Methods of Use of Anti-CD79b Immunoconjugates

Abstract

Provided herein are methods of treating B-cell proliferative disorders (such as follicular lymphoma and diffuse large B-cell lymphoma) using immunoconjugates comprising an anti-CD79b antibody in combination with a Bcl-2 inhibitor (such as venetoclax) and an anti-CD20 antibody (such as obinutuzumab or rituximab).

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 015,447, filed April 24, 2020, U.S. Provisional Patent Application No. 63 / 024,322, filed May 13, 2020, U.S. Provisional Patent Application No. 63 / 037,591, filed June 10, 2020, U.S. Provisional Patent Application No. 63 / 108,806, filed November 2, 2020, and U.S. Provisional Patent Application No. 63 / 120,684, filed December 2, 2020, each of which is incorporated by reference herein in its entirety.

[0002] Submitting a sequence listing as an ASCII text file The contents of the following submission regarding ASCII text files are incorporated herein by reference in their entirety: Computer Readable Format (CRF) of Sequence Listing (Filename: 146392050840 SEQLIST.TXT, Date Registered: April 20, 2021, Size: 63KB).

[0003] FIELD OF THE INVENTION The present disclosure relates to methods of treating B-cell proliferative disorders, such as follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), by administering an immunoconjugate comprising an anti-CD79b antibody in combination with a Bcl-2 inhibitor (e.g., venetoclax) and an anti-CD20 antibody (e.g., obinutuzumab or rituximab). [Background technology]

[0004] Background of the Invention Non-Hodgkin's lymphoma (NHL) is the most common hematologic malignancy in adults. NHL is most often of B-cell origin. It includes a variety of different subtypes of B-cell lymphoma, which are broadly divided into indolent and aggressive lymphomas, each with its own unique characteristics.

[0005] Follicular lymphoma (FL) is the most common subtype of indolent B-cell lymphoma, accounting for approximately 22% of all newly diagnosed cases of B-cell lymphoma (Armitage et al. (1998) [New approach to classifying non-Hodgkin's lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification Project.] J Clin Oncol. 16:2780-95). Approximately 90% of all cases harbor the t(14:18) translocation, which juxtaposes BCL2 with the IgH locus, resulting in deregulated Bcl-2 expression. FL remains incurable with currently available therapies. The addition of the anti-CD20 monoclonal antibody rituximab to commonly used induction chemotherapy regimens, including CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone or prednisone), CVP (cyclophosphamide, vincristine, and prednisone), fludarabine, or bendamustine (Zelenetz et al. (2014). "Non-Hodgkin's lymphoma, Version 2. 2014." J Natl Compr Canc Netw. 12:916-46; Dreyling et al. (2014). "Newly diagnosed and relapsed follicular lymphoma: ESMO clinical recommendations for diagnosis, treatment, and follow-up." Ann Oncol. 25:iii76-82), followed by rituximab maintenance therapy, has resulted in long-term remissions and improved patient outcomes (Alles et al. (2013). "Updated 6-year follow-up of the PRIMA study confirms the benefit of 2-year rituximab maintenance in follicular lymphoma patients responding to frontline immunochemotherapy.”Blood.Abstract 509).However, despite significant therapeutic progress with first-line chemoimmunotherapy, most patients ultimately relapse. Relapse is characterized by increased refractoriness and a decreased duration of response to subsequent lines of therapy. Therefore, FL remains a disease with a high unmet medical need.

[0006] Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive NHL; it accounts for approximately 30% of all NHL diagnosed each year (Armitage and Weisenburger 1998). The use of immunochemotherapy, most commonly rituximab plus CHOP (R-CHOP), for newly diagnosed DLBCL has resulted in significant improvements in survival in patients of all age groups (Pfreundschuh et al. 2011; Coiffier et al. 2010). However, nearly 40% of patients with DLBCL will ultimately die from relapsed disease or disease that is refractory to first-line therapy. Patients with a high-risk International Prognostic Index (IPI) have a 5-year PFS rate of 40% after treatment with R-CHOP (Zhou et al. 2014). Second-line treatments include high-dose chemotherapy regimens, such as rituximab plus ifosfamide, carboplatin, and etoposide, or rituximab plus cisplatin, cytosine arabinoside, and dexamethasone, followed by autologous stem cell transplantation (SCT). Approximately half of patients do not achieve complete remission after salvage treatment (Gisselbrecht et al., 2010). Furthermore, elderly patients or those with comorbidities are often considered ineligible for this aggressive treatment. Therefore, DLBCL remains a disease with a high unmet medical need.

[0007] Thus, there is a need in the art for new treatments to provide additional therapeutic options and improve outcomes for patients with non-Hodgkin's lymphoma (NHL), such as those with FL and DLBCL.

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

[0009] overview

[0010] In some aspects, provided herein are methods for treating follicular lymphoma (FL) in a human in need thereof, comprising administering to the human an effective amount of Formula (a) (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 1 to 8. A method is provided comprising administering to a human a complete response (CR) during or after administration of the immunoconjugate, (b) a selective Bcl-2 inhibitor, or a pharmaceutically acceptable salt thereof, and (c) an anti-CD20 antibody, 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 1 to 8. In some embodiments, p is 3 to 4, or 2 to 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. In some embodiments, the immunoconjugate is polatuzumab vedotin-piiq. In some embodiments, the selective Bcl-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof. In some embodiments, polatuzumab vedotin-piiq is administered at a dose of about 1.8 mg / kg, and venetoclax or a pharmaceutically acceptable salt thereof is administered at a dose of about 800 mg. In some embodiments, the anti-CD20 antibody is rituximab. In some embodiments, the anti-CD20 antibody is obinutuzumab. In some embodiments, polatuzumab vedotin-piiq is administered at a dose of about 1.8 mg / kg, venetoclax or a pharmaceutically acceptable salt thereof is administered at a dose of about 800 mg, and obinutuzumab is administered at a dose of about 1000 mg.In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to a plurality of humans results in a complete response in at least about 55%, at least about 57%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans during or after administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab. In some embodiments, the duration of the complete response is at least about 1 month, at least about 2 months, at least about 3 months, or longer. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to a plurality of humans results in an objective response in at least about 87%, at least about 90%, at least about 95%, or 100% of the humans during or after administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to a plurality of humans results in an objective response in at least about 70%, at least about 75%, at least about 78%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans during or after administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab does not result in Grade 3 or higher peripheral neuropathy in humans. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab does not result in tumor lysis syndrome in humans.In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to a plurality of humans results in Grade 3 or Grade 4 adverse events in about 64% or less of the humans. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to a plurality of humans results in Grade 3 or Grade 4 adverse events in about 59% or less of the humans. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to a plurality of humans results in Grade 3 or Grade 4 adverse events in about 73% or less of the humans. In some embodiments, polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab are administered during an induction phase, which optionally includes at least six 21-day cycles. In some embodiments, (i) on day 1 of the first 21-day cycle, polatuzumab vedotin-piiq is administered intravenously at a dose of about 1.8 mg / kg; on days 1-21 of the first 21-day cycle, venetoclax or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 800 mg; and on days 1, 8, and 15 of the first 21-day cycle, obinutuzumab is administered intravenously at a dose of about 1000 mg; and (ii) on days 2, 3, 4, 5, and 6 of the first 21-day cycle, polatuzumab vedotin-piiq is administered intravenously at a dose of about 1.8 mg / kg; on days 1-21 of the first 21-day cycle, venetoclax or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 800 mg; and on days 1, 8, and 15 of the first 21-day cycle, obinutuzumab is administered intravenously at a dose of about 1000 mg. On day 1 of each of the first and sixth 21-day cycles, polatuzumab vedotin-piiq is administered intravenously at a dose of about 1.8 mg / kg, on days 1-21 of each of the second, third, fourth, fifth, and sixth 21-day cycles, venetoclax or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 800 mg, and on day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, obinutuzumab is administered intravenously at a dose of about 1000 mg. In some embodiments, polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab are administered consecutively during the induction phase.In some embodiments, (i) on day 1 of a first 21-day cycle, venetoclax or a pharmaceutically acceptable salt thereof is administered before obinutuzumab, and obinutuzumab is administered before polatuzumab vedotin-piiq, and on days 8 and 15 of the first 21-day cycle, venetoclax or a pharmaceutically acceptable salt thereof is administered before obinutuzumab; (ii) on day 1 of each of a second, third, fourth, fifth, and sixth 21-day cycles, venetoclax or a pharmaceutically acceptable salt thereof is administered before obinutuzumab, and obinutuzumab is administered before polatuzumab vedotin-piiq. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab results in a complete response in humans after six 21-day cycles. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to a plurality of humans results in a complete response in at least about 55%, at least about 57%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans after six 21-day cycles. In some embodiments, the duration of the complete response is at least about 1 month, at least about 2 months, at least about 3 months, or longer. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to a plurality of humans results in an objective response in at least about 87%, at least about 90%, at least about 95%, or 100% of the humans after six 21-day cycles. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to multiple humans results in an objective response in at least about 70%, at least about 75%, at least about 78%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans after six 21-day cycles.In some embodiments, venetoclax or a pharmaceutically acceptable salt thereof and obinutuzumab are further administered during the maintenance phase after the sixth 21-day cycle of the induction phase, wherein venetoclax or a pharmaceutically acceptable salt thereof is administered orally once daily at a dose of about 800 mg during the maintenance phase, and obinutuzumab is administered intravenously once every two months at a dose of about 1000 mg during the maintenance phase. In some embodiments, venetoclax or a pharmaceutically acceptable salt thereof is administered for up to 8 months during the maintenance phase. In some embodiments, obinutuzumab is administered during the maintenance phase starting on day 1 of the second month after the sixth 21-day cycle of the induction phase. In some embodiments, obinutuzumab is administered for up to 24 months during the maintenance phase. In some embodiments, venetoclax or a pharmaceutically acceptable salt thereof and obinutuzumab are administered continuously during the maintenance phase. In some embodiments, venetoclax or a pharmaceutically acceptable salt thereof is administered before obinutuzumab on day 1 of each of months 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24 during the maintenance phase. In some embodiments, the anti-CD79b antibody comprises 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 anti-CD79b 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: 38. In some embodiments, the immunoconjugate is iradatuzumab vedotin.

[0010] In another aspect, provided herein is a method for treating follicular lymphoma (FL) in a human in need thereof, comprising administering to the human an effective amount of Formula (a) (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 1 to 8. Methods are provided that include administering to a subject an immunoconjugate 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 1 to 8; (b) venetoclax or a pharmaceutically acceptable salt thereof at a dose of about 800 mg; and (c) obinutuzumab at a dose of about 1000 mg. In some embodiments, administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to a plurality of humans results in a complete response in at least about 55%, at least about 57%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans during or after administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab. In some embodiments, the duration of the complete response is at least about 1 month, at least about 2 months, at least about 3 months, or longer. In some embodiments, administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to a plurality of humans results in an objective response in at least about 87%, at least about 90%, at least about 95%, or 100% of the humans during or after administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab.In some embodiments, administration of an immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to a plurality of humans results in an objective response in at least about 70%, at least about 75%, at least about 78%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans during or after administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab. In some embodiments, administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab does not result in Grade 3 or higher peripheral neuropathy in the human. In some embodiments, administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab does not result in tumor lysis syndrome in the human. In some embodiments, administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to multiple humans results in Grade 3 or Grade 4 adverse events in about 64% or less of the humans. In some embodiments, administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to multiple humans results in Grade 3 or Grade 4 adverse events in about 59% or less of the humans. In some embodiments, administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to multiple humans results in Grade 3 or Grade 4 adverse events in about 73% or less of the humans. In some embodiments, p is 3 to 4, or 2 to 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. In some embodiments, the immunoconjugate is polatuzumab vedotin-piiq.In some embodiments, polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab are administered during an induction phase, which optionally includes at least six 21-day cycles. In some embodiments, (i) on day 1 of the first 21-day cycle, polatuzumab vedotin-piiq is administered intravenously at a dose of about 1.8 mg / kg; on days 1-21 of the first 21-day cycle, venetoclax or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 800 mg; and on days 1, 8, and 15 of the first 21-day cycle, obinutuzumab is administered intravenously at a dose of about 1000 mg; and (ii) on days 2, 3, 4, 5, and 6 of the first 21-day cycle, polatuzumab vedotin-piiq is administered intravenously at a dose of about 1.8 mg / kg; on days 1-21 of the first 21-day cycle, venetoclax or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 800 mg; and on days 1, 8, and 15 of the first 21-day cycle, obinutuzumab is administered intravenously at a dose of about 1000 mg. On day 1 of each of the first and sixth 21-day cycles, polatuzumab vedotin-piiq is administered intravenously at a dose of about 1.8 mg / kg, on days 1-21 of each of the second, third, fourth, fifth, and sixth 21-day cycles, venetoclax or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 800 mg, and on day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, obinutuzumab is administered intravenously at a dose of about 1000 mg. In some embodiments, polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab are administered consecutively during the induction phase. In some embodiments, (i) on day 1 of a first 21-day cycle, venetoclax or a pharmaceutically acceptable salt thereof is administered before obinutuzumab, and obinutuzumab is administered before polatuzumab vedotin-piiq, and on days 8 and 15 of the first 21-day cycle, venetoclax or a pharmaceutically acceptable salt thereof is administered before obinutuzumab; (ii) on day 1 of each of a second, third, fourth, fifth, and sixth 21-day cycles, venetoclax or a pharmaceutically acceptable salt thereof is administered before obinutuzumab, and obinutuzumab is administered before polatuzumab vedotin-piiq.In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab results in a complete response in humans after six 21-day cycles. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to humans results in a complete response in at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of humans after six 21-day cycles. In some embodiments, the duration of the complete response is at least about 1 month, at least about 2 months, at least about 3 months, or longer. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to a plurality of humans results in an objective response in at least about 87%, at least about 90%, at least about 95%, or 100% of the humans after six 21-day cycles. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to a plurality of humans results in an objective response in at least about 70%, at least about 75%, at least about 78%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans after six 21-day cycles. In some embodiments, venetoclax or a pharmaceutically acceptable salt thereof and obinutuzumab are further administered during a maintenance phase following the sixth 21-day cycle of the induction phase, wherein venetoclax or a pharmaceutically acceptable salt thereof is administered orally once daily at a dose of about 800 mg during the maintenance phase, and obinutuzumab is administered intravenously once every two months at a dose of about 1000 mg during the maintenance phase. In some embodiments, venetoclax or a pharmaceutically acceptable salt thereof is administered for up to eight months during the maintenance phase. In some embodiments, obinutuzumab is administered during the maintenance phase beginning on the first day of the second month following the sixth 21-day cycle of the induction phase.In some embodiments, obinutuzumab is administered for up to 24 months during the maintenance phase. In some embodiments, venetoclax or a pharmaceutically acceptable salt thereof and obinutuzumab are administered sequentially during the maintenance phase. In some embodiments, venetoclax or a pharmaceutically acceptable salt thereof is administered before obinutuzumab on day 1 of each of months 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24 during the maintenance phase. In some embodiments, the anti-CD79b antibody comprises 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 anti-CD79b 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: 38. In some embodiments, the immunoconjugate is iradatuzumab vedotin.

[0011] In another aspect, provided herein is a method for treating follicular lymphoma (FL) in a human in need thereof, comprising administering to the human an effective amount of Formula (a) TIFF0007785016000003.tif26170 [wherein the Ab comprises: (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 1 to 8; (b) venetoclax or a pharmaceutically acceptable salt thereof at a dose of about 800 mg; and (c) obinutuzumab at a dose of about 1000 mg, wherein the human achieves a complete response (CR) during or after administration of the immunoconjugate, venetoclax, and obinutuzumab. In some embodiments, p is 3 to 4, or 2 to 5. In some embodiments, administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to a plurality of humans results in a complete response in at least about 55%, at least about 57%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans during or after administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab. In some embodiments, the duration of the complete response is at least about 1 month, at least about 2 months, at least about 3 months, or longer. In some embodiments, administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to a plurality of humans results in an objective response in at least about 87%, at least about 90%, at least about 95%, or 100% of the humans during or after administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab.In some embodiments, administration of an immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to a plurality of humans results in an objective response in at least about 70%, at least about 75%, at least about 78%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans during or after administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab. In some embodiments, administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab does not result in Grade 3 or higher peripheral neuropathy in the human. In some embodiments, administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab does not result in tumor lysis syndrome in the human. In some embodiments, administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to a plurality of humans results in Grade 3 or Grade 4 adverse events in about 64% or less of the humans. In some embodiments, administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to a plurality of humans results in Grade 3 or Grade 4 adverse events in about 59% or less of the humans. In some embodiments, administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to a plurality of humans results in Grade 3 or Grade 4 adverse events in about 73% or less of the humans. 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-piiq.In some embodiments, polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab are administered during an induction phase, which optionally includes at least six 21-day cycles. In some embodiments, (i) on day 1 of the first 21-day cycle, polatuzumab vedotin-piiq is administered intravenously at a dose of about 1.8 mg / kg; on days 1-21 of the first 21-day cycle, venetoclax or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 800 mg; and on days 1, 8, and 15 of the first 21-day cycle, obinutuzumab is administered intravenously at a dose of about 1000 mg; and (ii) on days 2, 3, 4, 5, and 6 of the first 21-day cycle, polatuzumab vedotin-piiq is administered intravenously at a dose of about 1.8 mg / kg; on days 1-21 of the first 21-day cycle, venetoclax or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 800 mg; and on days 1, 8, and 15 of the first 21-day cycle, obinutuzumab is administered intravenously at a dose of about 1000 mg. On day 1 of each of the first and sixth 21-day cycles, polatuzumab vedotin-piiq is administered intravenously at a dose of about 1.8 mg / kg, on days 1-21 of each of the second, third, fourth, fifth, and sixth 21-day cycles, venetoclax or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 800 mg, and on day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, obinutuzumab is administered intravenously at a dose of about 1000 mg. In some embodiments, polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab are administered consecutively during the induction phase. In some embodiments, (i) on day 1 of a first 21-day cycle, venetoclax or a pharmaceutically acceptable salt thereof is administered before obinutuzumab, and obinutuzumab is administered before polatuzumab vedotin-piiq, and on days 8 and 15 of the first 21-day cycle, venetoclax or a pharmaceutically acceptable salt thereof is administered before obinutuzumab; (ii) on day 1 of each of a second, third, fourth, fifth, and sixth 21-day cycles, venetoclax or a pharmaceutically acceptable salt thereof is administered before obinutuzumab, and obinutuzumab is administered before polatuzumab vedotin-piiq.In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab results in a complete response in humans after six 21-day cycles. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to humans results in a complete response in at least about 55%, at least about 57%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of humans after six 21-day cycles. In some embodiments, the duration of the complete response is at least about 1 month, at least about 2 months, at least about 3 months, or longer. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to a plurality of humans results in an objective response in at least about 87%, at least about 90%, at least about 95%, or 100% of the humans after six 21-day cycles. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to a plurality of humans results in an objective response in at least about 70%, at least about 75%, at least about 78%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans after six 21-day cycles. In some embodiments, venetoclax or a pharmaceutically acceptable salt thereof and obinutuzumab are further administered during a maintenance phase after the sixth 21-day cycle of the induction phase, wherein venetoclax or a pharmaceutically acceptable salt thereof is administered orally once daily at a dose of about 800 mg during the maintenance phase, and obinutuzumab is administered intravenously once every two months at a dose of about 1000 mg during the maintenance phase. In some embodiments, venetoclax or a pharmaceutically acceptable salt thereof is administered for up to 8 months during the maintenance phase.In some embodiments, obinutuzumab is administered during the maintenance phase starting on day 1 of the second month after the sixth 21-day cycle of the induction phase. In some embodiments, obinutuzumab is administered during the maintenance phase for up to 24 months. In some embodiments, venetoclax or a pharmaceutically acceptable salt thereof and obinutuzumab are administered consecutively during the maintenance phase. In some embodiments, venetoclax or a pharmaceutically acceptable salt thereof is administered before obinutuzumab on day 1 of each of months 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24 during the maintenance phase. In some embodiments, the anti-CD79b antibody comprises 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 anti-CD79b 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: 38. In some embodiments, the immunoconjugate is iradatuzumab vedotin.

[0012] In another aspect, a method of treating follicular lymphoma (FL) in a human in need thereof, comprising administering to the human, during an induction phase, effective amounts of: (a) polatuzumab vedotin-piiq at a dose of about 1.8 mg / kg, (b) venetoclax or a pharmaceutically acceptable salt thereof at a dose of about 800 mg, and (c) obinutuzumab at a dose of about 1000 mg, wherein the human achieves a complete response during or after the induction phase. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to a plurality of humans results in a complete response in at least about 55%, at least about 57%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans during or after the induction phase. In some embodiments, the duration of the complete response is at least about 1 month, at least about 2 months, at least about 3 months, or longer. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to a plurality of humans results in an objective response in at least about 87%, at least about 90%, at least about 95%, or 100% of the humans during or after the induction phase. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to a plurality of humans results in an objective response in at least about 70%, at least about 75%, at least about 78%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans during or after the induction phase. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab does not result in Grade 3 or higher peripheral neuropathy in humans. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab does not result in tumor lysis syndrome in humans.In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to a plurality of humans results in Grade 3 or Grade 4 adverse events in about 64% or less of the humans. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to a plurality of humans results in Grade 3 or Grade 4 adverse events in about 59% or less of the humans. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to a plurality of humans results in Grade 3 or Grade 4 adverse events in about 73% or less of the humans. In some embodiments, the induction phase comprises at least six 21-day cycles. In some embodiments, (i) on day 1 of a first 21-day cycle, polatuzumab vedotin-piiq is administered intravenously at a dose of about 1.8 mg / kg; on each of days 1 to 21 of a first 21-day cycle, venetoclax or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 800 mg; and on each of days 1, 8, and 15 of a first 21-day cycle, obinutuzumab is administered intravenously at a dose of about 1000 mg; and (ii) on days 2, 3, 4, 5, and 6 of a first 21-day cycle, venetoclax or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 800 mg. On day 1 of each of the first and sixth 21-day cycles, polatuzumab vedotin-piiq is administered intravenously at a dose of about 1.8 mg / kg, on days 1-21 of each of the second, third, fourth, fifth, and sixth 21-day cycles, venetoclax or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 800 mg, and on day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, obinutuzumab is administered intravenously at a dose of about 1000 mg. In some embodiments, polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab are administered consecutively during the induction phase.In some embodiments, (i) on day 1 of a first 21-day cycle, venetoclax or a pharmaceutically acceptable salt thereof is administered before obinutuzumab, and obinutuzumab is administered before polatuzumab vedotin-piiq, and on days 8 and 15 of the first 21-day cycle, venetoclax or a pharmaceutically acceptable salt thereof is administered before obinutuzumab; (ii) on day 1 of each of a second, third, fourth, fifth, and sixth 21-day cycles, venetoclax or a pharmaceutically acceptable salt thereof is administered before obinutuzumab, and obinutuzumab is administered before polatuzumab vedotin-piiq. In some embodiments, venetoclax or a pharmaceutically acceptable salt thereof and obinutuzumab are further administered during the maintenance phase after the sixth 21-day cycle of the induction phase, wherein venetoclax or a pharmaceutically acceptable salt thereof is administered orally once daily at a dose of about 800 mg during the maintenance phase, and obinutuzumab is administered intravenously once every two months at a dose of about 1000 mg during the maintenance phase. In some embodiments, venetoclax or a pharmaceutically acceptable salt thereof is administered for up to 8 months during the maintenance phase. In some embodiments, obinutuzumab is administered during the maintenance phase starting on day 1 of the second month after the sixth 21-day cycle of the induction phase. In some embodiments, obinutuzumab is administered for up to 24 months during the maintenance phase. In some embodiments, venetoclax or a pharmaceutically acceptable salt thereof and obinutuzumab are administered continuously during the maintenance phase. In some embodiments, on day 1 of each of months 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24 during the maintenance phase, venetoclax or a pharmaceutically acceptable salt thereof is administered before obinutuzumab.

[0013] In some embodiments that may be combined with any of the preceding aspects or embodiments, the method further comprises administering prophylactic treatment for tumor lysis syndrome (TLS), where the prophylactic treatment for tumor lysis syndrome (TLS), if it occurs, comprises a uric acid-reducing agent and / or a hydration regimen prior to the initiation of treatment. In some embodiments, the hydration regimen comprises administering about 2 to about 3 liters of fluid per day, the fluid being administered about 24 to about 48 hours before the initiation of treatment. In some embodiments, the fluid is administered orally or intravenously. In some embodiments, the uric acid-reducing agent is allopurinol. In some embodiments, allopurinol is administered orally at a dose of about 300 mg / day starting about 72 hours before the first administration of venetoclax or a pharmaceutically acceptable salt thereof, and administration of allopurinol continues for about 3 to about 7 days after the first administration of venetoclax or a pharmaceutically acceptable salt thereof. In some embodiments that may be combined with any of the preceding aspects or embodiments, the method further comprises administering granulocyte colony-stimulating factor (G-CSF) if a Grade 3 or Grade 4 adverse event of neutropenia occurs.

[0014] In some embodiments that may be combined with any of the preceding aspects or embodiments, the human has an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1, or 2 prior to treatment initiation. In some embodiments that may be combined with any of the preceding aspects or embodiments, the FL is relapsed or refractory to prior treatment for FL. In some embodiments, the prior treatment for FL comprises a chemoimmunotherapy regimen including an anti-CD20 monoclonal antibody. In some embodiments that may be combined with any of the preceding aspects or embodiments, the FL is histologically documented as CD20 positive. In some embodiments that may be combined with any of the preceding aspects or embodiments, the FL is fluorodeoxyglucose (FDG)-avid FL. In some embodiments that may be combined with any of the preceding aspects or embodiments, the FL is positron emission tomography (PET)-positive FL. In some embodiments that may be combined with any of the preceding aspects or embodiments, the human has at least one bidimensionally measurable lesion prior to treatment, the lesion measuring at least 1.5 centimeters in its longest dimension as measured by computed tomography (CT) scan or magnetic resonance imaging (MRI). In some embodiments that may be combined with any of the preceding aspects or embodiments, the FL is not grade 3b FL. In some embodiments that may be combined with any of the preceding aspects or embodiments, the human does not have peripheral neuropathy greater than grade 1 prior to treatment. In some embodiments that may be combined with any of the preceding aspects or embodiments, the FL has a histologic grade of 1, 2, or 3a prior to treatment. In some embodiments that may be combined with any of the preceding aspects or embodiments, the human has FL with bone marrow involvement prior to treatment. In some embodiments that may be combined with any of the preceding aspects or embodiments, the human has FL at Ann Arbor stage 1, 2, 3, or 4 prior to treatment.In some embodiments that may be combined with any of the preceding aspects or embodiments, the human has FL with a Follicular Lymphoma International Prognostic Index (FLIPI) score of 0, 1, 2, 3, 4, or 5 before treatment. In some embodiments that may be combined with any of the preceding aspects or embodiments, the human has received at least one prior treatment for FL. In some embodiments that may be combined with any of the preceding aspects or embodiments, the human has bulky disease greater than 7 centimeters before treatment. In some embodiments that may be combined with any of the preceding aspects or embodiments, the FL is refractory to prior treatment including an anti-CD20 agent. In some embodiments that may be combined with any of the preceding aspects or embodiments, the FL has progressed within 24 months of completing the initial treatment for FL. In some embodiments that may be combined with any of the preceding aspects or embodiments, the human has FL that has progressed within about 24 months of initiating initial anti-lymphoma treatment with chemoimmunotherapy, which is administered to the human prior to treatment with the methods provided herein. In some embodiments that may be combined with any of the preceding aspects or embodiments, the human has FL that has not progressed within about 24 months of the initiation of initial anti-lymphoma treatment with chemoimmunotherapy administered to the human prior to treatment with the methods provided herein. In some embodiments that may be combined with any of the preceding aspects or embodiments, the human has received one or two anti-lymphoma therapies prior to treatment with the methods provided herein. In some embodiments that may be combined with any of the preceding aspects or embodiments, the human has received three or more anti-lymphoma therapies prior to treatment with the methods provided herein. In some embodiments that may be combined with any of the preceding aspects or embodiments, the human has FL with a Follicular Lymphoma International Prognostic Index (FLIPI) score of 0 to 2 prior to treatment with the methods provided herein. In some embodiments that may be combined with any of the preceding aspects or embodiments, the human has FL with a Follicular Lymphoma International Prognostic Index (FLIPI) score of 3 to 5 prior to treatment with the methods provided herein.In some embodiments that may be combined with any of the preceding aspects or embodiments, the human has refractory FL prior to treatment with the methods provided herein. In some embodiments that may be combined with any of the preceding aspects or embodiments, the human has non-refractory FL prior to treatment with the methods provided herein.

[0015]

[0013] In another aspect, provided herein is a method for treating a human in need thereof, having follicular lymphoma (FL), using a selective Bcl2 inhibitor, or a pharmaceutically acceptable salt thereof, and an anti-CD20 antibody in combination, according to any of the methods of the present disclosure. formula (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 1 to 8.

[0016] In another aspect, provided herein is a method for the combined use of bentoclax, or a pharmaceutically acceptable salt thereof, and obnituzumab to treat a human in need thereof having follicular lymphoma (FL) according to any of the methods of the present disclosure. formula (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 1 to 8.

[0017] In another aspect, provided herein is a method for the combined use of bentoclax, or a pharmaceutically acceptable salt thereof, and obnituzumab to treat a human in need thereof having follicular lymphoma (FL) according to any of the methods of the present disclosure. formula (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 1 to 8.

[0018]

[0013] In another aspect, provided herein is a method for the manufacture of a medicament comprising administering to a subject in need thereof a compound comprising bentoclax, or a pharmaceutically acceptable salt thereof, and obnituzumab in combination for the treatment of a human having follicular lymphoma (FL) in accordance with any of the methods disclosed herein. formula (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 1 to 8.

[0019] In some embodiments that may be combined with any of the preceding aspects or embodiments, p is 3 to 4 or 2 to 5. In some embodiments that may be combined with any of the preceding aspects or 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 that may be combined with any of the preceding aspects or 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.

[0020] In another aspect, provided herein is a kit comprising polatuzumab vedotin-piiq for use in combination with venetoclax, or a pharmaceutically acceptable salt thereof, and obinutuzumab to treat a human in need thereof having follicular lymphoma (FL), according to any of the methods provided herein.

[0021] In another aspect, provided herein is polatuzumab vedotin-piiq for use in combination with venetoclax, or a pharmaceutically acceptable salt thereof, and obinutuzumab to treat a human in need thereof having follicular lymphoma (FL), according to any of the methods provided herein.

[0022] In another aspect, provided herein is polatuzumab vedotin-piiq for use in the manufacture of a medicament, in combination with venetoclax, or a pharmaceutically acceptable salt thereof, and obinutuzumab, to treat a human being in need of treatment having follicular lymphoma (FL), according to any of the methods provided herein.

[0023] In another aspect, a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof comprises administering to the human an effective amount of Formula (a) (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 1 to 8. A method is provided comprising administering to a human a complete response (CR) during or after administration of the immunoconjugate, (b) a selective Bcl-2 inhibitor, or a pharmaceutically acceptable salt thereof, and (c) an anti-CD20 antibody, 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 1 to 8. In some embodiments, p is 3 to 4, or 2 to 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. In some embodiments, the immunoconjugate is polatuzumab vedotin-piiq. In some embodiments, the selective Bcl-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof. In some embodiments, polatuzumab vedotin-piiq is administered at a dose of about 1.8 mg / kg, and venetoclax or a pharmaceutically acceptable salt thereof is administered at a dose of about 800 mg. In some embodiments, the anti-CD20 antibody is rituximab. In some embodiments, polatuzumab vedotin vetotin-piiq is administered at a dose of about 1.8 mg / kg, venetoclax or a pharmaceutically acceptable salt thereof is administered at a dose of about 800 mg, and rituximab is administered at a dose of about 375 mg / m 2In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in a complete response in at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans during or after administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to multiple humans results in a best complete response rate of at least about 35%, at least about 38%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100%. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in an objective response in at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 42%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans during or after administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab.In some embodiments, the duration of the complete response or objective response is at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months or more. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in a best overall response in at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans during or after administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in a 6-month progression-free survival rate of at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 42%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100%. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a human results in progression-free survival of the human for at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, or longer after administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab.In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a human results in survival of the human for 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, at least about 11 months, or longer after administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a human results in a reduction in the two-way sum of products (SPD) of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, or 100% compared to the SPD before administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in serious adverse events in no more than about 40%, no more than about 37%, no more than about 35%, or no more than about 30% of the humans. In some embodiments, polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab are administered during an induction phase, which optionally includes at least six 21-day cycles. In some embodiments, on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, polatuzumab vedotin-piiq is administered intravenously at a dose of about 1.8 mg / kg, on days 1-21 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, venetoclax or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 800 mg, and on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, rituximab is administered at a dose of about 375 mg / m. 2In some embodiments, polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab are administered consecutively during the induction phase. In some embodiments, on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, venetoclax or a pharmaceutically acceptable salt thereof is administered before rituximab, and rituximab is administered before polatuzumab vedotin-piiq. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab results in a complete response in humans after six 21-day cycles. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in a complete response in at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans after six 21-day cycles. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to multiple humans results in a best complete response rate of at least about 35%, at least about 38%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100%.In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in an objective response in at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 42%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans after six 21-day cycles. In some embodiments, the duration of the complete response or objective response is at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months or longer. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in a best overall response in at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans after six 21-day cycles. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in a best overall response in at least about 25%, at least about 27%, or at least about 29% of the humans after six 21-day cycles. , at least about 31%, at least about 35%, at least about 40%, at least about 42%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% 6-month progression-free survival. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a human results in progression-free survival of the human for at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, or longer after administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a human results in survival of the human for 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, at least about 11 months, or longer after administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a human results in a reduction in the two-way sum of products (SPD) of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, or 100% after six 21-day cycles compared to the SPD before administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans after six 21-day cycles results in serious adverse events in no more than about 40%, no more than about 37%, no more than about 35%, or no more than about 30% of humans.In some embodiments, venetoclax or a pharmaceutically acceptable salt thereof and rituximab are further administered during a consolidation phase after the sixth 21-day cycle of the induction phase, wherein venetoclax or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 800 mg per day during the consolidation phase, and rituximab is administered orally at a dose of about 375 mg / m every two months during the consolidation phase. 2 In some embodiments, venetoclax or a pharmaceutically acceptable salt thereof and rituximab are administered intravenously for up to 8 months during the consolidation phase. In some embodiments, rituximab is administered during the consolidation phase starting on day 1 of the second month after the sixth 21-day cycle of the induction phase. In some embodiments, venetoclax or a pharmaceutically acceptable salt thereof and rituximab are administered sequentially during the consolidation phase. In some embodiments, venetoclax or a pharmaceutically acceptable salt thereof is administered before rituximab on day 1 of each of months 2, 4, 6, and 8 during the consolidation phase. In some embodiments, the anti-CD79b antibody comprises 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 anti-CD79b 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: 38. In some embodiments, the immunoconjugate is iradatuzumab vedotin.

[0024] In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, comprising administering to the human an effective amount of Formula (a) (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 1 to 8; (b) venetoclax or a pharmaceutically acceptable salt thereof at a dose of about 800 mg; and (c) about 375 mg / m 2In some embodiments, the administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in a complete response in at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans during or after administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab. In some embodiments, administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in a best complete response rate of at least about 35%, at least about 38%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100%. In some embodiments, administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in an objective response in at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 42%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans during or after administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab. In some embodiments, the duration of the complete response or objective response is at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months or longer.In some embodiments, administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in a best overall response in at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans during or after administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab. In some embodiments, administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in a 6-month progression-free survival rate of at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 42%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100%. In some embodiments, administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a human results in progression-free survival of the human for at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, or more following administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab. In some embodiments, administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a human results in progression-free survival of the human for 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, at least about 11 months, or more following administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab.In some embodiments, administration of an immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a human results in a reduction in the two-way sum of products (SPD) of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, or 100% compared to the SPD before administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab. In some embodiments, administration of an immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in a serious adverse event in no more than about 40%, no more than about 37%, no more than about 35%, or no more than about 30% of the humans. In some embodiments, p is 3 to 4, or 2 to 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. In some embodiments, the immunoconjugate is polatuzumab vedotin-piiq. In some embodiments, polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab are administered during an induction phase, which optionally comprises at least six 21-day cycles. In some embodiments, on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, polatuzumab vedotin-piiq is administered intravenously at a dose of about 1.8 mg / kg, on days 1 to 21 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, venetoclax or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 800 mg, and on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, rituximab is administered orally at a dose of about 375 mg / m. 2In some embodiments, polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab are administered consecutively during the induction phase. In some embodiments, on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, venetoclax or a pharmaceutically acceptable salt thereof is administered before rituximab, and rituximab is administered after polatuzumab vedotin-piiq is administered before polatuzumab vedotin-piiq. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab results in a complete response in humans after six 21-day cycles. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to humans results in a complete response in at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of humans after six 21-day cycles. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to multiple humans results in a best complete response rate of at least about 35%, at least about 38%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100%. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in an objective response in at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 42%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans after six 21-day cycles.In some embodiments, the duration of complete response or objective response is at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months or more. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in a best overall response in at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of humans after six 21-day cycles. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in a 6-month progression-free survival rate of at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 42%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100%. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a human results in the human's progression-free survival for at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, or longer after administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a human results in the human's survival for 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, at least about 11 months, or longer after administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab.In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a human results in a reduction in the two-way sum of products (SPD) of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, or 100% after six 21-day cycles compared to the SPD before administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans after six 21-day cycles results in serious adverse events in no more than about 40%, no more than about 37%, no more than about 35%, or no more than about 30% of humans. In some embodiments, venetoclax or a pharmaceutically acceptable salt thereof and rituximab are further administered during a consolidation phase after the sixth 21-day cycle of the induction phase, wherein venetoclax or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 800 mg per day during the consolidation phase, and rituximab is administered orally at a dose of about 375 mg / m every two months during the consolidation phase. 2In some embodiments, venetoclax or a pharmaceutically acceptable salt thereof and rituximab are administered intravenously for up to 8 months during the consolidation phase. In some embodiments, rituximab is administered during the consolidation phase starting on day 1 of the second month after the sixth 21-day cycle of the induction phase. In some embodiments, venetoclax or a pharmaceutically acceptable salt thereof and rituximab are administered sequentially during the consolidation phase. In some embodiments, venetoclax or a pharmaceutically acceptable salt thereof is administered before rituximab on day 1 of each of months 2, 4, 6, and 8 during the consolidation phase. In some embodiments, the anti-CD79b antibody comprises 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 anti-CD79b 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: 38. In some embodiments, the immunoconjugate is iradatuzumab vedotin.

[0025] In another aspect, provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, comprising administering to the human an effective amount of Formula (a) (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 1 to 8; (b) venetoclax or a pharmaceutically acceptable salt thereof at a dose of about 800 mg; and (c) about 375 mg / m 2wherein the human achieves a complete response (CR) during or after administration of the immunoconjugate, venetoclax, and obinutuzumab. In some embodiments, p is 3 to 4, or 2 to 5. In some embodiments, administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in a complete response in at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans during or after administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab. In some embodiments, administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in a best complete response rate of at least about 35%, at least about 38%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100%. In some embodiments, administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in an objective response in at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least 42%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans during or after administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab.In some embodiments, the duration of the complete response or objective response is at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months or more. In some embodiments, the administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in a best overall response in at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans during or after administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab. In some embodiments, administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in a 6-month progression-free survival rate of at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 42%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100%. In some embodiments, administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a human results in progression-free survival of the human for at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, or more following administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab. In some embodiments, administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a human results in progression-free survival of the human for 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, at least about 11 months, or more following administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab.In some embodiments, administration of an immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a human results in a reduction in the two-way sum of products (SPD) of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, or 100% compared to the SPD before administration of the immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab. In some embodiments, administration of an immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in serious adverse events in no more than about 40%, no more than about 37%, no more than about 35%, or no more than about 30% of the humans. 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-piiq. In some embodiments, polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab are administered during an induction phase, optionally comprising at least six 21-day cycles. In some embodiments, polatuzumab vedotin-piiq 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 21-day cycles, and venetoclax or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 800 mg on days 1 to 21 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. , rituximab is approximately 375 mg / m 2In some embodiments, polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab are administered consecutively during the induction phase. In some embodiments, on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, venetoclax or a pharmaceutically acceptable salt thereof is administered before rituximab, and rituximab is administered before polatuzumab vedotin-piiq. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab results in a complete response in humans after six 21-day cycles. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in a complete response in at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans after six 21-day cycles. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to multiple humans results in a best complete response rate of at least about 35%, at least about 38%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100%.In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in an objective response in at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 42%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans after six 21-day cycles. In some embodiments, the duration of the complete response or objective response is at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months or longer. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in a best overall response in at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans after six 21-day cycles. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in a 6-month progression-free survival rate of at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 42%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100%.In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a human results in the human's progression-free survival for at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, or longer after administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a human results in the human's survival for 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, at least about 11 months, or longer after administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a human results in a reduction in the two-way sum of products (SPD) of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, or 100% after six 21-day cycles compared to the SPD before administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans after six 21-day cycles results in serious adverse events in no more than about 40%, no more than about 37%, no more than about 35%, or no more than about 30% of humans. In some embodiments, venetoclax or a pharmaceutically acceptable salt thereof and rituximab are further administered during a consolidation phase after the sixth 21-day cycle of the induction phase, wherein venetoclax or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 800 mg per day during the consolidation phase, and rituximab is administered orally at a dose of about 375 mg / m every two months during the consolidation phase. 2In some embodiments, venetoclax or a pharmaceutically acceptable salt thereof and rituximab are administered intravenously for up to 8 months during the consolidation phase. In some embodiments, rituximab is administered during the consolidation phase starting on day 1 of the second month after the sixth 21-day cycle of the induction phase. In some embodiments, venetoclax or a pharmaceutically acceptable salt thereof and rituximab are administered sequentially during the consolidation phase. In some embodiments, venetoclax or a pharmaceutically acceptable salt thereof is administered before rituximab on day 1 of each of months 2, 4, 6, and 8 during the consolidation phase. In some embodiments, the anti-CD79b antibody comprises 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 anti-CD79b 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: 38. In some embodiments, the immunoconjugate is iradatuzumab vedotin.

[0026]

[0013] In another aspect, provided herein is a method of treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, comprising administering, during an induction phase, effective amounts of: (a) polatuzumab vedotin-piiq at a dose of about 1.8 mg / kg, (b) venetoclax or a pharmaceutically acceptable salt thereof at a dose of about 800 mg, and (c) venetoclax or a pharmaceutically acceptable salt thereof at a dose of about 375 mg / m 2and rituximab at a dose of 0.05% or more, wherein the humans achieve a complete response during or after the induction phase. In some embodiments, the administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in a complete response in at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans during or after the induction phase. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to multiple humans results in a best complete response rate of at least about 35%, at least about 38%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100%. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in an objective response in at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 42%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans during or after the induction phase. In some embodiments, the duration of the complete response or objective response is at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months or longer.In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in a best overall response in at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans during or after the induction phase. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in a 6-month progression-free survival rate of at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 42%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100%. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a human results in the human's progression-free survival for at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, or longer after administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a human results in the human's survival for 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, at least about 11 months, or longer after administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab.In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a human results in a reduction in the two-way sum of products (SPD) of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, or 100% compared to the SPD before administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab. In some embodiments, administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in serious adverse events in about 40% or less, about 37% or less, about 35% or less, or about 30% or less of the humans. In some embodiments, the induction phase comprises at least six 21-day cycles. In some embodiments, on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, polatuzumab vedotin-piiq is administered intravenously at a dose of about 1.8 mg / kg, on days 1 to 21 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, venetoclax or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 800 mg, and on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, rituximab is administered orally at a dose of about 375 mg / m. 2In some embodiments, polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab are administered consecutively during the induction phase. In some embodiments, on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, venetoclax or a pharmaceutically acceptable salt thereof is administered before rituximab, and rituximab is administered before polatuzumab vedotin-piiq. In some embodiments, venetoclax or a pharmaceutically acceptable salt thereof and rituximab are further administered during a consolidation phase after the sixth 21-day cycle of the induction phase, wherein venetoclax or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 800 mg per day during the consolidation phase, and rituximab is administered at a dose of about 375 mg / m every two months during the consolidation phase. 2 In some embodiments, venetoclax or a pharmaceutically acceptable salt thereof and rituximab are administered intravenously for up to 8 months during the consolidation phase. In some embodiments, rituximab is administered during the consolidation phase starting on day 1 of the second month after the sixth 21-day cycle of the induction phase. In some embodiments, venetoclax or a pharmaceutically acceptable salt thereof and rituximab are administered sequentially during the consolidation phase. In some embodiments, venetoclax or a pharmaceutically acceptable salt thereof is administered before rituximab on day 1 of each of months 2, 4, 6, and 8 during the consolidation phase.

[0027] In some embodiments that may be combined with any of the preceding aspects or embodiments, the method further comprises administering prophylactic treatment for tumor lysis syndrome (TLS), where the prophylactic treatment for tumor lysis syndrome (TLS), if it occurs, comprises a uric acid-reducing agent and / or a hydration regimen prior to the initiation of treatment. In some embodiments, the hydration regimen comprises administering about 2 to about 3 liters of fluid per day, the fluid being administered about 24 to about 48 hours before the initiation of treatment. In some embodiments, the fluid is administered orally or intravenously. In some embodiments, the uric acid-reducing agent is allopurinol. In some embodiments, allopurinol is administered orally at a dose of about 300 mg / day starting about 72 hours before the first administration of venetoclax or a pharmaceutically acceptable salt thereof, and administration of allopurinol continues for about 3 to about 7 days after the first administration of venetoclax or a pharmaceutically acceptable salt thereof.

[0028] In some embodiments that may be combined with any of the preceding aspects or embodiments, the method further comprises administering granulocyte colony-stimulating factor (G-CSF) if a Grade 3 or Grade 4 adverse event of neutropenia occurs.

[0029] In some embodiments that may be combined with any of the preceding aspects or embodiments, the method further comprises administering a platelet transfusion if a Grade 3 or Grade 4 adverse event of thrombocytopenia occurs.

[0030] In some embodiments that may be combined with any of the preceding aspects or embodiments, the human has an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1, or 2 before treatment initiation. In some embodiments that may be combined with any of the preceding aspects or embodiments, the DLBCL is relapsed or refractory to prior treatment for DLBCL. In some embodiments, the prior treatment for DLBCL comprises a chemoimmunotherapy regimen including an anti-CD20 monoclonal antibody. In some embodiments that may be combined with any of the preceding aspects or embodiments, the DLBCL is histologically documented as CD20 positive. In some embodiments that may be combined with any of the preceding aspects or embodiments, the DLBCL is fluorodeoxyglucose (FDG)-avid DLBCL. In some embodiments that may be combined with any of the preceding aspects or embodiments, the DLBCL is positron emission tomography (PET)-positive DLBCL. In some embodiments that may be combined with any of the preceding aspects or embodiments, the human has at least one bidimensionally measurable lesion prior to treatment, the lesion measuring at least 1.5 centimeters in its longest dimension as measured by computed tomography (CT) scan or magnetic resonance imaging (MRI). In some embodiments that may be combined with any of the preceding aspects or embodiments, the human has no history of transformation from an indolent disease to DLBCL. In some embodiments that may be combined with any of the preceding aspects or embodiments, the human has no peripheral neuropathy greater than Grade 1 prior to treatment. In some embodiments that may be combined with any of the preceding aspects or embodiments, the human has DLBCL at Ann Arbor stage 1, 2, 3, or 4 prior to treatment. In some embodiments that may be combined with any of the preceding aspects or embodiments, the human has DLBCL with an International Prognostic Index (IPI) score of 0, 1, 2, 3, 4, or 5 prior to treatment.In some embodiments that may be combined with any of the preceding aspects or embodiments, the human has received at least one prior treatment for DLBCL. In some embodiments, the prior treatment for DLBCL includes chimeric antigen receptor (CAR) T-cell treatment for DLBCL. In some embodiments that may be combined with any of the preceding aspects or embodiments, the human has bulky disease of 7 centimeters or more prior to treatment. In some embodiments that may be combined with any of the preceding aspects or embodiments, the human has extranodal disease. In some embodiments that may be combined with any of the preceding aspects or embodiments, the DLBCL is refractory to prior treatment including an anti-CD20 agent. In some embodiments that may be combined with any of the preceding aspects or embodiments, the DLBCL has not responded, progressed, or relapsed within about 6 months after the last prior treatment for DLBCL administered to the human. In some embodiments that may be combined with any of the preceding aspects or embodiments, the DLBCL has not responded, progressed, or relapsed within about 6 months after the first prior treatment for DLBCL administered to the human. In some embodiments that may be combined with any of the preceding aspects or embodiments, the human has DLBCL with an activated B-cell (ABC) cell of origin. In some embodiments that may be combined with any of the preceding aspects or embodiments, the human has a DLBCL with a germinal center B cell (GCB) cell of origin. In some embodiments that may be combined with any of the preceding aspects or embodiments, the DLBCL is a BCL2-positive DLBCL. In some embodiments that may be combined with any of the preceding aspects or embodiments, the DLBCL is a BCL2-negative DLBCL. In some embodiments that may be combined with any of the preceding aspects or embodiments, the DLBCL is a dual-expression DLBCL. In some embodiments that may be combined with any of the preceding aspects or embodiments, the DLBCL is not a dual-expression DLBCL.

[0031]

[0013] In another aspect, provided herein is a method for treating a human in need thereof, having diffuse large B-cell lymphoma (DLBCL), using a selective Bcl2 inhibitor, or a pharmaceutically acceptable salt thereof, and an anti-CD20 antibody in combination, according to any of the methods provided herein. formula (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 1 to 8.

[0032]

[0013] In another aspect, provided herein is a method for treating a human in need thereof having diffuse large B-cell lymphoma (DLBCL) using bentoclax, or a pharmaceutically acceptable salt thereof, and rituximab, in combination, according to any of the methods disclosed herein. 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, and p is 1 to 8.

[0033]

[0013] In another aspect, provided herein is a method for treating a human in need thereof having diffuse large B-cell lymphoma (DLBCL) using bentoclax, or a pharmaceutically acceptable salt thereof, and rituximab, in combination, according to any of the methods disclosed herein. formula (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 1 to 8.

[0034]

[0013] In another aspect, provided herein is a method for the manufacture of a medicament comprising administering to a subject in need thereof a compound comprising benzoclax, or a pharmaceutically acceptable salt thereof, and rituximab in combination for the treatment of a human having diffuse large B-cell lymphoma (DLBCL) in accordance with any of the methods disclosed herein. formula (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 1 to 8.

[0035] In some embodiments that may be combined with any of the preceding aspects or embodiments, p is 3 to 4 or 2 to 5. In some embodiments that may be combined with any of the preceding aspects or 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 that may be combined with any of the preceding aspects or 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.

[0036] In another aspect, provided herein is a kit comprising polatuzumab vedotin-piiq for use in combination with venetoclax, or a pharmaceutically acceptable salt thereof, and rituximab to treat a human in need thereof having diffuse large B-cell lymphoma (DLBCL), according to any of the methods provided herein.

[0037] In another aspect, provided herein is polatuzumab vedotin-piiq for use in combination with venetoclax, or a pharmaceutically acceptable salt thereof, and rituximab to treat a human in need thereof having diffuse large B-cell lymphoma (DLBCL), according to any of the methods provided herein.

[0038] In another aspect, provided herein is polatuzumab vedotin-piiq for use in the manufacture of a medicament, in combination with venetoclax, or a pharmaceutically acceptable salt thereof, and rituximab, for treating a human in need thereof having diffuse large B-cell lymphoma (DLBCL), according to any of the methods provided herein. [Brief explanation of the drawings]

[0039] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with one or more color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0040] [Figure 1A-1B] 1A-1B show the design of the study described in Example 1. FIG. 1A shows a diagram of the dose escalation phase (Phase Ib) of the study described in Example 1. FIG. 1B shows a diagram of the expansion phase (Phase II) of the study described in Example 1. In FIGS. 1A-1B, C = cycle; CR = complete response; D = day; D1C6 = day 1 of cycle 6; DLBCL = diffuse large B-cell lymphoma; EOI = end of induction; FL = follicular lymphoma; G = obinutuzumab; IV = intravenous; M = month; PO = oral; Pola = polatuzumab vedotin; PR = partial response; QD = once daily; R = rituximab; RP2D = recommended Phase II dose; SD = stable disease; V = venetoclax. a After completion of induction treatment, all patients continue daily venetoclax treatment (for 1 month) until response is assessed at EOI. If response assessment at EOI indicates that the patient is not eligible for post-induction treatment, venetoclax will be discontinued.

[0041] [Figure 2A-2B] 2A-2B show diagrams of the dosing regimens used in the study described in Example 1. FIG. 2A shows the induction dosing regimen for patients with FL and DLBCL. FIG. 2B shows the post-induction dosing regimens for patients with FL and DLBCL, referred to as "maintenance" and "consolidation," respectively.

[0042] [Figure 3A-3B]Figures 3A-3B show a diagram of the dose escalation scheme used in the dose escalation phase of the study described in Example 1. Figure 3A is a diagram of the dose escalation scheme used in the FL dose escalation phase of the study. Dose escalation of polatuzumab vedotin and venetoclax administered in combination with fixed doses of obinutuzumab was performed using a 3+3 design. Figure 3B is a diagram of the dose escalation scheme used in the DLBCL dose escalation phase of the study. Venetoclax doses were escalated as shown.

[0043] [Figure 4A-4B] Figures 4A-4B show a diagram outlining the guidelines for administering obinutuzumab infusions to FL patients in the study described in Example 1. Figure 4A shows the guidelines for administering the first infusion of obinutuzumab. a All patients receive full premedication with oral corticosteroids, antihistamines, and oral analgesics / antipyretics before the first obinutuzumab infusion. b Supportive care includes acetaminophen / paracetamol and antihistamines such as diphenhydramine if not administered within the previous 4 hours. IV saline may be indicated. Patients may have required antihistamines, oxygen, corticosteroids (e.g., 100 mg oral prednisone or equivalent), and / or bronchodilators for bronchospasm, hives, or dyspnea. IRR = infusion-related reaction; IV = intravenous. Figure 4B shows the guidelines for administering the second and subsequent infusions of obinutuzumab. aPatients receive full premedication with oral corticosteroids, antihistamines, and oral analgesics / antipyretics prior to obinutuzumab infusion. In the event of a recurrent grade 3 IRR, obinutuzumab may be discontinued. bPatients experiencing wheezing, urticaria, or other symptoms of anaphylaxis receive full premedication before all subsequent doses.

[0044] [Figure 5A-5B]Figures 5A-5B show efficacy results from the FL dose escalation phase of the study described in Example 1. Figure 5A shows PET / CT images of patients with FL enrolled in Cohort 1 at initial screening (left panel) and at the end of induction treatment (right panel), resulting in significant signal reduction in cervical, axillary, mediastinal, and abdominal lymph nodes. Figure 5B is a waterfall plot summarizing the percent change in sum of perpendicular distances (SPD) from CT scans at the end of induction compared to baseline, separated by cohort. P = polatuzumab vedotin (associated number indicates dose in mg / kg), V = venetoclax (associated number indicates dose in mg), O = obinutuzumab (associated number indicates dose in mg).

[0045] [Figure 6] Figure 6 shows a diagram illustrating the design of the study described in Examples 1-2. The number of patients in the safety and efficacy evaluable population included in the interim analysis described in Example 2 is shown. RP2D = recommended Phase II dose; Pola = polatuzumab vedotin; Ven = venetoclax; G = obinutuzumab; IV = intravenous; PO = oral; CR = complete response; PR = partial response; SD = stable disease.

[0046] [Figure 7] Figure 7 shows a Swimlane plot depicting the time to response and duration of response for each patient in the efficacy-evaluable population in the interim analysis described in Example 2. Response was assessed by the investigator according to the modified Lugano 2014 criteria. Time since initiation of study treatment is shown on the x-axis (months). Each horizontal bar represents an individual patient. Symbols in the legend indicate the last day of obinutuzumab (G) treatment, the last day of polatuzumab vedotin (Pola) treatment, the last day of venetoclax (Ven) treatment, the occurrence of partial response (PR), and the occurrence of complete response (CR). Asterisks indicate patients continuing treatment.

[0047] [Figure 8]Figure 8 shows an overview of the study population of the Phase Ib / II study described in Example 1 at the time of the primary analysis described in Example 3. RP2D = recommended Phase II dose.

[0048] [Figure 9] Figure 9 provides a summary of grade 3-4 adverse events occurring in 5% or more of patients in the Phase Ib / II study described in Examples 1 and 3. Adverse events are reported by preferred terminology. The graph shows the number and percentage of patients who received G-CSF or platelet transfusions during the induction or consolidation phases of the study. SOC = System Organ Class.

[0049] [Figure 10] Figure 10 shows a Swimlane plot illustrating the time to response and duration of INV-assessed response observed in the efficacy-evaluable population of the Phase Ib / II study described in Examples 1 and 3. Each bar represents an individual patient. Months from treatment initiation are shown on the x-axis.

[0050] [Figure 11] Figure 11 shows an analysis of progression-free survival (PFS) of patients in the Phase Ib / II trials described in Examples 1 and 3. The median PFS duration (months) and 6-month PFS rate are shown on the graph. The number of patients at risk at each indicated time on the x-axis is shown below the graph. CI = confidence interval. PFS was assessed by the investigator.

[0051] [Figure 12] Figure 12 shows the percent change in the sum of two-way products (SPD; investigator-assessed) at the end of induction (EOI) for patients in the Phase Ib / II study described in Examples 1 and 3. The corresponding response, assessed using the modified Lugano criteria, is shown for each patient.

[0052] [Figure 13]Figure 13 shows a diagram illustrating the design of the studies described in Examples 1, 2, and 4. *21-day cycle. CR, complete response; G, obinutuzumab; IV, intravenous; PO, oral administration; Pola, polatuzumab vedotin; PR, partial response; RP2D, recommended phase 2 dose; SD, stable disease; Ven, venetoclax.

[0053] [Figure 14] FIG. 14 shows an overview of the primary analysis population described in Example 4. DETAILED DESCRIPTION OF THE INVENTION

[0054] Detailed Description 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-piiq is also referred to interchangeably as "polatuzumab vedotin-piiq," "huMA79bv28-MC-vc-PAB-MMAE," "DCDS4501A," or "RG7596."

[0055] Provided herein is a method for treating follicular lymphoma (FL) in a human in need thereof, comprising administering to the human an effective amount of Formula (a) (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 1 to 8. A method is provided, comprising administering to a human a Bcl-2 inhibitor and an anti-CD20 antibody, an immunoconjugate 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 1 to 8. In some embodiments, the anti-CD79b immunoconjugate is huMA79bv28-MC-vc-PAB-MMAE. In some embodiments, the immunoconjugate is polatuzumab vedotin-piiq (CAS Registry Number 1313206-42-6). In some embodiments, the anti-CD79b immunoconjugate is huMA79bv28-MC-vc-PAB-MMAE. In some embodiments, the immunoconjugate is polatuzumab vedotin-piiq (CAS Registry Number 1313206-42-6). In some embodiments, the immunoconjugate is polatuzumab vedotin-piiq. In some embodiments, the Bcl-2 inhibitor is venetoclax. 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.

[0056] Also provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, comprising administering to the human an effective amount of Formula (a) (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 1 to 8.

[0024] A method is provided, comprising administering to a human a Bcl-2 inhibitor and an anti-CD20 antibody, wherein the human achieves a complete response (CR) during or after treatment. In some embodiments, the anti-CD79b immunoconjugate is huMA79bv28-MC-vc-PAB-MMAE. In some embodiments, the immunoconjugate is polatuzumab vedotin-piiq (CAS Registry Number 1313206-42-6). In some embodiments, the anti-CD79b immunoconjugate is huMA79bv28-MC-vc-PAB-MMAE. In some embodiments, the immunoconjugate is polatuzumab vedotin-piiq (CAS Registry Number 1313206-42-6). In some embodiments, the immunoconjugate is polatuzumab vedotin-piiq. In some embodiments, the Bcl-2 inhibitor is venetoclax. In some embodiments, the anti-CD20 antibody is rituximab. In some embodiments, the anti-CD20 antibody is ofatumumab, ublituximab, and / or ibritumomab tiuxetan.

[0057] I. General techniques 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 one in the art. Such techniques are fully described in the literature, for example, "Molecular Cloning: A Laboratory Manual," 2nd 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.Ausubel 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).

[0058] II. Definition 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.

[0059] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to a "molecule" includes any combination of two or more such molecules, and the like.

[0060] The term "about," as used herein, refers to a normal range of error for the respective value, which would be readily understood by one of ordinary skill in the art. Reference herein to "about" a value or parameter includes (and describes) embodiments that are directed to the value or parameter itself.

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

[0062] The term "CD79b," as used herein, unless otherwise specified, 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 that results from processing within a cell. The term also encompasses naturally occurring variants of CD79b, e.g., splice variants, allelic variants, and isoforms. The CD79b polypeptides described herein can be isolated from a variety of sources, such as from human tissue types or from 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 CD79b polypeptide derived from nature. Such native-sequence CD79b polypeptides can be isolated from nature or can be produced by recombinant or synthetic techniques. 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.

[0063] 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. USA 85(1988) 208-12; Stamenkovic, I. et al., J. Exp. Med. 167(1988) 1975-80; Einfeld, DA et 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.

[0064] 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 CD20-expressing cells can occur by one or more of the following mechanisms: induction of cell death / apoptosis, ADCC, and CDC. Art-recognized synonyms for CD20 include B lymphocyte antigen CD20, B lymphocyte surface antigen B1, Leu-16, Bp35, BM5, and LF5.

[0065] The term "CD20 antigen expression" is intended to refer to a significant level of expression of the CD20 antigen on cells, such as T cells or B cells. In one embodiment, a patient treated according to the method 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 PCR-based detection of corresponding mRNA.

[0066] "Affinity" refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of a molecule X for its partner Y can generally be represented by a dissociation constant (Kd). Affinity can be measured by common methods known in the art, including those described herein. Specific illustrative explanations and exemplary embodiments for measuring binding affinity are described below.

[0067] An "affinity matured" antibody refers to an antibody that has one or more modifications in one or more hypervariable regions (HVRs) compared to a parent antibody that does not have such modifications, which improve the affinity of the antibody for its antigen.

[0068] The term "antibody" is used herein in the broadest sense and encompasses a variety of antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired antigen-binding activity.

[0069] "Antibody fragment" refers to a molecule other than an intact antibody that contains a portion of the intact antibody that binds the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv); and multispecific antibodies formed from antibody fragments.

[0070] An "antibody that binds to the same epitope" as a reference antibody refers to an antibody that blocks the reference antibody from binding to its antigen by 50% or more in a competition assay, and conversely, a reference antibody that blocks the antibody from binding to its antigen by 50% or more in a competition assay. Exemplary competition assays are provided herein.

[0071] The term "epitope" refers to the specific site on an antigen molecule to which an antibody binds.

[0072] 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.

[0073] The "class" of an antibody refers to the type of constant domain or constant region carried by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, some of which can be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy-chain constant domains corresponding to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0074] The term "anti-CD79b antibody" or "antibody that binds to CD79b" refers 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 certain embodiments, an antibody that binds to CD79b has a dissociation constant (Kd) of 1 μM or less, 100 nM or less, 10 nM or less, 1 nM or less, or 0.1 nM or less. In certain embodiments, the anti-CD79b antibody binds to an epitope of CD79b that is conserved among CD79b from different species.

[0075] 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 when targeting CD20. Preferably, the binding of an anti-CD20 antibody to an unrelated non-CD20 protein is less than about 10% of the binding of the antibody to CD20, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, an antibody that binds to CD20 has a dissociation constant (Kd) of 1 μM or less, 100 nM or less, 10 nM or less, 1 nM or less, or 0.1 nM or less. In certain embodiments, the anti-CD20 antibody binds to an epitope of CD20 that is conserved among CD20 from different species.

[0076] An "isolated" antibody is one that is separated from components of its natural environment. In some embodiments, the antibody is purified to greater than 95% or greater than 99% purity, for example, as determined by electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse-phase HPLC). For a review of methods for assessing antibody purity, see, 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 be referred to as "VH." The variable domain of a light chain may be referred to as "VL." These domains are generally the most variable parts of an antibody and contain the antigen-binding sites.

[0077] 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 such nucleic acid molecule(s) in a single vector or separate vectors, and wherein such nucleic acid molecule(s) are present in one or more locations within a host cell.

[0078] The term "monoclonal antibody," as used herein, refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., each individual antibody in the population is identical and / or binds to the same epitope, except for possible variant antibodies, including, for example, naturally occurring mutations or mutations that arise during the production of a monoclonal antibody preparation, of which such variants are generally present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and should not be construed as requiring production of the antibody by any particular method. For example, 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.

[0079] 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 composition.

[0080] "Native antibodies" refer to naturally occurring immunoglobulin molecules with various structures. For example, native IgG antibodies are heterotetrameric glycoproteins of approximately 150,000 daltons, composed of two identical disulfide-bonded light chains and two identical heavy chains. From the N-terminus to the C-terminus, each heavy chain contains 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 contains a variable region (VL), also called a variable light domain or light chain variable domain, followed by a constant light (CL) domain. Based on the amino acid sequence of its constant domain, the light chain of an antibody may be assigned to one of two types, called κ (kappa) or λ (lambda).

[0081] As used herein, the term "Fc region" is used to define the C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. This term includes native sequence Fc regions and variant Fc regions. In one embodiment, a human IgG heavy chain Fc region extends from Cys226 or from Pro230 to the carboxyl terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present. Unless otherwise specified herein, the numbering of amino acid residues in the Fc region or constant region follows the EU numbering system (also referred to as the EU index) as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0082] "Framework" or "FR" refers to variable domain residues other than hypervariable region (HVR) residues. The FR of a variable domain typically consists of four domains: FR1, FR2, FR3, and FR4. Thus, the HVR and FR sequences typically appear in VH (or VL) in the following order: FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0083] For purposes herein, an "acceptor human framework" is a framework that comprises the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or a human consensus framework, as defined below. An acceptor human framework "derived from" a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence or may contain amino acid sequence changes. In some embodiments, the number of amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, the VL acceptor human framework is identical in sequence to the VL human immunoglobulin framework sequence or the human consensus framework sequence.

[0084] The terms "full-length antibody," "intact antibody," and "whole antibody" are used interchangeably herein to 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.

[0085] The terms "host cell," "host cell line," and "host cell culture" are used interchangeably 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, but 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 in the invention.

[0086] A "human antibody" is an antibody having an amino acid sequence corresponding to an antibody produced by a human or human cell, or an antibody of non-human origin that utilizes human antibody-encoding sequences, such as the human antibody repertoire. This definition of human antibody specifically excludes humanized antibodies that contain non-human antigen-binding residues.

[0087] A "human consensus framework" is a framework that represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup as in Kabat et al., Sequences of Proteins of Immunological Interest, 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).

[0088] A "humanized" antibody refers to a chimeric antibody comprising amino acid residues derived from non-human HVRs and human FRs. In certain embodiments, a humanized antibody comprises substantially all of at least one, and typically two, variable domains, in which all or substantially all of the HVRs (e.g., CDRs) correspond to those of a non-human antibody and all or substantially all of the FRs correspond to those of 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 undergone humanization.

[0089] The term "hypervariable region" or "HVR," as used herein, refers to each of the regions of an antibody variable domain that are hypervariable in sequence and / or form structurally defined loops ("hypervariable loops"). Native four-chain antibodies generally contain six HVRs, three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3). HVRs generally contain amino acid residues from the hypervariable loops and / or from the "complementarity-determining regions" (CDRs), the latter of which have the highest sequence variability and / or are involved in antigen recognition. Exemplary hypervariable loops occur at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3). (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987).) Exemplary CDRs (CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3) are located at amino acid residues 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)). With the exception of CDR1 in VH, CDRs generally comprise amino acid residues that form hypervariable loops. CDRs also comprise "specificity-determining regions," or "SDRs," which are residues that contact antigen. The SDRs are contained within regions of the 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 in the variable domain (e.g., FR residues) are numbered herein according to Kabat et al., supra.

[0090] The term "variable region" or "variable domain" refers to the domain of an antibody heavy or light chain that is involved in binding to an antigen. The variable domains of the heavy and light chains of natural antibodies (VH and VL, respectively) generally 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 by screening a library of complementary VL or VH domains, respectively, using the VH or VL domain of an antibody that binds to the antigen. See, for example, Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

[0091] "Effector functions" refer to biological activities attributable to the Fc region of an antibody and vary 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; downregulation of cell surface receptors (e.g., B cell receptors); and B cell activation.

[0092]

[0023] A "CD79b polypeptide variant" refers to a CD79b polypeptide, preferably an active CD79b polypeptide, as defined herein, having at least about 80% amino acid sequence identity with 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 a 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 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, or 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, a CD79b variant polypeptide will be at least about 10 amino acids in length, or 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, 10 90, 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, or 600 amino acids in length, or longer.Optionally, the CD79b variant polypeptide has no more than one conservative amino acid substitution compared to a native CD79b polypeptide sequence, or no more than 2, 3, 4, 5, 6, 7, 8, 9, or 10 conservative amino acid substitutions compared to a native CD79b polypeptide sequence.

[0093] "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, 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 sequence alignment, including any algorithms necessary to achieve maximum alignment over the entire length of the sequences being compared. However, for purposes herein, percent amino acid sequence identity values ​​are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was 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.

[0094] 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 relative to a given amino acid sequence B (alternatively, it may be written as a given amino acid sequence A having or comprising a certain % amino acid sequence identity to, with, or relative 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 matches by the sequence alignment program ALIGN-2 in that program's alignment of A and B, and Y is the total number of amino acid residues in B. It will be understood that if the length of amino acid sequence A is different from the length of amino acid sequence B, the % amino acid sequence identity of A to B will differ from 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.

[0095] The term "vector," as used herein, refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. This term includes not only vectors as self-replicating nucleic acid structures, but also vectors that are integrated into the genome of a host cell into which they are introduced. Certain 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."

[0096] An "immunoconjugate" is an antibody conjugated to one or more heterologous molecules, including but not limited to, cytotoxic agents.

[0097] In the context of the formulas provided herein, "p" refers to the average number of drug moieties per antibody, which can range, for example, from about 1 to about 20 drug moieties per antibody, and in certain 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 3.5).

[0098] As used herein, the term "cytotoxic agent" refers to a substance that inhibits or prevents the function of cells and / or causes cell death or destruction. Cytotoxic agents include radioisotopes (e.g., At 211 , I 131 , I 125 , Y 90 ,Re 186 ,Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 , and radioactive isotopes 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 anti-tumor or anti-cancer agents disclosed below.

[0099] 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 abnormal blood vessel growth associated with nevus diseases, edema (e.g., associated with brain tumors), and Meigs' syndrome.More specific examples include, but are not limited to, relapsed or refractory NHL, front 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, nodal 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 / Refractory follicular lymphoma), intermediate-grade diffuse NHL, diffuse large cell lymphoma (DLBCL), aggressive NHL (including aggressive first-line NHL and aggressive relapsed NHL), NHL relapsing 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 lymphoma, precursor (peripheral) large granular lymphocytic leukemia, mycosis fungoides and / or Sézary syndrome, cutaneous (cutaneous) lymphoma, anaplastic large cell lymphoma, angiocentric lymphoma.

[0100] 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 certain embodiments, the individual or subject is human.

[0101] 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.

[0102] The term "pharmaceutical formulation" refers to a preparation in which the biological activity of the active ingredient contained in the preparation is in a form such that it is effective, and which does not contain additional components that are unacceptably toxic to the subject to which the formulation is administered.

[0103] 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.

[0104] As used herein, "treatment" (and grammatical variations thereof, 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 either prophylactically 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, reduction in the rate of disease progression, amelioration or remission of disease state, and remission or improved prognosis. In some embodiments, the antibodies described herein are used to delay the onset of disease or to slow the progression of the disease.

[0105] The term "CD79b-positive cancer" refers to a cancer comprising cells expressing CD79b on their surface. In some embodiments, cell surface expression of CD79b is determined using an antibody to CD79b, e.g., by immunohistochemistry, FACS, or the like. Alternatively, CD79b mRNA expression, which is believed to correlate with cell surface CD79b expression, can be determined by a method selected from in situ hybridization and RT-PCR (including quantitative RT-PCR).

[0106] As used herein, "in conjunction with" refers to the administration of one treatment modality with another treatment modality. Thus, "in conjunction with" refers to the administration of one treatment modality to an individual before, during, or after the administration of another treatment modality.

[0107] Chemotherapeutic agents are chemical compounds useful in the treatment of cancer. Examples of chemotherapeutic agents and their derivatives 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 (®, Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (sirolimus, RAPAMUNE®, Wyeth), lapatinib (TYKERB®, GSK572016, GlaxoSmithKline), Kline), lonafamib (SCH 66336), sorafenib (NEXAVAR®, Bayer Alkylating agents such as cyclophosphamide (CYTOXAN®), alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylmelamine; acetogenins (especially bullatacin and bullatacinone); camptothecins (including topotecan and irinotecan); bryostatin; kallistatin; CC-1065 (including synthetic analogs of adozelesin, carzelesin, and bizelesin); cryptophycins (especially cryptophycin 1 and cryptophycin 8); adrenocorticosteroids (including prednisone and prednisolone); cyproterone acetate;5α-reductase inhibitors, including finasteride and dutasteride; vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat; dolastatins; aldesleukin, talc; duocarmycins (including synthetic analogs, KW-2189 and CB1-TM1); eletarobin; pancratistatin; sarcodictine; spongistatins; chlorambucil, chromafadine, chlorophosphamide, estramustine, ifosfamide, mechlorestamine, mechlorestamine oxide hydrochloride, melphalan, nobembine, phenesterine, prednimustine, trofosfamide, nitrogen mustards such as uracil mustard, nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics such as enidine antibiotics (e.g., calicheamicin, particularly calicheamicin 1I and calicheamicin 1I (Angew Chem. Intl. Ed. Engl. 199433:183-186); dynemicins, including dynemicin A; bisphosphonates such as clodronate; neocarzinostatin chromophores and related enediyne antibiotic chromophores, as well as esperamicin (enediyne antibiotic chromophores), aclacinomycin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholinodoxorubicin, cyanomorpholin nodoxorubicin, 2-pyrrolinodoxorubicin, deoxydoxorubicin, epirubicin, esorubicin, everolimus, sotrataurin, idarubicin, marcelomycin, mitomycin such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, chelamycin, rodorubicin, streptozocin, tuberculin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate;Purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiosteine, and testolactone; antiadrenergics such as aminoglutethimide, mitotane, and trilosteine; folic acid supplements such as furoic acid; acegraton; aldophosphamide glycosides; aminolevulinic acid; etolactone Niruracil; Amsacrine; Bestravsil; Bisantrene; Edatraxate; Defofamine; Demecolcine; Diaziquione; Elfomitin; Elliptine acetate; Amepothilone; Etoglucide; Gallium nitrate; Hydroxyurea; Lentinan; Lonidynin; Maytansinoids such as maytansine and ansamitocin; Mitoguazone; Mitoxantrone; Mopidamol; Nitraerin; Pentostatin; Fenamet; Pirarubicin; Rosoxantrone; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; PSK (registered trademark) 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® (Cremophofree), an albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumburg, Illinois), and TAXOTERE® (docetaxel;Sanofi-Aventis), chlorambucil, GEMZAR® (gemcitabine), 6-thioguanine, mercaptopurine, methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ibosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); nobandrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELO DA®); ibandronate; CPT-11; the topoisomerase inhibitor RFS2000; 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 (an abbreviation for combination therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone), FOLFOX (oxaliplatin in conjunction with 5-FU and leucovorin; (商標) )). Additional examples of chemotherapeutic agents include bendamustine (or bendamustine-HCl) (Treanda®), ibrutinib, lenalidomide, and / or idelalisib (GS-1101).

[0108] Further examples of chemotherapeutic agents include "antihormonal agents," which act to regulate, reduce, block, or inhibit the effectiveness of hormones that can promote cancer growth, often in the form of systemic or body-wide treatments. They may themselves be hormones. Examples include antiestrogens and selective estrogen receptor modulators (SERMs), such as 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 E LHRH agonists such as LIGARD®, goserelin acetate, buserelin acetate, and triptorelin; antiandrogens such as flutamide, nilutamide, and bicalutamide; and aromatase inhibitors that inhibit the enzyme aromatase, which controls estrogen production in the adrenal glands, such as 4(5)-imidazole, aminoglutethimide, megestrol acetate (MEGASE®), exemestane (AROMASIN®), holmestein, fadrozole, vorozole (RIVISOR®), letrozole (FEMARA®), and anastrozole (ARIMIDEX®).Further included in such definition of chemotherapeutic agent are 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®); as well as troxacitabine. (1,3-dioxolane nucleoside cytosine analogs); antisense oligonucleotides, particularly those 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.

[0109] 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.

[0110] 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 agents in combination with compounds include apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, celelizumab pegol, cidofusituzumab, cidutuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, natalizumab, , nimotuzumab, norobizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pexelizumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, reslizumab, rovelizumab, lupizumab, sibrotuzumab, siplizumab, sontuzumab, tacatatuzumab tetraxetan, tadoxizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumab celmoreukin, tuxituuzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and interleukin-12 and anti-interleukin-12 (ABT-874 / J695, Wyeth Research and Abbott Laboratories), an all-human sequence, full-length IgG1λ antibody engineered to recognize the p40 protein.

[0111] The term "package insert" is used to refer to instructions typically included in commercial packaging for a therapeutic product, including information regarding the indications, uses, dosage, administration, concomitant therapy, contraindications and / or warnings regarding such therapeutic product.

[0112] "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 (-C(CH3)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)2CH2CH2CH2CH3), 3-methyl-2-pentyl (- CH(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 (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3).

[0113] The term "C1-C8 alkyl" as used herein refers to a straight or branched, saturated or unsaturated hydrocarbon having 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, while branched C1-C8 alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, and unsaturated C1-C8 alkyls. 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.

[0114] 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. 12Alkyl groups 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.

[0115] 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, while branched C1-C6 alkyls include, but are not limited to, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and 2-methylbutyl, and 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 can be unsubstituted or substituted with one or more groups as described above for the C1-C8 alkyl group.

[0116] As used herein, the term "C1-C4 alkyl" refers to a straight-chain or branched, saturated or unsaturated hydrocarbon having 1 to 4 carbon atoms. Representative "C1-C4 alkyl" groups include, but are not limited to, -methyl, -ethyl, -n-propyl, and -n-butyl, while branched-chain 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.

[0117] 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.

[0118] "Alkenyl" means an alkyl group having at least one site of unsaturation, i.e., a carbon-carbon sp 2 It is a C2-C18 hydrocarbon containing normal, secondary, tertiary, or cyclic carbon atoms with a double bond. Examples include, but are not limited to, ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2). "C2-C8 alkenyl" refers to an alkenyl having at least one unsaturated site, 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.

[0119] An "alkynyl" is a C2-C18 hydrocarbon containing normal, secondary, tertiary, or cyclic carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond. Examples include, but are not limited to, acetylene (-C≡CH) and propargyl (-CH2C≡CH). A "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.

[0120] "Alkylene" refers to a saturated, branched or straight-chain or cyclic hydrocarbon radical having 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 (--CH-), 1,2-ethyl (--CHCH-), 1,3-propyl (--CHCHCH-), 1,4-butyl (--CHCHCHCH-), and the like.

[0121] "C1-C 10 "Alkylene" is a group of the formula -(CH2) 1-10 - 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.

[0122] "Alkenylene" refers to an unsaturated, branched or straight-chain or cyclic hydrocarbon radical having 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-).

[0123] "Alkynylene" refers to an unsaturated, branched, or straight-chain or cyclic hydrocarbon radical having 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-).

[0124] "Aryl" refers to a carbocyclic aromatic group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. A carbocyclic aromatic group 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.

[0125] "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 a carbocyclic aromatic ring. 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.

[0126] 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 structures below. TIFF0007785016000017.tif25170 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.

[0127] "Arylalkyl" refers to an alkyl group consisting of a carbon atom, typically a terminal or sp 3 "(Aryl)" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a 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, 2-naphthophenylethan-1-yl, and the like. An arylalkyl group contains 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.

[0128] "Heteroarylalkyl" refers to a heteroaryl group consisting of a carbon atom, typically a terminal or sp 3This refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom is replaced with a heteroaryl radical. Typical heteroarylalkyl groups include, but are not limited to, 2-benzimidazolylmethyl, 2-furylethyl, and the like. Heteroarylalkyl groups contain 6 to 20 carbon atoms; for example, the alkyl portion of the heteroarylalkyl group, including the alkanyl, alkenyl, or alkynyl 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, such as a bicyclo[4,5], [5,5], [5,6], or [6,6] system.

[0129] "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 - , -NR2, -NR3, =NR, -CX3, -CN, -OCN, -SCN, -N=C=O, -NCS, -NO, -NO2, =N2, -N3, NC(=O)R, -C(=O)R, -C(=O)NR2, -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, —C(═S)NR, —C(═NR)NR (wherein each X is independently a halogen): F, Cl, Br, or I; each R is independently —H, C—C 18 Alkyl, C6-C20 Aryl, C3-C 14 The alkylene, alkenylene and alkynylene groups may be substituted in the same manner.

[0130] "Heteroaryl" and "heterocycle" refer to a ring system in which one or more ring atoms is a heteroatom, such as nitrogen, oxygen, and sulfur. The heterocycle radical contains 3 to 20 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S. The heterocycle can be a 3- to 7-membered monocycle (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or a 7- to 10-membered bicycle (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S), such as a bicyclo[4,5], [5,5], [5,6], or [6,6] system.

[0131] Exemplary heterocycles are described, for example, in Paquette, Leo A., "Principles of Modern Heterocyclic Chemistry" (WA Benjamin, New York, 1968), especially 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), especially volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566.

[0132] Examples of heterocycles include, but are not limited to, pyridyl, dihydropyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur-oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl. yl, 4-piperidonyl, 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, Isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl aryl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, and isatinoyl.

[0133] By way of example, and without limitation, a carbon-bonded heterocycle may be bonded at the 2-, 3-, 4-, 5-, or 6-position of a pyridine, the 3-, 4-, 5-, or 6-position of a pyridazine, the 2-, 4-, 5-, or 6-position of a pyrimidine, the 2-, 3-, 5-, or 6-position of a pyrazine, the 2-, 3-, 4-, or 5-position of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole, the 2-, 4-, or 5-position of an oxazole, imidazole, or thiazole, the 3-, 4-, or 5-position of an isoxazole, pyrazole, or isothiazole, the 2- or 3-position of an aziridine, the 2-, 3-, or 4-position of an azetidine, the 2-, 3-, 4-, 5-, 6-, 7-, or 8-position of a quinoline, or the 1-, 3-, 4-, 5-, 6-, 7-, or 8-position of an isoquinoline. Even more typically, the carbon-bonded 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.

[0134] By way of example, and without 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.

[0135] 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 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.

[0136] "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 heterocyclo can be unsubstituted or substituted with up to six 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.

[0137] "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. 20Heterocycles 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.

[0138] "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.

[0139] "Carbocycle" refers to 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.

[0140] 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.

[0141] "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.

[0142] "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, and the like, e.g., -(CR2). n O(CR2) n -, alkyloxy (e.g., polyethyleneoxy, PEG, polymethyleneoxy) and alkylamino (e.g., polyethyleneamino, Jeffamine™) repeating units; 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.

[0143] The term "chiral" refers to molecules that possess the property of being non-superimposable on their mirror image partners, while the term "achiral" refers to molecules that are superimposable on their mirror image partners.

[0144] 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.

[0145] "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 may separate under high-resolution analytical procedures such as electrophoresis and chromatography.

[0146] "Enantiomers" refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0147] 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 indicate the absolute configuration of the molecule about its chiral center. The prefixes d and l, or (+) and (-), are used to indicate the rotation characteristic of the compound of plane-polarized light, with (-) or 1 meaning that the compound is levorotatory. Compounds prefixed with (+) 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 may 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.

[0148] "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.

[0149] 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.

[0150] III. Methods for Treating Follicular Lymphoma Provided herein is a method for treating follicular lymphoma (FL) in a human in need thereof, comprising administering to the human an effective amount of Formula (a) (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 1 to 8.

[0024] A method is provided, comprising administering to a human a Bcl-2 inhibitor and an anti-CD20 antibody, wherein the human achieves a complete response (CR) during or after treatment. In some embodiments, the anti-CD79b immunoconjugate is huMA79bv28-MC-vc-PAB-MMAE. In some embodiments, the immunoconjugate is polatuzumab vedotin-piiq (CAS Registry Number 1313206-42-6). In some embodiments, the anti-CD79b immunoconjugate is huMA79bv28-MC-vc-PAB-MMAE. In some embodiments, the immunoconjugate is polatuzumab vedotin-piiq (CAS Registry Number 1313206-42-6). In some embodiments, the immunoconjugate is polatuzumab vedotin-piiq. In some embodiments, the Bcl-2 inhibitor is venetoclax. 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.

[0151] The term "co-administration" or "co-administering" refers to the administration of an anti-CD79b immunoconjugate, a Bcl-2 inhibitor, and an anti-CD20 antibody as two (or more) separate formulations (or as one single formulation comprising an anti-CD79b immunoconjugate, a Bcl-2 inhibitor, and an anti-CD20 antibody). When separate formulations are used, the co-administration can be simultaneous or sequential, preferably with a period of time during which all active agents simultaneously exert their biological activity. The anti-CD79b immunoconjugate, a Bcl-2 inhibitor, and an anti-CD20 antibody are co-administered simultaneously or sequentially.

[0152] The anti-CD79b immunoconjugates and additional therapeutic agents (e.g., Bcl-2 inhibitors and anti-CD20 antibodies) provided herein for use in any of the therapeutic methods described herein will be formulated, dosed, and administered in a manner consistent with good medical practice. Factors to consider 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 delivery of the agent, the method of administration, the administration schedule, and other factors known to medical practitioners. The immunoconjugates are optionally, but need not necessarily, formulated with one or more agents currently used to prevent or treat the disorder in question.

[0153] The amount and timing of co-administration of the anti-CD79b immunoconjugate and additional therapeutic agent will depend on the type (species, sex, age, weight, etc.) and condition of the patient being treated, as well as the severity of the disease or condition being treated. The anti-CD79b immunoconjugate, Bcl-2 inhibitor, and anti-CD20 antibody are suitably co-administered to the patient at one time or over a series of treatments, e.g., on the same or subsequent days.

[0154] In some embodiments, the dose of the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin-piiq) 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-CD79b 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 dose of the anti-CD79b immunoconjugate is about 1.4 mg / kg. In some embodiments, the dose of the anti-CD79b immunoconjugate is about 1.8 mg / kg. In some embodiments, the dose of the anti-CD79b immunoconjugate is about 2.4 mg / kg. In some embodiments, the dose of the anti-CD79b immunoconjugate is about 3.2 mg / kg. In some embodiments, the dose of the anti-CD79b immunoconjugate is about 3.6 mg / kg. In some embodiments of any method, the anti-CD79b immunoconjugate is administered q3wk (e.g., on day 1 of each 21-day cycle). In some embodiments, the anti-CD79b immunoconjugate is administered by intravenous infusion. In some embodiments, the dose administered by infusion ranges from about 1 mg to about 1,500 mg per administration. Alternatively, the 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 by injection is about 1 μg / m per administration. 2 ~Approx. 10,000μg / m 2 Alternatively, the dosage range is about 1 μg / m 2 ~Approx. 1000μg / m2, approx. 1μg / m 2 ~about 800μg / m2, about 1μg / m 2 ~about 600μg / m2, about 1μg / m2 ~about 400μg / m2, about 10μg / m 2 ~Approx. 500μg / m2, approx. 10μg / m 2 ~Approx. 300μg / m2, approx. 10μg / m 2 ~approximately 200 μg / m², and approximately 1 μg / m² 2 ~about 200μg / m 2 The dose can be administered once a day, once a week, multiple times a week but less than once a day, multiple times a month but less than once a day, multiple times a month but less than once a week, once a month, once every 21 days, or intermittently to alleviate or relieve the symptoms of the disease. Administration can be continued at any of the intervals and doses described herein until the tumor or symptoms of the B-cell proliferative disorder being treated are remitted. If such remission or relief is prolonged by such continued administration, administration can be continued after the remission or relief of symptoms is achieved.

[0155] In some embodiments, the dose of anti-CD20 antibody is about 300 to 1600 mg / m 2 and / or 300 to 2000 mg. In some embodiments, the dose of anti-CD20 antibody is about 300 mg / m 2 , 375 mg / m 2 , 600 mg / m 2 , 1000 mg / m 2 or 1250 mg / m 2 and / or 300 mg, 1000 mg, or 2000 mg. In some embodiments, the anti-CD20 antibody is rituximab and the administered dose is 375 mg / m 2 In some embodiments, the anti-CD20 antibody is obinutuzumab and the administered dose is 1000 mg. In some embodiments, the anti-CD20 antibody is administered q1w( すなわち, once a week). In some embodiments, the anti-CD20 antibody is administered on days 1, 8, and 15 of a 21-day cycle. In some embodiments, the anti-CD20 antibody is administered q3w (i.e., every 3 weeks, or once every 21 days). In some embodiments, the anti-CD20 antibody is administered on day 1 of a 21-day cycle. In some embodiments, the anti-CD20 antibody is administered on days 1, 8, and 15 of the first 21-day cycle and on day 1 of subsequent 21-day cycles (e.g., day 1 of cycles 2, 3, 4, 5, and 6). In some embodiments, the anti-CD20 antibody is administered once every two months. In some embodiments, the dose of the defucosylated anti-CD20 antibody (preferably the defucosylated humanized B-Ly1 antibody) can be 800 to 1600 mg (in one embodiment, 800 to 1200 mg, e.g., 1000 mg) or 400 to 1200 mg (in one embodiment, 800 to 1200 mg). In some embodiments, the dose is a single 1000 mg dose on a 3-week dosing schedule (e.g., once every 21 days).

[0156] In some embodiments, the dose of the Bcl-2 inhibitor (e.g., venetoclax) is about 100 mg to about 800 mg (e.g., about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg). In some embodiments, venetoclax is administered at a dose of about 100 mg to about 800 mg. In some embodiments, venetoclax is administered at a dose of about 100 mg. In some embodiments, venetoclax is administered at a dose of about 200 mg. In some embodiments, venetoclax is administered at a dose of about 400 mg. In some embodiments, venetoclax is administered at a dose of about 600 mg. In some embodiments, venetoclax is administered at a dose of about 800 mg.

[0157] The immunoconjugates provided herein (and any additional therapeutic agents, e.g., Bcl-2 inhibitors and anti-CD20 antibodies) for use in any of the therapeutic methods 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. Administration can be by any suitable route, e.g., injection, such as intravenous or subcutaneous injection, depending in part on whether the administration is brief or chronic. Various dosing schedules are contemplated herein, including, but not limited to, single administration or multiple administrations over various time points, bolus administration, and pulse infusion.

[0158] The anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin-piiq), Bcl-2 inhibitor (e.g., venetoclax), and anti-CD20 antibody (e.g., obinutuzumab or rituximab) can be administered by the same or different routes of administration. In some embodiments, the anti-CD79b immunoconjugate (e.g., polatuzumab vedotin-piiq) is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, inhalation, intrathecally, intracerebroventricularly, or intranasally. In some embodiments, the immunoconjugate (e.g., polatuzumab vedotin-piiq) is administered by intravenous infusion. In some embodiments, the anti-CD20 antibody (e.g., obinutuzumab or rituximab) is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implant, by inhalation, intrathecally, intracerebroventricularly, or intranasally. In some embodiments, the anti-CD20 antibody (e.g., rituximab or obinutuzumab) is administered by intravenous infusion. In some embodiments, the Bcl-2 inhibitor (e.g., venetoclax) is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implant, by inhalation, intrathecally, intravenously, intravenously, or intranasally. In some aspects, the Bcl-2 inhibitor (e.g., venetoclax) is administered orally, for example, by tablet, capsule, or any other suitable means for oral administration known in the art or described herein. In some embodiments, the anti-CD79b immunoconjugate and the anti-CD20 antibody (such as obinutuzumab or rituximab) are each administered via intravenous infusion, and the Bcl-2 inhibitor (e.g., venetoclax) is administered orally. Effective amounts of the anti-CD79b immunoconjugate, the Bcl-2 inhibitor (e.g., venetoclax), and the anti-CD20 antibody (e.g., obinutuzumab or rituximab) can be administered for the prevention or treatment of disease.

[0159] In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin-piiq) is administered at a dose of about 1.4 mg / kg to about 1.8 mg / kg. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin-piiq) is administered at a dose of about 1.4 mg / kg. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin-piiq) is administered at a dose of about 1.8 mg / kg. Alternatively or additionally, in some embodiments, the Bcl-2 inhibitor (e.g., venetoclax) is administered at a dose of about 200 mg to about 800 mg. In some embodiments, the Bcl-2 inhibitor (e.g., venetoclax) is administered at a dose of about 200 mg. In some embodiments, the Bcl-2 inhibitor (e.g., venetoclax) is administered at a dose of about 400 mg. In some embodiments, the Bcl-2 inhibitor (e.g., venetoclax) is administered at a dose of about 600 mg. In some embodiments, the Bcl-2 inhibitor (e.g., venetoclax) is administered at a dose of about 800 mg. Alternatively, or in further embodiments, the anti-CD20 antibody is obinutuzumab. In some embodiments, obinutuzumab is administered at a dose of about 1000 mg. Alternatively, or in further embodiments, the anti-CD20 antibody is rituximab. In some embodiments, rituximab is administered at a dose of about 375 mg / m 2 is administered at a dose of

[0160] In some embodiments, the anti-CD79b immunoconjugate (e.g., polatuzumab vedotin-piiq), Bcl-2 inhibitor (e.g., venetoclax), and anti-CD20 antibody (e.g., obinutuzumab or rituximab) are administered during an induction phase. The induction phase refers to the period of treatment during which the anti-CD79b immunoconjugate, Bcl-2 inhibitor, and anti-CD20 antibody are administered to a human. In some embodiments, the induction phase comprises less than one complete 21-day cycle. In some embodiments, the induction phase comprises one to six (e.g., one, two, three, four, five, or six) 21-day cycles. In some embodiments, the induction phase comprises at least six 21-day cycles. In some embodiments, the anti-CD79b immunoconjugate, Bcl-2 inhibitor (e.g., venetoclax), and anti-CD20 antibody (e.g., obinutuzumab or rituximab) are administered during at least six 21-day cycles.

[0161] In some embodiments, during the induction phase, on day 1 of a first 21-day cycle, the immunoconjugate is administered intravenously at a dose of about 1.4 mg / kg; the Bcl-2 inhibitor is venetoclax, and on days 1-21 of a first 21-day cycle, venetoclax is administered orally at a dose of about 200 mg; and the anti-CD20 antibody is obinutuzumab, and on days 1, 8, and 15 of a first 21-day cycle, obinutuzumab is administered orally at a dose of about 1000 mg. on day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, the immunoconjugate is administered intravenously at a dose of approximately 1.4 mg / kg; on days 1-21 of each of the second, third, fourth, fifth, and sixth 21-day cycles, venetoclax is administered orally at a dose of approximately 200 mg; and on day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, obinutuzumab is administered intravenously at a dose of approximately 1000 mg.

[0162] In some embodiments, during the induction phase, on day 1 of a first 21-day cycle, the immunoconjugate is administered intravenously at a dose of about 1.4 mg / kg; the Bcl-2 inhibitor is venetoclax, and on days 1-21 of each of the first 21-day cycle, venetoclax is administered orally at a dose of about 200 mg; and the anti-CD20 antibody is rituximab, and on days 1, 8, and 15 of each of the first 21-day cycle, rituximab is administered orally at a dose of about 375 mg / m 2 on Day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, the immunoconjugate is administered intravenously at a dose of about 1.4 mg / kg; on Days 1-21 of each of the second, third, fourth, fifth, and sixth 21-day cycles, venetoclax is administered orally at a dose of about 200 mg; and on Day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, rituximab is administered orally at a dose of about 375 mg / m 2 It is administered intravenously at a dose of

[0163] In some embodiments, during the induction phase, on day 1 of a first 21-day cycle, the immunoconjugate is administered intravenously at a dose of about 1.4 mg / kg; the Bcl-2 inhibitor is venetoclax, and on days 1-21 of a first 21-day cycle, venetoclax is administered orally at a dose of about 400 mg; and the anti-CD20 antibody is obinutuzumab, and on days 1, 8, and 15 of a first 21-day cycle, obinutuzumab is administered orally at a dose of about 1000 mg. on day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, the immunoconjugate is administered intravenously at a dose of approximately 1.4 mg / kg; on days 1-21 of each of the second, third, fourth, fifth, and sixth 21-day cycles, venetoclax is administered orally at a dose of approximately 400 mg; and on day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, obinutuzumab is administered intravenously at a dose of approximately 1000 mg.

[0164] In some embodiments, during the induction phase, on day 1 of a first 21-day cycle, the immunoconjugate is administered intravenously at a dose of about 1.4 mg / kg; the Bcl-2 inhibitor is venetoclax, and on days 1-21 of each of the first 21-day cycle, venetoclax is administered orally at a dose of about 400 mg; and the anti-CD20 antibody is rituximab, and on days 1, 8, and 15 of each of the first 21-day cycle, rituximab is administered orally at a dose of about 375 mg / m 2 on Day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, the immunoconjugate is administered intravenously at a dose of about 1.4 mg / kg; on Days 1-21 of each of the second, third, fourth, fifth, and sixth 21-day cycles, venetoclax is administered orally at a dose of about 400 mg; and on Day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, rituximab is administered orally at a dose of about 375 mg / m 2 It is administered intravenously at a dose of

[0165] In some embodiments, during the induction phase, on day 1 of a first 21-day cycle, the immunoconjugate is administered intravenously at a dose of about 1.4 mg / kg; the Bcl-2 inhibitor is venetoclax, and on days 1-21 of each of the first 21-day cycle, venetoclax is administered orally at a dose of about 600 mg; and the anti-CD20 antibody is obinutuzumab, and on days 1, 8, and 15 of the first 21-day cycle, obinutuzumab is administered orally at a dose of about 1000 mg. on day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, the immunoconjugate is administered intravenously at a dose of approximately 1.4 mg / kg; on days 1-21 of each of the second, third, fourth, fifth, and sixth 21-day cycles, venetoclax is administered orally at a dose of approximately 600 mg; and on day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, obinutuzumab is administered intravenously at a dose of approximately 1000 mg.

[0166] In some embodiments, during the induction phase, on day 1 of a first 21-day cycle, the immunoconjugate is administered intravenously at a dose of about 1.4 mg / kg; the Bcl-2 inhibitor is venetoclax, and on days 1-21 of each of the first 21-day cycle, venetoclax is administered orally at a dose of about 600 mg; and the anti-CD20 antibody is rituximab, and on days 1, 8, and 15 of each of the first 21-day cycle, rituximab is administered orally at a dose of about 375 mg / m 2 on Day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, the immunoconjugate is administered intravenously at a dose of about 1.4 mg / kg; on Days 1-21 of each of the second, third, fourth, fifth, and sixth 21-day cycles, venetoclax is administered orally at a dose of about 600 mg; and on Day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, rituximab is administered orally at a dose of about 375 mg / m 2 It is administered intravenously at a dose of

[0167] In some embodiments, during the induction phase, on day 1 of a first 21-day cycle, the immunoconjugate is administered intravenously at a dose of about 1.4 mg / kg; the Bcl-2 inhibitor is venetoclax, and on days 1-21 of a first 21-day cycle, venetoclax is administered orally at a dose of about 800 mg; and the anti-CD20 antibody is obinutuzumab, and on days 1, 8, and 15 of a first 21-day cycle, obinutuzumab is administered orally at a dose of about 1000 mg. On Day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, the immunoconjugate is administered intravenously at a dose of approximately 1.4 mg / kg; on Day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, venetoclax is administered orally at a dose of approximately 800 mg; and on Day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, obinutuzumab is administered intravenously at a dose of approximately 1000 mg.

[0168] In some embodiments, during the induction phase, on day 1 of a first 21-day cycle, the immunoconjugate is administered intravenously at a dose of about 1.4 mg / kg; the Bcl-2 inhibitor is venetoclax, and on days 1-21 of each of the first 21-day cycle, venetoclax is administered orally at a dose of about 800 mg; and the anti-CD20 antibody is rituximab, and on days 1, 8, and 15 of each of the first 21-day cycle, rituximab is administered orally at a dose of about 375 mg / m 2 on Day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, the immunoconjugate is administered intravenously at a dose of about 1.4 mg / kg; on Days 1-21 of each of the second, third, fourth, fifth, and sixth 21-day cycles, venetoclax is administered orally at a dose of about 800 mg; and on Day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, rituximab is administered orally at a dose of about 375 mg / m 2 It is administered intravenously at a dose of

[0169] In some embodiments, during the induction phase, on day 1 of a first 21-day cycle, the immunoconjugate is administered intravenously at a dose of about 1.8 mg / kg; the Bcl-2 inhibitor is venetoclax, and on days 1-21 of each of the first 21-day cycle, venetoclax is administered orally at a dose of about 200 mg; and the anti-CD20 antibody is obinutuzumab, and on days 1, 8, and 15 of the first 21-day cycle, obinutuzumab is administered orally at a dose of about 1000 mg. on day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, the immunoconjugate is administered intravenously at a dose of approximately 1.8 mg / kg; on days 1-21 of each of the second, third, fourth, fifth, and sixth 21-day cycles, venetoclax is administered orally at a dose of approximately 200 mg; and on day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, obinutuzumab is administered intravenously at a dose of approximately 1000 mg.

[0170] In some embodiments, during the induction phase, on day 1 of a first 21-day cycle, the immunoconjugate is administered intravenously at a dose of about 1.8 mg / kg, the Bcl-2 inhibitor is venetoclax, and on each of days 1-21 of a first 21-day cycle, venetoclax is administered orally at a dose of about 200 mg, and the anti-CD20 antibody is rituximab, and on each of days 1, 8, and 15 of the first 21-day cycle, rituximab is administered orally at a dose of about 375 mg / m 2 on Day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, the immunoconjugate is administered intravenously at a dose of about 1.8 mg / kg; on Days 1-21 of each of the second, third, fourth, fifth, and sixth 21-day cycles, venetoclax is administered orally at a dose of about 200 mg; and on Day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, rituximab is administered orally at a dose of about 375 mg / m 2 It is administered intravenously at a dose of

[0171] In some embodiments, during the induction phase, on day 1 of a first 21-day cycle, the immunoconjugate is administered intravenously at a dose of about 1.8 mg / kg; the Bcl-2 inhibitor is venetoclax, and on days 1-21 of each of the first 21-day cycle, venetoclax is administered orally at a dose of about 400 mg; and the anti-CD20 antibody is obinutuzumab, and on days 1, 8, and 15 of the first 21-day cycle, obinutuzumab is administered orally at a dose of about 1000 mg. on day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, the immunoconjugate is administered intravenously at a dose of approximately 1.8 mg / kg; on days 1-21 of each of the second, third, fourth, fifth, and sixth 21-day cycles, venetoclax is administered orally at a dose of approximately 400 mg; and on day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, obinutuzumab is administered intravenously at a dose of approximately 1000 mg.

[0172] In some embodiments, during the induction phase, on day 1 of a first 21-day cycle, the immunoconjugate is administered intravenously at a dose of about 1.8 mg / kg; the Bcl-2 inhibitor is venetoclax, and on days 1-21 of each of the first 21-day cycle, venetoclax is administered orally at a dose of about 400 mg; and the anti-CD20 antibody is rituximab, and on days 1, 8, and 15 of each of the first 21-day cycle, rituximab is administered orally at a dose of about 375 mg / m 2 on Day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, the immunoconjugate is administered intravenously at a dose of about 1.8 mg / kg; on Days 1-21 of each of the second, third, fourth, fifth, and sixth 21-day cycles, venetoclax is administered orally at a dose of about 400 mg; and on Day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, rituximab is administered orally at a dose of about 375 mg / m 2 It is administered intravenously at a dose of

[0173] In some embodiments, during the induction phase, on day 1 of a first 21-day cycle, the immunoconjugate is administered intravenously at a dose of about 1.8 mg / kg; the Bcl-2 inhibitor is venetoclax, and on days 1-21 of each of the first 21-day cycle, venetoclax is administered orally at a dose of about 600 mg; and the anti-CD20 antibody is obinutuzumab, and on days 1, 8, and 15 of the first 21-day cycle, obinutuzumab is administered orally at a dose of about 1000 mg. on day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, the immunoconjugate is administered intravenously at a dose of approximately 1.8 mg / kg; on days 1-21 of each of the second, third, fourth, fifth, and sixth 21-day cycles, venetoclax is administered orally at a dose of approximately 600 mg; and on day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, obinutuzumab is administered intravenously at a dose of approximately 1000 mg.

[0174] In some embodiments, during the induction phase, on day 1 of a first 21-day cycle, the immunoconjugate is administered intravenously at a dose of about 1.8 mg / kg; the Bcl-2 inhibitor is venetoclax, and on days 1-21 of each of the first 21-day cycle, venetoclax is administered orally at a dose of about 600 mg; and the anti-CD20 antibody is rituximab, and on days 1, 8, and 15 of each of the first 21-day cycle, rituximab is administered orally at a dose of about 375 mg / m 2 on Day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, the immunoconjugate is administered intravenously at a dose of about 1.8 mg / kg; on Days 1-21 of each of the second, third, fourth, fifth, and sixth 21-day cycles, venetoclax is administered orally at a dose of about 600 mg; and on Day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, rituximab is administered orally at a dose of about 375 mg / m 2 It is administered intravenously at a dose of

[0175] In some embodiments, during the induction phase, on day 1 of a first 21-day cycle, the immunoconjugate is administered intravenously at a dose of about 1.8 mg / kg; the Bcl-2 inhibitor is venetoclax, and on days 1-21 of each of the first 21-day cycle, venetoclax is administered orally at a dose of about 800 mg; and the anti-CD20 antibody is obinutuzumab, and on days 1, 8, and 15 of the first 21-day cycle, obinutuzumab is administered orally at a dose of about 1000 mg. on day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, the immunoconjugate is administered intravenously at a dose of approximately 1.8 mg / kg; on days 1-21 of each of the second, third, fourth, fifth, and sixth 21-day cycles, venetoclax is administered orally at a dose of approximately 800 mg; and on day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, obinutuzumab is administered intravenously at a dose of approximately 1000 mg.

[0176] In some embodiments, during the induction phase, on day 1 of a first 21-day cycle, the immunoconjugate is administered intravenously at a dose of about 1.8 mg / kg, the Bcl-2 inhibitor is venetoclax, and on days 1-21 of each of the first 21-day cycle, venetoclax is administered orally at a dose of about 800 mg, and the anti-CD20 antibody is rituximab, and on days 1, 8, and 15 of each of the first 21-day cycle, rituximab is administered orally at a dose of about 375 mg / m 2 on Day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, the immunoconjugate is administered intravenously at a dose of about 1.8 mg / kg; on Days 1-21 of each of the second, third, fourth, fifth, and sixth 21-day cycles, venetoclax is administered orally at a dose of about 800 mg; and on Day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, rituximab is administered orally at a dose of about 375 mg / m 2 It is administered intravenously at a dose of

[0177] Exemplary dosing and administration schedules for the induction phase are provided in Tables A-L below. [Table AH] TIFF0007785016000020.tif178170

[0178] In some embodiments, the anti-CD79b immunoconjugate, the Bcl-2 inhibitor, and the anti-CD20 antibody are administered sequentially during the induction phase. In some embodiments, on day 1 of a first 21-day cycle, the Bcl-2 inhibitor is administered before the anti-CD20 antibody, and the anti-CD20 antibody is administered before the immunoconjugate; on days 8 and 15 of the first 21-day cycle, the Bcl-2 inhibitor is administered before the anti-CD20 antibody; and on days 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, the Bcl-2 inhibitor is administered before the anti-CD20 antibody, and the anti-CD20 antibody is administered before the immunoconjugate.

[0179] In some embodiments, the immunoconjugate is polatuzumab vedotin-piiq, the anti-CD20 antibody is obinutuzumab, and the Bcl-2 inhibitor is venetoclax. In some embodiments, polatuzumab vedotin-piiq, venetoclax, and obinutuzumab are administered sequentially during the induction phase. In some embodiments, on day 1 of the first 21-day cycle, venetoclax is administered before obinutuzumab and obinutuzumab is administered before polatuzumab vedotin-piiq; on days 8 and 15 of the first 21-day cycle, venetoclax is administered before obinutuzumab; and on day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, venetoclax is administered before obinutuzumab and obinutuzumab is administered before polatuzumab vedotin-piiq.

[0180] In some embodiments, the immunoconjugate is polatuzumab vedotin-piiq, the anti-CD20 antibody is rituximab, and the Bcl-2 inhibitor is venetoclax. In some embodiments, polatuzumab vedotin-piiq, venetoclax, and rituximab are administered consecutively during the induction phase. In some embodiments, on day 1 of the first 21-day cycle, venetoclax is administered before rituximab, and rituximab is administered before polatuzumab vedotin-piiq; on days 8 and 15 of the first 21-day cycle, venetoclax is administered before rituximab, and rituximab is administered before polatuzumab vedotin-piiq; and on days 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, venetoclax is administered before rituximab, and rituximab is administered before polatuzumab vedotin-piiq.

[0181] In some embodiments, the anti-CD20 antibody is rituximab. In some embodiments, rituximab is administered at a dose of about 375 mg / m in combination with an anti-CD79b immunoconjugate and a Bcl-2 inhibitor according to any of the induction phases provided herein. 2 is administered at a dose of

[0182] In some embodiments, the anti-CD20 antibody is obinutuzumab. In some embodiments, obinutuzumab is administered at a dose of about 1000 mg in combination with an anti-CD79b immunoconjugate and a Bcl-2 inhibitor according to any of the induction phases provided herein.

[0183] In some embodiments, during the induction phase, on day 1 of a first 21-day cycle, the immunoconjugate (e.g., polatuzumab vedotin-piiq) is administered intravenously at a dose of about 1.4 mg / kg to about 1.8 mg / kg (e.g., 1.4 mg / kg or 1.8 mg / kg); the Bcl-2 inhibitor is venetoclax, and on each of days 1-21 of the first 21-day cycle, venetoclax is administered orally at a dose of about 200 mg to about 800 mg (e.g., any of 200 mg, 400 mg, 600 mg, or 800 mg); the anti-CD20 antibody is rituximab, and on each of days 1, 8, and 15 of the first 21-day cycle, rituximab is administered orally at a dose of about 375 mg / m 2 on day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, the immunoconjugate is administered intravenously at a dose of about 1.4 mg / kg to about 1.8 mg / kg (e.g., 1.4 mg / kg or 1.8 mg / kg); on days 1-21 of each of the second, third, fourth, fifth, and sixth 21-day cycles, venetoclax is administered orally at a dose of about 200 mg to about 800 mg (e.g., any of 200 mg, 400 mg, 600 mg, or 800 mg); and on day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, rituximab is administered orally at a dose of about 375 mg / m 2 It is administered intravenously at a dose of

[0184] In some embodiments, during the induction phase, on day 1 of a first 21-day cycle, the immunoconjugate (e.g., polatuzumab vedotin-piiq) is administered intravenously at a dose of about 1.4 mg / kg to about 1.8 mg / kg (e.g., 1.4 mg / kg or 1.8 mg / kg), the Bcl-2 inhibitor is venetoclax, and on each of days 1-21 of the first 21-day cycle, venetoclax is administered orally at a dose of about 200 mg to about 800 mg (e.g., any of 200 mg, 400 mg, 600 mg, or 800 mg), and the anti-CD20 antibody is rituximab, and on day 1 of the first 21-day cycle, rituximab is administered orally at a dose of about 375 mg / m 2 on day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, the immunoconjugate is administered intravenously at a dose of about 1.4 mg / kg to about 1.8 mg / kg (e.g., 1.4 mg / kg or 1.8 mg / kg); on days 1-21 of each of the second, third, fourth, fifth, and sixth 21-day cycles, venetoclax is administered orally at a dose of about 200 mg to about 800 mg (e.g., any of 200 mg, 400 mg, 600 mg, or 800 mg); and on day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, rituximab is administered orally at a dose of about 375 mg / m 2 It is administered intravenously at a dose of

[0185] In some embodiments, a human treated according to the methods provided herein achieves a complete response (CR) during or after treatment. In some embodiments, a human achieves a complete response during induction treatment. In some embodiments, a human achieves a complete response at the end of induction treatment (e.g., after six 21-day cycles). In some embodiments, a human achieves a complete response after six 21-day cycles. In some embodiments, a human achieves a complete response after one, two, three, four, five, or six 21-day cycles.

[0186] In some embodiments, of the humans treated, at least about 55%, at least about 57%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans achieve a complete response during or after treatment. In some embodiments, of the humans treated, at least about 55%, at least about 57%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans achieve a complete response during induction treatment. In some embodiments, at least about 55%, at least about 57%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of treated humans achieve a complete response at the end of induction treatment (e.g., after six 21-day cycles). In some embodiments, at least about 55%, at least about 57%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of treated humans achieve a complete response after six 21-day cycles. In some embodiments, in a plurality of humans treated, at least about 55%, at least about 57%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of humans achieve a complete response after 1, 2, 3, 4, 5, or 6 21-day cycles.

[0187] In some embodiments, the duration of complete response is at least about 1 month, at least about 2 months, at least about 3 months, or longer. In some embodiments, the duration of complete response is measured from the first appearance of complete response (e.g., as described below) to disease progression (e.g., by the modified Lugano 2014 criteria). In some embodiments, the duration of complete response is measured from the first appearance of complete response to relapse (e.g., by the modified Lugano 2014 criteria). In some embodiments, the duration of complete response is measured from the first appearance of complete response to disease progression or relapse (e.g., by the modified Lugano 2014 criteria). In some embodiments, the duration of complete response is measured from the first appearance of complete response to disease progression or relapse (e.g., by the modified Lugano 2014 criteria), or death from any cause.

[0188] In some embodiments, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% of the treated humans achieve an objective response during or after treatment. In some embodiments, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% of treated humans achieve an objective response during induction treatment.In some embodiments, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% of treated humans achieve an objective response at the end of induction treatment (e.g., after six 21-day cycles). In some embodiments, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% of treated humans achieve an objective response after six 21-day cycles.In some embodiments, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% of treated humans achieve an objective response after 1, 2, 3, 4, 5, or 6 21-day cycles.

[0189] Complete response is assessed according to the modified Lugano 2014 criteria, as described herein in Example 1. In some embodiments, complete response is assessed based on a PET-CT scan according to the modified Lugano 2014 criteria, as described herein in Example 1. In some embodiments, complete response is assessed based on a CT scan according to the modified Lugano 2014 criteria, as described herein in Example 1.

[0190] As used herein, objective response refers to a complete or partial response as assessed according to the modified Lugano 2014 criteria, as described in Example 1 herein. Thus, a human treated according to the methods provided herein who achieves an objective response achieves a complete or partial response as assessed according to the modified Lugano 2014 criteria, as described in Example 1 herein.

[0191] In some embodiments, objective response is assessed based on PET-CT scans according to the modified Lugano 2014 criteria, as described herein in Example 1. In some embodiments, objective response is assessed based on CT scans according to the modified Lugano 2014 criteria, as described herein in Example 1.

[0192] Further details regarding clinical staging and response criteria for lymphomas such as FL 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. (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 treatment methods provided herein can be monitored by techniques known in the art.

[0193] In some embodiments, the Bcl-2 inhibitor (e.g., venetoclax) and anti-CD20 antibody (e.g., obinutuzumab or rituximab) are further administered during a maintenance phase after induction, for example, after the sixth 21-day cycle. The maintenance phase or "post-induction treatment" refers to the treatment phase following the induction phase. In some embodiments, the maintenance phase begins immediately after the end of the induction phase. In some embodiments, the induction and maintenance phases are separated by a time interval. In some embodiments, the maintenance phase begins at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks after the end of the induction phase.

[0194] In some embodiments, during the maintenance phase, the Bcl-2 inhibitor (e.g., venetoclax) is administered orally once daily at a dose of about 200 mg to about 800 mg following the sixth 21-day cycle of the induction phase, and the anti-CD20 antibody (e.g., obinutuzumab or rituximab) is administered orally at a dose of about 1000 mg or about 375 mg / m on the first day of every other month beginning two months after the sixth 21-day cycle of the induction phase. 2 In some embodiments, the Bcl-2 inhibitor (e.g., venetoclax) is administered for up to 8 months during the maintenance phase. In some embodiments, the anti-CD20 antibody (e.g., obinutuzumab or rituximab) is administered for up to 24 months during the maintenance phase.

[0195] In some embodiments, during the maintenance phase, the Bcl-2 inhibitor is venetoclax, which is administered orally at a dose of about 200 mg once daily for up to 8 months after the sixth 21-day cycle of the induction 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 (e.g., day 1 of each of months 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24) starting two months after the sixth 21-day cycle of the induction phase for up to 24 months.

[0196] In some embodiments, during the maintenance phase, the Bcl-2 inhibitor is venetoclax, and the venetoclax is administered orally at a dose of about 200 mg once daily for up to 8 months after the sixth 21-day cycle of the induction phase, and the anti-CD20 antibody is rituximab, and the rituximab is administered orally at a dose of about 375 mg / m on Day 1 of every other month (e.g., Day 1 of each of months 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24) starting two months after the sixth 21-day cycle of the induction phase for up to 24 months. 2 It is administered intravenously at a dose of

[0197] In some embodiments, during the maintenance phase, the Bcl-2 inhibitor is venetoclax, which is administered orally at a dose of about 400 mg once daily for up to 8 months after the sixth 21-day cycle of the induction 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 (e.g., day 1 of each of months 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24) starting two months after the sixth 21-day cycle of the induction phase for up to 24 months.

[0198] In some embodiments, during the maintenance phase, the Bcl-2 inhibitor is venetoclax, and the venetoclax is administered orally at a dose of about 400 mg once daily for up to 8 months after the sixth 21-day cycle of the induction phase, and the anti-CD20 antibody is rituximab, and the rituximab is administered orally at a dose of about 375 mg / m on Day 1 of every other month (e.g., Day 1 of each of months 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24) starting two months after the sixth 21-day cycle of the induction phase for up to 24 months. 2 It is administered intravenously at a dose of

[0199] In some embodiments, during the maintenance phase, the Bcl-2 inhibitor is venetoclax, which is administered orally at a dose of about 600 mg once daily for up to 8 months after the sixth 21-day cycle of the induction 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 (e.g., day 1 of each of months 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24) starting two months after the sixth 21-day cycle of the induction phase for up to 24 months.

[0200] In some embodiments, during the maintenance phase, the Bcl-2 inhibitor is venetoclax, and the venetoclax is administered orally at a dose of about 600 mg once daily for up to 8 months after the sixth 21-day cycle of the induction phase, and the anti-CD20 antibody is rituximab, and the rituximab is administered orally at a dose of about 375 mg / m on Day 1 of every other month (e.g., Day 1 of each of months 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24) starting two months after the sixth 21-day cycle of the induction phase for up to 24 months. 2 It is administered intravenously at a dose of

[0201] In some embodiments, during the maintenance phase, the Bcl-2 inhibitor is venetoclax, which is administered orally at a dose of about 800 mg once daily for up to 8 months after the sixth 21-day cycle of the induction 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 (e.g., day 1 of each of months 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24) starting two months after the sixth 21-day cycle of the induction phase for up to 24 months.

[0202] In some embodiments, during the maintenance phase, the Bcl-2 inhibitor is venetoclax, and the venetoclax is administered orally at a dose of about 800 mg once daily for up to 8 months after the sixth 21-day cycle of the induction phase, and the anti-CD20 antibody is rituximab, and the rituximab is administered orally at a dose of about 375 mg / m on Day 1 of every other month (e.g., Day 1 of each of months 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24) starting two months after the sixth 21-day cycle of the induction phase for up to 24 months. 2 It is administered intravenously at a dose of

[0203] Exemplary dosing and administration schedules for the maintenance phase are provided in Tables I-L below. [Table IL]

[0204] In some embodiments, the anti-CD20 antibody is rituximab. In some embodiments, rituximab is administered at a dose of about 375 mg / m 2 In some embodiments, rituximab is administered in combination with a Bcl-2 inhibitor (e.g., venetoclax) according to any maintenance phase provided herein. In some embodiments, during the maintenance phase, the Bcl-2 inhibitor is venetoclax, which is administered orally at a dose of about 200 mg to about 800 mg (e.g., about 200 mg, about 400 mg, about 600 mg, or about 800 mg) once daily for up to eight months after the sixth 21-day cycle of the induction phase, and the anti-CD20 antibody is rituximab, which is administered orally at a dose of about 375 mg / m on day 1 of every other month (e.g., day 1 of each of months 2, 4, 6, and 8) for up to eight months, starting two months after the sixth 21-day cycle of the induction phase. 2 It is administered intravenously at a dose of

[0205] In some embodiments, a month contains 28 days.

[0206] Any one of the exemplary induction phases provided herein (e.g., shown in Tables A-H) can be followed by any one of the exemplary maintenance phases provided herein (e.g., shown in Tables I-L).

[0207] In some embodiments, during the induction phase, on day 1 of a first 21-day cycle, the immunoconjugate is administered intravenously at a dose of about 1.8 mg / kg; on each of days 1-21 of a first 21-day cycle, venetoclax is administered orally at a dose of about 800 mg; on each of days 1, 8, and 15 of a first 21-day cycle, obinutuzumab is administered intravenously at a dose of about 1000 mg; and on days 2, 3, 4, 5, and 6 of a first 21-day cycle, venetoclax is administered orally at a dose of about 1000 mg. On day 1 of each of the first and sixth 21-day cycles, the immunoconjugate is administered intravenously at a dose of about 1.8 mg / kg, venetoclax is administered orally at a dose of about 800 mg on each of days 1-21 of each of the second, third, fourth, fifth, and sixth 21-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 21-day cycles. In some embodiments, the induction phase is followed by a maintenance phase, during which venetoclax is administered at a dose of about 800 mg and obinutuzumab is administered at a dose of about 1000 mg. In some embodiments, during the maintenance phase, venetoclax is administered orally at a dose of about 800 mg once daily for 8 months after the sixth 21-day cycle of the induction phase, and obinutuzumab is administered intravenously at a dose of about 1000 mg on the first day of every other month (i.e., every two months) for 24 months, starting two months after the sixth 21-day cycle of the induction phase.

[0208] In some embodiments, during the induction phase, on day 1 of a first 21-day cycle, the immunoconjugate is administered intravenously at a dose of about 1.8 mg / kg; on days 1-21 of each of the first 21-day cycle, venetoclax is administered orally at a dose of about 800 mg; and on days 1, 8, and 15 of the first 21-day cycle, rituximab is administered orally at a dose of about 375 mg / m 2on Day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, the immunoconjugate is administered intravenously at a dose of about 1.8 mg / kg; on Days 1-21 of each of the second, third, fourth, fifth, and sixth 21-day cycles, venetoclax is administered orally at a dose of about 800 mg; and on Day 1 of each of the second, third, fourth, fifth, and sixth 21-day cycles, rituximab is administered orally at a dose of about 375 mg / m 2 In some embodiments, the induction phase is followed by a maintenance phase, during which venetoclax is administered at a dose of about 800 mg and rituximab is administered intravenously at a dose of about 375 mg / m 2 In some embodiments, during the maintenance phase, venetoclax is administered orally at a dose of about 800 mg once daily for 8 months after the sixth 21-day cycle of the induction phase, and rituximab is administered orally at a dose of about 375 mg / m on the first day of every other month (i.e., every two months) for 24 months starting two months after the sixth 21-day cycle of the induction phase. 2 It is administered intravenously at a dose of

[0209] In some embodiments, the Bcl-2 inhibitor (e.g., venetoclax) and the anti-CD20 antibody (e.g., rituximab or obinutuzumab) are administered sequentially during the maintenance phase. In some embodiments, the Bcl-2 inhibitor (e.g., venetoclax) is administered before the anti-CD20 antibody (e.g., rituximab or obinutuzumab) on day 1 of every other month during the maintenance phase (e.g., on day 1 of each of months 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24). In some embodiments, venetoclax is administered before obinutuzumab on day 1 of each of months 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24 during the maintenance phase. In some embodiments, venetoclax is administered before rituximab on day 1 of each of months 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24 during the maintenance phase.

[0210] In some embodiments, the Bcl-2 inhibitor, e.g., venetoclax, is administered for up to 8 months during the maintenance phase (e.g., up to about 1 month, up to about 2 months, up to about 3 months, up to about 4 months, up to about 5 months, up to about 6 months, up to about 7 months, or up to about 8 months).

[0211] In some embodiments, the anti-CD20 antibody, eg, obinutuzumab or rituximab, is administered during the maintenance phase beginning on the first day of the second month after the sixth 21-day cycle of the induction phase. In some embodiments, the anti-CD20 antibody, e.g., obinutuzumab or rituximab, is administered for up to 24 months during the maintenance phase (e.g., up to about 1 month, up to about 2 months, up to about 3 months, up to about 4 months, up to about 5 months, up to about 6 months, up to about 7 months, up to about 8 months, up to about 9 months, up to about 10 months, up to about 11 months, up to about 12 months, up to about 13 months, up to about 14 months, up to about 15 months, up to about 16 months, up to about 17 months, up to about 18 months, up to about 19 months, up to about 20 months, up to about 21 months, up to about 22 months, up to about 23 months, or up to about 24 months). In some embodiments, the anti-CD20 antibody is obinutuzumab, and obinutuzumab is administered for up to 24 months during the maintenance phase (e.g., up to about 1 month, up to about 2 months, up to about 3 months, up to about 4 months, up to about 5 months, up to about 6 months, up to about 7 months, up to about 8 months, up to about 9 months, up to about 10 months, up to about 11 months, up to about 12 months, up to about 13 months, up to about 14 months, up to about 15 months, up to about 16 months, up to about 17 months, up to about 18 months, up to about 19 months, up to about 20 months, up to about 21 months, up to about 22 months, up to about 23 months, or up to about 24 months). In some embodiments, the anti-CD20 antibody is rituximab, and the rituximab is administered for up to 8 months during the maintenance phase (e.g., up to about 1 month, up to about 2 months, up to about 3 months, up to about 4 months, up to about 5 months, up to about 6 months, up to about 7 months, or up to about 8 months).

[0212] In some embodiments, the individual has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2. In some embodiments, the individual has relapsed or refractory (R / R) FL after treatment with at least one prior chemoimmunotherapy regimen including an anti-CD20 monoclonal antibody. In some embodiments, the individual has histologically documented CD20-positive non-Hodgkin's lymphoma (e.g., FL). In some embodiments, the individual has fluorodeoxyglucose (FDG)-avid lymphoma (i.e., PET-positive lymphoma). In some embodiments, the individual has at least one bidimensionally measurable lesion (its greatest dimension greater than 1.5 cm by CT scan or magnetic resonance imaging [MRI]). In some embodiments, the individual does not have a known CD20-negative status at the time of disease recurrence or progression. In some embodiments, the individual has not undergone a prior allogeneic stem cell transplant (SCT). In some embodiments, the individual has not completed an autologous SCT within 100 days prior to initiation of treatment with the methods provided herein. In some embodiments, the individual does not have grade 3b FL. In some embodiments, the individual does not have a history of transformation from indolent disease to diffuse large B-cell lymphoma (DLBCL). In some embodiments, the individual does not have peripheral neuropathy of grade 1 or higher. In some embodiments, the individual does not have CNS lymphoma or leptomeningeal infiltration. In some embodiments, the individual is not receiving more than 20 mg of a corticosteroid, such as prednisone, per day. In some embodiments, the individual is receiving up to 100 mg of a corticosteroid, such as prednisone, per day for up to 5 days. In some embodiments, the individual is not receiving warfarin treatment.In some embodiments, the individual has not taken strong or moderate CYP3A inhibitors, such as fluconazole, ketoconazole, and clarithromycin, or strong or moderate CYP3A inducers, such as rifampin and carbamazepine, within seven days prior to the start of treatment with any of the methods provided herein. In some embodiments, the individual has not consumed grapefruit, grapefruit products, Seville oranges, Seville orange products (e.g., marmalade containing Seville oranges), starfruit, or starfruit products within three days prior to the start of treatment with any of the methods provided herein. In some embodiments, the individual has no history of progressive multifocal leukoencephalopathy (PML). In some embodiments, the individual has received at least one prior treatment for FL, for example, 1, 2, 3, 4, 5, 6, 7, or more prior treatments for FL. In some embodiments, the individual has histological grade 1, 2, or 3a FL. In some embodiments, the individual has FL with bone marrow infiltration. In some embodiments, the individual has FL with an Ann Arbor status of 1 to 2, or 3 to 4. In some embodiments, the individual has a Follicular Lymphoma International Prognostic Index (FLIPI) score of about 0 to about 5, e.g., any of 0, 1, 2, 3, 4, or 5. In some embodiments, the individual has bulky disease (e.g., greater than 7 cm). In some embodiments, the individual is refractory to treatment with an anti-CD20 agent (e.g., no response, progression, or recurrence of FL within 6 months of completing FL treatment with an anti-CD20 agent). In some embodiments, the individual is refractory to the last prior treatment for FL (e.g., no response, progression, or recurrence within 6 months of completing the last prior FL treatment). In some embodiments, the individual had disease progression within 24 months of completing initial FL treatment. In some embodiments, the individual had disease progression within 24 months of completing the last prior FL treatment. In some embodiments, the individual had disease progression within 24 months of completing FL treatment.

[0213] In some embodiments, humans treated according to the methods provided herein do not experience Grade 3 or higher peripheral neuropathy. In some embodiments, in a plurality treated according to the methods provided herein, about 64% or less of humans experience Grade 3 or Grade 4 adverse events. In some embodiments, after administration of the immunoconjugate, Bcl-2 inhibitor, and anti-CD20 antibody, humans do not experience Grade 3 or higher peripheral neuropathy. In some embodiments, in a plurality treated according to the methods provided herein, about 64% or less (e.g., any of 64% or less, 60% or less, 55% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, 5% or less, 2.5% or less, 2% or less, or 1% or less) of humans experience Grade 3 or Grade 4 adverse events.

[0214] In some embodiments, in a plurality treated according to the methods provided herein, about 59% or less (e.g., any of 59% or less, 55% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, 5% or less, 2.5% or less, 2% or less, or 1% or less) of people experience a Grade 3 or Grade 4 adverse event.

[0215] In some embodiments, in a plurality treated according to the methods provided herein, about 75% or less (e.g., any of 75% or less, 70% or less, 65% or less, 60% or less, 55% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, 5% or less, 2.5% or less, 2% or less, 1% or less) of humans experience a Grade 3 or Grade 4 adverse event. In some embodiments, in a plurality treated according to the methods provided herein, about 73% or less of humans experience a Grade 3 or Grade 4 adverse event.

[0216] In some embodiments, after administration of polatuzumab vedotin-piiq, venetoclax, and obinutuzumab, the human does not experience grade 3 or higher peripheral neuropathy. In some embodiments, after administration of polatuzumab vedotin-piiq, venetoclax, and obinutuzumab, the human does not develop tumor lysis syndrome. In some embodiments, among humans treated with polatuzumab vedotin-piiq, venetoclax, and obinutuzumab according to the methods provided herein, about 64% or less of the humans experience grade 3 or grade 4 adverse events.

[0217] In some embodiments, the methods of treating FL provided herein further comprise administering a prophylactic treatment for tumor lysis syndrome (TLS), e.g., as described in Example 1 herein. In some embodiments, the prophylactic treatment for tumor lysis syndrome (TLS) comprises a uric acid-reducing agent and / or a hydration regimen prior to the initiation of treatment. In some embodiments, the hydration regimen comprises administering about 2 to about 3 liters of fluid (e.g., water, saline, or other suitable fluid) per day, the fluid being administered from about 24 hours to about 48 hours prior to the initiation of treatment. In some embodiments, the fluid is administered orally or intravenously. In some embodiments, the fluid is administered orally. In some embodiments, the fluid is administered intravenously. In some embodiments, the uric acid-reducing agent is allopurinol. In some embodiments, allopurinol is administered orally at a dose of about 300 mg / day beginning about 72 hours prior to the first dose of venetoclax, and administration of allopurinol continues for about 3 to about 7 days after the first dose of venetoclax. In some embodiments, prophylactic treatment of tumor lysis syndrome (TLS) involves intravenous administration of rasburicase to a human with elevated uric acid levels prior to the initiation of treatment, and the rasburicase is administered until serum uric acid and other evidence of TLS (e.g., laboratory test results) normalize.

[0218] In some embodiments, the methods of treating FL provided herein further comprise treating or preventing an adverse event described herein in Example 1. In some embodiments, the methods of treating FL provided herein further comprise treating a hematological adverse event, e.g., the development of neutropenia, as described herein in Example 1. In some embodiments, the methods of treating FL provided herein further comprise administering granulocyte colony-stimulating factor (G-CSF) if a grade 3 or grade 4 adverse event of neutropenia occurs.

[0219] IV. Methods of Treating Diffuse Large B-Cell Lymphoma Also provided herein is a method for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, comprising administering to the human an effective amount of Formula (a) (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 1 to 8. A method is provided, comprising administering to a human a Bcl-2 inhibitor and an anti-CD20 antibody, an immunoconjugate 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 1 to 8. In some embodiments, the anti-CD79b immunoconjugate is huMA79bv28-MC-vc-PAB-MMAE. In some embodiments, the immunoconjugate is polatuzumab vedotin-piiq (CAS Registry Number 1313206-42-6). In some embodiments, the anti-CD79b immunoconjugate is huMA79bv28-MC-vc-PAB-MMAE. In some embodiments, the immunoconjugate is polatuzumab vedotin-piiq (CAS Registry Number 1313206-42-6). In some embodiments, the immunoconjugate is polatuzumab vedotin-piiq. In some embodiments, the Bcl-2 inhibitor is venetoclax. In some embodiments, the anti-CD20 antibody is rituximab. In some embodiments, the anti-CD20 antibody is obinutuzumab. In some embodiments, the anti-CD20 antibody is ofatumumab, ublituximab, and / or ibritumomab tiuxetan.

[0220] The term "co-administration" or "co-administering" refers to the administration of an anti-CD79b immunoconjugate, a Bcl-2 inhibitor, and an anti-CD20 antibody as two (or more) separate formulations (or as one single formulation comprising an anti-CD79b immunoconjugate, a Bcl-2 inhibitor, and an anti-CD20 antibody). When separate formulations are used, the co-administration can be simultaneous or sequential, preferably with a period of time during which all active agents simultaneously exert their biological activity. The anti-CD79b immunoconjugate, a Bcl-2 inhibitor, and an anti-CD20 antibody are co-administered simultaneously or sequentially.

[0221] The anti-CD79b immunoconjugates and additional therapeutic agents (e.g., Bcl-2 inhibitors and anti-CD20 antibodies) provided herein for use in any of the therapeutic methods described herein will be formulated, dosed, and administered in a manner consistent with good medical practice. Factors to consider 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 delivery of the agent, the method of administration, the administration schedule, and other factors known to medical practitioners. The immunoconjugates are optionally, but need not necessarily, formulated with one or more agents currently used to prevent or treat the disorder in question.

[0222] The amount and timing of co-administration of the anti-CD79b immunoconjugate and additional therapeutic agent will depend on the type (species, sex, age, weight, etc.) and condition of the patient being treated, as well as the severity of the disease or condition being treated. The anti-CD79b immunoconjugate, Bcl-2 inhibitor, and anti-CD20 antibody are suitably co-administered to the patient at one time or over a series of treatments, e.g., on the same or subsequent days.

[0223] In some embodiments, the dose of the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin-piiq) 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-CD79b 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 dose of the anti-CD79b immunoconjugate is about 1.4 mg / kg. In some embodiments, the dose of the anti-CD79b immunoconjugate is about 1.8 mg / kg. In some embodiments, the dose of the anti-CD79b immunoconjugate is about 2.4 mg / kg. In some embodiments, the dose of the anti-CD79b immunoconjugate is about 3.2 mg / kg. In some embodiments, the dose of the anti-CD79b immunoconjugate is about 3.6 mg / kg. In some embodiments of any method, the anti-CD79b immunoconjugate is administered q3wk or q3w (e.g., on day 1 of each 21-day cycle, once every 3 weeks, or once every 21 days). In some embodiments, the anti-CD79b immunoconjugate is administered by intravenous infusion. In some embodiments, the dose administered by infusion ranges from about 1 mg to about 1,500 mg per administration. Alternatively, the 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 by injection is about 1 μg / m per administration. 2 ~Approx. 10,000μg / m 2 Alternatively, the dosage range is about 1 μg / m 2 ~about 1000μg / m 2 , about 1μg / m 2 ~about 800μg / m2 , about 1μg / m 2 ~about 600μg / m 2 , about 1μg / m 2 ~about 400μg / m 2 , about 10μg / m 2 ~about 500μg / m 2 , about 10μg / m 2 ~about 300μg / m 2 , about 10μg / m 2 ~about 200μg / m 2 , and approximately 1 μg / m 2 ~about 200μg / m 2 The dose can be administered once a day, once a week, multiple times a week but less than once a day, multiple times a month but less than once a day, multiple times a month but less than once a week, once a month, once every 21 days, or intermittently to alleviate or relieve the symptoms of the disease. Administration can be continued at any of the intervals and doses described herein until the tumor or symptoms of the B-cell proliferative disorder being treated are remitted. If such remission or relief is prolonged by such continued administration, administration can be continued after the remission or relief of symptoms is achieved.

[0224] In some embodiments, the dose of anti-CD20 antibody is about 300 to 1600 mg / m 2 and / or 300 to 2000 mg. In some embodiments, the dose of anti-CD20 antibody is about 300 mg / m 2 , 375 mg / m 2 , 600 mg / m 2 , 1000 mg / m 2 or 1250 mg / m 2 and / or 300 mg, 1000 mg, or 2000 mg. In some embodiments, the anti-CD20 antibody is rituximab and the administered dose is 375 mg / m 2In some embodiments, the anti-CD20 antibody is obinutuzumab and the administered dose is 1000 mg. In some embodiments, the anti-CD20 antibody is administered q1w (i.e., once a week). In some embodiments, the anti-CD20 antibody is administered on days 1, 8, and 15 of a 21-day cycle. In some embodiments, the anti-CD20 antibody is administered q3w (i.e., every 3 weeks, or once every 21 days). In some embodiments, the anti-CD20 antibody is administered on day 1 of a 21-day cycle. In some embodiments, the anti-CD20 antibody is administered on days 1, 8, and 15 of an initial 21-day cycle and on day 1 of subsequent 21-day cycles (e.g., day 1 of cycles 2, 3, 4, 5, and 6). In some embodiments, the anti-CD20 antibody is administered once every two months. In some embodiments, the dose of the defucosylated anti-CD20 antibody (preferably the defucosylated humanized B-Ly1 antibody) can be 800 to 1600 mg (in one embodiment, 800 to 1200 mg, e.g., 1000 mg) or 400 to 1200 mg (in one embodiment, 800 to 1200 mg). In some embodiments, the dose is a single 1000 mg dose on a 3-week dosing schedule (e.g., once every 21 days).

[0225] In some embodiments, the dose of the Bcl-2 inhibitor (e.g., venetoclax) is about 100 mg to about 800 mg (e.g., about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg). In some embodiments, venetoclax is administered at a dose of about 100 mg to about 800 mg. In some embodiments, venetoclax is administered at a dose of about 100 mg. In some embodiments, venetoclax is administered at a dose of about 200 mg. In some embodiments, venetoclax is administered at a dose of about 400 mg. In some embodiments, venetoclax is administered at a dose of about 600 mg. In some embodiments, venetoclax is administered at a dose of about 800 mg.

[0226] The immunoconjugates provided herein (and any additional therapeutic agents, e.g., Bcl-2 inhibitors and anti-CD20 antibodies) for use in any of the therapeutic methods 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. Administration can be by any suitable route, e.g., injection, such as intravenous or subcutaneous injection, depending in part on whether the administration is brief or chronic. Various dosing schedules are contemplated herein, including, but not limited to, single administration or multiple administrations over various time points, bolus administration, and pulse infusion.

[0227] The anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin-piiq), Bcl-2 inhibitor (e.g., venetoclax), and anti-CD20 antibody (e.g., rituximab or obinutuzumab) can be administered by the same or different routes of administration. In some embodiments, the anti-CD79b immunoconjugate (e.g., polatuzumab vedotin-piiq) is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, inhalation, intrathecally, intracerebroventricularly, or intranasally. In some embodiments, the immunoconjugate (e.g., polatuzumab vedotin-piiq) is administered by intravenous infusion. In some embodiments, the anti-CD20 antibody (e.g., rituximab or obinutuzumab) is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implant, by inhalation, intrathecally, intracerebroventricularly, or intranasally. In some embodiments, the anti-CD20 antibody (e.g., rituximab or obinutuzumab) is administered by intravenous infusion. In some embodiments, the Bcl-2 inhibitor (e.g., venetoclax) is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implant, by inhalation, intrathecally, intravenously, intravenously, or intranasally. In some embodiments, the Bcl-2 inhibitor (e.g., venetoclax) is administered orally, for example, by tablet, capsule, or any other suitable means for oral administration known in the art or described herein. In some embodiments, the anti-CD79b immunoconjugate and the anti-CD20 antibody (e.g., rituximab or obinutuzumab) are each administered via intravenous infusion, and the Bcl-2 inhibitor (e.g., venetoclax) is administered orally. Effective amounts of the anti-CD79b immunoconjugate, the Bcl-2 inhibitor (e.g., venetoclax), and the anti-CD20 antibody (e.g., rituximab or obinutuzumab) can be administered for the prevention or treatment of disease.

[0228] In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin-piiq) is administered at a dose of about 1.4 mg / kg to about 1.8 mg / kg. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin-piiq) is administered at a dose of about 1.4 mg / kg. In some embodiments, the anti-CD79b immunoconjugate (e.g., huMA79bv28-MC-vc-PAB-MMAE or polatuzumab vedotin-piiq) is administered at a dose of about 1.8 mg / kg. Alternatively or additionally, in some embodiments, the Bcl-2 inhibitor (e.g., venetoclax) is administered at a dose of about 200 mg to about 800 mg. In some embodiments, the Bcl-2 inhibitor (e.g., venetoclax) is administered at a dose of about 200 mg. In some embodiments, the Bcl-2 inhibitor (e.g., venetoclax) is administered at a dose of about 400 mg. In some embodiments, the Bcl-2 inhibitor (e.g., venetoclax) is administered at a dose of about 600 mg. In some embodiments, the Bcl-2 inhibitor (e.g., venetoclax) is administered at a dose of about 800 mg. Alternatively or additionally, in some embodiments, the anti-CD20 antibody is rituximab. In some embodiments, rituximab is administered at a dose of about 375 mg / m 2 Alternatively or further, in some embodiments, the anti-CD20 antibody is obinutuzumab. In some embodiments, obinutuzumab is administered at a dose of about 1000 mg. In some embodiments, polatuzumab vedotin-piiq is administered at a dose of about 1.8 mg / kg, venetoclax is administered at a dose of about 400 mg, about 600 mg, or about 800 mg, and rituximab is administered at a dose of about 375 mg / m 2In some embodiments, polatuzumab vedotin-piiq is administered at a dose of about 1.8 mg / kg, venetoclax is administered at a dose of about 400 mg, about 600 mg, or about 800 mg, and obinutuzumab is administered at a dose of about 1000 mg. In some embodiments, polatuzumab vedotin-piiq is administered at a dose of about 1.8 mg / kg, venetoclax is administered at a dose of about 400 mg, about 600 mg, or about 800 mg, and rituximab is administered at a dose of about 375 mg / m 2 In some embodiments, polatuzumab vedotin-piiq is administered at a dose of about 1.8 mg / kg, venetoclax is administered at a dose of about 400 mg, and obinutuzumab is administered at a dose of about 1000 mg. In some embodiments, polatuzumab vedotin-piiq is administered at a dose of about 1.8 mg / kg, venetoclax is administered at a dose of about 600 mg, and rituximab is administered at a dose of about 375 mg / m 2 In some embodiments, polatuzumab vedotin-piiq is administered at a dose of about 1.8 mg / kg, venetoclax is administered at a dose of about 600 mg, and obinutuzumab is administered at a dose of about 1000 mg. In some embodiments, polatuzumab vedotin-piiq is administered at a dose of about 1.8 mg / kg, venetoclax is administered at a dose of about 800 mg, and rituximab is administered at a dose of about 375 mg / m 2 In some embodiments, polatuzumab vedotin-piiq is administered at a dose of about 1.8 mg / kg, venetoclax is administered at a dose of about 800 mg, and obinutuzumab is administered at a dose of about 1000 mg.

[0229] In some embodiments, the anti-CD79b immunoconjugate (e.g., polatuzumab vedotin-piiq), Bcl-2 inhibitor (e.g., venetoclax), and anti-CD20 antibody (e.g., obinutuzumab or rituximab) are administered during an induction phase. The induction phase refers to the period of treatment during which the anti-CD79b immunoconjugate, Bcl-2 inhibitor, and anti-CD20 antibody are administered to a human. In some embodiments, the induction phase comprises less than one complete 21-day cycle. In some embodiments, the induction phase comprises one to six (e.g., one, two, three, four, five, or six) 21-day cycles. In some embodiments, the induction phase comprises at least six 21-day cycles.

[0230] In some embodiments, during the induction phase, on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, the immunoconjugate is administered intravenously at a dose of about 1.8 mg / kg, and on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, the anti-CD20 antibody is administered intravenously at a dose of about 375 mg / m 2 or about 1000 mg intravenously, and on each of days 1-21 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, the Bcl-2 inhibitor is administered orally at a dose of about 400 mg, about 600 mg, or about 800 mg.

[0231] In some embodiments, during the induction phase, on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, polatuzumab vedotin-piiq is administered intravenously at a dose of about 1.8 mg / kg, and on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, rituximab is administered intravenously at a dose of about 375 mg / m 2 Venetoclax is administered intravenously at a dose of about 400 mg, about 600 mg, or about 800 mg on each of days 1 through 21 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles.

[0232] In some embodiments, during the induction phase, polatuzumab vedotin-piiq 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 21-day cycles; obinutuzumab is administered intravenously at a dose of about 1000 mg on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles; and venetoclax is administered orally at a dose of about 400 mg, about 600 mg, or about 800 mg on days 1 through 21 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles.

[0233] In some embodiments, during the induction phase, on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, polatuzumab vedotin-piiq is administered intravenously at a dose of about 1.8 mg / kg, and on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, rituximab is administered intravenously at a dose of about 375 mg / m 2 Venetoclax is administered intravenously at a dose of approximately 400 mg on days 1 through 21 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, and venetoclax is administered orally at a dose of approximately 400 mg on days 1 through 21 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles.

[0234] In some embodiments, during the induction phase, polatuzumab vedotin-piiq 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 21-day cycles, obinutuzumab is administered intravenously at a dose of about 1000 mg on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, and venetoclax is administered orally at a dose of about 400 mg on each of days 1-21 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles.

[0235] In some embodiments, during the induction phase, on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, polatuzumab vedotin-piiq is administered intravenously at a dose of about 1.8 mg / kg, and on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, rituximab is administered intravenously at a dose of about 375 mg / m 2 Venetoclax is administered intravenously at a dose of approximately 600 mg on days 1 through 21 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, and orally at a dose of approximately 600 mg on days 1 through 21 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles.

[0236] In some embodiments, during the induction phase, polatuzumab vedotin-piiq 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 21-day cycles, obinutuzumab is administered intravenously at a dose of about 1000 mg on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, and venetoclax is administered orally at a dose of about 600 mg on each of days 1-21 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles.

[0237] In some embodiments, during the induction phase, polatuzumab vedotin-piiq 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 21-day cycles, and rituximab is administered intravenously at a dose of about 375 mg / m on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles. 2 Venetoclax is administered intravenously at a dose of approximately 800 mg on days 1 through 21 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, and venetoclax is administered orally at a dose of approximately 800 mg on days 1 through 21 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles.

[0238] In some embodiments, during the induction phase, polatuzumab vedotin-piiq 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 21-day cycles, obinutuzumab is administered intravenously at a dose of about 1000 mg on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, and venetoclax is administered orally at a dose of about 800 mg on each of days 1-21 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles.

[0239] In some embodiments, the immunoconjugate, Bcl-2 inhibitor, and anti-CD20 antibody are administered during the induction phase. In some embodiments, the Bcl-2 inhibitor is administered before the anti-CD20 antibody, and the anti-CD20 antibody is administered before the immunoconjugate on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles.

[0240] In some embodiments, the anti-CD20 antibody is rituximab. In some embodiments, rituximab is administered at a dose of about 375 mg / m in combination with an anti-CD79b immunoconjugate and a Bcl-2 inhibitor according to any of the induction phases provided herein. 2 is administered at a dose of

[0241] In some embodiments, the anti-CD20 antibody is obinutuzumab. In some embodiments, obinutuzumab is administered at a dose of about 1000 mg in combination with an anti-CD79b immunoconjugate and a Bcl-2 inhibitor according to any of the induction phases provided herein.

[0242] In some embodiments, polatuzumab vedotin-piiq, venetoclax, and rituximab are administered sequentially during the induction phase. In some embodiments, on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, venetoclax is administered before rituximab, and rituximab is administered before polatuzumab vedotin-piiq. In some embodiments, polatuzumab vedotin-piiq, venetoclax, and obinutuzumab are administered sequentially during the induction phase. In some embodiments, on day 1 of each of the first, second, third, fourth, fifth, and sixth 21-day cycles, venetoclax is administered before obinutuzumab, and obinutuzumab is administered before polatuzumab vedotin-piiq.

[0243] In some embodiments, a human treated according to the methods provided herein achieves a complete response (CR) during or after treatment. In some embodiments, a human achieves a complete response during induction treatment. In some embodiments, a human achieves a complete response at the end of induction treatment (e.g., after six 21-day cycles). In some embodiments, a human achieves a complete response after six 21-day cycles. In some embodiments, a human achieves a complete response after one, two, three, four, five, or six 21-day cycles.

[0244] In some embodiments, at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the people treated achieve a complete response during or after treatment. In some embodiments, at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the treated humans achieve a complete response during induction treatment. In some embodiments, at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the treated humans achieve a complete response at the end of induction treatment (e.g., after six 21-day cycles). In some embodiments, at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the treated people achieve a complete response after six 21-day cycles.In some embodiments, at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the treated humans achieve a complete response after one, two, three, four, five, or six 21-day cycles. In some embodiments, at least about 29% of the treated humans achieve a complete response during or after treatment. In some embodiments, at least about 29% of the treated humans achieve a complete response during induction treatment. In some embodiments, at least about 29% of the treated humans achieve a complete response at the end of induction treatment (e.g., after six 21-day cycles). In some embodiments, among the plurality of humans treated, at least about 29% of the humans achieve a complete response after six 21-day cycles. In some embodiments, among the plurality of humans treated, at least about 29% of the humans achieve a complete response after one, two, three, four, five, or six 21-day cycles. In some embodiments, among the plurality of humans treated, at least about 31% of the humans achieve a complete response during or after treatment. In some embodiments, among the plurality of humans treated, at least about 31% of the humans achieve a complete response during induction treatment. In some embodiments, among the plurality of humans treated, at least about 31% of the humans achieve a complete response at the end of induction treatment (e.g., after six 21-day cycles). In some embodiments, among the plurality of humans treated, at least about 31% of the humans achieve a complete response after six 21-day cycles. In some embodiments, among the plurality of humans treated, at least about 31% of the humans achieve a complete response after one, two, three, four, five, or six 21-day cycles.

[0245] In some embodiments, treatment of a plurality of humans with the methods provided herein results in a best complete response rate of at least about 35%, at least about 38%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100%. In some embodiments, treatment of a plurality of humans with the methods provided herein results in a best complete response rate of at least about 38%. In some embodiments, the best complete response rate refers to the proportion of humans, among a plurality of humans treated according to the methods provided herein, who achieve a complete response at any time after the start of treatment.

[0246] In some embodiments, the duration of complete response is at least about 1 month, at least about 2 months, at least about 3 months, 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, at least about 11 months, or at least about 12 months or more. In some embodiments, the duration of complete response is at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months or more. In some embodiments, the duration of complete response is at least about 3 months or more. In some embodiments, the duration of complete response is at least about 4 months or more. In some embodiments, the duration of complete response is at least about 5 months or more. In some embodiments, the duration of complete response is at least about 6 months or more. In some embodiments, the duration of complete response is at least about 7 months or more. In some embodiments, the duration of complete response is measured from the first appearance of complete response (e.g., as described below) to disease progression (e.g., by the modified Lugano 2014 criteria). In some embodiments, the duration of complete response is measured from the first appearance of complete response to relapse (e.g., by the modified Lugano 2014 criteria). In some embodiments, the duration of complete response is measured from the first appearance of complete response to disease progression or relapse (e.g., by the modified Lugano 2014 criteria). In some embodiments, the duration of complete response is measured from the first appearance of complete response to disease progression or relapse (e.g., by the modified Lugano 2014 criteria), or death from any cause.

[0247] In some embodiments, at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the treated humans achieve an objective response during or after treatment. In some embodiments, at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the treated humans achieve an objective response during induction treatment. In some embodiments, at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of treated humans achieve an objective response at the end of induction treatment (e.g., after six 21-day cycles). In some embodiments, at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of treated humans achieve an objective response after six 21-day cycles.In some embodiments, at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the treated humans achieve an objective response after one, two, three, four, five, or six 21-day cycles. In some embodiments, at least about 29% of the treated humans achieve an objective response during or after treatment. In some embodiments, at least about 29% of the treated humans achieve an objective response during induction treatment. In some embodiments, at least about 29% of the treated humans achieve an objective response at the end of induction treatment (e.g., after six 21-day cycles). In some embodiments, among the plurality of humans treated, at least about 29% of humans achieve an objective response after six 21-day cycles. In some embodiments, among the plurality of humans treated, at least about 29% of humans achieve an objective response after one, two, three, four, five, or six 21-day cycles. In some embodiments, among the plurality of humans treated, at least about 42% of humans achieve an objective response during or after treatment. In some embodiments, among the plurality of humans treated, at least about 42% of humans achieve an objective response during induction treatment. In some embodiments, among the plurality of humans treated, at least about 42% of humans achieve an objective response at the end of induction treatment (e.g., after six 21-day cycles). In some embodiments, among the plurality of humans treated, at least about 42% of humans achieve an objective response after six 21-day cycles. In some embodiments, among the plurality of humans treated, at least about 42% of humans achieve an objective response after one, two, three, four, five, or six 21-day cycles.

[0248] As used herein, objective response refers to a complete or partial response as assessed according to the modified Lugano 2014 criteria, as described in Example 1 herein. Thus, a human treated according to the methods provided herein who achieves an objective response achieves a complete or partial response as assessed according to the modified Lugano 2014 criteria, as described in Example 1 herein.

[0249] In some embodiments, objective response is assessed based on PET-CT scans according to the modified Lugano 2014 criteria, as described herein in Example 1. In some embodiments, objective response is assessed based on CT scans according to the modified Lugano 2014 criteria, as described herein in Example 1.

[0250] In some embodiments, the duration of the objective response is at least about 1 month, at least about 2 months, at least about 3 months, 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, at least about 11 months, or at least about 12 months or more. In some embodiments, the duration of the objective response is at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months or more. In some embodiments, the duration of the objective response is at least about 3 months or more. In some embodiments, the duration of the objective response is at least about 4 months or more. In some embodiments, the duration of the objective response is at least about 5 months or more. In some embodiments, the duration of the objective response is at least about 6 months or more. In some embodiments, the duration of the objective response is at least about 7 months or more. In some embodiments, the duration of objective response is measured from the first appearance of an objective response (e.g., as described herein) to disease progression (e.g., by the modified Lugano 2014 criteria). In some embodiments, the duration of objective response is measured from the first appearance of an objective response to relapse (e.g., by the modified Lugano 2014 criteria). In some embodiments, the duration of objective response is measured from the first appearance of an objective response to disease progression or relapse (e.g., by the modified Lugano 2014 criteria). In some embodiments, the duration of objective response is measured from the first appearance of an objective response to disease progression or relapse (e.g., by the modified Lugano 2014 criteria) or death from any cause.

[0251] In some embodiments, of the humans treated, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans achieve a best overall response (BOR) during or after treatment. In some embodiments, of the humans treated, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans achieve a best overall response (BOR) during induction treatment. In some embodiments, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the treated humans achieve a best overall response (BOR) at the end of induction treatment (e.g., after six 21-day cycles). In some embodiments, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the treated humans achieve a best overall response (BOR) after six 21-day cycles. In some embodiments, among the plurality of humans treated, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans achieve a best overall response (BOR) after one, two, three, four, five, or six 21-day cycles. In some embodiments, among the plurality of humans treated, at least about 65% of the humans achieve a best overall response (BOR) during or after treatment. In some embodiments, among the plurality of humans treated, at least about 65% of the humans achieve a best overall response (BOR) during induction treatment. In some embodiments, among the plurality of humans treated, at least about 65% of the humans achieve a best overall response (BOR) at the end of induction treatment (e.g., after six 21-day cycles).In some embodiments, among the treated humans, at least about 65% of the humans achieve a best overall response (BOR) after six 21-day cycles. In some embodiments, among the treated humans, at least about 65% of the humans achieve a best overall response (BOR) after one, two, three, four, five, or six 21-day cycles. In some embodiments, the duration of the BOR is at least about 1 month, at least about 2 months, at least about 3 months, 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, at least about 11 months, or at least about 12 months or more. In some embodiments, the duration of the BOR is at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months or more. In some embodiments, the duration of the BOR is at least about 3 months or more. In some embodiments, the duration of the BOR is at least about 4 months or more. In some embodiments, the duration of BOR is at least about 5 months or more. In some embodiments, the duration of BOR is at least about 6 months or more. In some embodiments, the duration of BOR is at least about 7 months or more. In some embodiments, the duration of BOR is measured from the first appearance of complete or partial response (e.g., as described below) to disease progression (e.g., according to the modified Lugano 2014 criteria). In some embodiments, the duration of BOR is measured from the first appearance of complete or partial response to relapse (e.g., according to the modified Lugano 2014 criteria). In some embodiments, the duration of BOR is measured from the first appearance of complete or partial response to disease progression or relapse (e.g., according to the modified Lugano 2014 criteria). In some embodiments, the duration of BOR is measured from the first appearance of complete or partial response to disease progression or relapse (e.g., according to the modified Lugano 2014 criteria) or death from any cause.

[0252] In some embodiments, best overall response (BOR) refers to the best response of a complete or partial response (i.e., relative to the occurrence of a complete or partial response) as assessed according to the modified Lugano 2014 criteria, as described in Example 1 herein. In some embodiments, a human treated according to the methods provided herein who achieves a best overall response achieves a complete or partial response as assessed according to the modified Lugano 2014 criteria, as described in Example 1 herein. In some embodiments, response is assessed based on a PET-CT scan according to the modified Lugano 2014 criteria, as described in Example 1 herein. In some embodiments, response is assessed based on a CT scan according to the modified Lugano 2014 criteria, as described in Example 1 herein.

[0253] Complete response will be assessed according to the modified Lugano 2014 criteria, as described in Example 1 herein.

[0254] Further details regarding clinical staging 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. (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 treatment methods provided herein can be monitored by techniques known in the art.

[0255] In some embodiments, treatment of a plurality of humans with the methods provided herein results in a 6-month progression-free survival rate of at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 42%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans. In some embodiments, treatment of a plurality of humans with the methods provided herein results in a 6-month progression-free survival rate of at least about 27% of the humans. In some embodiments, treatment of a plurality of humans with the methods provided herein results in a 6-month progression-free survival rate of at least about 42% of the humans. In some embodiments, treatment of a plurality of humans with the methods provided herein results in a 6-month progression-free survival rate of at least about 57% of the humans. In some embodiments, treatment of a plurality of humans with the methods provided herein results in a 6-month progression-free survival rate of at least about 60% of the plurality of humans.

[0256] In some embodiments, progression-free survival refers to the proportion of humans treated according to the methods provided herein who are progression-free six months after initiation of treatment, for example, with an immunoconjugate (e.g., polatuzumab vedotin-piiq), a Bcl-2 inhibitor (e.g., venetoclax), and an anti-CD20 antibody (e.g., rituximab or obinutuzumab). In some embodiments, progression-free survival refers to the time from initiation of treatment with an immunoconjugate (e.g., polatuzumab vedotin-piiq), a Bcl-2 inhibitor (e.g., venetoclax), and an anti-CD20 antibody (e.g., rituximab or obinutuzumab) to the first occurrence of disease progression or recurrence, or death from any cause.

[0257] In some embodiments, treatment of a human with the methods provided herein results in a human progression-free survival of at least about 1 month, at least about 2 months, at least about 3 months, 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...

Claims

1. 1. A medicament for treating follicular lymphoma (FL) in a human in need thereof, comprising: administering to the human effective amounts of an immunoconjugate, a selective Bcl-2 inhibitor, or a pharmaceutically acceptable salt thereof, and an anti-CD20 antibody; the medicament comprises an immunoconjugate, a selective Bcl-2 inhibitor or a pharmaceutically acceptable salt thereof, and an anti-CD20 antibody; 10. The immunoconjugate of claim 1, wherein 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 1 to 8. Including, the human achieves a complete response (CR) during or after administration of the immunoconjugate, the selective Bcl-2 inhibitor or a pharmaceutically acceptable salt thereof, and the anti-CD20 antibody; the immunoconjugate is administered at a dose of about 1.8 mg / kg; the selective Bcl-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof administered at a dose of about 800 mg; the anti-CD20 antibody is obinutuzumab; Medicine.

2. A medicament for treating follicular lymphoma (FL) in a human in need thereof, comprising a selective Bcl-2 inhibitor or a pharmaceutically acceptable salt thereof, in combination with an anti-CD20 antibody, the medicament comprising: 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 1 to 8. an effective amount of an immunoconjugate comprising the human achieves a complete response (CR) during or after administration of the immunoconjugate, the selective Bcl-2 inhibitor or a pharmaceutically acceptable salt thereof, and the anti-CD20 antibody; the immunoconjugate is administered at a dose of about 1.8 mg / kg; the selective Bcl-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof administered at a dose of about 800 mg; the anti-CD20 antibody is obinutuzumab; Medicine.

3. (a) p is 3-4 or 2-5; and / or (b) 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; The pharmaceutical composition according to claim 1 or 2.

4. (a) 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 (b) the immunoconjugate is polatuzumab vedotin-piiq; The pharmaceutical composition according to any one of claims 1 to 3.

5. the obinutuzumab is administered at a dose of about 1000 mg, and optionally the immunoconjugate is polatuzumab vedotin, and further optionally (a) administration of polatuzumab vedotin-piiq, the venetoclax or a pharmaceutically acceptable salt thereof, and the obinutuzumab to a plurality of humans results in a complete response during or after administration of the polatuzumab vedotin-piiq, the venetoclax or a pharmaceutically acceptable salt thereof, and the obinutuzumab in at least about 55%, at least about 57%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans; (b) the duration of the complete response is at least about 1 month, at least about 2 months, at least about 3 months, or longer; (c) administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to a plurality of human beings results in an objective response in at least about 87%, at least about 90%, at least about 95%, or 100% of the human beings during or after administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab; or administration of polatuzumab vedotin-piiq, the venetoclax or a pharmaceutically acceptable salt thereof, and the obinutuzumab results in an objective response in at least about 70%, at least about 75%, at least about 78%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans during or after administration of the venetoclax or a pharmaceutically acceptable salt thereof, and the obinutuzumab; (d) administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab does not result in Grade 3 or greater peripheral neuropathy in the human; (e) administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab does not result in tumor lysis syndrome in the human; and / or (f) administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to a plurality of humans results in a Grade 3 or Grade 4 adverse event in about 59% or less of the humans, in about 64% or less of the humans, or in about 73% or less of the humans. The pharmaceutical composition according to any one of claims 1 to 4.

6. the polatuzumab vedotin-piiq, the venetoclax or a pharmaceutically acceptable salt thereof, and the obinutuzumab are administered during an induction phase, optionally comprising at least six 21-day cycles; and further optionally, (a) on day 1 of a first 21-day cycle, the polatuzumab vedotin-piiq is administered intravenously at a dose of about 1.8 mg / kg; on each of days 1 to 21 of a first 21-day cycle, the venetoclax or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 800 mg; and on each of days 1, 8, and 15 of a first 21-day cycle, the obinutuzumab is administered intravenously at a dose of about 1000 mg; on day 1 of each of a second, third, fourth, fifth, and sixth 21-day cycle, the polatuzumab vedotin-piiq is administered intravenously at a dose of about 1.8 mg / kg; on days 1-21 of each of a second, third, fourth, fifth, and sixth 21-day cycle, the venetoclax or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 800 mg; and on day 1 of each of a second, third, fourth, fifth, and sixth 21-day cycle, the obinutuzumab is administered intravenously at a dose of about 1000 mg; (b) the polatuzumab vedotin-piiq, the venetoclax or a pharmaceutically acceptable salt thereof, and the obinutuzumab are administered consecutively during the induction phase; Optionally, (i) on day 1 of a first 21-day cycle, the venetoclax or pharmaceutically acceptable salt thereof is administered before the obinutuzumab, and the obinutuzumab is administered before the polatuzumab vedotin-piiq, and on days 8 and 15 of a first 21-day cycle, the venetoclax or pharmaceutically acceptable salt thereof is administered before the obinutuzumab, and (ii) on day 1 of each of a second, third, fourth, fifth, and sixth 21-day cycles, the venetoclax or pharmaceutically acceptable salt thereof is administered before the obinutuzumab, and the obinutuzumab is administered before the polatuzumab vedotin-piiq; (c) administration of the polatuzumab vedotin-piiq, the venetoclax or a pharmaceutically acceptable salt thereof, and the obinutuzumab results in a complete response in the human after six 21-day cycles; and / or administration of the polatuzumab vedotin-piiq, the venetoclax or a pharmaceutically acceptable salt thereof, and the obinutuzumab to a plurality of humans results in a complete response in at least about 55%, at least about 57%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans after six 21-day cycles; optionally, the duration of the complete response is at least about 1 month, at least about 2 months, at least about 3 months, or longer; (d) administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to a plurality of humans results in an objective response in at least about 87%, at least about 90%, at least about 95%, or 100% of the humans after six 21-day cycles; (e) administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab to a plurality of humans results in an objective response in at least about 70%, at least about 75%, at least about 78%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans after six 21-day cycles; and / or (f) the venetoclax or a pharmaceutically acceptable salt thereof and the obinutuzumab are further administered during a maintenance phase after a sixth 21-day cycle of the induction phase, wherein the venetoclax or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 800 mg once daily during the maintenance phase, and the obinutuzumab is administered intravenously at a dose of about 1000 mg once every two months during the maintenance phase; Optionally, (i) the venetoclax or a pharmaceutically acceptable salt thereof is administered for up to 8 months during the maintenance phase; (ii) the obinutuzumab is administered during a maintenance phase starting on day 1 of the second month after the sixth 21-day cycle of the induction phase; (iii) the obinutuzumab is administered for up to 24 months during the maintenance phase; and / or (iv) the venetoclax or a pharmaceutically acceptable salt thereof and the obinutuzumab are administered sequentially during the maintenance phase, optionally with the venetoclax or a pharmaceutically acceptable salt thereof administered before the obinutuzumab on Day 1 of each of months 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24 during the maintenance phase. The pharmaceutical composition according to claim 5.

7. (a) the anti-CD79b antibody comprises 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; (b) the anti-CD79b 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: 38; or (c) the immunoconjugate is iradatuzumab vedotin; The pharmaceutical composition according to any one of claims 1 to 3.

8. 1. A medicament comprising an immunoconjugate in combination with venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab for treating follicular lymphoma (FL) in a human being in need thereof, wherein effective amounts of the immunoconjugate at a dose of about 1.8 mg / kg, venetoclax or a pharmaceutically acceptable salt thereof at a dose of about 800 mg, and obinutuzumab at a dose of about 1000 mg are administered to the human being; the immunoconjugate comprising: (a) 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 1 to 8. Pharmaceuticals, including

9. 1. A medicament comprising venetoclax or a pharmaceutically acceptable salt thereof for treating follicular lymphoma (FL) in combination with an immunoconjugate and obinutuzumab in a human being in need thereof, wherein effective amounts of the immunoconjugate at a dose of about 1.8 mg / kg, venetoclax or a pharmaceutically acceptable salt thereof at a dose of about 800 mg, and obinutuzumab at a dose of about 1000 mg are administered to the human being; the immunoconjugate comprising: (a) 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 1 to 8. Pharmaceuticals, including

10. 1. A medicament for treating follicular lymphoma (FL) in combination with an immunoconjugate and venetoclax or a pharmaceutically acceptable salt thereof in a human being in need thereof, comprising obinutuzumab, wherein effective amounts of the immunoconjugate at a dose of about 1.8 mg / kg, venetoclax or a pharmaceutically acceptable salt thereof at a dose of about 800 mg, and obinutuzumab at a dose of about 1000 mg are administered to the human being; the immunoconjugate comprising: (a) 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 1 to 8. Pharmaceuticals, including

11. 1. A medicament comprising an immunoconjugate and venetoclax or a pharmaceutically acceptable salt thereof for treating follicular lymphoma (FL) in combination with obinutuzumab in a human being in need thereof, wherein effective amounts of the immunoconjugate at a dose of about 1.8 mg / kg, venetoclax or a pharmaceutically acceptable salt thereof at a dose of about 800 mg, and obinutuzumab at a dose of about 1000 mg are administered to the human being; the immunoconjugate comprising: (a) 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 1 to 8. Pharmaceuticals, including

12. 1. A medicament for treating follicular lymphoma (FL) in a human in need thereof, comprising venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab, in combination with an immunoconjugate, wherein effective amounts of the immunoconjugate at a dose of about 1.8 mg / kg, venetoclax or a pharmaceutically acceptable salt thereof at a dose of about 800 mg, and obinutuzumab at a dose of about 1000 mg are administered to the human; the immunoconjugate comprising: (a) 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 1 to 8. Pharmaceuticals, including

13. 1. A medicament for treating follicular lymphoma (FL) in combination with venetoclax or a pharmaceutically acceptable salt thereof, comprising an immunoconjugate and obinutuzumab, in a human being in need thereof, wherein effective amounts of the immunoconjugate at a dose of about 1.8 mg / kg, venetoclax or a pharmaceutically acceptable salt thereof at a dose of about 800 mg, and obinutuzumab at a dose of about 1000 mg, the immunoconjugate comprising: (a) 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 1 to 8. Pharmaceuticals, including

14. 1. A medicament for treating follicular lymphoma (FL) in a human in need thereof, comprising an immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab, wherein effective amounts of the immunoconjugate at a dose of about 1.8 mg / kg, venetoclax or a pharmaceutically acceptable salt thereof at a dose of about 800 mg, and obinutuzumab at a dose of about 1000 mg are administered to the human; the immunoconjugate comprising: (a) 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 1 to 8. Pharmaceuticals, including

15. 1. A medicament comprising an effective amount of an immunoconjugate at a dose of about 1.8 mg / kg for treating follicular lymphoma (FL) in combination with venetoclax or a pharmaceutically acceptable salt thereof at a dose of about 800 mg, and obinutuzumab at a dose of about 1000 mg in a human in need thereof; the immunoconjugate comprising: 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 1 to 8. Pharmaceuticals, including

16. 1. A medicament for treating follicular lymphoma (FL) in a human in need thereof, comprising: effective amounts of the immunoconjugate at a dose of about 1.8 mg / kg, venetoclax or a pharmaceutically acceptable salt thereof at a dose of about 800 mg, and obinutuzumab at a dose of about 1000 mg are administered to the human; the medicament comprises an immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab; the immunoconjugate comprising: 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 1 to 8. Including, The pharmaceutical agent, wherein the human achieves a complete response (CR) during or after administration of the immunoconjugate, the venetoclax or a pharmaceutically acceptable salt thereof, and the obinutuzumab.

17. 1. A medicament comprising an effective amount of an immunoconjugate at a dose of about 1.8 mg / kg for treating follicular lymphoma (FL) in combination with venetoclax or a pharmaceutically acceptable salt thereof at a dose of about 800 mg, and obinutuzumab at a dose of about 1000 mg in a human in need thereof; the immunoconjugate comprising: 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 1 to 8. Including, The pharmaceutical agent, wherein the human achieves a complete response (CR) during or after administration of the immunoconjugate, the venetoclax or a pharmaceutically acceptable salt thereof, and the obinutuzumab.

18. 1. A medicament for treating follicular lymphoma (FL) in a human in need thereof, comprising: effective amounts of polatuzumab vedotin-piiq at a dose of about 1.8 mg / kg, venetoclax or a pharmaceutically acceptable salt thereof at a dose of about 800 mg, and obinutuzumab at a dose of about 1000 mg are administered to the human during an induction phase; the medicament comprises polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and obinutuzumab; The pharmaceutical, wherein the human achieves a complete response during or after the induction period.

19. 1. A pharmaceutical composition comprising an effective amount of polatuzumab vedotin-piiq at a dose of about 1.8 mg / kg, in combination with venetoclax or a pharmaceutically acceptable salt thereof at a dose of about 800 mg, and obinutuzumab at a dose of about 1000 mg, during an induction phase, for treating follicular lymphoma (FL) in a human in need thereof, wherein the human achieves a complete response during or after the induction phase.

20. (a) a prophylactic treatment for tumor lysis syndrome (TLS) is further administered to the human, wherein the prophylactic treatment for TLS comprises a uric acid-reducing agent and / or a hydration regimen prior to initiation of treatment; Optionally, (i) said hydration regimen comprises administering about 2 to about 3 liters of fluid per day, said fluid being administered from about 24 hours to about 48 hours before the start of said treatment, and optionally said fluid being administered orally or intravenously; and / or (ii) the uric acid-reducing agent is allopurinol, and optionally the allopurinol is administered orally at a dose of about 300 mg / day starting about 72 hours before the first administration of venetoclax or a pharmaceutically acceptable salt thereof, and administration of allopurinol continues for about 3 to about 7 days after the first administration of venetoclax or a pharmaceutically acceptable salt thereof; (b) if a Grade 3 or Grade 4 adverse event of neutropenia occurs, granulocyte colony-stimulating factor (G-CSF) is further administered to the human; (c) the human has an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 prior to initiation of treatment; (d) the FL is relapsed or refractory to prior treatment for FL, and optionally, the prior treatment for FL comprises a chemoimmunotherapeutic regimen comprising an anti-CD20 monoclonal antibody; (e) the FL is histologically documented to be CD20 positive; (f) the FL is fluorodeoxyglucose (FDG)-avid FL; (g) the FL is a positron emission tomography (PET)-positive FL; (h) the human has at least one bidimensionally measurable lesion prior to treatment, the lesion measuring at least 1.5 centimeters in its greatest dimension as measured by computed tomography (CT) scan or magnetic resonance imaging (MRI); (i) the FL is not grade 3b FL; (j) the human does not have peripheral neuropathy greater than Grade 1 prior to treatment; (k) the FL has a histologic grade of 1, 2, or 3a before treatment; (l) the human has FL with bone marrow involvement prior to treatment; (m) the human has FL with Ann Arbor stage 1, 2, 3, or 4 prior to treatment; (n) the human has FL with a Follicular Lymphoma International Prognostic Index (FLIPI) score of 0, 1, 2, 3, 4, or 5 prior to treatment; (o) the human has received at least one prior treatment for FL; (p) the human has a bulky mass lesion greater than 7 centimeters prior to treatment; (q) the FL is refractory to prior treatment including an anti-CD20 agent; and / or (r) the FL has progressed within 24 months of completing the first treatment for the FL; The pharmaceutical composition according to any one of claims 1 to 19.

21. 21. For use in combination with a selective Bcl-2 inhibitor or a pharmaceutically acceptable salt thereof, and an anti-CD20 antibody, to treat a human in need thereof, having follicular lymphoma (FL) according to any one of claims 1 to 20. 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 1 to 8. A kit comprising an immunoconjugate comprising:

22. 21. For use in combination with venetoclax or a pharmaceutically acceptable salt thereof and obinutuzumab to treat a human in need thereof, having follicular lymphoma (FL) according to any one of claims 1 to 20. 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 1 to 8. A kit comprising an immunoconjugate comprising:

23. A kit comprising venetoclax or a pharmaceutically acceptable salt thereof and polatuzumab vedotin-piiq for use in combination with obinutuzumab for treating a human in need thereof, having follicular lymphoma (FL) according to any one of claims 1 to 6 and 8 to 20.

24. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, comprising: administering to the human effective amounts of an immunoconjugate, a selective Bcl-2 inhibitor, or a pharmaceutically acceptable salt thereof, and an anti-CD20 antibody; the medicament comprises an immunoconjugate, a selective Bcl-2 inhibitor or a pharmaceutically acceptable salt thereof, and an anti-CD20 antibody; 10. The immunoconjugate of claim 1, wherein 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 1 to 8. Including, the human achieves a complete response (CR) during or after administration of the immunoconjugate, the selective Bcl-2 inhibitor or a pharmaceutically acceptable salt thereof, and the anti-CD20 antibody; the immunoconjugate is administered at a dose of about 1.8 mg / kg; the selective Bcl-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof administered at a dose of about 800 mg; the anti-CD20 antibody is rituximab; Medicine.

25. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, comprising a selective Bcl-2 inhibitor or a pharmaceutically acceptable salt thereof, in combination with an anti-CD20 antibody, the medicament comprising 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 1 to 8. an immunoconjugate comprising the human achieves a complete response (CR) during or after administration of the immunoconjugate, the selective Bcl-2 inhibitor or a pharmaceutically acceptable salt thereof, and the anti-CD20 antibody; the immunoconjugate is administered at a dose of about 1.8 mg / kg; the selective Bcl-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof administered at a dose of about 800 mg; the anti-CD20 antibody is rituximab; Medicine.

26. (a) p is 3-4 or 2-5; and / or (b) 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; The pharmaceutical composition according to claim 24 or 25.

27. (a) 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 (b) the immunoconjugate is polatuzumab vedotin-piiq; The pharmaceutical composition according to any one of claims 24 to 26.

28. The rituximab is administered at a concentration of about 375 mg / m ２ and optionally wherein the immunoconjugate is polatuzumab vedotin-piiq, and further optionally wherein (a) administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in a complete response in at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans during or after administration of the polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab; (b) administering the polatuzumab vedotin-piiq, the venetoclax or a pharmaceutically acceptable salt thereof, and the rituximab to a plurality of humans results in a best complete response rate of at least about 35%, at least about 38%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100%; (c) administering polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of human beings results in an objective response during or after administration of the polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab in at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 42%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the human beings; (d) administering the polatuzumab vedotin-piiq, the venetoclax or a pharmaceutically acceptable salt thereof, and the rituximab to a plurality of humans results in a best overall response in at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans during or after administration of the polatuzumab vedotin-piiq, the venetoclax or a pharmaceutically acceptable salt thereof, and the rituximab. (e) administering polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of human beings results in a 6-month progression-free survival rate of at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 42%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100%; (f) administering the polatuzumab vedotin-piiq, the venetoclax or a pharmaceutically acceptable salt thereof, and the rituximab to the human being results in progression-free survival of the human being for at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, or longer after administration of the polatuzumab vedotin-piiq, the venetoclax or a pharmaceutically acceptable salt thereof, and the rituximab; (g) administering the polatuzumab vedotin-piiq, the venetoclax or a pharmaceutically acceptable salt thereof, and the rituximab to the human being results in survival of the human being for 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, at least 11 months, or longer after administration of the polatuzumab vedotin-piiq, the venetoclax or a pharmaceutically acceptable salt thereof, and the rituximab; (h) administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to the human being results in a reduction in the two-way sum of products (SPD) of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, or 100%, compared to the SPD before administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab; and / or (i) administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in a serious adverse event in about 40% or less, about 37% or less, about 35% or less, or about 30% or less of the humans; The pharmaceutical composition according to any one of claims 24 to 27.

29. the polatuzumab vedotin-piiq, the venetoclax or a pharmaceutically acceptable salt thereof, and the rituximab are administered during an induction phase, optionally comprising at least six 21-day cycles, and further optionally comprising: (a) on day 1 of each of a first, second, third, fourth, fifth, and sixth 21-day cycle, the polatuzumab vedotin-piiq is administered intravenously at a dose of about 1.8 mg / kg; on days 1 to 21 of each of a first, second, third, fourth, fifth, and sixth 21-day cycle, the venetoclax or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 800 mg; and on day 1 of each of a first, second, third, fourth, fifth, and sixth 21-day cycle, the rituximab is administered orally at a dose of about 375 mg / m ２ It is administered intravenously at a dose of; (b) the polatuzumab vedotin-piiq, the venetoclax or a pharmaceutically acceptable salt thereof, and the rituximab are administered consecutively during the induction phase, optionally, on Day 1 of each of a first, second, third, fourth, fifth, and sixth 21-day cycles, the venetoclax or a pharmaceutically acceptable salt thereof is administered before the rituximab and the rituximab is administered before the polatuzumab vedotin-piiq; (c) the administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab results in a complete response in the human after six 21-day cycles; (d) administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in a complete response in at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans after six 21-day cycles; (e) administering the polatuzumab vedotin-piiq, the venetoclax or a pharmaceutically acceptable salt thereof, and the rituximab to a plurality of human beings results in a best complete response rate of at least about 35%, at least about 38%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100%; (f) administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in an objective response in at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 42%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans after six 21-day cycles; (g) administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in a best complete response in at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the humans after six 21-day cycles; (h) administering polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of human beings results in a 6-month progression-free survival rate of at least about 25%, at least about 27%, at least about 29%, at least about 31%, at least about 35%, at least about 40%, at least about 42%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100%; (i) administering polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to the human being results in progression-free survival of the human being for at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, or longer after administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab; (j) administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to the human being results in survival of the human being for 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, at least 11 months, or longer after administration of the polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab; (k) administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to the human being results in a reduction in the two-way sum of products (SPD) of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, or 100%, after six 21-day cycles, compared to the SPD before administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab; (l) administration of polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab to a plurality of humans results in a serious adverse event in about 40% or less, about 37% or less, about 35% or less, or about 30% or less of the humans after six 21-day cycles; and / or (m) the venetoclax or a pharmaceutically acceptable salt thereof and the rituximab are further administered during a consolidation phase after a sixth 21-day cycle of the induction phase, wherein the venetoclax or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 800 mg once daily during the consolidation phase, and the rituximab is administered orally at a dose of about 375 mg / m once every two months during the consolidation phase. ２ is administered intravenously at a dose of Optionally, i. the venetoclax or a pharmaceutically acceptable salt thereof and the rituximab are administered for up to 8 months during the consolidation phase; and / or the rituximab is administered during the consolidation phase starting on day 1 of the second month after the sixth 21-day cycle of the induction phase; and / or ii. the venetoclax or a pharmaceutically acceptable salt thereof and the rituximab are administered sequentially during the consolidation phase, optionally with the venetoclax or a pharmaceutically acceptable salt thereof administered before the rituximab on Day 1 of each of months 2, 4, 6, and 8 during the consolidation phase; The pharmaceutical composition of claim 28.

30. 30. The method of claim 28 or 29, wherein the duration of the complete response or the objective response is at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, or longer.

31. (a) the anti-CD79b antibody comprises 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; (b) the anti-CD79b 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: 38; or (c) the immunoconjugate is iradatuzumab vedotin; The pharmaceutical composition according to any one of claims 24 to 26.

32. 1. A medicament comprising an immunoconjugate for treating diffuse large B-cell lymphoma (DLBCL) in combination with venetoclax or a pharmaceutically acceptable salt thereof, and rituximab in a human in need thereof, the medicament comprising effective amounts of the immunoconjugate at a dose of about 1.8 mg / kg, venetoclax or a pharmaceutically acceptable salt thereof at a dose of about 800 mg, and rituximab at a dose of about 375 mg / m ２ a dose of rituximab is administered to the human; the immunoconjugate comprising: 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 1 to 8. Pharmaceuticals, including

33. 1. A medicament comprising venetoclax or a pharmaceutically acceptable salt thereof for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, in combination with an immunoconjugate and rituximab, the medicament comprising effective amounts of the immunoconjugate at a dose of about 1.8 mg / kg, venetoclax or a pharmaceutically acceptable salt thereof at a dose of about 800 mg, and rituximab at a dose of about 375 mg / m ２ a dose of rituximab is administered to the human; the immunoconjugate comprising: 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 1 to 8. Pharmaceuticals, including

34. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, and venetoclax or a pharmaceutically acceptable salt thereof, in a human in need thereof, comprising rituximab, the immunoconjugate being administered in effective amounts of: the immunoconjugate at a dose of about 1.8 mg / kg; venetoclax or a pharmaceutically acceptable salt thereof at a dose of about 800 mg; and venetoclax or a pharmaceutically acceptable salt thereof at a dose of about 375 mg / m ２ a dose of rituximab is administered to the human; the immunoconjugate comprising: 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 1 to 8. Pharmaceuticals, including

35. 1. A medicament comprising an immunoconjugate and venetoclax or a pharmaceutically acceptable salt thereof for treating diffuse large B-cell lymphoma (DLBCL) in combination with rituximab in a human in need thereof, the medicament comprising effective amounts of the immunoconjugate at a dose of about 1.8 mg / kg, venetoclax or a pharmaceutically acceptable salt thereof at a dose of about 800 mg, and venetoclax or a pharmaceutically acceptable salt thereof at a dose of about 375 mg / m ２ a dose of rituximab is administered to the human; the immunoconjugate comprising: 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 1 to 8. Pharmaceuticals, including

36. 1. A pharmaceutical composition comprising venetoclax or a pharmaceutically acceptable salt thereof, and rituximab, in combination with an immunoconjugate, for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, wherein the immunoconjugate is administered in effective amounts of: venetoclax or a pharmaceutically acceptable salt thereof, and rituximab; ２ a dose of rituximab is administered to the human; the immunoconjugate comprising: 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 1 to 8. Pharmaceuticals, including

37. 1. A medicament comprising an immunoconjugate and rituximab for treating diffuse large B-cell lymphoma (DLBCL) in combination with venetoclax or a pharmaceutically acceptable salt thereof in a human in need thereof, the medicament comprising effective amounts of the immunoconjugate at a dose of about 1.8 mg / kg, venetoclax or a pharmaceutically acceptable salt thereof at a dose of about 800 mg, and rituximab at a dose of about 375 mg / m ２ a dose of rituximab is administered to the human; the immunoconjugate comprising: 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 1 to 8. Pharmaceuticals, including

38. 1. A pharmaceutical composition for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, comprising an immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab, the composition comprising effective amounts of the immunoconjugate at a dose of about 1.8 mg / kg, venetoclax or a pharmaceutically acceptable salt thereof at a dose of about 800 mg, and rituximab at a dose of about 375 mg / m ２ a dose of rituximab is administered to the human; the immunoconjugate comprising: 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 1 to 8. Pharmaceuticals, including

39. In a human in need of treatment for diffuse large B-cell lymphoma (DLBCL), a dose of about 800 mg of venetoclax or a pharmaceutically acceptable salt thereof, and a dose of about 375 mg / m ２ 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) comprising an effective amount of an immunoconjugate at a dose of about 1.8 mg / kg in combination with rituximab at a dose of the immunoconjugate comprising: 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 1 to 8. Pharmaceuticals, including

40. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, comprising: effective amounts of the immunoconjugate at a dose of about 1.8 mg / kg, venetoclax or a pharmaceutically acceptable salt thereof at a dose of about 800 mg, and ２ a dose of rituximab is administered to the human; the medicament comprises an immunoconjugate, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab; 10. The immunoconjugate of claim 1, wherein 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 1 to 8. Including, wherein the human achieves a complete response (CR) during or after administration of the immunoconjugate, the venetoclax or a pharmaceutically acceptable salt thereof, and the rituximab.

41. In a human in need of treatment for diffuse large B-cell lymphoma (DLBCL), a dose of about 800 mg of venetoclax or a pharmaceutically acceptable salt thereof, and a dose of about 375 mg / m ２ 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) comprising an effective amount of an immunoconjugate at a dose of about 1.8 mg / kg in combination with rituximab at a dose of 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 1 to 8. Including, wherein the human achieves a complete response (CR) during or after administration of the immunoconjugate, the venetoclax or a pharmaceutically acceptable salt thereof, and the rituximab.

42. 1. A medicament for treating diffuse large B-cell lymphoma (DLBCL) in a human in need thereof, comprising: During the induction phase, effective amounts of polatuzumab vedotin-piiq at a dose of about 1.8 mg / kg, venetoclax or a pharmaceutically acceptable salt thereof at a dose of about 800 mg, and venetoclax or a pharmaceutically acceptable salt thereof at a dose of about 375 mg / m ２ a dose of rituximab is administered to the human; the medicament comprises polatuzumab vedotin-piiq, venetoclax or a pharmaceutically acceptable salt thereof, and rituximab; The pharmaceutical, wherein the human achieves a complete response during or after the induction period.

43. In a human in need of treatment for diffuse large B-cell lymphoma (DLBCL), during an induction phase, a dose of about 800 mg of venetoclax or a pharmaceutically acceptable salt thereof and a dose of about 375 mg / m ２ 1. A medicament comprising an effective amount of polatuzumab vedotin-piiq at a dose of about 1.8 mg / kg for the treatment of diffuse large B-cell lymphoma (DLBCL) in combination with rituximab at a dose of about 1.8 mg / kg, wherein the human achieves a complete response during or after the induction phase.

44. (a) a prophylactic treatment for tumor lysis syndrome (TLS) is further administered, wherein said prophylactic treatment for TLS comprises a uric acid-reducing agent and / or a hydration regimen prior to initiation of treatment; Optionally, i. said hydration regimen comprises administering about 2 to about 3 liters of fluid per day, said fluid being administered from about 24 hours to about 48 hours before the start of said treatment, and optionally said fluid being administered orally or intravenously; and / or ii. the uric acid-reducing agent is allopurinol, optionally administered orally at a dose of about 300 mg / day starting about 72 hours before the first dose of venetoclax or a pharmaceutically acceptable salt thereof, and wherein administration of allopurinol continues for about 3 to about 7 days after administration of the first dose of venetoclax or a pharmaceutically acceptable salt thereof; (b) if a Grade 3 or Grade 4 adverse event of neutropenia occurs, granulocyte colony-stimulating factor (G-CSF) is further administered to the human; (c) if a Grade 3 or Grade 4 adverse event of thrombocytopenia occurs, a platelet transfusion is further administered to the human; (d) the human has an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 prior to initiation of treatment; (e) the DLBCL is relapsed or refractory to prior treatment for DLBCL, and optionally, the prior treatment for DLBCL comprises a chemoimmunotherapeutic regimen comprising an anti-CD20 monoclonal antibody; (f) the DLBCL is histologically documented to be CD20 positive; (g) the DLBCL is fluorodeoxyglucose (FDG)-avid DLBCL; (h) the DLBCL is positron emission tomography (PET)-positive DLBCL; (i) the human has at least one bidimensionally measurable lesion prior to treatment, the lesion measuring at least 1.5 centimeters in its greatest dimension as measured by computed tomography (CT) scan or magnetic resonance imaging (MRI); (j) the human does not have a history of transformation from an indolent disease to DLBCL; (k) the human does not have peripheral neuropathy greater than Grade 1 prior to treatment; (l) the human has DLBCL with an Ann Arbor stage of 1, 2, 3, or 4 prior to treatment; (m) the human has DLBCL with an International Prognostic Index (IPI) score of 0, 1, 2, 3, 4, or 5 prior to treatment; (n) the human has received at least one prior treatment for DLBCL, and optionally, the prior treatment for DLBCL comprises chimeric antigen receptor (CAR) T cell treatment for DLBCL; (o) the human has a bulky mass lesion of 7 centimeters or greater prior to treatment; (p) the human has extranodal disease; (q) the DLBCL is refractory to prior treatment including an anti-CD20 agent; (r) the DLBCL has not responded, progressed, or recurred within about 6 months after the last prior treatment for DLBCL administered to the human; (s) the DLBCL has not responded, progressed, or recurred within about 6 months after the first prior treatment for DLBCL administered to the human; and / or (t) the DLBCL is i. DLBCL with activated B cell (ABC) cell of origin; ii. DLBCL with a germinal center B cell (GCB) cell of origin; iii. BCL2 positive DLBCL, iv. BCL2 negative DLBCL, v. Double Expressor DLBCL, or vi. Non-double expressor DLBCL That is, The pharmaceutical composition according to any one of claims 24 to 43.

45. 45. A compound of formula (I) for use in combination with a selective Bcl-2 inhibitor or a pharmaceutically acceptable salt thereof, and an anti-CD20 antibody to treat a human in need thereof, having diffuse large B-cell lymphoma (DLBCL) according to any one of claims 24 to 44. 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 1 to 8. A kit comprising an immunoconjugate comprising:

46. 45. A compound of formula (I) for use in combination with venetoclax or a pharmaceutically acceptable salt thereof and rituximab for treating a human in need thereof having diffuse large B-cell lymphoma (DLBCL) according to any one of claims 24 to 44. 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 1 to 8. A kit comprising an immunoconjugate comprising:

47. 45. A kit comprising venetoclax, or a pharmaceutically acceptable salt thereof, and polatuzumab vedotin-piiq, for use in combination with rituximab, for treating a human in need thereof having diffuse large B-cell lymphoma (DLBCL) according to any one of claims 24-30 and 32-44.

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