboxylate, and arylhydrazide groups that can react with electrophilic groups on linker moieties and linker reagents, including aldehyde, ketone, carboxyl, and maleimide groups, to form covalent bonds.

[0303]

[0309] Non-limiting exemplary cross-linking reagents that can be used to prepare anti-CD79b immunoconjugates are described herein in the section entitled "Exemplary Linkers." Methods for using such cross-linking reagents to link two moieties, including proteinaceous and chemical moieties, are known in the art. In some embodiments, a fusion protein comprising an anti-CD79b antibody and a cytotoxic agent can be produced, for example, by recombinant techniques or peptide synthesis. A recombinant DNA molecule can contain a region encoding the antibody and the cytotoxic portion of the conjugate, either adjacent to each other or separated by a region encoding a linker peptide that does not disrupt the desired properties of the conjugate. In yet another embodiment, an anti-CD79b antibody can be conjugated to a "receptor" (such as streptavidin) for use in tumor pretargeting, in which case the antibody-receptor conjugate is administered to a patient, followed by the use of a clearing agent to remove unbound conjugate from the circulation, followed by the administration of a "ligand" (e.g., avidin) conjugated to a cytotoxic agent (e.g., a drug or radionuclide). Further details regarding anti-CD79b immunoconjugates are provided in U.S. Pat. No. 8,545,850 and WO 2016 / 049214, the contents of which are expressly incorporated by reference herein in their entireties.

[0304]

[0310] In some embodiments, provided is a compound of formula: and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26; and p is between 1 and 8; wherein Ab is an anti-CD79b antibody comprising: (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26; and p is between 1 and 8, the method comprising administering to the individual effective amounts of the immunoconjugate, an immunomodulatory agent (e.g., lenalidomide), and an anti-CD20 antibody (e.g., obinutuzumab or rituximab). In some embodiments, the individual achieves at least stable disease (SD) (e.g., at least SD, at least partial response (PR), or complete response (CR)) during or after treatment with the immunoconjugate, an immunomodulatory agent (e.g., lenalidomide), and an anti-CD20 antibody (e.g., obinutuzumab or rituximab). In some embodiments, the immunoconjugate is for use in the methods described herein. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody comprising (i) a VH comprising the amino acid sequence of SEQ ID NO: 19 and (ii) a VL comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, the immunoconjugate is polatuzumab vedotin.

[0305]

[0311] In some embodiments, provided is a compound of formula (I) in the manufacture of a medicament for treating diffuse large B-cell lymphoma (DLBCL), e.g., relapsed / refractory DLBCL, in an individual (human individual) in need thereof. (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26, and p is between 1 and 8, wherein the medicament is for (e.g., for formulation with) an immunomodulatory agent (e.g., lenalidomide) and an anti-CD20 antibody (e.g., obinutuzumab or rituximab). In some embodiments, the individual achieves at least stable disease (SD) (e.g., at least SD, at least partial response (PR), or complete response (CR)) during or after treatment with the medicament, immunomodulatory agent (e.g., lenalidomide), and anti-CD20 antibody (e.g., obinutuzumab or rituximab). In some embodiments, the medicament (i.e., the medicament comprising the immunoconjugate) is for use in the methods described herein. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody comprising (i) a VH comprising the amino acid sequence of SEQ ID NO: 19 and (ii) a VL comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, the immunoconjugate is polatuzumab vedotin.

[0306]

[0312] In some embodiments, provided is a compound of formula: TIFF2024520901000052.tif27170, wherein Ab is an anti-CD79b antibody comprising (i) a VH comprising the amino acid sequence of SEQ ID NO: 19 and (ii) a VL comprising the amino acid sequence of SEQ ID NO: 20, and p is between 2 and 5; the method comprises administering to the individual effective amounts of (a) the immunoconjugate, (b) lenalidomide, and (c) obinutuzumab, wherein the immunoconjugate is administered at a dose of between about 1.4 and about 1.8 mg / kg, the lenalidomide is administered at a dose of between about 10 mg and 20 mg, and the obinutuzumab is administered at a dose of 1000 mg. In some embodiments, the individual achieves at least stable disease (SD) (e.g., at least SD, at least partial response (PR), or complete response (CR)) during or after treatment with the immunoconjugate, lenalidomide, and obinutuzumab. In some embodiments, the immunoconjugate is for use with the methods described herein. In some embodiments, p is between 3 and 4. In some embodiments, p is 3.5. In some embodiments, p is 3.4. In some embodiments, the immunoconjugate In some embodiments, the immunoconjugate comprises an anti-CD79b antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 36, and a light chain comprising the amino acid sequence of SEQ ID NO: 35. In some embodiments, the immunoconjugate comprises an anti-CD79 antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 37 and a light chain comprising the amino acid sequence of SEQ ID NO: 35. In some embodiments, the immunoconjugate comprises an anti-CD79 antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 36 and a light chain comprising the amino acid sequence of SEQ ID NO: 38. In some embodiments, the immunoconjugate is polatuzumab vedotin.

[0307]

[0313] In some embodiments, provided is a compound of formula: TIFF2024520901000053.tif27170, wherein Ab is an anti-CD79b antibody comprising (i) a VH comprising the amino acid sequence of SEQ ID NO: 19 and (ii) a VL comprising the amino acid sequence of SEQ ID NO: 20, and p is between 2 and 5, the method comprising administering to the individual effective amounts of (a) the immunoconjugate, (b) lenalidomide, and (c) rituximab, wherein the immunoconjugate is administered at a dose of between about 1.4 and about 1.8 mg / kg, the lenalido...

Claims

1. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human in need of such treatment, comprising administering to the human effective amounts of an immunoconjugate, an immunomodulatory agent, and an anti-CD20 antibody; The immunoconjugate has the formula: wherein Ab is an anti-CD79b antibody comprising: (i) a hypervariable region H1 (HVR-H1) comprising the amino acid sequence of SEQ ID NO:21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO:22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO:23; (iv) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO:25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26; p is between 1 and 8. having The human achieves at least a complete remission during or after treatment with the immunoconjugate, the immunomodulator, and the anti-CD20 antibody.

2. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human in need of such treatment, in combination with an immunomodulatory agent and an anti-CD20 antibody, comprising: The medicament comprises an effective amount of: formula: wherein Ab is an anti-CD79b antibody comprising: (i) a hypervariable region H1 (HVR-H1) comprising the amino acid sequence of SEQ ID NO:21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO:22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO:23; (iv) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO:25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26; p is between 1 and 8. and an immunoconjugate having the formula: The human achieves at least a complete remission during or after treatment with the immunoconjugate, the immunomodulator, and the anti-CD20 antibody.

3. (a) of the treated humans, at least about 25%, at least about 27%, at least about 29%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the humans achieve complete remission during or after treatment with the immunoconjugate, the immunomodulator, and the anti-CD20 antibody; (b) of the treated humans, at least about 70%, at least about 74%, at least about 80%, at least about 90%, or 100% of the humans achieve a best overall response during or after treatment with the immunoconjugate, the immunomodulatory agent, and the anti-CD20 antibody; (c) of the treated humans, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the humans achieve a best complete remission during or after treatment with the immunoconjugate, the immunomodulatory agent, and the anti-CD20 antibody; (d) of the treated humans, at least about 30%, at least about 35%, at least about 39%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the humans achieve an objective response during or after treatment with the immunoconjugate, the immunomodulatory agent, and the anti-CD20 antibody; (e) the duration of complete remission, best complete remission, objective response, or best overall response, as assessed from the time of first occurrence of the complete remission, best complete remission, objective response, or best overall response, is at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, or longer; (f) the human survives for a period of at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, or longer, without disease progression, as assessed from initiation of treatment with the immunoconjugate, immunomodulatory agent, and anti-CD20 antibody; and / or (g) the human survives for a period of at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or longer, assessed from initiation of treatment with the immunoconjugate, the immunomodulatory agent, and the anti-CD20 antibody. The pharmaceutical composition according to claim 1 or 2. (a) an anti-CD79b antibody comprising (i) a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO:19, and (ii) a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO:20; (b) the anti-CD79b antibody comprises (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 36, and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 35; and / or (c) the immunoconjugate is polatuzumab vedotin; The pharmaceutical composition according to claim 1 or 2.

5. (a) the immunomodulatory agent is lenalidomide; and / or (b) the anti-CD20 antibody is rituximab; The pharmaceutical composition according to claim 1 or 2.

6. The method of claim 1, wherein the immunoconjugate is polatuzumab vedotin administered at a dose of about 1.8 mg / kg, the immunomodulator is lenalidomide administered at a dose of between about 10 mg and about 20 mg, and the anti-CD20 antibody is about 375 mg / m ２ The pharmaceutical composition according to claim 1 or 2, which is rituximab administered at a dose of

7. Polatuzumab vedotin, lenalidomide, and rituximab were administered in 28-day cycles during the induction phase: Polatuzumab vedotin is administered intravenously at a dose of approximately 1.8 mg / kg on day 1 of each 28-day cycle; lenalidomide is administered orally at a dose of between about 10 mg and about 20 mg on each of days 1-21 of each 28-day cycle; Rituximab is approximately 375 mg / m ２ administered intravenously on day 1 of each 28-day cycle at a dose of Optionally, (a) the induction phase comprises at least six 28-day cycles; (b) polatuzumab vedotin, lenalidomide, and rituximab are administered sequentially; and / or (c) lenalidomide is administered prior to rituximab and rituximab is administered prior to polatuzumab vedotin on day 1 of a 28-day cycle; The pharmaceutical composition according to claim 6.

8. (a) of the treated humans, at least about 25%, at least about 27%, at least about 29%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the humans achieve complete remission after six 28-day cycles; (b) of the treated humans, at least about 70%, at least about 74%, at least about 80%, at least about 90%, or 100% of the humans achieve a best overall response after six 28-day cycles; (c) of the treated humans, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the humans achieve a best complete remission after six 28-day cycles; (d) at least about 30%, at least about 35%, at least about 39%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the treated humans achieve an objective response after six 28-day cycles; (e) the duration of complete remission, best complete remission, objective response, or best overall response, as assessed from the time of first occurrence of the complete remission, best complete remission, objective response, or best overall response, is at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, or longer; (f) the human survives for a period of at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, or longer, without disease progression, as assessed from the initiation of treatment with polatuzumab vedotin, lenalidomide, and rituximab; and / or (g) the human survives for a period of at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or longer, as assessed from the initiation of treatment with polatuzumab vedotin, lenalidomide, and rituximab. The pharmaceutical composition according to claim 1 or 2.

9. The pharmaceutical composition of claim 7, wherein lenalidomide and rituximab are further administered during the consolidation phase after the sixth 28-day cycle of the induction phase.

10. lenalidomide is administered orally at a dose of about 10 mg on each of days 1-21 of each month during the consolidation phase; Rituximab at about 375 mg / m ２ to be administered intravenously on the first day of every other month during the consolidation phase at a dose of Optionally, (a) lenalidomide is administered for up to 6 months during the consolidation phase; (b) rituximab is administered on day 1 of each of months 1, 3, and 5 during the consolidation phase; (c) lenalidomide and rituximab are administered sequentially during the consolidation phase; and / or (d) lenalidomide is administered prior to rituximab on day 1 of each of months 1, 3, and 5 during the consolidation phase; The pharmaceutical composition according to claim 9.

11. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human in need of such treatment, comprising administering to the human effective amounts of an immunoconjugate, an immunomodulatory agent, and an anti-CD20 antibody; The immunoconjugate has the formula: wherein Ab is an anti-CD79b antibody comprising: (i) a hypervariable region H1 (HVR-H1) comprising the amino acid sequence of SEQ ID NO:21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO:22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO:23; (iv) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO:25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26; p is between 1 and 8. having The human does not exhibit disease progression within at least about four months after initiation of treatment with the immunoconjugate, the immunomodulator, and the anti-CD20 antibody.

12. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human in need of such treatment, in combination with an immunomodulatory agent and an anti-CD20 antibody, comprising: The medicament comprises an effective amount of a compound of the formula: wherein Ab is an anti-CD79b antibody comprising: (i) a hypervariable region H1 (HVR-H1) comprising the amino acid sequence of SEQ ID NO:21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO:22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO:23; (iv) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO:25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26; p is between 1 and 8. and an immunoconjugate having the formula: The human does not exhibit disease progression within at least about four months after initiation of treatment with the immunoconjugate, the immunomodulator, and the anti-CD20 antibody.

13. (a) of the treated humans, at least about 25%, at least about 27%, at least about 29%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the humans achieve complete remission during or after treatment with the immunoconjugate, the immunomodulator, and the anti-CD20 antibody; (b) of the treated humans, at least about 70%, at least about 74%, at least about 80%, at least about 90%, or 100% of the humans achieve a best overall response during or after treatment with the immunoconjugate, the immunomodulatory agent, and the anti-CD20 antibody; (c) of the treated humans, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the humans achieve a best complete remission during or after treatment with the immunoconjugate, the immunomodulatory agent, and the anti-CD20 antibody; (d) of the treated humans, at least about 30%, at least about 35%, at least about 39%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the humans achieve an objective response during or after treatment with the immunoconjugate, the immunomodulatory agent, and the anti-CD20 antibody; (e) the duration of complete remission, best complete remission, objective response, or best overall response, as assessed from the time of first occurrence of the complete remission, best complete remission, objective response, or best overall response, is at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, or longer; (f) the human survives for a period of at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, or longer, without disease progression, as assessed from initiation of treatment with the immunoconjugate, immunomodulatory agent, and anti-CD20 antibody; and / or (g) the human survives for a period of at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or longer, assessed from initiation of treatment with the immunoconjugate, the immunomodulatory agent, and the anti-CD20 antibody. The pharmaceutical composition according to claim 11 or 12.

14. (a) an anti-CD79b antibody comprising (i) a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO:19, and (ii) a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO:20; (b) the anti-CD79b antibody comprises (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 36, and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 35; and / or (c) the immunoconjugate is polatuzumab vedotin; The pharmaceutical composition according to claim 11 or 12.

15. (a) the immunomodulatory agent is lenalidomide; and / or (b) the anti-CD20 antibody is rituximab; The pharmaceutical composition according to claim 11 or 12.

16. The method of claim 1, wherein the immunoconjugate is polatuzumab vedotin administered at a dose of about 1.8 mg / kg, the immunomodulator is lenalidomide administered at a dose of between about 10 mg and about 20 mg, and the anti-CD20 antibody is about 375 mg / m ２ The pharmaceutical composition according to claim 11 or 12, which is rituximab administered at a dose of

17. Polatuzumab vedotin, lenalidomide, and rituximab were administered in 28-day cycles during the induction phase: Polatuzumab vedotin is administered intravenously at a dose of about 1.8 mg / kg on day 1 of each 28-day cycle; lenalidomide is administered orally at a dose of between about 10 mg and about 20 mg on each of days 1-21 of each 28-day cycle; Rituximab at about 375 mg / m ２ administered intravenously on day 1 of each 28-day cycle at a dose of Optionally, (a) the induction phase comprises at least six 28-day cycles; (b) polatuzumab vedotin, lenalidomide, and rituximab are administered sequentially; and / or (c) lenalidomide is administered prior to rituximab and rituximab is administered prior to polatuzumab vedotin on day 1 of a 28-day cycle; The pharmaceutical composition according to claim 16.

18. (a) of the treated humans, at least about 25%, at least about 27%, at least about 29%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the humans achieve complete remission after six 28-day cycles; (b) of the treated humans, at least about 70%, at least about 74%, at least about 80%, at least about 90%, or 100% of the humans achieve a best overall response after six 28-day cycles; (c) of the treated humans, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of the humans achieve a best complete remission after six 28-day cycles; (d) at least about 30%, at least about 35%, at least about 39%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% of treated humans achieve an objective response after six 28-day cycles; (e) the duration of complete remission, best complete remission, objective response, or best overall response, as assessed from the time of first occurrence of the complete remission, best complete remission, objective response, or best overall response, is at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, or longer; (f) the human survives for a period of at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, or longer, without disease progression, as assessed from the initiation of treatment with polatuzumab vedotin, lenalidomide, and rituximab; and / or (g) the human survives for a period of at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or longer, as assessed from the initiation of treatment with polatuzumab vedotin, lenalidomide, and rituximab. The pharmaceutical composition according to claim 11 or 12.

19. The pharmaceutical composition of claim 17, wherein lenalidomide and rituximab are further administered during the consolidation phase after the sixth 28-day cycle of the induction phase.

20. lenalidomide is administered orally at a dose of about 10 mg on each of days 1-21 of each month during the consolidation phase; Rituximab at about 375 mg / m ２ administered intravenously on the first day of every other month during the consolidation phase at a dose of Optionally, (a) lenalidomide is administered for up to 6 months during the consolidation phase; (b) rituximab is administered on day 1 of each of months 1, 3, and 5 during the consolidation phase; (c) lenalidomide and rituximab are administered sequentially during the consolidation phase; and / or (d) lenalidomide is administered prior to rituximab on day 1 of each of months 1, 3, and 5 during the consolidation phase; The pharmaceutical composition according to claim 19.

21. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human in need of such treatment, comprising administering to the human effective amounts of an immunoconjugate, lenalidomide, and rituximab; The im conjugate has the formula: wherein Ab is an anti-CD79b antibody comprising (i) a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 19, and (ii) a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 20; p is between 2 and 5. having The immunoconjugate is administered at a dose of about 1.8 mg / kg, lenalidomide is administered at a dose between about 10 mg and about 20 mg, and rituximab is administered at a dose of about 375 mg / m ２ is administered at a dose of The medicament, wherein the human achieves at least a complete remission during or after treatment with the immunoconjugate, lenalidomide, and rituximab.

22. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in combination with lenalidomide and rituximab in a human in need of such treatment, comprising: The medicament comprises an effective amount of: formula: wherein Ab is an anti-CD79b antibody comprising (i) a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 19, and (ii) a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 20; and p is between 2 and 5; the immunoconjugate is administered at a dose of about 1.8 mg / kg, lenalidomide is administered at a dose between about 10 mg and about 20 mg, and rituximab is administered at a dose of about 375 mg / m; The medicament, wherein the human achieves at least a complete remission during or after treatment with the immunoconjugate, lenalidomide, and rituximab.

23. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human in need of such treatment, comprising: Effective amounts of polatuzumab vedotin, lenalidomide, and rituximab are administered to a human in 28-day cycles during an induction phase; During the induction phase, polatuzumab vedotin is administered at a dose of about 1.8 mg / kg, lenalidomide is administered at a dose of about 20 mg, and rituximab is administered at a dose of about 375 mg / m ２ is administered at a dose of The human achieves a complete remission during or after the induction period. Medicine.

24. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human in need of such treatment, in combination with lenalidomide and rituximab, comprising: the medicament comprising an effective amount of polatuzumab vedotin; Polatuzumab vedotin, lenalidomide, and rituximab are administered to humans in 28-day cycles during the induction phase; During the induction phase, polatuzumab vedotin is administered at a dose of about 1.8 mg / kg, lenalidomide is administered at a dose of about 20 mg, and rituximab is administered at a dose of about 375 mg / m 2 ; The human achieves a complete remission during or after the induction period. Medicine.

25. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a plurality of humans in need of such treatment, comprising administering to the humans effective amounts of polatuzumab vedotin, lenalidomide, and rituximab in 28-day cycles during an induction phase; During the induction phase, polatuzumab vedotin is administered at a dose of about 1.8 mg / kg, lenalidomide is administered at a dose of about 20 mg, and rituximab is administered at a dose of about 375 mg / m ２ is administered at a dose of At least about 25% of the people achieve a complete remission during or after the induction phase; Medicine.

26. A pharmaceutical agent for treating diffuse large B-cell lymphoma (DLBCL) in a plurality of humans in need of such treatment, comprising: the medicament comprising an effective amount of polatuzumab vedotin; Polatuzumab vedotin, lenalidomide, and rituximab are administered to humans in 28-day cycles during the induction phase; During the induction phase, polatuzumab vedotin is administered at a dose of about 1.8 mg / kg, lenalidomide is administered at a dose of about 20 mg, and rituximab is administered at a dose of about 375 mg / m 2 ; At least about 25% of the people achieve a complete remission during or after the induction phase; Medicine.

27. (a) the human, or a human among said plurality of humans, has undergone at least one prior therapy for DLBCL; (b) the human, or a human among said plurality of humans, has undergone at least two prior therapies for DLBCL; (c) the human, or a human among the plurality of humans, has undergone a prior therapy for DLBCL, including chemoimmunotherapy involving an anti-CD20 antibody; (d) the human, or a human among the plurality of humans, has had a prior bone marrow transplant for DLBCL; (e) the human, or a human among the plurality of humans, has received a prior chimeric antigen receptor (CAR)-T cell therapy for DLBCL; (f) the human, or a human among said plurality of humans, has DLBCL that was refractory to a first, prior treatment for DLBCL; (g) the human, or a human among said plurality of humans, has DLBCL that was resistant to a most recent prior therapy for DLBCL; (h) the DLBCL is relapsed / refractory DLBCL; (i) the DLBCL is relapsed / refractory DLBCL following treatment with at least one prior chemoimmunotherapeutic regimen comprising an anti-CD20 antibody; (j) the human, or a human among said plurality of humans, has experienced disease progression following treatment with high-dose chemotherapy and autologous hematopoietic stem cell transplant; (k) the DLBCL is CD20-positive DLBCL; (l) DLBCL is a positron emission tomography (PET) positive lymphoma; (m) the human, or a human among said plurality of humans, is not eligible for autologous hematopoietic stem cell transplant; (n) the human, or a human among said plurality of humans, does not have central nervous system (CNS) lymphoma or leptomeningeal involvement; (o) the human, or a human of said plurality of humans, has at least one bidimensionally measurable lesion, optionally with at least one bidimensionally measurable lesion greater than 1.5 cm in its greatest dimension, as assessed by computed tomography (CT) scan or magnetic resonance imaging (MRI); (p) the human, or a human among the plurality of humans, has not undergone a prior allogeneic hematopoietic stem cell transplant (SCT); (q) the human, or a human among said plurality of humans, has no prior history of transformation of indolent disease to DLBCL; (r) the human, or a human among said plurality of humans, does not have Grade 2 or greater nervous system disease; (s) the human, or a human among said plurality of humans, has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2; (t) the human, or a human among said plurality of humans, has Ann Arbor stage III or IV DLBCL; and / or (u) the human, or a human among the plurality of humans, has DLBCL with an International Prognostic Index between 3 and 5; The pharmaceutical composition according to any one of claims 1, 2, 11, 12, or 21-26.

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