EP4045090A1 - Methods of using anti-cd79b immunoconjugates to treat diffuse large b-cell lymphoma - Google Patents

Methods of using anti-cd79b immunoconjugates to treat diffuse large b-cell lymphoma

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Publication number
EP4045090A1
EP4045090A1 EP20750817.7A EP20750817A EP4045090A1 EP 4045090 A1 EP4045090 A1 EP 4045090A1 EP 20750817 A EP20750817 A EP 20750817A EP 4045090 A1 EP4045090 A1 EP 4045090A1
Authority
EP
European Patent Office
Prior art keywords
gemcitabine
oxaliplatin
immunoconjugate
seq
amino acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
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EP20750817.7A
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German (de)
English (en)
French (fr)
Inventor
Juana Elva HERNANDEZ MONTALVO
Naseer Ul Din QAYUM
Jamie Harue HIRATA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Genentech Inc
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F Hoffmann La Roche AG
Genentech Inc
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Application filed by F Hoffmann La Roche AG, Genentech Inc filed Critical F Hoffmann La Roche AG
Publication of EP4045090A1 publication Critical patent/EP4045090A1/en
Pending legal-status Critical Current

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    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
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    • A61K47/6867—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from a cell of a blood cancer
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    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A—HUMAN NECESSITIES
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    • C—CHEMISTRY; METALLURGY
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    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
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Definitions

  • the present disclosure relates to methods of treating B-cell proliferative disorders, e.g. , Diffuse Large B-Cell Lymphoma (DLBCL) by administering an immunoconjugate comprising an anti-CD79b antibody in combination with an anti-CD20 antibody (e.g., rituximab) and one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin).
  • an immunoconjugate comprising an anti-CD79b antibody in combination with an anti-CD20 antibody (e.g., rituximab) and one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin).
  • Non-Hodgkin lymphoma is the most common hematologic malignancy in the world and the thirteenth most common cancer overall (Bray et al., (2016) CA Cancer J Clin, 68:394-424).
  • Diffuse large B-cell lymphoma (DLBCL) is an aggressive subtype of NHL, accounting for approximately 32.5% of all NHL cases.
  • DLBCL originates from mature B-cells and has a median survival of ⁇ 1 year in untreated patients (Rovira et al., (2015) Ann Hematol, 378:1396-1407).
  • a majority of DLBCL cells express CD20, a membrane antigen that is important in cell cycle initiation and differentiation (Anderson et al., (1984) Blood, 63:1424- 1433).
  • First-line treatment of DLBCL has consisted of an anti-CD20 monoclonal antibody treatment in combination with a multi-agent chemotherapy
  • DLBCL diffuse large B-cell lymphoma
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin.
  • 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 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.
  • p is between 2 and 5. In certain embodiments, p is between 3 and 4.
  • the immunoconjugate is polatuzumab vedotin-piiq.
  • 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 iladatuzumab vedotin. In certain embodiments, p is between 2 and 5. In certain embodiments, p is 2.
  • the immunoconjugate is administered at a dose that is from about 1 mg/kg to about 5 mg /kg. In some embodiments, the immunoconjugate is administered at a dose of about 1.2 mg/kg, about 1.8 mg/kg, about 2.4 mg/kg, about 3.6 mg/kg, or about 4.8 mg/kg. In some embodiments, the immunoconjugate is administered at a dose of about 1.8 mg/kg.
  • the immunoconjugate is administered at a dose of about 1.8 mg/kg
  • the rituximab is administered at a dose of about 375 mg/m 2
  • the gemcitabine is administered at a dose of about 1000 mg/m 2
  • the oxaliplatin is administered at a dose of about 100 mg/m 2 .
  • the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for one or more 21 -day cycles.
  • the immunoconjugate is administered at a dose of about 1.8 mg/kg each cycle
  • the rituximab is administered at a dose of about 375 mg/m 2 each cycle
  • the gemcitabine is administered at a dose of about 1000 mg/m 2 each cycle
  • the oxaliplatin is administered at a dose of about 100 mg/m 2 each cycle.
  • the immunoconjugate and the rituximab are administered intravenously on Day 1 of each 21 -day cycle
  • the gemcitabine and the oxaliplatin are administered intravenously on Day 2 of each 21 -day cycle.
  • the rituximab is administered before the immunoconjugate.
  • the gemcitabine is administered before the oxaliplatin.
  • the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for up to eight 21 -day cycles. In certain embodiments, the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for eight 21 -day cycles.
  • DLBCL diffuse large B-cell lymphoma
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for up to eight 21 -day cycles, wherein during each cycle the immunoconjugate is administered at a dose of about 1.8 mg/kg, the rituximab is administered at a dose of about 375 mg/m 2 , the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of about 100 mg/m 2 ; and wherein the immunoconjugate and the rituxima
  • DLBCL diffuse large B-cell lymphoma
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for at least one 21 -day cycle, wherein during each cycle the immunoconjugate is administered at a dose of about 1.8 mg/kg, the rituximab is administered at a dose of about 375 mg/m 2 , the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of about 100 mg/m 2 ; and wherein the immunoconjugate and the rituxima
  • DLBCL diffuse large B-cell lymphoma
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for up to eight 21 -day cycles, wherein during each cycle the immunoconjugate is administered at a dose of about 1.4 mg/kg, the rituximab is administered at a dose of about 375 mg/m 2 , the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of about 100 mg/m 2 ; and wherein the immunoconjugate and the rituxima
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for at least one 21 -day cycle, wherein during each cycle the immunoconjugate is administered at a dose of about 1.4 mg/kg, the rituximab is administered at a dose of about 375 mg/m 2 , the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of about 100 mg/m 2 ; and wherein the immunoconjugate and the rituxima
  • DLBCL diffuse large B-cell lymphoma
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for up to eight 21 -day cycles, wherein during each cycle the immunoconjugate is administered at a dose of about 1.8 mg/kg, the rituximab is administered at a dose of about 375 mg/m 2 , the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of about 75 mg/m 2 ; and wherein the immunoconjugate and the rituxima
  • DLBCL diffuse large B-cell lymphoma
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for at least one 21 -day cycle, wherein during each cycle the immunoconjugate is administered at a dose of about 1.8 mg/kg, the rituximab is administered at a dose of about 375 mg/m 2 , the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of about 75 mg/m 2 ; and wherein the immunoconjugate and the rituxima
  • DLBCL diffuse large B-cell lymphoma
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for up to eight 21 -day cycles, wherein during each cycle the immunoconjugate is administered at a dose of about 1.4 mg/kg, the rituximab is administered at a dose of about 375 mg/m 2 , the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of about 75 mg/m 2 ; and wherein the immunoconjugate and the rituxima
  • DLBCL diffuse large B-cell lymphoma
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for at least one 21 -day cycle, wherein during each cycle the immunoconjugate is administered at a dose of about 1.4 mg/kg, the rituximab is administered at a dose of about 375 mg/m 2 , the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of about 75 mg/m 2 ; and wherein the immunoconjugate and the rituxima
  • the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for at least two, at least three, at least four, at least five, at least six, or at least seven 21 -day cycles. In some embodiments, the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for eight 21 -day cycles. In some embodiments, the rituximab is administered before the immunoconjugate. In some embodiments, the gemcitabine is administered before the oxaliplatin. In some embodiments, the immunoconjugate is polatuzumab vedotin-piiq.
  • the human has received at least one prior therapy for DLBCL. In some embodiments, the human has received at least one prior systemic therapy for DLBCL. In some embodiments, the human has received at least two prior therapies for DLBCL.
  • the DLBCL is histologically-confirmed DLBCL, not otherwise specified (NOS) or the human has a history of transformation of indolent disease to DLBCL. In certain embodiments, the DLBCL is relapsed or refractory DLBCL. In certain embodiments, the human has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
  • EOG Eastern Cooperative Oncology Group
  • the human does not have a planned autologous or allogeneic stem cell transplantation (SCT), In certain embodiments, the human has not had prior therapy with a combination of gemcitabine and a platinum-based agent. In certain embodiments, the human does not have peripheral neuropathy of greater than Grade 1 according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0. In certain embodiments, the human does not have primary or secondary central nervous system lymphoma. In some embodiments, the human is not a candidate for hematopoietic stem cell transplantation (HSCT) prior to administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • SCT planned autologous or allogeneic stem cell transplantation
  • the human has not had prior therapy with a combination of gemcitabine and a platinum-based agent.
  • the human does not have peripheral neuropathy of greater than Grade 1 according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0.
  • the human does not have
  • the human is not a candidate for autologous hematopoietic stem cell transplantation (HSCT) prior to administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • the human has received at least two prior therapies for DLBCL.
  • the human has not received a prior therapy with polatuzumab vedotin-piiq for DLBCL.
  • the human is an adult.
  • the human adult has relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified.
  • the human after administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin, the human does not experience peripheral neuropathy of Grade 3 or greater that does not resolve to Grade 1 or lower within 14 days.
  • peripheral neuropathy of Grade 3 or greater that does not resolve to Grade 1 or lower within 14 days.
  • 33% or fewer experience peripheral neuropathy of Grade 3 or greater that does not resolve to Grade 1 or lower within 14 days.
  • peripheral neuropathy of Grade 3 or greater does not resolve to Grade 1 or lower within 14 days.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin does not result in peripheral neuropathy of Grade 3 or greater in the human that does not resolve to Grade 1 or lower within 14 days.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin does not result in peripheral neuropathy of Grade 4 or greater in the human. In some embodiments, administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin does not result in neurotoxicity of Grade 4 or greater in the human. In some embodiments, after administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin, the human does not experience peripheral neuropathy of Grade 4 or greater.
  • the human after administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin, the human does not experience neurotoxicity of Grade 4 or greater.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in 33% or fewer of the humans in the plurality experiencing peripheral neuropathy of Grade 3 or greater that does not resolve to Grade 1 or lower within 14 days.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in less than about 40% of the humans in the plurality experiencing peripheral neuropathy of Grade 3 or greater that does not resolve to Grade 1 or lower within 14 days. In some embodiments, administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in less than about 8% of the humans in the plurality experiencing peripheral neuropathy of Grade 3 or greater.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in less than about 6% of the humans in the plurality experiencing peripheral neuropathy that results in discontinuation of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin have been administered for at least four 21 -day cycles.
  • DLBCL diffuse large B-cell lymphoma
  • Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein, after administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin, the human does not experience peripheral neuropathy of Grade 3 or greater that does not resolve to Grade 1 or lower within 14
  • DLBCL diffuse large B-cell lymphoma
  • Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin does not result in peripheral neuropathy of Grade 3 or greater in the human that does not resolve to Grade 1 or lower within 14 days
  • 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 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.
  • p is between 2 and 5. In certain embodiments, p is between 3 and 4.
  • the immunoconjugate is polatuzumab vedotin-piiq.
  • a method for treating diffuse large B-cell lymphoma comprising administering to the human an effective amount of: (a) an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin
  • a method for treating diffuse large B-cell lymphoma comprising administering to the human an effective amount of: (a) an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin
  • 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 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.
  • p is between 2 and 5. In certain embodiments, p is between 3 and 4, In certain embodiments, the immunoconjugate is polatuzumab vedotin-piiq.
  • the immunoconjugate is administered at a dose of about 1.8 mg/kg
  • the rituximab is administered at a dose of about 375 mg/m 2
  • the gemcitabine is administered at a dose of about 1000 mg/m 2
  • the oxaliplatin is administered at a dose of about 100 mg/m 2 .
  • the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for one or more 21 -day cycles.
  • the immunoconjugate is administered at a dose of about 1.8 mg/kg each cycle
  • the rituximab is administered at a dose of about 375 mg/m 2 each cycle
  • the gemcitabine is administered at a dose of about 1000 mg/m 2 each cycle
  • the oxaliplatin is administered at a dose of about 100 mg/m 2 each cycle.
  • the immunoconjugate and the rituximab are administered intravenously on Day 1 of each 21 -day cycle
  • the gemcitabine and the oxaliplatin are administered intravenously on Day 2 of each 21-day cycle.
  • the rituximab is administered before the immunoconjugate.
  • the gemcitabine is administered before the oxaliplatin.
  • the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for up to eight 21 -day cycles. In certain embodiments, the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for eight 21 -day cycles.
  • DLBCL diffuse large B-cell lymphoma
  • Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for up to eight 21 -day cycles, wherein during each cycle the immunoconjugate is administered at a dose of about 1.8 mg/kg, the rituximab is administered at a dose of about 375 mg/m 2 , the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of about 100 mg/m 2 ; wherein the immunoconjugate and the rituximab are administered intravenously on Day 1 of each
  • DLBCL diffuse large B-cell lymphoma
  • Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for at least one 21 -day cycle, wherein during each cycle the immunoconjugate is administered at a dose of about 1.8 mg/kg, the rituximab is administered at a dose of about 375 mg/m 2 , the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of about 100 mg/m 2 ; wherein the immunoconjugate and the rituximab are administered intravenously on Day 1 of each
  • DLBCL diffuse large B-cell lymphoma
  • Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for up to eight 21 -day cycles, wherein during each cycle the immunoconjugate is administered at a dose of about 1.8 mg/kg, the rituximab is administered at a dose of about 375 mg/m 2 , the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of about 100 mg/m 2 ; wherein the immunoconjugate and the rituximab are administered intravenously on Day 1 of each
  • DLBCL diffuse large B-cell lymphoma
  • Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for at least one 21 -day cycle, wherein during each cycle the immunoconjugate is administered at a dose of about 1.8 mg/kg, the rituximab is administered at a dose of about 375 mg/m 2 , the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of about 100 mg/m 2 ; wherein the immunoconjugate and the rituximab are administered intravenously on Day 1 of each
  • DLBCL diffuse large B-cell lymphoma
  • Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for up to eight 21 -day cycles, wherein during each cycle the immunoconjugate is administered at a dose of about 1.8 mg/kg, the rituximab is administered at a dose of about 375 mg/m 2 , the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of about 100 mg/m 2 ; wherein the immunoconjugate and the rituximab are administered intravenously on Day 1 of each
  • Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for at least one 21 -day cycle, wherein during each cycle the immunoconjugate is administered at a dose of about 1.8 mg/kg, the rituximab is administered at a dose of about 375 mg/m 2 , the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of about 100 mg/m 2 ; wherein the immunoconjugate and the rituximab are administered intravenously on Day 1 of each
  • DLBCL diffuse large B-cell lymphoma
  • Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for up to eight 21 -day cycles, wherein during each cycle the immunoconjugate is administered at a dose of about 1.8 mg/kg, the rituximab is administered at a dose of about 375 mg/m 2 , the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of about 100 mg/m 2 ; wherein the immunoconjugate and the rituximab are administered intravenously on Day 1 of each
  • DLBCL diffuse large B-cell lymphoma
  • Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for at least one 21 -day cycle, wherein during each cycle the immunoconjugate is administered at a dose of about 1.8 mg/kg, the rituximab is administered at a dose of about 375 mg/m 2 , the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of about 100 mg/m 2 ; wherein the immunoconjugate and the rituximab are administered intravenously on Day 1 of each
  • the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin have been administered for at least four 21 -day cycles.
  • the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for at least two, at least three, at least four, at least five, at least six, or at least seven 21 -day cycles.
  • the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for eight 21 -day cycles.
  • the rituximab is administered before the immunoconjugate.
  • the gemcitabine is administered before the oxaliplatin.
  • the immunoconjugate is polatuzumab vedotin-piiq.
  • 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.
  • 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.
  • the immunoconjugate is iladatuzumab vedotin.
  • p is between 2 and 5. In certain embodiments, p is 2.
  • the human has received at least one prior therapy for DLBCL. In some embodiments, the human has received at least one prior systemic therapy for DLBCL. In some embodiments, the human has received at least two prior therapies for DLBCL.
  • the DLBCL is histologically-confirmed DLBCL, not otherwise specified (NOS) or the human has a history of transformation of indolent disease to DLBCL. In certain embodiments, the DLBCL is relapsed or refractory DLBCL.
  • the human has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. In certain embodiments, the human does not have a planned autologous or allogeneic stem cell transplantation (SCT).
  • SCT planned autologous or allogeneic stem cell transplantation
  • the human has not had prior therapy with a combination of gemcitabine and a platinum-based agent.
  • the human does not have peripheral neuropathy of greater than Grade 1 according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0.
  • the human does not have primary or secondary central nervous system lymphoma.
  • the human is not a candidate for hematopoietic stem cell transplantation (HSCT) prior to administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • HSCT hematopoietic stem cell transplantation
  • the human is not a candidate for autologous hematopoietic stem cell transplantation (HSCT) prior to administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • the human has received at least two prior therapies for DLBCL.
  • the human has not received a prior therapy with polatuzumab vedotin-piiq for DLBCL.
  • the human is an adult.
  • the human adult has relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin does not result in peripheral neuropathy of Grade 3 or greater in the human that does not resolve to Grade 1 or lower within 14 days. In some embodiments, administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin does not result in peripheral neuropathy of Grade 4 or greater in the human. In some embodiments, administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin does not result in neurotoxicity of Grade 4 or greater in the human.
  • the human after administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin, the human does not experience peripheral neuropathy of Grade 4 or greater. In some embodiments, after administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin, the human does not experience neurotoxicity of Grade 4 or greater. In some embodiments, administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in 33% or fewer of the humans in the plurality experiencing peripheral neuropathy of Grade 3 or greater that does not resolve to Grade 1 or lower within 14 days.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in less than about 40% of the humans in the plurality experiencing peripheral neuropathy of Grade 3 or greater that does not resolve to Grade 1 or lower within 14 days. In some embodiments, administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in less than about 8% of the humans in the plurality experiencing peripheral neuropathy of Grade 3 or greater.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in less than about 6% of the humans in the plurality experiencing peripheral neuropathy that results in discontinuation of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin have been administered for at least four 21-day cycles.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in a complete response in the human.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in a partial response in the human.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in progression-free survival of the human.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in progression-free survival of the human for at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 24 months, or at least about 25 months after the start of treatment with the immunoconjugate, the ritux
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in progression-free survival of the human for at least about 4 months after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin. In some embodiments, administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in progression- free survival of the human for at least about 5 months after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in progression-free survival of the human for at least about 6 months after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin. In some embodiments, administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in progression-free survival of the human for at least about 9.5 months after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in progression-free survival of the human for at least about 11 months after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin. In some embodiments, administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in progression-free survival of the human for at least about 14 months after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in an increase in progression-free survival of the human compared to administration of rituximab, gemcitabine, and oxaliplatin to a corresponding human.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase in progression-free survival of the humans in the plurality compared to a corresponding plurality of humans administered rituximab, gemcitabine, and oxaliplatin.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in event-free survival of the human.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in event- free survival of the human for at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 24 months, or at least about 25 months after the start of treatment with the immunoconjugate, the ritux
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in event-free survival of the human for at least about 4 months after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin. In some embodiments, administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in event-free survival of the human for at least about 5 months after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in event-free survival of the human for at least about 6 months after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin. In some embodiments, administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in event-free survival of the human for at least about 9.5 months after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in event-free survival of the human for at least about 11 months after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin. In some embodiments, administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in event-free survival of the human for at least about 14 months after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in an increase in event-free survival of the human compared to administration of rituximab, gemcitabine, and oxaliplatin to a corresponding human.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase in event-free survival of the humans in the plurality compared to a corresponding plurality of humans administered rituximab, gemcitabine, and oxaliplatin.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in survival of the human for at least about 10 months or more, at least about 11 months or more, at least about 12 months or more, at least about 13 months or more, at least about 14 months or more, or at least about 15 months or more after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in a median overall survival of the humans in the plurality of at least about 10 months or more, at least about 11 months or more, at least about 12 months or more, at least about 13 months or more, at least about 14 months or more, or at least about 15 months or more after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in an increase in survival of the human compared to administration of rituximab, gemcitabine, and oxaliplatin to a corresponding human.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase in the median overall survival of the humans in the plurality compared to a corresponding plurality of humans administered rituximab, gemcitabine, and oxaliplatin.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin does not result in tumor lysis syndrome in the human.
  • the methods provided herein further comprise administering a prophylactic treatment for tumor lysis syndrome to the human before, during, and/or after administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to the human.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin does not result in an infection in the human.
  • the infection is a pneumocystis infection or a herpesvirus infection.
  • the methods provided herein further comprise administering a prophylactic treatment for infections to the human before, during, and/or after administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to the human.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin does not result in neutropenia in the human.
  • the methods provided herein further comprise administering a prophylactic treatment for neutropenia to the human before, during, and/or after administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to the human.
  • the prophylactic treatment for neutropenia comprises administering G-CSF to the human.
  • the methods provided herein further comprise stopping treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin if Grade 3 or Grade 4 neutropenia occurs in the human after administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • the methods further comprise resuming treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin if absolute neutrophil count (ANC) increases to >1000/ ⁇ L in the human.
  • the methods further comprise administering one or more growth factors to treat neutropenia.
  • the one or more growth factors comprise G-CSF.
  • the methods further comprise resuming treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin without a dose reduction of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin if ANC recovers to > lOOO/ ⁇ L in the human on or before Day 7 of a 21-day cycle.
  • the methods further comprise resuming treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin, wherein the dose of the immunoconjugate is reduced to 1.4 mg/kg if ANC recovers to > 1000/ ⁇ L in the human after Day 7 of a 21 -day cycle.
  • the methods further comprise discontinuing treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin if a prior dose reduction of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin occurred.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin does not result in Hepatitis B reactivation in the human.
  • the methods provided herein further comprise administering a prophylactic treatment for Hepatitis B reactivation to the human before, during, and/or after administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to the human.
  • the methods provided herein further comprise administering anti-viral medication to the human if Hepatitis B reactivation is detected in the human.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin does not result in one or more adverse events selected from the group consisting of drug-induced liver injury, progressive multifocal leukoencephalopathy, systemic hypersensitivity reaction, anaphylactic reaction, anaphylactoid reaction, and second malignancy.
  • administering results in an increase in the complete response rate (CRR) compared to a corresponding plurality of humans administered rituximab, gemcitabine, and oxaliplatin.
  • CRR complete response rate
  • administering results in an increase in the objective response rate (ORR) compared to a corresponding plurality of humans administered rituximab, gemcitabine, and oxaliplatin.
  • ORR objective response rate
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase in the best overall response rate (BOR) compared to a corresponding plurality of humans administered rituximab, gemcitabine, and oxaliplatin.
  • BOR overall response rate
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase in the duration of response (DOR) compared to a corresponding plurality of humans administered rituximab, gemcitabine, and oxaliplatin.
  • DOR duration of response
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in a 1 -year progression-free survival rate of at least about 30% or greater, at least about 40% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of the humans in the plurality.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in a 2-year progression-free survival rate of at least about 63% or greater, at least about 65% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of the humans in the plurality.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in a 5 -year progression-free survival rate of at least about 14% or greater, at least about 15% or greater, at least about 20% or greater, at least about 30% or greater, at least about 40% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of the humans in the plurality.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase in the 1-year, 2-year, 3.5-year, or 5 -year progression-free survival rate compared to a corresponding plurality of humans administered rituximab, gemcitabine, and oxaliplatin.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in a 1 -year overall survival rate of at least about 42% or greater, at least about 45% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of the humans in the plurality.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in a 2-year overall survival rate of at least about 67% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of the humans in the plurality.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in a 3.5 -year overall survival rate of at least about 38% or greater, at least about 40% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of the humans in the plurality.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in a 5 -year overall survival rate of at least about 15% or greater, at least about 20% or greater, at least about 30% or greater, at least about 40% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of the humans in the plurality.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase in the 1 -year, 2-year, 3.5-year, or 5 -year overall survival rate compared to a corresponding plurality of humans administered rituximab, gemcitabine, and oxaliplatin.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in a 2-year event-free survival rate of at least about 44% or greater, at least about 45% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of the humans in the plurality.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase in the 1-year, 2-year, 3.5 -year, or 5 -year event-free survival rate compared to a corresponding plurality of humans administered rituximab, gemcitabine, and oxaliplatin.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an objective response rate of at least about 44% or greater, at least about 45% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of the humans in the plurality.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in a complete response rate of at least about 35% or greater, at least about 40% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of the humans in the plurality.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in a partial response rate of at least about 10% or greater, at least about 20% or greater, at least about 30% or greater, at least about 40% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of the humans in the plurality.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase in the partial response rate compared to a corresponding plurality of humans administered rituximab, gemcitabine, and oxaliplatin.
  • kits comprising an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, for use in combination with rituximab, gemcitabine, and oxaliplatin for treating a human in need thereof having diffuse large B-cell lymphoma (DLBCL) according to any of the preceding embodiments.
  • DLBCL diffuse large B-cell lymphoma
  • kits comprising polatuzumab vedotin-piiq for use in combination with rituximab, gemcitabine, and oxaliplatin for treating a human in need thereof having diffuse large B-cell lymphoma (DLBCL) according to according to any of the preceding embodiments.
  • DLBCL diffuse large B-cell lymphoma
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8 for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with rituximab, gemcitabine, and oxaliplatin according to any of the preceding embodiments.
  • DLBCL diffuse large B-cell lymphoma
  • rituximab for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8.
  • Ab is an anti-CD79b antibody comprising (i) an HVR
  • the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8.
  • oxaliplatin for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and rituximab according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8.
  • Ab is an anti-CD79b antibody comprising (i) an HVR
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8 for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with rituximab, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein after administration of the immunoconjugate, the r
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8 for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with rituximab, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein administration of the immunoconjugate, the rit
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8 for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with rituximab, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein, among a plurality of humans treated, after administration
  • DLBCL diffuse large B-cell
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8 for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with rituximab, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein administration of the immunoconjugate, the rit
  • rituximab for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein after administration of the immunocon
  • rituximab for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein administration of the immunoconjugate
  • rituximab for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein, among a plurality
  • rituximab for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- LI 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 wherein p is between 1 and 8, wherein administration of the immunoconjugate
  • the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein after administration of the immunocon
  • the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein administration of the immunoconjugate
  • the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein, among a plurality
  • the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein administration of the immunoconjugate
  • oxaliplatin for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and rituximab according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein, after administration of the immuno
  • oxaliplatin for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and rituximab according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein administration of the immunoconjugate
  • oxaliplatin for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and rituximab according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- LI 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 wherein p is between 1 and 8, wherein, among a plurality of
  • oxaliplatin for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and rituximab according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein administration of the immunoconjugate
  • DLBCL diffuse large B-cell lymphoma
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, (b) obinutuzumab, (c) gemcitabine, and (d) oxaliplatin.
  • 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 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.
  • p is between 2 and 5. In certain embodiments, p is between 3 and 4.
  • the immunoconjugate is polatuzumab vedotin-piiq.
  • 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 iladatuzumab vedotin. In certain embodiments, p is between 2 and 5. In certain embodiments, p is 2.
  • the immunoconjugate is administered at a dose of about 1,8 mg/kg
  • the obinutuzumab is administered at a dose of about 1000 mg
  • the gemcitabine is administered at a dose of about 1000 mg/m 2
  • the oxaliplatin is administered at a dose of about 100 mg/m 2 .
  • the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin are administered for one or more 21 -day cycles.
  • the immunoconjugate is administered at a dose of about 1.8 mg/kg each cycle, the obinutuzumab is administered at a dose of about 1000 mg each cycle, the gemcitabine is administered at a dose of about 1000 mg/m 2 each cycle, and the oxaliplatin is administered at a dose of about 100 mg/m 2 each cycle.
  • the obinutuzumab is administered before the immunoconjugate.
  • the gemcitabine is administered before the oxaliplatin.
  • the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin are administered for up to eight 21 -day cycles. In certain embodiments, the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin are administered for eight 21 -day cycles.
  • DLBCL diffuse large B-cell lymphoma
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) obinutuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin are administered for up to eight 21 -day cycles, wherein during each cycle the immunoconjugate is administered at a dose of about 1.8 mg/kg, the obinutuzumab is administered at a dose of about 1000 mg, the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of about 100 mg/m 2 .
  • DLBCL diffuse large B-cell lymphoma
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) obinutuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin are administered for at least one 21 -day cycle, wherein during each cycle the immunoconjugate is administered at a dose of about 1.8 mg/kg, the obinutuzumab is administered at a dose of about 1000 mg, the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of about 100 mg/m 2 .
  • DLBCL diffuse large B-cell lymphoma
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) obinutuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin are administered for up to eight 21 -day cycles, wherein during each cycle the immunoconjugate is administered at a dose of about 1.4 mg/kg, the obinutuzumab is administered at a dose of about 1000 mg, the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of about 100 mg/m 2 .
  • DLBCL diffuse large B-cell lymphoma
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) obinutuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin are administered for at least one 21 -day cycle, wherein during each cycle the immunoconjugate is administered at a dose of about 1.4 mg/kg, the obinutuzumab is administered at a dose of about 1000 mg, the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of about 100 mg/m 2 .
  • DLBCL diffuse large B-cell lymphoma
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) obinutuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin are administered for up to eight 21 -day cycles, wherein during each cycle the immunoconjugate is administered at a dose of about 1.8 mg/kg, the obinutuzumab is administered at a dose of about 1000 mg, the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of about 75 mg/m 2 .
  • DLBCL diffuse large B-cell lymphoma
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) obinutuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin are administered for at least one 21 -day cycle, wherein during each cycle the immunoconjugate is administered at a dose of about 1.8 mg/kg, the obinutuzumab is administered at a dose of about 1000 mg, the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of about 75 mg/m 2 .
  • DLBCL diffuse large B-cell lymphoma
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) obinutuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin are administered for up to eight 21 -day cycles, wherein during each cycle the immunoconjugate is administered at a dose of about 1.4 mg/kg, the obinutuzumab is administered at a dose of about 1000 mg, the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of about 75 mg/m 2 .
  • DLBCL diffuse large B-cell lymphoma
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) obinutuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin are administered for at least one 21 -day cycle, wherein during each cycle the immunoconjugate is administered at a dose of about 1.4 mg/kg, the obinutuzumab is administered at a dose of about 1000 mg, the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of about 75 mg/m 2 .
  • the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin are administered for at least two, at least three, at least four, at least five, at least six, or at least seven 21 -day cycles. In some embodiments, the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin are administered for eight 21 -day cycles. In some embodiments, the obinutuzumab is administered before the immunoconjugate. In some embodiments, the gemcitabine is administered before the oxaliplatin. In some embodiments, the immunoconjugate is polatuzumab vedotin-piiq.
  • the human has received at least one prior therapy for DLBCL. In some embodiments, the human has received at least one prior systemic therapy for DLBCL. In some embodiments, the human has received at least two prior therapies for DLBCL.
  • the DLBCL is histologically-confirmed DLBCL, not otherwise specified (NOS) or the human has a history of transformation of indolent disease to DLBCL. In certain embodiments, the DLBCL is relapsed or refractory DLBCL.
  • the human has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. In certain embodiments, the human does not have a planned autologous or allogeneic stem cell transplantation (SCT).
  • SCT planned autologous or allogeneic stem cell transplantation
  • the human has not had prior therapy with a combination of gemcitabine and a platinum-based agent.
  • the human does not have peripheral neuropathy of greater than Grade 1 according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0.
  • the human does not have primary or secondary central nervous system lymphoma.
  • the human is not a candidate for hematopoietic stem cell transplantation (HSCT) prior to administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin.
  • HSCT hematopoietic stem cell transplantation
  • the human is not a candidate for autologous hematopoietic stem cell transplantation (HSCT) prior to administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin.
  • the human has received at least two prior therapies for DLBCL.
  • the human has not received a prior therapy with polatuzumab vedotin-piiq for DLBCL.
  • the human is an adult.
  • the human adult has relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified.
  • the human after administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin, the human does not experience peripheral neuropathy of Grade 3 or greater that does not resolve to Grade 1 or lower within 14 days.
  • peripheral neuropathy of Grade 3 or greater that does not resolve to Grade 1 or lower within 14 days.
  • 33% or fewer experience peripheral neuropathy of Grade 3 or greater that does not resolve to Grade 1 or lower within 14 days.
  • the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin 33% or fewer of the humans in the plurality experience peripheral neuropathy of Grade 3 or greater that does not resolve to Grade 1 or lower within 14 days.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin does not result in peripheral neuropathy of Grade 3 or greater in the human that does not resolve to Grade 1 or lower within 14 days.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin does not result in peripheral neuropathy of Grade 4 or greater in the human. In some embodiments, administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin does not result in neurotoxicity of Grade 4 or greater in the human. In some embodiments, after administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin, the human does not experience peripheral neuropathy of Grade 4 or greater.
  • the human after administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin, the human does not experience neurotoxicity of Grade 4 or greater.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in 33% or fewer of the humans in the plurality experiencing peripheral neuropathy of Grade 3 or greater that does not resolve to Grade 1 or lower within 14 days.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in less than about 40% of the humans in the plurality experiencing peripheral neuropathy of Grade 3 or greater that does not resolve to Grade 1 or lower within 14 days. In some embodiments, administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in less than about 8% of the humans in the plurality experiencing peripheral neuropathy of Grade 3 or greater.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in less than about 6% of the humans in the plurality experiencing peripheral neuropathy that results in discontinuation of treatment with the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin.
  • the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin have been administered for at least four 21 -day cycles.
  • DLBCL diffuse large B-cell lymphoma
  • Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, (b) obinutuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein, after administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin, the human does not experience peripheral neuropathy of Grade 3 or greater that does not resolve to Grade 1 or lower within 14
  • DLBCL diffuse large B-cell lymphoma
  • Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, (b) obinutuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin does not result in peripheral neuropathy of Grade 3 or greater in the human that does not resolve to Grade 1 or lower within 14 days
  • 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 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.
  • p is between 2 and 5. In certain embodiments, p is between 3 and 4, In certain embodiments, the immunoconjugate is polatuzumab vedotin-piiq.
  • a method for treating diffuse large B-cell lymphoma comprising administering to the human an effective amount of: (a) an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, (b) obinutuzumab, (c) gemcitabine, and (d) oxaliplatin
  • a method for treating diffuse large B-cell lymphoma comprising administering to the human an effective amount of: (a) an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, (b) obinutuzumab, (c) gemcitabine, and (d) oxaliplatin
  • 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 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.
  • p is between 2 and 5. In certain embodiments, p is between 3 and 4.
  • the immunoconjugate is polatuzumab vedotin-piiq.
  • the immunoconjugate is administered at a dose of about 1.8 mg/kg
  • the obinutuzumab is administered at a dose of about 1000 mg
  • the gemcitabine is administered at a dose of about 1000 mg/m 2
  • the oxaliplatin is administered at a dose of about 100 mg/m 2 .
  • the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin are administered for one or more 21 -day cycles.
  • the immunoconjugate is administered at a dose of about 1.8 mg/kg each cycle, the obinutuzumab is administered at a dose of about 1000 mg each cycle, the gemcitabine is administered at a dose of about 1000 mg/m 2 each cycle, and the oxaliplatin is administered at a dose of about 100 mg/m 2 each cycle.
  • the obinutuzumab is administered before the immunoconjugate.
  • the gemcitabine is administered before the oxaliplatin.
  • the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin are administered for up to eight 21 -day cycles. In certain embodiments, the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin are administered for eight 21 -day cycles.
  • DLBCL diffuse large B-cell lymphoma
  • Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) obinutuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin are administered for up to eight 21 -day cycles, wherein during each cycle the immunoconjugate is administered at a dose of about 1.8 mg/kg, the obinutuzumab is administered at a dose of about 1000 mg, the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of about 100 mg/m 2 ; and wherein, after administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the o
  • DLBCL diffuse large B-cell lymphoma
  • Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) obinutuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin are administered for at least one 21 -day cycle, wherein during each cycle the immunoconjugate is administered at a dose of about 1.8 mg/kg, the obinutuzumab is administered at a dose of about 1000 mg, the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of about 100 mg/m 2 ; and wherein, after administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the o
  • DLBCL diffuse large B-cell lymphoma
  • Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) obinutuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin are administered for up to eight 21 -day cycles, wherein during each cycle the immunoconjugate is administered at a dose of about 1.8 mg/kg, the obinutuzumab is administered at a dose of about 1000 mg, the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of about 100 mg/m 2 ; and wherein administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxa
  • DLBCL diffuse large B-cell lymphoma
  • Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) obinutuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin are administered for at least one 21 -day cycle, wherein during each cycle the immunoconjugate is administered at a dose of about 1.8 mg/kg, the obinutuzumab is administered at a dose of about 1000 mg, the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of about 100 mg/m 2 ; and wherein administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxa
  • DLBCL diffuse large B-cell lymphoma
  • Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) obinutuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin are administered for up to eight 21 -day cycles, wherein during each cycle the immunoconjugate is administered at a dose of about 1.8 mg/kg, the obinutuzumab is administered at a dose of about 1000 mg, the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of about 100 mg/m 2 ; and wherein, among a plurality of humans treated, after administration of the immunoconjugate, the obinutuzumab,
  • DLBCL diffuse large B-cell lymphoma
  • Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) obinutuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin are administered for at least one 21 -day cycle, wherein during each cycle the immunoconjugate is administered at a dose of about 1.8 mg/kg, the obinutuzumab is administered at a dose of about 1000 mg, the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of about 100 mg/m 2 ; and wherein, among a plurality of humans treated, after administration of the immunoconjugate, the obinutuzumab,
  • DLBCL diffuse large B-cell lymphoma
  • Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) obinutuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin are administered for up to eight 21 -day cycles, wherein during each cycle the immunoconjugate is administered at a dose of about 1.8 mg/kg, the obinutuzumab is administered at a dose of about 1000 mg, the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of about 100 mg/m 2 ; and wherein administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxa
  • DLBCL diffuse large B-cell lymphoma
  • Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) obinutuzumab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin are administered for at least one 21 -day cycle, wherein during each cycle the immunoconjugate is administered at a dose of about 1.8 mg/kg, the obinutuzumab is administered at a dose of about 1000 mg, the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of about 100 mg/m 2 ; and wherein administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxa
  • the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin have been administered for at least four 21 -day cycles.
  • the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin are administered for at least two, at least three, at least four, at least five, at least six, or at least seven 21 -day cycles. In some embodiments, the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin are administered for eight 21 -day cycles. In some embodiments, the obinutuzumab is administered before the immunoconjugate. In some embodiments, the gemcitabine is administered before the oxaliplatin.
  • the immunoconjugate is polatuzumab vedotin-piiq.
  • 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.
  • 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.
  • the immunoconjugate is iladatuzumab vedotin.
  • p is between 2 and 5. In certain embodiments, p is 2.
  • the human has received at least one prior therapy for DLBCL. In some embodiments, the human has received at least one prior systemic therapy for DLBCL. In some embodiments, the human has received at least two prior therapies for DLBCL.
  • the DLBCL is histologically-confirmed DLBCL, not otherwise specified (NOS) or the human has a history of transformation of indolent disease to DLBCL, In certain embodiments, the DLBCL is relapsed or refractory DLBCL.
  • the human has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. In certain embodiments, the human does not have a planned autologous or allogeneic stem cell transplantation (SCT).
  • SCT planned autologous or allogeneic stem cell transplantation
  • the human has not had prior therapy with a combination of gemcitabine and a platinum-based agent.
  • the human does not have peripheral neuropathy of greater than Grade 1 according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0.
  • the human does not have primary or secondary central nervous system lymphoma.
  • the human is not a candidate for hematopoietic stem cell transplantation (HSCT) prior to administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin.
  • HSCT hematopoietic stem cell transplantation
  • the human is not a candidate for autologous hematopoietic stem cell transplantation (HSCT) prior to administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin.
  • the human has received at least two prior therapies for DLBCL.
  • the human has not received a prior therapy with polatuzumab vedotin-piiq for DLBCL.
  • the human is an adult.
  • the human adult has relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin does not result in peripheral neuropathy of Grade 3 or greater in the human that does not resolve to Grade 1 or lower within 14 days. In some embodiments, administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin does not result in peripheral neuropathy of Grade 4 or greater in the human. In some embodiments, administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin does not result in neurotoxicity of Grade 4 or greater in the human.
  • the human after administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin, the human does not experience peripheral neuropathy of Grade 4 or greater. In some embodiments, after administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin, the human does not experience neurotoxicity of Grade 4 or greater. In some embodiments, administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in 33% or fewer of the humans in the plurality experiencing peripheral neuropathy of Grade 3 or greater that does not resolve to Grade 1 or lower within 14 days.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in less than about 40% of the humans in the plurality experiencing peripheral neuropathy of Grade 3 or greater that does not resolve to Grade 1 or lower within 14 days. In some embodiments, administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in less than about 8% of the humans in the plurality experiencing peripheral neuropathy of Grade 3 or greater.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in less than about 6% of the humans in the plurality experiencing peripheral neuropathy that results in discontinuation of treatment with the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin.
  • the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin have been administered for at least four 21 -day cycles.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin results in a complete response in the human.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin results in a partial response in the human.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin results in progression- free survival of the human.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin results in progression-free survival of the human for at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 24 months, or at least about 25 months after the start of treatment with the immunoconjugate, the obinutu
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin results in progression-free survival of the human for at least about 4 months after the start of treatment with the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin. In some embodiments, administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin results in progression-free survival of the human for at least about 5 months after the start of treatment with the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin results in progression-free survival of the human for at least about 6 months after the start of treatment with the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin. In some embodiments, administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin results in progression- free survival of the human for at least about 9.5 months after the start of treatment with the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin results in progression-free survival of the human for at least about 11 months after the start of treatment with the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin. In some embodiments, administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin results in progression-free survival of the human for at least about 14 months after the start of treatment with the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin results in an increase in progression-free survival of the human compared to administration of obinutuzumab, gemcitabine, and oxaliplatin to a corresponding human.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase in progression- free survival of the humans in the plurality compared to a corresponding plurality of humans administered obinutuzumab, gemcitabine, and oxaliplatin.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin results in event-free survival of the human.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin results in event- free survival of the human for at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 24 months, or at least about 25 months after the start of treatment with the immunoconjugate, the obinutu
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin results in event-free survival of the human for at least about 4 months after the start of treatment with the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin. In some embodiments, administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin results in event-free survival of the human for at least about 5 months after the start of treatment with the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin results in event-free survival of the human for at least about 6 months after the start of treatment with the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin. In some embodiments, administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin results in event-free survival of the human for at least about 9.5 months after the start of treatment with the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin results in event-free survival of the human for at least about 11 months after the start of treatment with the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin. In some embodiments, administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin results in event-free survival of the human for at least about 14 months after the start of treatment with the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin results in an increase in event-free survival of the human compared to administration of obinutuzumab, gemcitabine, and oxaliplatin to a corresponding human.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase in event-free survival of the humans in the plurality compared to a corresponding plurality of humans administered obinutuzumab, gemcitabine, and oxaliplatin.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin results in survival of the human for at least about 10 months or more, at least about 11 months or more, at least about 12 months or more, at least about 13 months or more, at least about 14 months or more, or at least about 15 months or more after the start of treatment with the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in a median overall survival of the humans in the plurality of at least about 10 months or more, at least about 11 months or more, at least about 12 months or more, at least about 13 months or more, at least about 14 months or more, or at least about 15 months or more after the start of treatment with the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin results in an increase in survival of the human compared to administration of obinutuzumab, gemcitabine, and oxaliplatin to a corresponding human.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase in the median overall survival of the humans in the plurality compared to a corresponding plurality of humans administered obinutuzumab, gemcitabine, and oxaliplatin.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin does not result in tumor lysis syndrome in the human.
  • the methods provided herein further comprise administering a prophylactic treatment for tumor lysis syndrome to the human before, during, and/or after administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin to the human.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin does not result in an infection in the human.
  • the infection is a pneumocystis infection or a herpesvirus infection.
  • the methods provided herein further comprise administering a prophylactic treatment for infections to the human before, during, and/or after administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin to the human.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin does not result in neutropenia in the human.
  • the methods provided herein further comprise administering a prophylactic treatment for neutropenia to the human before, during, and/or after administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin to the human.
  • the prophylactic treatment for neutropenia comprises administering G-CSF to the human.
  • the methods provided herein further comprise stopping treatment with the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin if Grade 3 or Grade 4 neutropenia occurs in the human after administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin.
  • the methods further comprise resuming treatment with the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin if absolute neutrophil count (ANC) increases to >1000/ ⁇ L in the human.
  • the methods further comprise administering one or more growth factors to treat neutropenia.
  • the one or more growth factors comprise G-CSF.
  • the methods further comprise resuming treatment with the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin without a dose reduction of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin if ANC recovers to > 1000/ ⁇ L in the human on or before Day 7 of a 21 -day cycle.
  • the methods further comprise resuming treatment with the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin, wherein the dose of the immunoconjugate is reduced to 1.4 mg/kg if ANC recovers to > 1000/ ⁇ L in the human after Day 7 of a 21-day cycle.
  • the methods further comprise discontinuing treatment with the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin if a prior dose reduction of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin occurred.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin does not result in Hepatitis B reactivation in the human.
  • the methods provided herein further comprise administering a prophylactic treatment for Hepatitis B reactivation to the human before, during, and/or after administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin to the human.
  • the methods provided herein further comprise administering anti-viral medication to the human if Hepatitis B reactivation is detected in the human.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin does not result in one or more adverse events selected from the group consisting of drug-induced liver injury, progressive multifocal leukoencephalopathy, systemic hypersensitivity reaction, anaphylactic reaction, anaphylactoid reaction, and second malignancy.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase in the complete response rate (CRR) compared to a corresponding plurality of humans administered obinutuzumab, gemcitabine, and oxaliplatin.
  • CRR complete response rate
  • administering results in an increase in the objective response rate (ORR) compared to a corresponding plurality of humans administered obinutuzumab, gemcitabine, and oxaliplatin.
  • ORR objective response rate
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase in the best overall response rate (BOR) compared to a corresponding plurality of humans administered obinutuzumab, gemcitabine, and oxaliplatin.
  • BOR overall response rate
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase in the duration of response (DOR) compared to a corresponding plurality of humans administered obinutuzumab, gemcitabine, and oxaliplatin.
  • DOR duration of response
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in a 1-year progression-free survival rate of at least about 30% or greater, at least about 40% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of the humans in the plurality.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in a 2-year progression-free survival rate of at least about 63% or greater, at least about 65% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of the humans in the plurality.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in a 5 -year progression-free survival rate of at least about 14% or greater, at least about 15% or greater, at least about 20% or greater, at least about 30% or greater, at least about 40% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of the humans in the plurality.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase in the 1-year, 2 -year, 3.5 -year, or 5 -year progression-free survival rate compared to a corresponding plurality of humans administered obinutuzumab, gemcitabine, and oxaliplatin.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in a 1 -year overall survival rate of at least about 42% or greater, at least about 45% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of the humans in the plurality.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in a 2-year overall survival rate of at least about 67% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of the humans in the plurality.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in a 3.5-year overall survival rate of at least about 38% or greater, at least about 40% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of the humans in the plurality.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in a 5 -year overall survival rate of at least about 15% or greater, at least about 20% or greater, at least about 30% or greater, at least about 40% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of the humans in the plurality.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase in the 1 -year, 2-year, 3.5-year, or 5 -year overall survival rate compared to a corresponding plurality of humans administered obinutuzumab, gemcitabine, and oxaliplatin.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in a 2-year event-free survival rate of at least about 44% or greater, at least about 45% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of the humans in the plurality.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase in the 1-year, 2 -year, 3.5-year, or 5- year event-free survival rate compared to a corresponding plurality of humans administered obinutuzumab, gemcitabine, and oxaliplatin.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an objective response rate of at least about 44% or greater, at least about 45% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of the humans in the plurality.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in a complete response rate of at least about 35% or greater, at least about 40% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of the humans in the plurality.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in a partial response rate of at least about 10% or greater, at least about 20% or greater, at least about 30% or greater, at least about 40% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of the humans in the plurality.
  • administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase in the partial response rate compared to a corresponding plurality of humans administered obinutuzumab, gemcitabine, and oxaliplatin.
  • kits comprising an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, for use in combination with obinutuzumab, gemcitabine, and oxaliplatin for treating a human in need thereof having diffuse large B-cell lymphoma (DLBCL) according to any of the preceding embodiments.
  • DLBCL diffuse large B-cell lymphoma
  • kits comprising polatuzumab vedotin-piiq for use in combination with obinutuzumab, gemcitabine, and oxaliplatin for treating a human in need thereof having diffuse large B-cell lymphoma (DLBCL) according to according to any of the preceding embodiments.
  • DLBCL diffuse large B-cell lymphoma
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8 for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with obinutuzumab, gemcitabine, and oxaliplatin according to any of the preceding embodiments.
  • DLBCL diffuse large B-cell lymphoma
  • obinutuzumab for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8.
  • Ab is an anti-CD79b antibody comprising (i) an HVR
  • the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8.
  • oxaliplatin for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and obinutuzumab according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8.
  • Ab is an anti-CD79b antibody comprising (i) an HVR
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8 for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with obinutuzumab, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein after administration of the immunoconjugate, the obi
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8 for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with obinutuzumab, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein administration of the immunoconjugate, the obinut
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8 for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with obinutuzumab, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein, among a plurality of humans treated, after administration
  • DLBCL diffuse large B-cell
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-Hl 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 wherein p is between 1 and 8 for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with obinutuzumab, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein administration of the immunoconjugate, the obinut
  • obinutuzumab for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein after administration of the immunocon
  • obinutuzumab for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein administration of the immunoconjugate
  • obinutuzumab for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein, among a plurality
  • obinutuzumab for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein administration of the immunoconjugate
  • the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein after administration of the immunocon
  • the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein administration of the immunoconjugate
  • the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein, among a plurality
  • gemcitabine for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, obinutuzumab, and oxaliplatin according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula
  • Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein administration of the immunoconjugate, the obinutuzumab, the gemcitabine, and the oxaliplatin to a plurality of humans results in 33% or fewer of the humans in the plurality experiencing peripheral neuropathy of Grade 3 or greater that does not resolve to Grade 1 or lower within 14 days.
  • oxaliplatin for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and obinutuzumab according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein, after administration of the immuno
  • oxaliplatin for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and obinutuzumab according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein administration of the immunoconjugate
  • oxaliplatin for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and obinutuzumab according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- LI 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 wherein p is between 1 and 8, wherein, among a plurality of
  • oxaliplatin for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and obinutuzumab according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein administration of the immunoconjugate
  • a method for treating relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human in need thereof comprising administering to the human polatuzumab vedotin-piiq at a dose of 1.8 mg/kg, rituximab at a dose of 375 mg/m 2 , gemcitabine at a dose of 1000 mg/m 2 , and oxaliplatin at a dose of 100 mg/m 2 .
  • a method for treating relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human in need thereof comprising administering to the human polatuzumab vedotin-piiq at a dose of 1.8 mg/kg, rituximab at a dose of 375 mg/m 2 , gemcitabine at a dose of 1000 mg/m 2 , and oxaliplatin at a dose of 100 mg/m 2 , wherein the polatuzumab vedotin-piiq, the rituximab, the gemcitabine, and the oxaliplatin are administered for at least one 21 -day cycle, wherein the polatuzumab vedotin-piiq and the rituximab are administered intravenously on Day 1 of each 21 -day cycle, and wherein the gemcitabine and the oxa
  • a method for treating relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human in need thereof comprising administering to the human iladatuzumab vedotin at a dose of 4.8 mg/kg, rituximab at a dose of 375 mg/m 2 , gemcitabine at a dose of 1000 mg/m 2 , and oxaliplatin at a dose of 100 mg/m 2 .
  • a method for treating relapsed or refractory diffuse large B-cell lymphoma comprising administering to the human iladatuzumab vedotin at a dose of 3.6 mg/kg, rituximab at a dose of 375 mg/m 2 , gemcitabine at a dose of 1000 mg/m 2 , and oxaliplatin at a dose of 100 mg/m 2 .
  • a method for treating relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human in need thereof comprising administering to the human iladatuzumab vedotin at a dose of 4.8 mg/kg, rituximab at a dose of 375 mg/m 2 , gemcitabine at a dose of 1000 mg/m 2 , and oxaliplatin at a dose of 100 mg/m 2 , wherein the iladatuzumab vedotin, the rituximab, the gemcitabine, and the oxaliplatin are administered for at least one 21 -day cycle, wherein the iladatuzumab vedotin and the rituximab are administered intravenously on Day 1 of each 21 -day cycle, and wherein the gemcitabine and the oxaliplatin are administered intravenously on Day
  • a method for treating relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human in need thereof comprising administering to the human iladatuzumab vedotin at a dose of 3.6 mg/kg, rituximab at a dose of 375 mg/m 2 , gemcitabine at a dose of 1000 mg/m 2 , and oxaliplatin at a dose of 100 mg/m 2 , wherein the iladatuzumab vedotin, the rituximab, the gemcitabine, and the oxaliplatin are administered for at least one 21 -day cycle, wherein the iladatuzumab vedotin and the rituximab are administered intravenously on Day 1 of each 21 -day cycle, and wherein the gemcitabine and the oxaliplatin are administered intravenously on Day
  • a method for treating relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human in need thereof comprising administering to the human polatuzumab vedotin-piiq at a dose of 1.8 mg/kg, obinutuzumab at a dose of 1000 mg, gemcitabine at a dose of 1000 mg/m 2 , and oxaliplatin at a dose of 100 mg/m 2 .
  • a method for treating relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human in need thereof comprising administering to the human polatuzumab vedotin-piiq at a dose of 1.8 mg/kg, obinutuzumab at a dose of 1000 mg, gemcitabine at a dose of 1000 mg/m 2 , and oxaliplatin at a dose of 100 mg/m 2 , wherein the polatuzumab vedotin-piiq, the obinutuzumab, the gemcitabine, and the oxaliplatin are administered for at least one 21 -day cycle, wherein the polatuzumab vedotin-piiq and the obinutuzumab are administered intravenously on Day 1 of each 21 -day cycle, and wherein the gemcitabine and the oxaliplatin are administered intra
  • a method for treating relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human in need thereof comprising administering to the human iladatuzumab vedotin at a dose of 4.8 mg/kg, obinutuzumab at a dose of 1000 mg, gemcitabine at a dose of 1000 mg/m 2 , and oxaliplatin at a dose of 100 mg/m 2 .
  • a method for treating relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human in need thereof comprising administering to the human iladatuzumab vedotin at a dose of 3.6 mg/kg, obinutuzumab at a dose of 1000 mg, gemcitabine at a dose of 1000 mg/m 2 , and oxaliplatin at a dose of 100 mg/m 2 .
  • a method for treating relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human in need thereof comprising administering to the human iladatuzumab vedotin at a dose of 4.8 mg/kg, obinutuzumab at a dose of 1000 mg, gemcitabine at a dose of 1000 mg/m 2 , and oxaliplatin at a dose of 100 mg/m 2 , wherein the iladatuzumab vedotin, the obinutuzumab, the gemcitabine, and the oxaliplatin are administered for at least one 21 -day cycle, wherein the iladatuzumab vedotin and the obinutuzumab are administered intravenously on Day 1 of each 21 -day cycle, and wherein the gemcitabine and the oxaliplatin are administered intravenously on Day 2 of each 21
  • a method for treating relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) in a human in need thereof comprising administering to the human iladatuzumab vedotin at a dose of 3.6 mg/kg, obinutuzumab at a dose of 1000 mg, gemcitabine at a dose of 1000 mg/m 2 , and oxaliplatin at a dose of 100 mg/m 2 , wherein the iladatuzumab vedotin, the obinutuzumab, the gemcitabine, and the oxaliplatin are administered for at least one 21 -day cycle, wherein the iladatuzumab vedotin and the obinutuzumab are administered intravenously on Day 1 of each 21 -day cycle, and wherein the gemcitabine and the oxaliplatin are administered intravenously on Day 2 of each 21
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8 for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with rituximab, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein the immunoconjugate, the rituximab, gemcitabine, and ox
  • rituximab for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- LI 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 wherein p is between 1 and 8, wherein the immunoconjugate, the immunoconjugate, the immunoconjugate,
  • the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein the immunoconjugate,
  • oxaliplatin for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and rituximab according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein the immunoconjugate,
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8 for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with rituximab, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein after administration of the immunoconjugate, the r
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8 for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with rituximab, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein administration of the immunoconjugate, the rit
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8 for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with rituximab, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein, among a plurality of humans treated, after administration
  • DLBCL diffuse large B-cell
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8 for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with rituximab, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein administration of the immunoconjugate, the rit
  • rituximab for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein after administration of the immunocon
  • rituximab for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein administration of the immunoconjugate
  • rituximab for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein, among a plurality
  • rituximab for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein administration of the immunoconjugate
  • the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- LI 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 wherein p is between 1 and 8, wherein after administration of the immunoconjugate
  • the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein administration of the immunoconjugate
  • the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein, among a plurality
  • the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein administration of the immunoconjugate
  • oxaliplatin for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and rituximab according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- LI 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 wherein p is between 1 and 8, wherein, after administration of the immunocon
  • oxaliplatin for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and rituximab according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein administration of the immunoconjugate
  • oxaliplatin for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and rituximab according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein, among a plurality
  • oxaliplatin for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and rituximab according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula
  • Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in 33% or fewer of the humans in the plurality experiencing peripheral neuropathy of Grade 3 or greater that does not resolve to Grade 1 or lower within 14 days; and wherein the immunoconjugate, the
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8 for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with obinutuzumab, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein the immunoconjugate, the obinutuzum
  • obinutuzumab for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein the immunoconjugate,
  • the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein the immunoconjugate,
  • oxaliplatin for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and obinutuzumab according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein the immunoconjugate,
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8 for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with obinutuzumab, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein after administration of the immunoconjugate, the obi
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- LI 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 wherein p is between 1 and 8 for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with obinutuzumab, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein administration of the immunoconjugate, the obinutu
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8 for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with obinutuzumab, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein, among a plurality of humans treated, after administration
  • DLBCL diffuse large B-cell
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8 for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with obinutuzumab, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein administration of the immunoconjugate, the obinut
  • obinutuzumab for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein after administration of the immunocon
  • obinutuzumab for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein administration of the immunoconjugate
  • obinutuzumab for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein, among a plurality
  • obinutuzumab for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and oxaliplatin according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein administration of the immunoconjugate
  • the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein after administration of the immunocon
  • the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein administration of the immunoconjugate
  • the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein, among a plurality
  • the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- LI 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 wherein p is between 1 and 8, wherein administration of the immunoconjugate
  • oxaliplatin for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and obinutuzumab according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein, after administration of the immuno
  • oxaliplatin for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and obinutuzumab according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein administration of the immunoconjugate
  • oxaliplatin for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and obinutuzumab according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein, among a plurality
  • oxaliplatin for use in a method of treating diffuse large B-cell lymphoma (DLBCL) in combination with an immunoconjugate, gemcitabine, and obinutuzumab according to any of the preceding embodiments, wherein the immunoconjugate comprises the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:26, and wherein p is between 1 and 8, wherein administration of the immunoconjugate
  • FIG. 1 is a schematic of the overall design of the study described in Example 1.
  • R-GemOx rituximab plus gemcitabine plus oxaliplatin;
  • R/R DLBCL relapsed or refractory diffuse large B-cell lymphoma.
  • FIG. 2 is a schematic of the Stage 1 (Safety Run-in) of the study described in Example 1.
  • EOT end of treatment
  • RCT randomized controlled trial (Stage 2).
  • FIGS. 3A-3B show the experimental treatment and control treatment regimens of the study described in Example 1.
  • FIG. 3 A is a schematic of the experimental treatment regimen (Pola-R-GemOx) of the study described in Example 1.
  • Diamonds represent doses of rituximab (375 mg/m 2 ); circles represent doses of polatuzumab vedotin (1.8 mg/kg); thin arrows represent doses of gemcitabine (1000 mg/m 2 ); wide arrows represent doses of oxaliplatin (100 mg/m 2 ); a rituximab is administered before polatuzumab vedotin; b gemcitabine is administered before oxaliplatin.
  • FIG. 1 is a schematic of the experimental treatment regimen (Pola-R-GemOx) of the study described in Example 1.
  • Diamonds represent doses of rituximab (375 mg/m 2 ); circles represent doses of polatuzumab
  • 3B is a schematic of the control treatment regimen (R-GemOx) of the study described in Example 1.
  • Diamonds represent doses of rituximab (375 mg/m 2 ); thin arrows represent doses of gemcitabine (1000 mg/m 2 ); wide arrows represent doses of oxaliplatin (100 mg/m 2 ); a gemcitabine is administered before oxaliplatin.
  • polyatuzumab vedotin-piiq refers to an anti-CD79b immunoconjugate having the IUPHAR/BPS Number 8404, the KEGG Number D10761, or the CAS Registry Number 1313206-42-6.
  • Polatuzumab vedotin-piiq is also interchangeably referred to as “polatuzumab vedotin”, “huMA79bv28-MC-vc-PAB-MMAE”, “DCDS4501A”, or “RG7596.”
  • DLBCL diffuse large B- cell lymphoma
  • an individual e.g., a human
  • an effective amount of an anti-CD79b immunoconjugate e.g., polatuzumab vedotin-piiq
  • an anti-CD20 agent e.g., an anti-CD20 antibody such as rituximab
  • one or more chemotherapeutic agents e.g, gemcitabine and oxaliplatin.
  • the method comprises treating an individual having diffuse large B-cell lymphoma (DLBCL), e.g., relapsed/reffactory DLBCL, by administering to the individual (a) an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-Hlthat comprises the amino acid sequence of GYTFSSYWIE (SEQ ID NO: 21); (ii) an HVR-H2 comprising the amino acid sequence of GEILPGGGDTNYNEIFKG (SEQ ID NO: 22); (iii) an HVR-H3 comprising the amino acid sequence of TRRVPIRLDY (SEQ ID NO: 23); (iv) an HVR-L1 comprising the amino acid sequence of KASQSVDYEGDSFLN (SEQ ID NO: 24); (v) an HVR-L2 comprising the amino acid sequence of AASNLES (SEQ ID NO: 25); and (vi) an HVR-L3 comprising the amino acid
  • the immunoconjugate is administered at a dose between about 1.4 mg/kg and about 1.8 mg/kg
  • the anti-CD20 agent e.g., rituximab
  • the gemcitabine is administered at a dose of about 1000 mg/m 2
  • the oxaliplatin is administered at a dose of about 100 mg/m 2 .
  • CD79b refers to any native CD79b from any vertebrate source, including mammals such as primates (e.g., humans, cynomologus monkey (“cyno”)) and rodents (e.g., mice and rats), unless otherwise indicated.
  • Human CD79b is also referred herein to as “Igp,” “B29, ⁇ > ⁇ > it DNA225786,” or “PR036249.”
  • An exemplary CD79b sequence including the signal sequence is shown in SEQ ID NO: 1.
  • An exemplary CD79b sequence without the signal sequence is shown in SEQ ID NO: 2.
  • CD79b encompasses “full-length,” unprocessed CD79b, as well as any form of CD79b that results from processing in the cell.
  • the term also encompasses naturally occurring variants of CD79b, e.g., splice variants, allelic variants, and isoforms.
  • the CD79b polypeptides described herein may be isolated from a variety of sources, such as from human tissue types or from another source, or prepared by recombinant or synthetic methods.
  • a “native sequence CD79b polypeptide” comprises a polypeptide having the same amino acid sequence as the corresponding CD79b polypeptide derived from nature. Such native sequence CD79b polypeptides can be isolated from nature or can be produced by recombinant or synthetic means.
  • CD79b polypeptide specifically encompasses naturally-occurring truncated or secreted forms of the specific 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.
  • CD20 refers to the human B-lymphocyte antigen CD20 (also known as CD20, B-lymphocyte surface antigen Bl, Leu-16, Bp35, BM5, and LF5; the sequence is characterized by the SwissProt database entry PI 1836) is a hydrophobic transmembrane protein with a molecular weight of approximately 35 kD located on pre-B and mature B lymphocytes. (Valentine, M.A., et al., J. Biol. Chem. 264(19) (1989 11282-11287; Tedder, T.F., et al, Proc. Natl. Acad. Sci. U.S.A.
  • the corresponding human gene is Membrane-spanning 4-domains, subfamily A, member 1, also known as MS4A1. This gene encodes a member of the membrane-spanning 4A gene family, Members of this nascent protein family are characterized by common structural features and similar intron/exon splice boundaries and display unique expression patterns among hematopoietic cells and nonlymphoid tissues.
  • This gene encodes the B-lymphocyte surface molecule which plays a role in the development and differentiation of B-cells into plasma cells.
  • This family member is localized to 1 lql2, among a cluster of family members.
  • Alternative splicing of this gene results in two transcript variants which encode the same protein.
  • CD20 and CD20 antigen are used interchangeably herein, and include any variants, isoforms, and species homologs of human CD20 which are naturally expressed by cells or are expressed on cells transfected with the CD20 gene. Binding of an antibody of the invention to the CD20 antigen mediate the killing of cells expressing CD20 (e.g., a tumor cell) by inactivating CD20. The killing of the cells expressing CD20 may occur by one or more of the following mechanisms: Cell death/apoptosis induction, ADCC and CDC. Synonyms of CD20, as recognized in the art, include B-lymphocyte antigen CD20, B-lymphocyte surface antigen Bl, Leu- 16, Bp35, BM5, and LF5.
  • the term “expression of the CD20” antigen is intended to indicate a significant level of expression of the CD20 antigen in a cell, e.g., a T- or B- Cell.
  • a cell e.g., a T- or B- Cell.
  • patients to be treated according to the methods of this invention express significant levels of CD20 on a B- cell tumor or cancer.
  • Patients having a “CD20 expressing cancer” can be determined by standard assays known in the art. E.g., CD20 antigen expression is measured using immunohistochemical (IHC) detection, FACS or via PCR-based detection of the corresponding mRNA.
  • IHC immunohistochemical
  • Bind refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen).
  • binding affinity refers to intrinsic binding affinity which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen).
  • the affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (Kd). Affinity can be measured by common methods known in the art, including those described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described in the following.
  • An “affinity matured” antibody refers to an antibody with one or more alterations in one or more hypervariable regions (HVRs), compared to a parent antibody which does not possess such alterations, such alterations resulting in an improvement in the affinity of the antibody for antigen.
  • HVRs hypervariable regions
  • antibody herein is used in the broadest sense and encompasses various 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.
  • an “antibody fragment” refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds.
  • 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.
  • an “antibody that binds to the same epitope” as a reference antibody refers to an antibody that blocks binding of the reference antibody to its antigen in a competition assay by 50% or more, and conversely, the reference antibody blocks binding of the antibody to its antigen in a competition assay by 50% or more.
  • An exemplary competition assay is provided herein.
  • epitope refers to the particular site on an antigen molecule to which an antibody binds.
  • 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.
  • the “class” of an antibody refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGi, IgGz, IgGs, IgG 4 , IgAi, and IgAz.
  • the heavy chain constant domains that correspond to the different classes of immunoglobulins are called ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ , respectively.
  • anti-CD79b antibody or “an antibody that binds to CD79b” refers to an antibody that is capable of binding CD79b with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting CD79b.
  • the extent of 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, e.g., by a radioimmunoassay (RIA).
  • an antibody that binds to CD79b has a dissociation constant (Kd) of ⁇ 1 ⁇ , ⁇ 100 nM, ⁇ 10 nM, ⁇ 1 nM, or ⁇ 0.1 nM.
  • anti-CD79b antibody binds to an epitope of CD79b that is conserved among CD79b from different species.
  • anti-CD20 antibody refers to an antibody that is capable of binding CD20 with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting CD20.
  • the extent of 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, e.g., by a radioimmunoassay (RIA).
  • an antibody that binds to CD20 has a dissociation constant (Kd) of ⁇ 1 ⁇ , ⁇ 100 nM, ⁇ 10 nM, ⁇ 1 nM, or ⁇ 0.1 nM.
  • anti-CD20 antibody binds to an epitope of CD20 that is conserved among CD20 from different species.
  • an “isolated” antibody is one which has been separated from a component of its natural environment.
  • an antibody is purified to greater than 95% or 99% purity as determined by, for example, electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse phase HPLC).
  • electrophoretic e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis
  • chromatographic e.g., ion exchange or reverse phase HPLC.
  • the “variable region” or “variable domain” of an antibody refers to the amino-terminal domains of the heavy or light chain of the antibody.
  • variable domain of the heavy chain may be referred to as “VH.”
  • variable domain of the 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.
  • isolated nucleic acid encoding an anti-CD79b antibody refers to one or more nucleic acid molecules encoding antibody heavy and light chains (or fragments thereof), including such nucleic acid molecule(s) in a single vector or separate vectors, and such nucleic acid molecule(s) present at one or more locations in a host cell.
  • the term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and/or bind the same epitope, except for possible variant antibodies, e.g., containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts.
  • polyclonal antibody preparations 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.
  • the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
  • the monoclonal antibodies to be used in accordance with the present invention may be made by a variety of techniques, including but not limited to the hybridoma method, 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 making monoclonal antibodies being described herein.
  • a “naked antibody” refers to an antibody that is not conjugated to a heterologous moiety (e.g., a cytotoxic moiety) or radiolabel.
  • the naked antibody may be present in a pharmaceutical formulation.
  • “Native antibodies” refer to naturally occurring immunoglobulin molecules with varying structures.
  • native IgG antibodies are heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light chains and two identical heavy chains that are disulfide-bonded. From N- to C-terminus, each heavy chain has a variable region (VH), also called a variable heavy domain or a heavy chain variable domain, followed by three constant domains (CHI, CH2, and CH3). Similarly, from N- to C-terminus, each light chain has a variable region (VL), also called a variable light domain or a light chain variable domain, followed by a constant light (CL) domain.
  • VH variable region
  • VL variable region
  • CL constant light
  • the light chain of an antibody may be assigned to one of two types, called kappa (K) and lambda ( ⁇ ), based on the amino acid sequence of its constant domain.
  • the term “Fc region” herein is used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region.
  • the term includes native sequence Fc regions and variant Fc regions.
  • a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl-terminus of the heavy chain.
  • the C-terminal lysine (Lys447) of the Fc region may or may not be present.
  • EU numbering system also called the EU index
  • EU index as described in Rabat et al., Sequences of Proteins of Immunological Interest, 5 th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.
  • “Framework” or “FR” refers to variable domain residues other than hypervariable region (HVR) residues.
  • the FR of a variable domain generally consists of four FR domains: FR1, FR2, FR3, and FR4, Accordingly, the HVR and FR sequences generally appear in the following sequence in VH (orVL): FR 1 -H 1 (LI )-FR2-H2(L2)-FR3-H3 (L3)-FR4.
  • an “acceptor human framework” for the purposes herein is a framework comprising the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or a human consensus framework, as defined below.
  • An acceptor human framework “derived from” a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence thereof, or it may contain amino acid sequence changes. In some embodiments, the number of amino acid changes are 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.
  • the VL acceptor human framework is identical in sequence to the VL human immunoglobulin framework sequence or human consensus framework sequence.
  • full length antibody “intact antibody,” and “whole antibody” are used herein interchangeably to refer to an antibody having a structure substantially similar to a native antibody structure or having heavy chains that contain an Fc region as defined herein.
  • host cell refers 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 progeny derived therefrom without regard to the number of passages. Progeny may not be completely identical in nucleic acid content to a 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 herein.
  • a “human antibody” is one which possesses an amino acid sequence which corresponds to that of an antibody produced by a human or a human cell or derived from a non- human source that utilizes human antibody repertoires or other human antibody-encoding sequences. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues.
  • a “human consensus framework” is a framework which represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences.
  • the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences.
  • 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.
  • the subgroup is subgroup kappa I as in Kabat et al., supra.
  • the subgroup is subgroup III as in Kabat et al., supra.
  • a “humanized” antibody refers to a chimeric antibody comprising amino acid residues from non-human HVRs and amino acid residues from human FRs.
  • a humanized antibody will comprise 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 optionally may 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.
  • hypervariable region refers to each of the regions of an antibody variable domain which are hypervariable in sequence and/or form structurally defined loops (“hypervariable loops”).
  • native four-chain antibodies comprise six HVRs; three in the VH (HI, H2, H3), and three in the VL (LI, L2, L3).
  • HVRs generally comprise amino acid residues from the hypervariable loops and/or from the “complementarity determining regions” (CDRs), the latter being of highest sequence variability and/or involved in antigen recognition.
  • CDRs complementarity determining regions
  • Exemplary hypervariable loops occur at amino acid residues 26-32 (LI), 50-52 (L2), 91-96 (L3), 26-32 (HI), 53-55 (H2), and 96-101 (H3).
  • Exemplary CDRs CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 occur at amino acid residues 24-34 of LI, 50-56 of L2, 89-97 of L3, 31-35B of HI, 50-65 of H2, and 95-102 of H3.
  • CDRs generally comprise the amino acid residues that form the hypervariable loops.
  • CDRs also comprise “specificity determining residues,” or “SDRs,” which are residues that contact antigen. SDRs are contained within regions of the CDRs called abbreviated-CDRs, or a-CDRs.
  • Exemplary a-CDRs (a-CDR-Ll, a-CDR-L2, a-CDR-L3, a-CDR-Hl, a-CDR-H2, and a-CDR-H3) occur at amino acid residues 31-34 of LI, 50-55 of L2, 89-96 of L3, 31-35B of HI, 50-58 of H2, and 95-102 of H3.
  • HVR residues and other residues in the variable domain are numbered herein according to Rabat et al., supra.
  • variable region refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen.
  • the variable domains of the heavy chain and light chain (VH and VL, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three hypervariable regions (HVRs).
  • FRs conserved framework regions
  • HVRs hypervariable regions
  • antibodies that bind a particular antigen may be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al, J. Immunol. 150:880- 887 (1993); Clarkson et al., Nature 352:624-628 (1991).
  • “Effector functions” refer to those biological activities attributable to the Fc region of an antibody, which vary with the antibody isotype. Examples of antibody effector functions include: Clq binding and complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g., B-cell receptor); and B-cell activation.
  • CD79b polypeptide variant means 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 as disclosed herein, a CD79b polypeptide sequence lacking the signal peptide as disclosed herein, an extracellular domain of a CD79b polypeptide, with or without the signal peptide, as disclosed herein or any other fragment of a full-length CD79b polypeptide sequence as disclosed herein (such as those encoded by a nucleic acid that represents only a portion of the complete coding sequence for a full-length CD79b polypeptide).
  • CD79b polypeptide variants include, for instance, CD79b polypeptides wherein one or more amino acid residues are added, or deleted, at the N- or C- terminus of the full-length native amino acid sequence.
  • a CD79b polypeptide variant will have at least about 80% amino acid sequence identity, alternatively at least about 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity, to a full-length native sequence CD79b polypeptide sequence as disclosed herein, a CD79b polypeptide sequence lacking the signal peptide as disclosed herein, an extracellular domain of a CD79b polypeptide, with or without the signal peptide, as disclosed herein or any other specifically defined fragment of a full-length CD79b polypeptide sequence as disclosed herein.
  • CD79b variant polypeptides are at least about 10 amino acids in length, alternatively at least about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600 amino acids in length, or more.
  • CD79b variant polypeptides will have no more than one conservative amino acid substitution as compared to the native CD79b polypeptide sequence, alternatively no more than 2, 3, 4, 5, 6, 7, 8, 9, or 10 conservative amino acid substitution as compared to the native CD79b polypeptide sequence.
  • 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 with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, 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 aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.
  • % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN -2.
  • the ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087.
  • the ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, California, or may be compiled from the source code.
  • the ALIGN -2 program should be compiled for use on a UNIX operating system, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.
  • % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B is calculated as follows:
  • vector refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked.
  • the term includes the vector as a self- replicating nucleic acid structure as well as the vector incorporated into the genome of a host cell into which it has been introduced.
  • Certain vectors are capable of directing the expression of nucleic acids to which they are operatively linked. Such vectors are referred to herein as “expression vectors.”
  • an “immunoconjugate” is an antibody conjugated to one or more heterologous molecule(s), including but not limited to a cytotoxic agent.
  • p refers to the average number of drug moieties per antibody, which can range, e.g., 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 a composition comprising a mixture of antibody-drug compounds of Formula I where the average drug loading per antibody is about 2 to about 5, or about 3 to about 4, (e.g., about 3.5).
  • cytotoxic agent refers to a substance that inhibits or prevents a cellular function and/or causes cell death or destruction.
  • Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., At 211 , 1 131 , 1 125 , 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, adriamicin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents); growth inhibitory agents; enzymes and fragments thereof such as nucleolytic enzymes; 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 the various antitumor or anticancer agents disclosed below.
  • cancer refers 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 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 vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), and Meigs
  • 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, extranodal marginal zone — MALT lymphoma, nodal marginal zone lymphoma, hairy cell leukemia, plasmacytoma and/or plasma cell myeloma, low grade/follicular lymphoma, intermediate grade/follicular NHL, mantle cell lymphoma, follicle center lymphoma (f
  • mammals include, but are not limited to, domesticated 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).
  • domesticated animals e.g., cows, sheep, cats, dogs, and horses
  • primates e.g., humans and non- human primates such as monkeys
  • rabbits e.g., mice and rats
  • rodents e.g., mice and rats.
  • the individual or subject is a human.
  • an “effective amount” of an agent refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result.
  • pharmaceutical formulation refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered.
  • a “pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject.
  • a pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.
  • treatment refers to clinical intervention in an attempt to alter the natural course of the individual being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, reduction of free light chain, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.
  • the antibodies described herein are used to delay development of a disease or to slow the progression of a disease.
  • CD79b-positive cancer refers to a cancer comprising cells that express CD79b on their surface.
  • expression of CD79b on the cell surface is determined, for example, using antibodies to CD79b in a method such as immunohistochemistry, FACS, etc.
  • CD79b mRNA expression is considered to correlate to CD79b expression on the cell surface and can be determined by a method selected from in situ hybridization and RT-PCR (including quantitative RT-PCR).
  • conjunction with or “in combination with” refer to administration of one treatment modality in addition to another treatment modality.
  • in conjunction with or “in combination with” refer to administration of one treatment modality before, during, or after administration of the other treatment modality to the individual.
  • a “chemotherapeutic agent” is a chemical compound useful in the treatment of cancer.
  • chemotherapeutic agents include erlotinib (TARCEVA ® , Genentech/OSI Pharm.), bortezomib (VELCADE ® , Millennium Pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG (geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX ® , AstraZeneca), sunitib (SUTENT ® , Pfizer/Sugen), letrozole (FEMARA ® , Novartis), imatinib mesylate (GLEEVEC ® , Novartis), finasunate (VATALANIB ® , Novartis), oxaliplatin (ELOXATIN ® , Sanofi), 5-FU
  • dynemicin including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN ® (doxorubicin), morpholino-doxombicin, cyanomorpholino-doxombicin, 2- pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, es
  • chemotherapeutic agents include anti-hormonal agents that act to regulate, reduce, block, or inhibit the effects of hormones that can promote the growth of cancer, and are often in the form of systemic, or whole-body treatment. They may be hormones themselves.
  • anti-estrogens and selective estrogen receptor modulators include, for example, tamoxifen (including NOLVADEX® tamoxifen), raloxifene (EVISTA®), droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (FARESTON®); anti-progesterones; estrogen receptor down-regulators (ERDs); estrogen receptor antagonists such as fulvestrant (FASLODEX®); agents that function to suppress or shut down the ovaries, for example, leutinizing hormone-releasing hormone (LHRH) agonists such as leuprolide acetate (LUPRON® and ELIGARD®), goserelin acetate, buserelin acetate and tripterelin; anti-androgens such as flutamide, nilutamide and bicalutamide; and aromatas
  • LHRH le
  • chemotherapeutic agents includes bisphosphonates such as clodronate (for example, BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid/zoledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®); as well as troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); anti-sense oligonucleotides, particularly those that inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, such as, for example, PKC-alpha, Raf, H-Ras, and epidermal growth factor receptor (EGF-R); vaccines such as THERATOPE® vaccine and gene therapy vaccines, for example, ALLOVECTIN® vaccine, LEUVECTIN® vaccine, and VAXID® vaccine.
  • bisphosphonates such
  • the chemotherapeutic agent includes topoisomerase 1 inhibitor (e.g., LURTOTECAN®); an anti-estrogen such as fulvestrant; a Kit inhibitor such as imatinib or EXEL-0862 (a tyrosine kinase inhibitor); EGFR inhibitor such as erlotinib or cetuximab; an anti- VEGF inhibitor such as bevacizumab; arinotecan; rmRH (e.g., ABARELIX®); lapatinib and lapatinib ditosylate (an ErbB-2 and EGFR dual tyrosine kinase small-molecule inhibitor also known as GW572016); 17AAG (geldanamycin derivative that is a heat shock protein (Hsp) 90 poison), and pharmaceutically acceptable salts, acids or derivatives of any of the above.
  • topoisomerase 1 inhibitor e.g., LURTOTECAN®
  • an anti-estrogen such as ful
  • Chemotherapetuic agent also includes antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen personal), ublituximab, ofatumumab, ibritumomab tiuxetan, pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).
  • antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITU
  • Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds include: apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab,
  • package insert is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, combination therapy, contraindications and/or warnings concerning the use of such therapeutic products.
  • Alkyl is C 1 -C 18 hydrocarbon containing normal, secondary, tertiary, or cyclic carbon atoms. Examples are methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1 -propyl (n-Pr, n-propyl, - CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, -CH(CH 3 ) 2 ), 1 -butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ), 2- methyl-1 -propyl (i-Bu, i-butyl, -CH 2 CH(CH 3 ), 2-butyl (s-Bu, s-butyl, -CH(CH 3 )CH 2 CH 3 ), 2- methyl-2 -propyl (t-Bu, t-butyl, -C(CH 3 ) 3), 1 -pent
  • C 1 -C 8 alkyl refers to a straight chain or branched, saturated or unsaturated hydrocarbon having from 1 to 8 carbon atoms.
  • Representative “C 1 -C 8 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 C 1 -C 8 alkyls include, but are not limited to, -isopropyl, -.sec-butyl, -isobutyl, -tert- butyl, -isopentyl, 2-methylbutyl, unsaturated C 1 -C 8 alkyls include, but are not limited to, -vinyl, -allyl
  • a C 1 -C 8 alkyl group can be unsubstituted or substituted with one or more groups including, but not limited to, -C 1 -C 8 alkyl, -O-(C 1 -C 8 alkyl), -aryl, -C(O)R’, -OC(O)R’, - C(O)OR’, -C(O)NH 2 , -C(O)NHR’, -C(O)N(R’) 2 -NHC(O)R’, -SO 3 R’, -S(O) 2 R’, -S(O)R’, -OH, - halogen, -N 3 , -NH 2 , -NH(R’), -N(R’) 2 and -CN; where each R’ is independently selected from H, -C 1 -C 8 alkyl and aryl.
  • C 1 -C 12 alkyl refers to a straight chain or branched, saturated or unsaturated hydrocarbon having from 1 to 12 carbon atoms.
  • a C 1 -C 12 alkyl group can be unsubstituted or substituted with one or more groups including, but not limited to, -C 1 -C 8 alkyl, -O-(C 1 -C 8 alkyl), -aryl, -C(O)R’, -OC(O)R’, -C(O)OR’, -C(O)NH 2 , -C(O)NHR’, - C(O)N(R’) 2 -NHC(O)R’, -SO 3 R’ -S(O) 2 R’, -S(O)R’, -OH, -halogen, -N 3 , -NH 2 , -NH(R’), - N(R’) 2 and -CN; where each R’
  • C 1 -C 6 alkyl refers to a straight chain or branched, saturated or unsaturated hydrocarbon having from 1 to 6 carbon atoms.
  • Representative “C 1 -C 6 alkyl” groups include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -and n-hexyl; while branched C 1 -C 6 alkyls include, but are not limited to, -isopropyl, -sec-butyl, - isobutyl, -tert-butyl, -isopentyl, and 2-methylbutyl; unsaturated C 1 -C 6 alkyls include, but are not limited to, -vinyl, -allyl, -1-butenyl, -2-butenyl, and -isobutylenyl, -1 -penteny
  • C 1 -C 4 alkyl refers to a straight chain or branched, saturated or unsaturated hydrocarbon having from 1 to 4 carbon atoms.
  • Representative “C 1 -C 4 alkyl” groups include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl; while branched C 1 -C 4 alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl; unsaturated C 1 - C 4 alkyls include, but are not limited to, -vinyl, -allyl, -1-butenyl, -2-butenyl, and -isobutylenyl.
  • a C 1 -C 4 alkyl group can be unsubstituted or substituted with one or more groups, as described above for C 1 -C 8 alkyl group
  • Alkoxy is an alkyl group singly bonded to an oxygen.
  • exemplary alkoxy groups include, but are not limited to, methoxy (-OCH 3 ) and ethoxy (-OCH 2 CH 3 ).
  • a “C 1 -C 5 alkoxy” is an alkoxy group with 1 to 5 carbon atoms. Alkoxy groups may can be unsubstituted or substituted with one or more groups, as described above for alkyl groups.
  • a “C 2 -C 8 alkenyl” is a hydrocarbon containing 2 to 8 normal, secondary, tertiary, or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp 2 double bond.
  • Alkynyl is C2-C I g 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: acetylenic (-C ⁇ CH) and propargyl (-CH 2 C ⁇ CH).
  • a “C 2 -C 8 alkynyl” is a hydrocarbon containing 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.
  • Alkylene refers to a saturated, branched or straight chain or cyclic hydrocarbon radical of 1-18 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 2 -) 1,2-ethyl (-CH 2 CH 2 -), 1,3- propyl (-CH 2 CH 2 CH 2 -), 1,4-butyl (-CH 2 CH 2 CH 2 CH 2 -), and the like.
  • a “C 1 -C 10 alkylene” is a straight chain, saturated hydrocarbon group of the formula - (CH 2 )I-I O -.
  • Examples of a C 1 -C 10 alkylene include methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, ocytylene, nonylene, and decalene.
  • alkenylene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical of 2-18 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.
  • Alkynylene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical of 2-18 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 (-CH 2 ⁇ C- ), and 4-pentynyl (-CH 2 CH 2 CH 2 ⁇ C- ).
  • Aryl refers to a carbocyclic aromatic group.
  • aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.
  • a carbocyclic aromatic group or a heterocyclic aromatic group can be unsubstituted or substituted with one or more groups including, but not limited to, -C 1 -C 8 alkyl, -O-(C 1 -C 8 alkyl), -aryl, -C(O)R’, -OC(O)R’, - C(O)OR’, -C(O)NH 2 , -C(O)NHR’, -C(O)N(R’) 2 -NHC(O)R’, -S(O) 2 R’, -S(O)R’, -OH, -halogen, -N3 , -NH 2 , -NH(R’), -N(R’) 2 and -CN; wherein each
  • a “ C 5 -C 20 aryl” is an aryl group with 5 to 20 carbon atoms in the carbocyclic aromatic rings. Examples of C 5 -C 20 aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. A C 5 -C 20 aryl group can be substituted or unsubstituted as described above for aryl groups.
  • a “C 5 -C 14 aryl” is an aryl group with 5 to 14 carbon atoms in the carbocyclic aromatic rings. Examples of C 5 -C 14 aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. A C 5 -C 14 aryl group can be substituted or unsubstituted as described above for aryl groups.
  • arylene is an aryl group which has two covalent bonds and can be in the ortho, meta, or para configurations as shown in the following structures: in which the phenyl group can be unsubstituted or substituted with up to four groups including, but not limited to, -C 1 -C 8 alkyl, -O-(C 1 -C 8 alkyl), -aryl, -C(O)R’, -OC(O)R’, -C(O)0R’, - C(O)NH 2 , -C(O)NHR’, -C(O)N(R’) 2 -NHC(O)R’, -S(O) 2 R’, -S(O)R’, -OH, -halogen, -N 3 , -NH 2 , -NH(R’), -N(R’) 2 and -CN; wherein each R’ is independently selected from H, -C 1 -C 8 alkyl, -O
  • Arylalkyl refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with an aryl radical.
  • Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-l-yl, 2- phenylethen-l-yl, naphthylmethyl, 2-naphthylethan-l-yl, 2-naphthylethen-l-yl, naphthobenzyl, 2- naphthophenylethan-l-yl and the like.
  • the arylalkyl group comprises 6 to 20 carbon atoms, e.g., the alkyl moiety, including alkanyl, alkenyl or alkynyl groups, of the arylalkyl group is 1 to 6 carbon atoms and the aryl moiety is 5 to 14 carbon atoms,
  • Heteroarylalkyl refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with a heteroaryl radical.
  • Typical heteroarylalkyl groups include, but are not limited to, 2- benzimidazolylmethyl, 2-furylethyl, and the like.
  • the heteroarylalkyl group comprises 6 to 20 carbon atoms, e.g., the alkyl moiety, including alkanyl, alkenyl or alkynyl groups, of the heteroarylalkyl group is 1 to 6 carbon atoms and the heteroaryl moiety is 5 to 14 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S.
  • the heteroaryl moiety of the heteroarylalkyl group may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S), for example: a bicyclo [4,5], [5,5], [5,6], or [6,6] system.
  • Substituted alkyl mean alkyl, aryl, and arylalkyl respectively, in which one or more hydrogen atoms are each independently replaced with a substituent.
  • Typical substituents include, but are not limited to, -X, -R, -O-, -OR, -SR, -S-
  • Heteroaryl and “heterocycle” refer to a ring system in which one or more ring atoms is a heteroatom, e.g., nitrogen, oxygen, and sulfur.
  • the heterocycle radical comprises 3 to 20 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S.
  • a heterocycle may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S), for example: a bicyclo [4,5], [5,5], [5,6], or [6,6] system.
  • heterocycles are described, e.g., in Paquette, Leo A., “Principles of Modem Heterocyclic Chemistry” (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566.
  • heterocycles include by way of example and not limitation pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, bis- tetrahydrofuranyl, tetrahydropyrany 1 , bis-tetrahydropyr
  • carbon bonded heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a ftiran, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline.
  • carbon bonded heterocycles include 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.
  • nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3 -imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, lH-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or ⁇ -carboline.
  • nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1 -pyrrolyl, 1 -imidazolyl, 1- pyrazolyl, and 1-piperidinyl.
  • a “C 3 -C 8 heterocycle” refers to an aromatic or non-aromatic C 3 -C 8 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.
  • C 3 -C 8 heterocycle 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 C 3 -C 8 heterocycle can be unsubstituted or substituted with up to seven groups including, but not limited to, -C 1 -C 8 alkyl, -O-(C 1 -C 8 alkyl), -aryl, -C(O)R’, -OC(O)R’, -C(O)0R’, -C(O)NH 2 , - C(O)NHR’, -C(O)N(R’) 2 -NHC(O)R’, -S(O) 2 R’, -S(O)R’, -OH, -halogen, -N 3 , -NH 2 , -NH(R’), - N(R’) 2 and -CN; wherein each R’ is independently selected from H, -C 1 -C 8 alkyl and aryl.
  • C 3 -C 8 heterocyclo refers to a C 3 -C 8 heterocycle group defined above wherein one of the heterocycle group’s hydrogen atoms is replaced with a bond.
  • a C 3 -C 8 heterocyclo can be unsubstituted or substituted with up to six groups including, but not limited to, -C 1 -C 8 alkyl, -O- (C 1 -C 8 alkyl), -aryl, -C(O)R’, -OC(O)R’, -C(O)0R’, -C(O)NH 2 , -C(O)NHR’, -C(O)N(R’) 2 - NHC(O)R’, -S(O) 2 R’, -S(O)R’, -OH, -halogen, -N 3 , -NH 2 , -NH(R’), -N(R’) 2 and -CN; wherein each R’ is independently selected
  • a “ C 3 -C 20 heterocycle” refers to an aromatic or non-aromatic C 3 -C 8 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.
  • a C 3 -C 20 heterocycle can be unsubstituted or substituted with up to seven groups including, but not limited to, -C 1 -C 8 alkyl, -O-(C 1 -C 8 alkyl), -aryl, -C(O)R’, - 0C(O)R’, -C(O)0R’, -C(O)NH 2 , -C(O)NHR’, -C(O)N(R’) 2 -NHC(O)R’, -S(O) 2 R’, -S(O)R’, - OH, -halogen, -N 3 , -NH 2 , -NH(R’), -N(R’) 2 and -CN; wherein each R’ is independently selected from H, -C 1 -C 8 alkyl and aryl.
  • C 3 -C 20 heterocyclo refers to a C 3 -C 20 heterocycle group defined above wherein one of the heterocycle group’s hydrogen atoms is replaced with a bond.
  • Carbocycle means a saturated or unsaturated ring having 3 to 7 carbon atoms as a monocycle or 7 to 12 carbon atoms as a bicycle.
  • Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms.
  • Bicyclic carbocycles have 7 to 12 ring atoms, e.g., 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-l-enyl, l-cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, 1 -cyclohex- 1-enyl, 1- cyclohex-2-enyl, l-cyclohex-3-enyl, cycloheptyl, and cyclooctyl.
  • a “C 3 -C 8 carbocycle” is a 3-, 4-, 5-, 6-, 7- or 8-membered saturated or unsaturated non-aromatic carbocyclic ring.
  • Representative C 3 -C 8 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 C 3 -C 8 carbocycle group can be unsubstituted or substituted with one or more groups including, but not limited to, -C 1 -C 8 alkyl, - 0-(C 1 -C 8 alkyl), -aryl, -C(O)R’, -OC(O)R’, -C(O)OR’, -C(O)NH 2 , -C(O)NHR’, -C(O)N(R’) 2 - NHC(O)R’, -S(O) 2 R’, -S(O)R’, -OH, -halogen, -N 3 , -NH 2 , -NH(R’), -N(R’) 2 and -CN; where each R’ is independently selected from H, -C 1 -C 8 alkyl and aryl.
  • C 3 -C 8 carbocyclo refers to a C 3 -C 8 carbocycle group defined above wherein one of the carbocycle groups’ hydrogen atoms is replaced with a bond.
  • Linker refers to a chemical moiety comprising a covalent bond or a chain of atoms that covalently attaches an antibody to a drug moiety.
  • linkers include a divalent radical such as an alkyldiyl, an aryldiyl, a heteroaryldiyl, moieties such as:
  • linkers can comprise one or more amino acid residues, such as valine, phenylalanine, lysine, and homolysine.
  • stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
  • 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, e.g., melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography.
  • Enantiomers refer to two stereoisomers of a compound which are non- superimposable mirror images of one another.
  • d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory.
  • a compound prefixed with (+) or d is dextrorotatory.
  • these stereoisomers are identical except that they are mirror images of one another.
  • 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 referred to as a racemic mixture or a 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.
  • leaving group refers to a functional group that can be substituted by another functional group. Certain leaving groups are well known in the art, and examples include, but are not limited to, a halide (e.g ., chloride, bromide, or iodide), methanesulfonyl (mesyl), p- toluenesulfonyl (tosyl), trifluoromethylsulfonyl (triflate), and trifluoromethylsulfonate.
  • halide e.g ., chloride, bromide, or iodide
  • methanesulfonyl methanesulfonyl
  • p- toluenesulfonyl tosyl
  • triflate trifluoromethylsulfonate
  • an “amino -protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound.
  • Suitable amino-protecting groups include, but are not limited to, acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benryloxycarbonyl (CBZ) and 9-fluorenylmethylenoxycarbonyl (Fmoc).
  • BOC t-butoxycarbonyl
  • CBZ benryloxycarbonyl
  • Fmoc 9-fluorenylmethylenoxycarbonyl
  • a B-cell proliferative disorder such as diffuse large B-cell lymphoma (DLBCL), e.g., relapsed/refractory DLBCL
  • an individual e.g., a human individual
  • administering comprising administering to the individual an effective amount of (a) an immunoconjugate comprising an antibody which binds CD79b linked to a cytotoxic agent, (b) an anti-CD20 antibody, and (c) one or more chemotherapeutic agents.
  • an immunoconjugate comprising an antibody which binds CD79b linked to a cytotoxic agent
  • an anti-CD20 antibody e.g., an anti-CD20 antibody
  • the anti-CD79b immunoconjugate is polatuzumab vedotin- piiq.
  • the anti-CD20 antibody is rituximab.
  • the one or more chemotherapeutic agents comprise gemcitabine.
  • the one or more chemotherapeutic agents comprise oxaliplatin.
  • the one or more chemotherapeutic agents are gemcitabine and oxaliplatin.
  • co-administration refers to the administration of the anti-CD79b immunoconjugate, the anti-CD20 antibody, and the one or more chemotherapeutic agents as two (or more) separate formulations (or as one single formulation comprising the anti- CD79b immunoconjugate, the anti-CD20 antibody, and the one or more chemotherapeutic agents). Where separate formulations are used, the co-administration can be simultaneous or sequential in any order, wherein preferably there is a time period while all active agents simultaneously exert their biological activities. In some embodiments, the anti-CD79b immunoconjugate, the anti-CD20 antibody, and the one or more chemotherapeutic agents are co- administered either simultaneously or sequentially.
  • the dose is administered either on the same day in two or more separate administrations, or one or more of the agents is administered on day 1 (e.g., on day 1 of a 21 -day cycle), the other agent(s) are co-administered on about day 2 (e.g., on day 2 of a 21- day cycle).
  • the term “sequentially” means within 7 days after the dose of the first component, e.g. , within 4 days, 3 days, 2 days, or 1 day after the dose of the first component; and the term “simultaneously” means at the same time.
  • the term “sequentially” means within less than 1 day after the dose of the first component, e.g., within any of less than 24 hours, less than 20 hours, less than 15 hours, less than 10 hours, less than 12 hours, less than 8 hours, less than 6 hours, less than 3 hours, less than 2 hours, or less than 1 hour after the dose of the first component.
  • the anti-CD79b immunoconjugate and the anti-CD20 antibody are co-administered sequentially on about Day 1 of each 21 -day cycle and the one or more chemotherapeutic agents are co-administered sequentially on about Day 2 of each 21 -day cycle.
  • Anti-CD79b immunoconjugates, the anti-CD20 antibodies, and the one or more chemotherapeutic agents provided herein for use in any of the therapeutic methods described herein would be formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context 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 scheduling of administration, and other factors known to medical practitioners.
  • the immunoconjugate need not be, but is optionally formulated with one or more agents currently used to prevent or treat the disorder in question.
  • the amount of co-administration of the anti-CD79b immunoconjugate, the anti-CD20 antibody, and the one or more chemotherapeutic agents, and the timing of co-administration will depend on the type (species, gender, age, weight, etc.) and condition of the patient being treated and the severity of the disease or condition being treated.
  • the anti-CD79b immunoconjugate, the anti-CD20 antibody, and the one or more chemotherapeutic agents are suitably co-administered to the patient at one time or over a series of treatments, e.g., on the same day or on the day after.
  • the dosage of anti-CD79b immunoconjugate (such as polatuzumab vedotin-piiq) is between about any of 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 anti- CD79b immunoconjugate is about any of 1.4 mg/kg, 1.5 mg/kg. 1.6 mg/kg.
  • the dosage of anti-CD79b immunoconjugate is about 1.4 mg/kg.
  • the dosage of anti-CD79b immunoconjugate is about 1.8 mg/kg. In some embodiments, the dosage of anti-CD79b immunoconjugate is about 2.4 mg/kg. In some embodiments, the dosage of anti-CD79b immunoconjugate is about 3.2 mg/kg. In some embodiments, the dosage of anti-CD79b immunoconjugate is about 3.6 mg/kg. In some embodiments of any of the methods, the anti-CD79b immunoconjugate is administered q3wk. In some embodiments of any of the methods, the anti-CD79b immunoconjugate is administered once in each 21 -day cycle.
  • the anti-CD79b immunoconjugate is administered on about day 1 of each 21 -day cycle. In some embodiments, the anti-CD79b immunoconjugate is administered via intravenous infusion. In some embodiments, the dosage administered via infusion is in the range of about 1 mg to about 2,000 mg per dose, generally every three weeks (e.g., on day 1 of each 21 -day cycle) for a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or more doses. In some embodiments, the dosage administered via infusion is in the range of about 1 mg to about 2,000 mg per dose, generally on about day 1 of each 21 -day cycle for up to eight 21 -day cycles.
  • the dosage range is of about 1 mg to about 2,000 mg, about 1 mg to about 1,800 mg, about 400 mg to about 1200 mg, about 600 mg to about 1000 mg, about 10 mg to about 500 mg, about 10 mg to about 300 mg, about lOmg to about 200 mg, and about 1 mg to about 200 mg.
  • the dosage administered via infusion is in the range of about 1 ⁇ g/m 2 to about 10,000 ⁇ g/m 2 per dose, generally on about day 1 of each 21-day cycle for a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or more.
  • the dosage administered via infusion is in the range of about 1 ⁇ g/m 2 to about 10,000 ⁇ g/m 2 per dose, generally one dose every three weeks ⁇ e.g., on day 1 of each 21 -day cycle) for up to eight 21 -day cycles.
  • the dosage range is of about 1 ⁇ g/m 2 to about 1000 ⁇ g/m 2 , about 1 ⁇ g/m 2 to about 800 ⁇ g/m 2 , about 1 ⁇ g/m 2 to about 600 ⁇ g/m 2 , about 1 ⁇ g/m 2 to about 400 ⁇ g/m 2 , about 10 ⁇ g/m 2 to about 500 ⁇ g/m 2 , about 10 ⁇ g/m 2 to about 300 ⁇ g/m 2 , about 10 ⁇ g/m 2 to about 200 ⁇ g/m 2 , and about 1 ⁇ g/m 2 to about 200 ⁇ g/m 2 .
  • the dose may be administered once per week, multiple times per week, but less than once per day, multiple times per month but less than once per day, multiple times per month but less than once per week, once per month, once every three weeks, once every 21 days, once each 21 -day cycle, on day 1 of each 21 -day cycle, or intermittently to relieve or alleviate symptoms of the disease. Administration may continue at any of the disclosed intervals for up to eight 21 -day cycles or until remission of the tumor or symptoms of the B-cell proliferative disorder (e.g., DLBCL) being treated. Administration may continue after remission or relief of symptoms is achieved where such remission or relief is prolonged by such continued administration.
  • the B-cell proliferative disorder e.g., DLBCL
  • the dosage of the anti-CD20 antibody is between about 300-1600 mg/m 2 and/or 300-2000 mg. In some embodiments, the dosage of the anti-CD20 antibody is about any of 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 dosage administered is 375 mg/m 2 . In some embodiments, the anti-CD20 antibody is administered q3w (i.e., every 3 weeks).
  • the anti-CD20 antibody is administered once in each 21 -day cycle (e.g., on day 1 of each 21 -day cycle).
  • the anti-CD20 antibody is rituximab.
  • the dosage of rituximab may be 375 mg/m 2 on day 1 of each 21 -day cycle.
  • the dosage of rituximab may be 375 mg/m 2 on day 1 of each 21 -day cycle for up to eight 21 -day cycles.
  • the dosage of rituximab may be 375 mg/m 2 on day 1 of each 21 -day cycle for eight 21 -day cycles.
  • the anti-CD20 antibody may be administered once per week, multiple times per month but less than once per week, once per month, once every three weeks, once every 21 days, once each 21 -day cycle, on day 1 of each 21 -day cycle, or intermittently to relieve or alleviate symptoms of the disease. Administration may continue at any of the disclosed intervals for up to eight 21 -day cycles or until remission of the tumor or symptoms of the B-cell proliferative disorder (e.g., DLBCL) being treated. Administration may continue after remission or relief of symptoms is achieved where such remission or relief is prolonged by such continued administration.
  • the B-cell proliferative disorder e.g., DLBCL
  • the dosage of the one or more chemotherapeutic agents is between about 50 mg/m 2 to about 2000 mg/m 2 . In some embodiments, the dosage of the one or more chemotherapeutic agents is between about 50 mg/m 2 to about 100 mg/m 2 , about 100 mg/m 2 to about 200 mg/m 2 , about 200 mg/m 2 to about 300 mg/m 2 , about 300 mg/m 2 to about 400 mg/m 2 , about 400 mg/m 2 to about 500 mg/m 2 , about 500 mg/m 2 to about 600 mg/m 2 , about 600 mg/m 2 to about 700 mg/m 2 , about 700 mg/m 2 to about 800 mg/m 2 , about 800 mg/m 2 to about 900 mg/m 2 , about 900 mg/m 2 to about 1000 mg/m 2 , about 1000 mg/m 2 to about 1100 mg/m 2 , about 1100 mg/m 2 to about 1200 mg/m 2 , about 1200 mg/m 2 to about 1300
  • the dosage of the one or more chemotherapeutic agents comprises a dose of gemcitabine of about 500 mg/m 2 to about 1500 mg/m 2 (e.g., about 500 mg/m 2 to about 600 mg/m 2 , about 600 mg/m 2 to about 700 mg/m 2 , about 700 mg/m 2 to about 800 mg/m 2 , about 800 mg/m 2 to about 900 mg/m 2 , about 900 mg/m 2 to about 1000 mg/m 2 , about 1000 mg/m 2 to about 1100 mg/m 2 , about 1100 mg/m 2 to about 1200 mg/m 2 , about 1200 mg/m 2 to about 1300 mg/m 2 , about 1300 mg/m 2 to about 1400 mg/m 2 , about 1400 mg/m 2 to about 1500 mg/m 2 ).
  • gemcitabine of about 500 mg/m 2 to about 1500 mg/m 2 (e.g., about 500 mg/m 2 to about 600 mg/m 2 , about 600 mg/m 2 to about 700 mg/m 2
  • the dosage of the one or more chemotherapeutic agents comprises a dose of gemcitabine of about 1000 mg/m 2 .
  • the dose of gemcitabine is administered q3w or about once in each 21 -day cycle (e.g., on day 2 of each 21 day cycle).
  • the dose of gemcitabine is administered once in each 21 -day cycle (e.g., on day 2 of each 21 -day cycle) for up to eight 21 -day cycles.
  • the dose of gemcitabine is administered once in each 21 -day cycle (e.g., on day 2 of each 21 -day cycle) for eight 21 -day cycles.
  • the dosage of the one or more chemotherapeutic agents comprises a dose of oxaliplatin of between about 50 mg/m 2 to about 200 mg/m 2 (e.g. , 50 mg/m 2 to about 100 mg/m 2 or about 100 mg/m 2 to about 200 mg/m 2 ). In some embodiments, the dosage of the one or more chemotherapeutic agents comprises a dose of oxaliplatin of about 100 mg/m 2 . In some embodiments, the dose of oxaliplatin is administered q3w or about once in each 21 -day cycle (e.g., on day 2 of each 21 day cycle). In some embodiments, the dose of oxaliplatin is administered once in each 21 -day cycle (e.g.
  • the dose of gemcitabine is administered once in each 21 -day cycle (e.g., on day 2 of each 21 -day cycle) for eight 21 -day cycles.
  • the one or more chemotherapeutic agents comprise gemcitabine and oxaliplatin, and the gemcitabine and the oxaliplatin are administered intravenously on about day 2 of each 21 -day cycle.
  • the one or more chemotherapeutic agents comprise gemcitabine and oxaliplatin, and the gemcitabine and the oxaliplatin are administered intravenously on day 2 of each 21 -day cycle for up to about eight cycles.
  • the one or more chemotherapeutic agents are administered once per week, multiple times per week, but less than once per day, multiple times per month but less than once per day, multiple times per month but less than once per week, once per month, once every three weeks, once in each 21 -day cycle, on about day 2 of each 21 -day cycle, or intermittently to relieve or alleviate symptoms of the disease.
  • Administration may continue at any of the disclosed intervals for up to about eight 21 -day cycles or until remission of the tumor or symptoms of the B-cell proliferative disorder being treated. Administration may continue after remission or relief of symptoms is achieved where such remission or relief is prolonged by such continued administration.
  • Exemplary dosing regimens for the combination therapy of anti-CD79b immunoconjugates (such as polatuzumab vedotin-piiq) and other agents include, but are not limited to, anti-CD79b immunoconjugate (such as huMA79bv28 -MC-vc-P AB-MMAE) administered at about 1.4-5 mg/kg on about day 1 of each 21 day cycle, plus an anti-CD20 antibody (e.g., rituximab) administered at about 300-1600 mg/m 2 on about day 1 of each 21 day cycle, plus one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) administered at about 50 mg/m 2 to about 2000 mg/m 2 (e.g., gemcitabine administered at about 500 mg/m 2 to about 2000 mg/m 2 and oxaliplatin administered at about 50 mg/m 2 to about 200 mg/m 2 ) on about day 2 of each 21 day cycle.
  • the anti-CD79b immunoconjugate (such as polatuzumab vedotin-piiq) is administered at about 1.8 mg/kg on about day 1 of each 21 day cycle
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine administered at about 1000 mg/m 2 and oxaliplatin administered at about 100 mg/m 2
  • the anti-CD79b immunoconjugate is administered at about 1.8 mg/kg.
  • the anti-CD79b immunoconjugate is polatuzumab vedotin-piiq and is administered at about 1.8 mg/kg. In some embodiments, the anti-CD20 antibody is administered at about 375 mg/m 2 . In some embodiments, the anti-CD20 antibody is rituximab and is administered at about 375 mg/m 2 . In some embodiments, the one or more chemotherapeutic agents comprise gemcitabine administered at about 1000 mg/m 2 and oxaliplatin administered at about 100 mg/m 2 .
  • the anti-CD79b immunoconjugate is polatuzumab vedotin-piiq and is administered at about 1.8 mg/kg
  • the anti-CD20 antibody is rituximab and is administered at about 375 mg/m 2
  • the one or more chemotherapeutic agents are gemcitabine administered at about 1000 mg/m 2 and oxaliplatin administered at about 100 mg/m 2 .
  • An immunoconjugate provided herein, an anti-CD20 antibody provided herein, and one or more chemotherapeutic agents provided herein for use in any of the therapeutic methods described herein can be administered by any suitable means, including parenteral, intrapulmonary, and intranasal, and, if desired for local treatment, intralesional administration.
  • Parenteral infusions include intramuscular, intravenous (e.g., intravenous infusion), intraarterial, intraperitoneal, or subcutaneous administration.
  • Dosing can be by any suitable route, e.g., by injections, such as intravenous or subcutaneous injections, depending in part on whether the administration is brief or chronic.
  • Various dosing schedules including, but not limited to single or multiple administrations over various time-points, bolus administration, and pulse infusion are contemplated herein.
  • DLBCL diffuse large B-cell lymphoma
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 that comprises 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 wherein p is between 1 and 8; (b) an anti-CD20 antibody
  • the immunoconjugate comprises an anti-CD79b antibody that comprises a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 19 and a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 20.
  • VH heavy chain variable domain
  • VL light chain variable domain
  • Also provided herein are methods for treating diffuse large B-cell lymphoma (DLBCL, e.g., relapsed/reffactory DLBCL) in an individual (a human individual) in need thereof comprising administering to the individual an effective amount of: (a) an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, (b) rituximab
  • DLBCL diffuse large B-cell lymphoma
  • methods for treating diffuse large B-cell lymphoma comprising administering to the individual an effective amount of: (a) an immunoconjugate comprising the formula
  • Ab is an anti-CD79b antibody comprising (i) an HVR-Hl 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 wherein p is between 1 and 8, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin does not result in peripheral neuropathy of Grade 3 or greater (e.g., any of Grade 3 or greater, Grade
  • Also provided herein are methods for treating diffuse large B-cell lymphoma (DLBCL, e.g., relapsed/refractory DLBCL) in an individual (a human individual) in need thereof comprising administering to the individual an effective amount of: (a) an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, (b) rituximab,
  • fewer than about 40% e.g., any of fewer than about 40%, about 39% or fewer, about 38% or fewer, about 37% or fewer, about 36% or fewer, about 35% or fewer, about 34% or fewer, about 33% or fewer, about 32% or fewer, about 31% or fewer, about 30% or fewer, about 29% or fewer, about 28% or fewer, about 27% or fewer, about 26% or fewer, about 25% or fewer, about 24% or fewer, about 23% or fewer, about 22% or fewer, about 21% or fewer, about 20% or fewer, about 19% or fewer, about 18% or fewer, about 17% or fewer, about 16% or fewer, about 15% or fewer, about 14% or fewer, about 13% or fewer, about 12% or
  • Also provided herein are methods for treating diffuse large B-cell lymphoma (DLBCL, e.g., relapsed/refractory DLBCL) in an individual (a human individual) in need thereof comprising administering to the individual an effective amount of: (a) an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (iv) an HVR- L1 comprising the amino acid sequence of SEQ ID NO: 24; (v) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (vi) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26, and wherein p is between 1 and 8, (b) rituximab,
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in fewer than about 40% (e.g., any of fewer than about 40%, about 39% or fewer, about 38% or fewer, about 37% or fewer, about 36% or fewer, about 35% or fewer, about 34% or fewer, about 33% or fewer, about 32% or fewer, about 31% or fewer, about 30% or fewer, about 29% or fewer, about 28% or fewer, about 27% or fewer, about 26% or fewer, about 25% or fewer, about 24% or fewer, about 23% or fewer, about 22% or fewer, about 21% or fewer, about 20% or fewer, about 19% or fewer, about 18% or fewer, about 17% or fewer, about 16% or fewer, about 15% or fewer, about 14% or fewer, about 13% or fewer, about 12% or fewer,
  • the immunoconjugate comprises an anti-CD79b antibody that 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 immunoconjugate comprises an anti-CD79b antibody that 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 comprises an anti-CD79b antibody that comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 36 and a light chain comprising the amino acid sequence of SEQ ID NO: 35.
  • p is between 2 and 7, between 2 and 6, between 2 and 5, between 3 and 5, or between 3 and 4. In some embodiments, p is between 2 and 5. In some embodiments, p is between 3 and 4. In some embodiments, p is 3.5.
  • the anti-CD79b immunoconjugate is polatuzumab vedotin-piiq. In some embodiments, the anti-CD20 antibody is rituximab.
  • the one or more chemotherapeutic agents comprise any of the chemotherapeutic agents provided herein. In some embodiments, the one or more chemotherapeutic agents comprise gemcitabine. In some embodiments, the one or more chemotherapeutic agents comprise oxaliplatin.
  • the one or more chemotherapeutic agents are gemcitabine and oxaliplatin.
  • 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.
  • 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.
  • the immunoconjugate is iladatuzumab vedotin.
  • p is between 2 and 5. In certain embodiments, p is 2.
  • the immunoconjugate is administered at a dose that is from about 1 mg/kg to about 5 mg /kg. In some embodiments, the immunoconjugate is administered at a dose of about 1.2 mg/kg, about 1.8 mg/kg, about 2.4 mg/kg, about 3.6 mg/kg, or about 4.8 mg/kg. In some embodiments, the immunoconjugate is administered at a dose of about 1.8 mg/kg.
  • Iladatuzumab vedotin refers to an anti-CD79b immunoconjugate having the International Nonproprietary Names for Pharmaceutical Substances (INN) Number 10647, or the CAS Registry Number 1906205-77-3. Iladatuzumab vedotin is also interchangeably referred to as “DCDS0780A” or “R07032005”.
  • the anti-CD79b immunoconjugate e.g., polatuzumab vedotin-piiq), the anti-CD20 antibody (such as rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) may be administered by the same route of administration or by different routes of administration.
  • the anti-CD79b immunoconjugate is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally.
  • the anti-CD20 antibody (such as rituximab) is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally.
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • the anti-CD79b immunoconjugate, the anti-CD20 antibody (such as rituximab), and the one or more chemotherapeutic agents are each administered via intravenous infusion.
  • An effective amount of the anti- CD79b immunoconjugate (e.g., polatuzumab vedotin-piiq), the anti-CD20 antibody (such as rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) may be administered for the prevention or treatment of disease.
  • the anti-CD79b immunoconjugate (e.g., polatuzumab vedotin- piiq) is administered at a dose between about 1.4 mg/kg to about 2 mg/kg (e.g., about 1.4 mg/kg to about 1.6 mg/kg, about 1.6 mg/kg to about 1.8 mg/kg, or about 1.8 mg/kg to about 2 mg/kg).
  • the anti-CD79b immunoconjugate is administered at a dose of 1.8 mg/kg.
  • the anti-CD79b immunoconjugate is polatuzumab vedotin-piiq.
  • the polatuzumab vedotin-piiq is administered at a dose of 1.8 mg/kg.
  • the anti-CD20 antibody e.g., rituximab
  • the anti-CD20 antibody is administered at a dose of between about 300-1800 mg/m 2 (e.g., about 300 mg/m 2 to about 600 mg/m 2 , about 600 mg/m 2 to about 900 mg/m 2 , about 900 mg/m 2 to about 1200 mg/m 2 , about 1200 mg/m 2 to about 1500 mg/m 2 , or about 1500 mg/m 2 to about 1800 mg/m 2 ) and/or about 300-2000 mg (e.g, about 300 mg to about 600 mg, about 600 mg to about 900 mg, about 900 mg to about 1200 mg, about 1200 mg to about 1500 mg, about 1500 mg to about 1750 mg, or about 1750 mg to about 2000 mg).
  • the anti-CD20 antibody is rituximab.
  • the rituximab is administered at a dose of about 375 mg/m 2 .
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • the one or more chemotherapeutic agents comprise gemcitabine. In some embodiments, gemcitabine is administered at a dose of about 1000 mg/m 2 . In some embodiments, the one or more chemotherapeutic agents comprise oxaliplatin. In some embodiments, the oxaliplatin is administered at a dose of about 100 mg/m 2 . In some embodiments, the one or more chemotherapeutic agents are gemcitabine and oxaliplatin, and the gemcitabine is administered at a dose of about 1000 mg/m 2 and the oxaliplatin is administered at a dose of about 100 mg/m 2 .
  • the anti-CD20 antibody is rituximab.
  • the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the rituximab is administered at a dose of about 375 mg/m 2
  • the gemcitabine is administered at a dose of about 1000 mg/m 2
  • the oxaliplatin is administered at a dose of about 100 mg/m 2 .
  • the polatuzumab vedotin-piiq is administered at a dose of about 1.8 mg/kg
  • the rituximab is administered at a dose of about 375 mg/m 2
  • the gemcitabine is administered at a dose of about 1000 mg/m 2
  • the oxaliplatin is administered at a dose of about 100 mg/m 2 .
  • the anti-CD79b immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitahine and oxaliplatin
  • 21 -day cycle e.g., any of about one, about two, about three, about four, about five, about six, about seven, or about eight, or more 21 -day cycles.
  • the anti-CD79b immunoconjugate e.g., polatuzumab vedotin- piiq
  • the anti-CD20 antibody e.g. , rituximab
  • the one or more chemotherapeutic agents e.g., gemcitahine and oxaliplatin
  • are administered for up to eight 21 -day cycles e.g., any of about one, about two, about three, about four, about five, about six, about seven, or about eight 21 -day cycles).
  • the immunoconjugate (e.g., polatuzumab vedotin-piiq) is administered intravenously on about Day 1 of each 21 -day cycle.
  • the immunoconjugate is polatuzumab vedotin-piiq and the polatuzumab vedotin-piiq is administered intravenously on about Day 1 of each 21 -day cycle.
  • the anti-CD20 antibody e.g., rituximab
  • the anti-CD20 antibody is rituximab, and the rituximab is administered on about Day 1 of each 21 -day cycle.
  • the one or more chemotherapeutic agents e.g., gemcitahine and oxaliplatin
  • the chemotherapeutic agents are gemcitahine and oxaliplatin and the gemcitahine and oxaliplatin are administered intravenously on about Day 2 of each 21 -day cycle.
  • the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitahine and oxaliplatin
  • the immunoconjugate and the anti-CD20 antibody are administered intravenously on about Day 1 of each 21 -day cycle
  • the one or more chemotherapeutic agents are administered intravenously on about Day 2 of each 21 -day cycle.
  • the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitahine and oxaliplatin
  • the immunoconjugate and the anti-CD20 antibody are administered intravenously on about Day 1 of each 21 -day cycle
  • the one or more chemotherapeutic agents are administered intravenously on about Day 2 of each 21 -day cycle.
  • the one or more chemotherapeutic agents are gemcitabine and oxaliplatin.
  • the anti-CD20 antibody is rituximab.
  • the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the rituximab, the gemcitabine, and the oxaliplatin are administered for up to eight 21 -day cycles, wherein the immunoconjugate and the rituximab are administered intravenously on about Day 1 of each 21 -day cycle, and wherein the gemcitabine and the oxaliplatin are administered intravenously on about Day 2 of each 21 -day cycle.
  • the immunoconjugate (e.g., polatuzumab vedotin-piiq) is administered at a dose of about 1.8 mg/kg, the rituximab is administered at a dose of about 375 mg/m 2 , the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of about 100 mg/m 2 , wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for up to eight 21 -day cycles, and wherein the immunoconjugate and the rituximab are administered on Day 1 of each 21 -day cycle and the gemcitabine and the oxaliplatin are administered on Day 2 of each 21 -day cycle.
  • the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the rituximab is administered at a dose
  • the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the rituximab e.g., the gemcitabine, and the oxaliplatin are administered for at least one 21 -day cycle
  • the immunoconjugate and the rituximab are administered intravenously on about Day 1 of each 21- day cycle
  • the gemcitabine and the oxaliplatin are administered intravenously on about Day 2 of each 21 -day cycle.
  • the immunoconjugate (e.g., polatuzumab vedotin-piiq) is administered at a dose of about 1.8 mg/kg, the rituximab is administered at a dose of about 375 mg/m 2 , the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of about 100 mg/m 2 , wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for at least one 21 -day cycles, and wherein the immunoconjugate and the rituximab are administered on Day 1 of each 21 -day cycle and the gemcitabine and the oxaliplatin are administered on Day 2 of each 21 -day cycle.
  • the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the rituximab is administered at a dose
  • DLBCL diffuse large B-cell lymphoma
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate is administered at a dose of about 1.8 mg/kg, the rituximab is administered at a dose of about 375 mg/m 2 , the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of
  • DLBCL diffuse large B-cell lymphoma
  • DLBCL diffuse large B-cell lymphoma
  • a human individual in need thereof comprising administering to the individual an effective amount of: (a) an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5; (b) rituximab; (c) gemcitabine; and (d) oxaliplatin; wherein the immunoconjugate is administered at a dose of about 1.8 mg/kg, the rituximab is administered at a dose of about 375 mg/m 2 , the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the oxaliplatin is administered at a dose of
  • DLBCL diffuse large B-cell lymphoma
  • Also provided herein are methods of treating diffuse large B-cell lymphoma (DLBCL, e.g., relapsed/reffactory DLBCL) in an individual (a human individual) in need thereof comprising administering to the individual an effective amount of: (a) an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for up to eight 21 -day cycles, wherein during each cycle the immunoconjugate is administered at a dose of about 1.8 mg/kg, the rituximab is administered at a dose
  • Also provided herein are methods of treating diffuse large B-cell lymphoma (DLBCL, e.g., relapsed/ refractory DLBCL) in an individual (a human individual) in need thereof comprising administering to the individual an effective amount of: (a) an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for at least one 21 -day cycle, wherein during each cycle the immunoconjugate is administered at a dose of about 1.8 mg/kg, the rituximab is administered at a dose
  • Also provided herein are methods of treating diffuse large B-cell lymphoma (DLBCL, e.g., relapsed/refractory DLBCL) in an individual (a human individual) in need thereof comprising administering to the individual an effective amount of: (a) an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for up to eight 21 -day cycles, wherein during each cycle the immunoconjugate is administered at a dose of about 1.8 mg/kg, the rituximab is administered at a dose of
  • Also provided herein are methods of treating diffuse large B-cell lymphoma (DLBCL, e.g., relapsed/refractory DLBCL) in an individual (a human individual) in need thereof comprising administering to the individual an effective amount of: (a) an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for at least one 21 -day cycle, wherein during each cycle the immunoconjugate is administered at a dose of about 1.8 mg/kg, the rituximab is administered at a dose of
  • the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin have been administered for at least four 21 -day cycles.
  • methods of treating diffuse large B-cell lymphoma e.g.
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for up to eight 21 -day cycles, wherein during each cycle the immunoconjugate is administered at a dose of about 1.8 mg/kg, the rituximab is administered at a dose of about 375 mg/m 2 , the gemcitabine is administered at a dose of about 1000 mg/m 2 , and the
  • the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin have been administered for at least four 21 -day cycles.
  • fewer than about 40% e.g., any of fewer than about 40%, about 39% or fewer, about 38% or fewer, about 37% or fewer, about 36% or fewer, about 35% or fewer, about 34% or fewer, about 33% or fewer, about 32% or fewer, about 31% or fewer, about 30% or fewer, about 29% or fewer, about 28% or fewer, about 27% or fewer, about 26% or fewer, about 25% or fewer, about 24% or fewer, about 23% or fewer, about 22% or fewer, about 21% or fewer, about 20% or fewer, about 19% or fewer, about 18% or fewer, about 17% or fewer, about 16% or fewer, about 15% or fewer, about 14% or fewer, about 13% or fewer, about 12% or
  • Also provided herein are methods of treating diffuse large B-cell lymphoma (DLBCL, e.g., relapsed/refractory DLBCL) in an individual (a human individual) in need thereof comprising administering to the individual an effective amount of: (a) an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for up to eight 21 -day cycles, wherein during each cycle the immunoconjugate is administered at a dose of about 1.8 mg/kg, the rituximab is administered at a dose of
  • the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin have been administered for at least four 21 -day cycles.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in fewer than about 40% (e.g., any of fewer than about 40%, about 39% or fewer, about 38% or fewer, about 37% or fewer, about 36% or fewer, about 35% or fewer, about 34% or fewer, about 33% or fewer, about 32% or fewer, about 31% or fewer, about 30% or fewer, about 29% or fewer, about 28% or fewer, about 27%o or fewer, about 26% or fewer, about 25% or fewer, about 24% or fewer, about 23% or fewer, about 22% or fewer, about 21% or fewer, about 20% or fewer, about 19% or fewer, about 18% or fewer, about 17% or fewer, about 16% or fewer, about 15% or fewer, about 14% or fewer, about 13% or fewer, about 12% or fewer
  • Also provided herein are methods of treating diffuse large B-cell lymphoma (DLBCL, e.g., relapsed/refractory DLBCL) in an individual (a human individual) in need thereof comprising administering to the individual an effective amount of: (a) an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (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 wherein p is between 2 and 5, (b) rituximab, (c) gemcitabine, and (d) oxaliplatin; wherein the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for at least one 21 -day cycle, wherein during each cycle the immunoconjugate is administered at a dose of about 1.8 mg/kg, the rituximab is administered at a dose of
  • the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin have been administered for at least four 21 -day cycles.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in fewer than about 40% (e.g., any of fewer than about 40%, about 39% or fewer, about 38% or fewer, about 37% or fewer, about 36% or fewer, about 35% or fewer, about 34% or fewer, about 33% or fewer, about 32% or fewer, about 31% or fewer, about 30% or fewer, about 29% or fewer, about 28% or fewer, about 27% or fewer, about 26% or fewer, about 25% or fewer, about 24% or fewer, about 23% or fewer, about 22% or fewer, about 21% or fewer, about 20% or fewer, about 19% or fewer, about 18% or fewer, about 17% or fewer, about 16% or fewer, about 15% or fewer, about 14% or fewer, about 13% or fewer, about 12% or fewer,
  • the anti-CD20 antibody e.g., rituximab
  • the anti-CD20 antibody is administered before (e.g., any of up to about 1 hour, up to about 2 hours, up to about 4 hours, up to about 6 hours, up to about 12 hours, up to about 16 hours, up to about 18 hours, up to about 22 hours, up to about 24 hours, or up to about 1 day, up to about 2 days, up to about 3 days, or more before) the immunoconjugate (e.g., polatuzumab vedotin-piiq).
  • the anti-CD20 antibody is rituximab, and the rituximab is administered before the immunoconjugate.
  • the immunoconjugate is administered before (e.g., any of up to about 1 hour, up to about 2 hours, up to about 4 hours, up to about 6 hours, up to about 12 hours, up to about 16 hours, up to about 18 hours, up to about 22 hours, up to about 24 hours, or up to about 1 day, up to about 2 days, up to about 3 days, or more before) the anti-CD20 antibody.
  • the anti-CD20 antibody is rituximab
  • the immunoconjugate is administered before the rituximab.
  • the one or more chemotherapeutic agents are administered sequentially.
  • the chemotherapeutic agents are gemcitabine and oxaliplatin.
  • the gemcitabine is administered before (e.g., any of up to about 1 hour, up to about 2 hours, up to about 4 hours, up to about 6 hours, up to about 12 hours, up to about 16 hours, up to about 18 hours, up to about 22 hours, up to about 24 hours, or up to about 1 day, up to about 2 days, up to about 3 days, or more before) the oxaliplatin.
  • the oxaliplatin is administered before (e.g., any of up to about 1 hour, up to about 2 hours, up to about 4 hours, up to about 6 hours, up to about 12 hours, up to about 16 hours, up to about 18 hours, up to about 22 hours, up to about 24 hours, or up to about 1 day, up to about 2 days, up to about 3 days, or more before) the gemcitabine.
  • the immunoconjugate, the anti-CD20 antibody, and the one or more chemotherapeutic agents are administered for any of one, two, three, four, five, six, seven, or eight 21 -day cycles.
  • the chemotherapeutic agents are gemcitabine and oxaliplatin.
  • the anti-CD20 antibody is rituximab.
  • the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for any of one, two, three, four, five, six, seven, or eight 21 -day cycles.
  • the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for eight 21 -day cycles.
  • the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for at least two, at least three, at least four, at least five, at least six, or at least seven 21 -day cycles. In some embodiments, the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin are administered for eight 21 -day cycles. In some embodiments, the rituximab is administered before the immunoconjugate. In some embodiments, the gemcitabine is administered before the oxaliplatin. In some embodiments, the immunoconjugate is polatuzumab vedotin-piiq.
  • the human has received at least one prior therapy for DLBCL.
  • the human is an adult.
  • the human has histologically confirmed diffuse large B-cell lymphoma, not otherwise specified (NOS), or the human has a history of transformation of indolent disease to DLBCL.
  • NOS diffuse large B-cell lymphoma
  • the human has received at least one prior systemic therapy for DLBCL.
  • the human has received at least two prior therapies for DLBCL.
  • the human has received prior autologous hematopoietic stem cell transplantation (HSCT) (chemotherapy followed by consolidative autologous HSCT is counted as one line of prior therapy).
  • HSCT autologous hematopoietic stem cell transplantation
  • the human has received a prior allogeneic HSCT and the human is no longer receiving immunosuppressive therapy and has no active graft versus host disease (GVHD) (chemotherapy followed by allogeneic HSCT is counted as one line of prior therapy).
  • the human received prior local therapies, e.g. , radiotherapy.
  • the DLBCL is relapsed or refractory.
  • the DLBCL is relapsed if it recurs following a response that lasted ⁇ 6 months from completion of the last line of therapy.
  • the DLBCL is refractory if it progresses during prior therapy or progresses within 6 months ( ⁇ 6 months) of prior therapy.
  • the human has at least one bi- dimensionally measurable lesion, e.g., a lesion that is greater than 1.5 cm in its longest dimension as measured by computed tomography (CT) or magnetic resonance imaging (MRI).
  • CT computed tomography
  • MRI magnetic resonance imaging
  • the human has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
  • the human does not have a planned autologous or allogeneic stem cell transplantation (SCT).
  • SCT planned autologous or allogeneic stem cell transplantation
  • the human has not had prior therapy with a combination of gemcitabine and a platinum-based agent.
  • the human does not have peripheral neuropathy of greater than Grade 1 according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0.
  • the human does not have primary or secondary central nervous system (CNS) lymphoma. In some embodiments, the human does not have Richter’s transformation or prior capillary leak syndrome (CLL). In some embodiments, the human is not a candidate for hematopoietic stem cell transplantation (HSCT) prior to administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin. In some embodiments, the human is not a candidate for autologous hematopoietic stem cell transplantation (HSCT) prior to administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • CNS central nervous system
  • CLL capillary leak syndrome
  • the human has received at least two prior therapies for DLBCL. In some embodiments, the human has not received a prior therapy with polatuzumab vedotin-piiq for DLBCL. In some embodiments, the human is an adult. In some embodiments, the human adult has relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified.
  • DLBCL diffuse large B-cell lymphoma
  • NOS not otherwise specified
  • DLBCL that does not fit the distinctive clinical presentation, tissue morphology, neoplastic cell phenotype, and/or pathogen-associated criteria of other DLBCL subtypes.
  • DLBC NOS is generally an aggressive disease representing about 80-85% of all DLBCL cases.
  • DLBCL NOS pateints reated with standard chemotherapy regimens have an overall long-term survival rate of about 65%. See, e.g., Grimm et al (2019) Annals of Diagnostic Pathology, 38:6-10.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin does not result in peripheral neuropathy of Grade 3 or greater (e.g., any of Grade 3 or greater, Grade 4 or greater, or Grade 5 or greater) in the human that does not resolve to Grade 1 or lower within 14 days.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin does not result in peripheral neuropathy of Grade 4 or greater (e.g., any of Grade 4 or greater, or Grade 5 or greater) in the human.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in 33% or fewer (e.g., any of about 33% or fewer, about 32% or fewer, about 31% or fewer, about 30% or fewer, about 29% or fewer, about 28% or fewer, about 27% or fewer, about 26% or fewer, about 25% or fewer, about 24% or fewer, about 23% or fewer, about 22% or fewer, about 21% or fewer, about 20% or fewer, about 19% or fewer, about 18% or fewer, about 17% or fewer, about 16% or fewer, about 15% or fewer, about 14% or fewer, about 13% or fewer, about 12% or fewer, about 11% or fewer, about 10% or fewer, about 9% or fewer, about 8% or fewer, about 7% or fewer, about 6% or fewer, about 5% or fewer,
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in fewer than about 40% (e.g., any of fewer than about 40%, about 39% or fewer, about 38% or fewer, about 37% or fewer, about 36% or fewer, about 35% or fewer, about 34% or fewer, about 33% or fewer, about 32% or fewer, about 31% or fewer, about 30% or fewer, about 29% or fewer, about 28% or fewer, about 27% or fewer, about 26% or fewer, about 25% or fewer, about 24% or fewer, about 23% or fewer, about 22% or fewer, about 21% or fewer, about 20% or fewer, about 19% or fewer,
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in less than about 8% (e.g., less than any of about 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%) of the humans in the plurality experiencing peripheral neuropathy of Grade 3 or greater (e.g., any of Grade 3 or greater, Grade 4 or greater, or Grade 5 or greater).
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in less than about 6% (e.g., less than any of about 6%, 5%, 4%, 3%, 2%, or 1%) of the humans in the plurality experiencing peripheral neuropathy that results in discontinuation of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin have been administered for at least four 21 -day cycles.
  • the human after administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin, the human does not experience peripheral neuropathy of Grade 4 or greater (e.g., any of Grade 4 or greater, or Grade 5 or greater).
  • peripheral neuropathy of Grade 4 or greater e.g., any of Grade 4 or greater, or Grade 5 or greater
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin does not result peripheral neuropathy of Grade 4 or greater (e.g., any of Grade 4 or greater, or Grade 5 or greater) in the human.
  • the human after administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin, the human does not experience neurotoxicity of Grade 4 or greater (e.g., any of Grade 4 or greater, or Grade 5 or greater).
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin does not result in neurotoxicity of Grade 4 or greater (e.g., any of Grade 4 or greater, or Grade 5 or greater) in the human.
  • neurotoxicity refers to sensory and/or motor peripheral neuropathy.
  • the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin have been administered for at least four 21 -day cycles.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in survival of the human for at least about 10 months or more, at least about 11 months or more, at least about 12 months or more, at least about 13 months or more, at least about 14 months or more, or at least about 15 months or more after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in a median overall survival of the humans in the plurality of at least about 10 months or more, at least about 11 months or more, at least about 12 months or more, at least about 13 months or more, at least about 14 months or more, or at least about 15 months or more after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • administration of the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g ., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • OS overall survival
  • OS is measured from the first administration of the immunoconjugate, the anti-CD20 antibody, and the one or more chemotherapeutic agents to the time of an occurrence of death from any cause.
  • OS e.g., median OS, is measured in days, weeks, months, or years.
  • administration of the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • OS e.g., median OS, of any of at least about 1.1 fold, at least about 1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 3.5 fold, at least about 4 fold, at least about 4.5 fold, at least about 5 fold, at least about 5.5 fold, or at least about 6 fold, or more, e.g., as compared to administration of an anti- CD20 antibody (e.g., rituximab) and one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin).
  • an anti- CD20 antibody e.g., rituximab
  • OS e.g., the median OS
  • OS can be estimated according to any method known in the art.
  • OS e.g., the median OS
  • Kaplan-Meier methodology estimates of treatment effect are expressed as hazard ratios for death using a stratified Cox proportional-hazards analysis (e.g., including 95% confidence limits).
  • the Brookmeyer-Crowley methodology is used to construct the 95% confidence interval for the median OS.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in an increase in survival of the human, e.g., of any of at least about 1.1 fold, at least about 1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 3.5 fold, at least about 4 fold, at least about 4.5 fold, at least about 5 fold, at least about 5.5 fold, or at least about 6 fold, or more, compared to administration of rituximab, gemcitabine, and oxaliplatin to a corresponding human.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase in overall survival of the humans in the plurality, e.g., median OS, of any of at least about 1.1 fold, at least about 1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 3.5 fold, at least about 4 fold, at least about 4.5 fold, at least about 5 fold, at least about 5.5 fold, or at least about 6 fold, or more, compared to a corresponding plurality of humans administered rituximab, gemcitabine, and oxaliplatin.
  • median OS e.g., median OS
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in a 1 -year overall survival rate of at least about 42% or greater, at least about 45% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of the humans in the plurality.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in a 2-year overall survival rate of at least about 67% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of the humans in the plurality.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in a 3.5-year overall survival rate of at least about 38% or greater, at least about 40% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of the humans in the plurality.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in a 5 -year overall survival rate of at least about 15% or greater, at least about 20% or greater, at least about 30% or greater, at least about 40% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of the humans in the plurality.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase, e.g., of any of at least about 1.1 fold, at least about 1 ,5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 3.5 fold, at least about 4 fold, at least about 4.5 fold, at least about 5 fold, at least about 5.5 fold, or at least about 6 fold, or more, in the 1-year, 2-year, 3.5 -year, or 5 -year overall survival rate compared to a corresponding plurality of humans administered rituximab, gemcitabine, and oxaliplatin.
  • a 1-year overall survival rate refers to the proportion of humans in a plurality of humans administered the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin that do not have an occurrence of death from any cause at 1 year after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • a 2- year overall survival rate refers to the proportion of humans in a plurality of humans administered the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin that do not have an occurrence of death from any cause at 2 years after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • a 3.5 -year overall survival rate refers to the proportion of humans in a plurality of humans administered the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin that do not have an occurrence of death from any cause at 3.5 years after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • a 5- year overall survival rate refers to the proportion of humans in a plurality of humans administered the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin that do not have an occurrence of death from any cause at 5 years after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in progression-free survival of the human.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in progression-free survival of the human for at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 24 months, or at least about 25 months after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the o
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in progression-free survival of the human for at least about 4 months after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin. In some embodiments, administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in progression-free survival of the human for at least about 5 months after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in progression-free survival of the human for at least about 6 months after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin. In some embodiments, administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in progression-free survival of the human for at least about 9.5 months after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in progression-free survival of the human for at least about 11 months after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin. In some embodiments, administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in progression-free survival of the human for at least about 14 months after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • administration of the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • PFS time of progression free survival
  • PFS is measured from the first administration of the immunoconjugate (e.g., polatuzumab vedotin-piiq), the anti-CD20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) to the time of a first occurrence of disease progression according to the Lugano 2014 response criteria (Cheson et al., (2014) J Clin Oncol 32:3059-3068), or death from any cause.
  • PFS is measured in days, weeks, months, or years.
  • administration of the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • an anti-CD20 antibody e.g, rituximab
  • one or more chemotherapeutic agents
  • PFS is calculated using the Kaplan-Meier methodology.
  • estimates of treatment effect are expressed as hazard ratios using a stratified Cox proportional-hazards analysis (e.g., including 95% confidence limits).
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in an increase in progression-free survival, e.g., of any of at least about 1.1 fold, at least about 1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 3.5 fold, at least about 4 fold, at least about 4.5 fold, at least about 5 fold, at least about 5.5 fold, or at least about 6 fold, or more, compared to administration of rituximab, gemcitabine, and oxaliplatin to a corresponding human.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase in progression-free survival (e.g., median progression-free survival) of the humans in the plurality, e.g, of any of at least about 1.1 fold, at least about 1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 3.5 fold, at least about 4 fold, at least about 4.5 fold, at least about 5 fold, at least about 5.5 fold, or at least about 6 fold, or more, compared to the progression-free survival (e.g., median progression-free survival) of a corresponding plurality of humans administered rituximab, gemcitabine, and oxaliplatin.
  • progression-free survival e.g., median progression-free survival
  • progression- free survival is measured from the first administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to the first occurrence of disease progression (based on response including PET CT data or not including any PET data) according to Lugano 2014 response criteria, or death from any cause.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in a 1-year progression-free survival rate of at least about 30% or greater, at least about 40% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of the humans in the plurality.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in a 2-year progression-free survival rate of at least about 63% or greater, at least about 65% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of the humans in the plurality.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in a 5 -year progression-free survival rate of at least about 14% or greater, at least about 15% or greater, at least about 20% or greater, at least about 30% or greater, at least about 40% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of the humans in the plurality.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase, e.g., of any of at least about 1.1 fold, at least about 1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 3.5 fold, at least about 4 fold, at least about 4.5 fold, at least about 5 fold, at least about 5.5 fold, or at least about 6 fold, or more, in the 1-year, 2-year, 3.5 -year, or 5 -year progression-free survival rate compared to a corresponding plurality of humans administered rituximab, gemcitabine, and oxaliplatin.
  • a 1 -year progression-free survival rate refers to the proportion of humans in a plurality of humans administered the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin that do not have an occurrence of disease progression (based on response including PET CT data or not including any PET data) according to Lugano 2014 response criteria, or death from any cause, at 1 year after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • a 2- year progression-free survival rate refers to the proportion of humans in a plurality of humans administered the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin that do not have an occurrence of disease progression (based on response including PET CT data or not including any PET data) according to Lugano 2014 response criteria, or death from any cause, at 2 years after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • a 3.5 -year progression-free survival rate refers to the proportion of humans in a plurality of humans administered the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin that do not have an occurrence of disease progression (based on response including PET CT data or not including any PET data) according to Lugano 2014 response criteria, or death from any cause, at 3.5 years after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • a 5- year progression-free survival rate refers to the proportion of humans in a plurality of humans administered the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin that do not have an occurrence of disease progression (based on response including PET CT data or not including any PET data) according to Lugano 2014 response criteria, or death from any cause, at 5 years after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • OS and PFS are assessed in patients who undergo HSCT.
  • the response to administration of the immunoconjugate e.g polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • the response to administration of the immunoconjugate e.g., polatuzumab vedotin-piiq), the anti-CD20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) according to the methods provided herein is measured by positron emission tomography (PET) and/or computed tomography (CT) scans.
  • PET positron emission tomography
  • CT computed tomography
  • the response to treatment according to the methods provided herein is assessed using the 2014 Lugano Criteria (Cheson et al., (2014) J Clin Oncol 32:3059-3068).
  • the response to treatment according to the methods provided herein is assessed during treatment or at the end of treatment. In some embodiments, the response to treatment according to the methods provided herein is assessed in a patient in comparison to assessments prior to administration of treatment according to the methods provided herein.
  • CT scans are performed every 6 months. In some embodiments, PET scans are performed before and at the end of administration of treatment according to the methods provided herein. In some embodiments, PET and/or CT (e.g., PET-CT) scans include the skull-base to mid-thigh. In some embodiments, full-body PET-CT scans are performed. In some embodiments, CT scans include intravenous contrast, which can include, without limitation, chest, neck, abdomen, and pelvic scans.
  • radiographic assessments of tumors are performed, for example, if disease progression or relapse is suspected.
  • bone response to treatment according to the methods provided herein is assessed using bone marrow biopsies, which can be performed according to any method known in the art.
  • bone marrow biopsies are performed in patients with negative bone signal on PET-CT.
  • PET-CT and/or CT scans are obtained prior to administration of treatment according to the methods provided herein, and as clinically indicated during and after administration of treatment according to the methods provided herein.
  • PET-CT and/or CT scans are performed for up to two years after administration of treatment according to the methods provided herein.
  • a complete response comprises a complete metabolic response based on PET-CT, according to Lugano 2014 response criteria (Cheson et al., (2014) J Clin Oncol 32:3059-3068).
  • administration of the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • results in an increase in the complete response rate (CRR) e.g., as compared to administration of an anti-CD20 antibody (e.g., rituximab) and one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin).
  • CRR refers to the proportion of patients who achieve complete metabolic response at the end of treatment with the immunoconjugate (e.g., polatuzumab vedotin-piiq), the anti-CD20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin), e.g., based on positron emission tomography and computed tomography (PET-CT) analyses according to the Lugano 2014 response criteria.
  • the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • administration of the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti- CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • an anti-CD20 antibody e.g., rituximab
  • the CRR is determined without including PET data.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase in the complete response rate (CRR), e.g., of any of at least about 1.1 fold, at least about 1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 3.5 fold, at least about 4 fold, at least about 4.5 fold, at least about 5 fold, at least about 5.5 fold, or at least about 6 fold, or more, compared to a corresponding plurality of humans administered rituximab, gemcitabine, and oxaliplatin.
  • CRR complete response rate
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in a complete response rate of at least about 35% or greater, at least about 40% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of the humans in the plurality.
  • a partial response comprises a partial metabolic response including PET CT data, according to Lugano 2014 response criteria.
  • administration of the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • ORR objective response rate
  • ORR refers to the proportion of patients who achieve complete or partial metabolic responses at the end of treatment with the immunoconjugate (e.g., polatuzumab vedotin-piiq), the anti-CD20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin), e.g., based on positron emission tomography and computed tomography (PET-CT) analyses according to the Lugano 2014 response criteria.
  • the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • ORR refers to the proportion of patients who achieve complete or partial metabolic responses at the end of treatment with the immunoconjugate (e.g., polatuzumab vedotin-piiq), the anti-CD20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin), e.g., according to the Lugano 2014 response criteria.
  • the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • administration of the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g ., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • an anti-CD20 antibody e.g., rituximab
  • ORR is determined without including PET data.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase in the objective response rate (ORR), e.g., of any of at least about 1.1 fold, at least about 1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 3.5 fold, at least about 4 fold, at least about 4.5 fold, at least about 5 fold, at least about 5.5 fold, or at least about 6 fold, or more, compared to a corresponding plurality of humans administered rituximab, gemcitabine, and oxaliplatin.
  • ORR objective response rate
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an objective response rate of at least about 44% or greater, at least about 45% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of the humans in the plurality.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in a partial response rate of at least about 10% or greater, at least about 20% or greater, at least about 30% or greater, at least about 40% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of the humans in the plurality.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase in the partial response rate, e.g., of any of at least about 1.1 fold, at least about 1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 3.5 fold, at least about 4 fold, at least about 4.5 fold, at least about 5 fold, at least about 5.5 fold, or at least about 6 fold, or more, compared to a corresponding plurality of humans administered rituximab, gemcitabine, and oxaliplatin.
  • the partial response rate refers to the proportion of patients who achieve partial metabolic responses at the end of treatment with the immunoconjugate (e.g., polatuzumab vedotin-piiq), the anti-CD20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin), e.g., based on positron emission tomography and computed tomography (PET-CT) analyses according to the Lugano 2014 response criteria.
  • the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • the partial response rate refers to the proportion of patients who achieve partial metabolic responses at the end of treatment with the immunoconjugate (e.g., polatuzumab vedotin-piiq), the anti-CD20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin), e.g., according to the Lugano 2014 response criteria.
  • the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • administration of the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • BOR best overall response
  • BOR refers to the best response during treatment with the immunoconjugate (e.g., polatuzumab vedotin-piiq), the anti-CD20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin), e.g., based on positron emission tomography and computed tomography (PET-CT) or CT analyses according to the Lugano 2014 response criteria.
  • the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • administration of the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • an anti-CD20 antibody e.g., rituximab
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase in the best overall response rate (BOR), e.g., of any of at least about 1.1 fold, at least about 1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 3.5 fold, at least about 4 fold, at least about 4.5 fold, at least about 5 fold, at least about 5.5 fold, or at least about 6 fold, or more, compared to a corresponding plurality of humans administered rituximab, gemcitabine, and oxaliplatin.
  • BOR overall response rate
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in event-free survival of the human.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in event-free survival of the human for at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 24 months, or at least about 25 months after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the o
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in event-free survival of the human for at least about 4 months after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin. In some embodiments, administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in event-free survival of the human for at least about 5 months after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in event-free survival of the human for at least about 6 months after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin. In some embodiments, administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in event-free survival of the human for at least about 9.5 months after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in event-free survival of the human for at least about 11 months after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin. In some embodiments, administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in event-free survival of the human for at least about 14 months after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • administration of the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • results in an increase in the event-free survival (EFS eff ) time e.g., as compared to administration of an anti- CD20 antibody (e.g., rituximab) and one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin).
  • EFS eff refers to the time from the first administration of the immunoconjugate (e.g., polatuzumab vedotin-piiq), the anti-CD20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) to the time of an occurrence of any of disease progression or relapse, death due to any cause, or initiation of another anti-lymphoma treatment.
  • the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • EFS eff is measured in days, weeks, months, or years.
  • administration of the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • an anti-CD20 antibody e.g., rituximab
  • the methods used for analysis of PFS are used to analyze EFS eff .
  • event-free survival is measured from the time of first administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to the first occurrence of any of (i) Disease progression or relapse (based on response including PET CT data or not including any PET data); (ii) Death due to any cause; or (iii) Initiation of a new anti-lymphoma treatment (NALT).
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin results in an increase in event-free survival of the human, e.g., of any of at least about 1.1 fold, at least about 1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 3.5 fold, at least about 4 fold, at least about 4.5 fold, at least about 5 fold, at least about 5.5 fold, or at least about 6 fold, or more, compared to administration of rituximab, gemcitabine, and oxaliplatin to a corresponding human.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase in event-free survival of the humans in the plurality, e.g., of any of at least about 1.1 fold, at least about 1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 3.5 fold, at least about 4 fold, at least about 4.5 fold, at least about 5 fold, at least about 5.5 fold, or at least about 6 fold, or more, compared to a corresponding plurality of humans administered rituximab, gemcitabine, and oxaliplatin.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in a 2-year event-free survival rate of at least about 44% or greater, at least about 45% or greater, at least about 50% or greater, at least about 60% or greater, at least about 70% or greater, at least about 80% or greater, at least about 90% or greater, at least about 95% or greater, or about 100% of the humans in the plurality.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase in the 1-year, 2-year, 3.5 -year, or 5 -year event-free survival rate, e.g., of any of at least about 1.1 fold, at least about 1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 3.5 fold, at least about 4 fold, at least about 4.5 fold, at least about 5 fold, at least about 5.5 fold, or at least about 6 fold, or more, compared to a corresponding plurality of humans administered rituximab, gemcitabine, and oxaliplatin.
  • a 1-year event-free survival rate refers to the proportion of humans in a plurality of humans administered the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin that do not have an occurrence of any of (i) Disease progression or relapse (based on response including PET CT data or not including any PET data), (ii) Death due to any cause, or (iii) Initiation of a new anti-lymphoma treatment (NALT) at 1 year after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • NALT new anti-lymphoma treatment
  • a 2-year event-free survival rate refers to the proportion of humans in a plurality of humans administered the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin that do not have an occurrence of any of (i) Disease progression or relapse (based on response including PET CT data or not including any PET data), (ii) Death due to any cause, or (iii) Initiation of a new anti-lymphoma treatment (NALT) at 2 years after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • NALT new anti-lymphoma treatment
  • a 3.5 -year event-free survival rate refers to the proportion of humans in a plurality of humans administered the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin that do not have an occurrence of any of (i) Disease progression or relapse (based on response including PET CT data or not including any PET data), (ii) Death due to any cause, or (iii) Initiation of a new anti-lymphoma treatment (NALT) at 3.5 years after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • NALT new anti-lymphoma treatment
  • a 5 -year event-free survival rate refers to the proportion of humans in a plurality of humans administered the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin that do not have an occurrence of any of (i) Disease progression or relapse (based on response including PET CT data or not including any PET data), (ii) Death due to any cause, or (iii) Initiation of a new anti-lymphoma treatment (NALT) at 5 years after the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • NALT new anti-lymphoma treatment
  • event-free survival is measured from the time of first administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin, or from the start of treatment with the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin, to the first occurrence of any of (i) Disease progression or relapse (based on response including PET CT data or not including any PET data); (ii) Death due to any cause; or (iii) Initiation of a new anti-lymphoma treatment (NALT).
  • NALT new anti-lymphoma treatment
  • administration of the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • DOR is measured in patients administered treatment according to the methods provided herein, who have an objective response using the Lugano 2014 Criteria from the date of the first occurrence of a complete or partial response until the first date that progressive disease or death occur. In some embodiments, DOR is measured in days, weeks, months, or years.
  • administration of the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • an anti-CD20 antibody e.g., rituximab
  • the methods used for analysis of PFS are used to analyze DOR, except that DOR analysis is not stratified,
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in an increase in the duration of response (DOR), e.g., of any of at least about 1.1 fold, at least about 1.5 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 3.5 fold, at least about 4 fold, at least about 4.5 fold, at least about 5 fold, at least about 5.5 fold, or at least about 6 fold, or more, compared to a corresponding plurality of humans administered rituximab, gemcitabine, and oxaliplatin.
  • DOR duration of response
  • response to treatment with the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • PRO patient-reported outcome
  • PRO instruments include, without limitation, FACT/GOG-Ntxl2 neuropathy (Kopec et al., (2006) J Supportive Oncol, 4:W1-W8; Calhoun et al., (2003) Int J Gynecol Cancer, 13:741-748), EQ-5D- 5L (EuroQol (1990) Health Policy, 16:199-208; Brooks (1996) Health Policy, 37:53-72;
  • adverse events after administration of the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • NCI CTCAE v5.0 National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5 (NCI CTCAE v5.0), Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity 12-Item Scale (FACT/GOG-Ntxl2), clinical laboratory test results, electrocardiograms (ECG), and/or vital signs.
  • adverse events leading to withdrawal of treatment adverse events leading to dose reduction or interruption, Grade ⁇ 3 adverse events, adverse events leading to death, serious adverse events, and/or adverse events of special interest are analyzed.
  • adverse events as provided herein are analyzed with respect to exposure to the immunoconjugate (e.g., polatuzumab vedotin-piiq), the anti-CD20 antibody (e.g., rituximab), and/or the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin).
  • the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin.
  • occurrences of peripheral neuropathy in patients administered the immunoconjugate e.g ., polatuzumab vedotin-piiq), the anti-CD20 antibody (e.g ., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin), according to the methods provided herein, are assessed by FACT/GOG-Ntxl2 score and/or by NCI CTCAE v5.0.
  • Symptoms of peripheral neuropathy include, but are not limited to hypoesthesia, hyperesthesia, paresthesia, dysesthesia, discomfort, a burning sensation, weakness, gait disturbance, or neuropathic pain.
  • the rate of occurrences of peripheral neuropathy is calculated.
  • all patients with an occurrence of peripheral neuropathy are followed up after termination of treatment according to the methods provided herein until resolution or stabilization.
  • less than 50% e.g., less than any of about 50%, 45%, 40%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%,
  • ⁇ Grade 3 e.g., any of Grade 3 or greater, Grade 4 or greater, or Grade 5 or greater
  • peripheral neuropathy that does not resolve to ⁇ Grade 1 within 14 days (e.g., within any of 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days,
  • ⁇ Grade 3 e.g., any of Grade 3 or greater, Grade 4 or greater, or Grade 5 or greater
  • peripheral neuropathy that does not resolve to ⁇ Grade 1 within 14 days.
  • less than about 33% of patients administered the immunoconjugate e.g., polatuzumab vedotin-piiq), the anti-CD20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g, gemcitabine and oxaliplatin) according to the methods provided herein experience a ⁇ Grade 3 (e.g., any of Grade 3 or greater, Grade 4 or greater, or Grade 5 or greater) peripheral neuropathy that does not resolve to ⁇ Grade 1 within 14 days.
  • a ⁇ Grade 3 e.g., any of Grade 3 or greater, Grade 4 or greater, or Grade 5 or greater
  • ⁇ Grade 3 e.g., any of Grade 3 or greater, Grade 4 or greater, or Grade 5 or greater
  • peripheral neuropathy that does not resolve to ⁇ Grade 1 within 14 days.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin does not result in peripheral neuropathy of Grade 4 or greater (e.g., any of Grade 4 or greater, or Grade 5 or greater) in the human.
  • peripheral neuropathy of Grade 4 or greater e.g., any of Grade 4 or greater, or Grade 5 or greater
  • the human does not experience peripheral neuropathy of Grade 4 or greater (e.g., any of Grade 4 or greater, or Grade 5 or greater).
  • the human after administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin, the human does not experience neurotoxicity of Grade 4 or greater (e.g., any of Grade 4 or greater, or Grade 5 or greater).
  • neurotoxicity refers to sensory and/or motor peripheral neuropathy.
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in 33% or fewer (e.g., any of about 33% or fewer, about 32% or fewer, about 31% or fewer, about 30% or fewer, about 29% or fewer, about 28% or fewer, about 27% or fewer, about 26% or fewer, about 25% or fewer, about 24% or fewer, about 23% or fewer, about 22% or fewer, about 21% or fewer, about 20% or fewer, about 19% or fewer, about 18% or fewer, about 17% or fewer, about 16% or fewer, about 15% or fewer, about 14% or fewer, about 13% or fewer, about 12% or fewer, about 11% or fewer, about 10% or fewer, about 9% or fewer, about 8% or fewer, about 7% or fewer, about 6% or fewer, about 5% or fewer,
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to a plurality of humans results in less than about 40% (e.g., less than any of about 40%, 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or 0.5%) of the humans in the plurality experiencing peripheral neuropathy of Grade 3 or greater (e.g., any of Grade 3 or greater, Grade 4 or greater, or Grade 5 or greater) that does not resolve to Grade 1 or lower within 14 days (e.g., within any of 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days
  • occurrences of drug-induced liver injury are assessed.
  • the immunogenicity of the immunoconjugate when administered according to the methods provided herein is assessed.
  • the immunogenicity of the immunoconjugate when administered according to the methods provided herein is assessed by measuring anti-drug antibodies (ADA) against the immunoconjugate.
  • ADA anti-drug antibodies
  • AD are measured using a validated antibody-bridging enzyme-linked immunosorbent assay (ELISA) in patient serum samples.
  • ELISA antibody-bridging enzyme-linked immunosorbent assay
  • the incidence of adverse events in patients administered the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • the incidence of adverse events in patients administered the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • the doses of the immunoconjugate e.g, polatuzumab vedotin- piiq
  • the anti-CD20 antibody e.g. , rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • adverse events are based on laboratory test results obtained within 72 hours before infusion of Day 1 of a cycle.
  • symptoms are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5 (NCI CTCAE v5.0).
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin does not result in neutropenia in the human.
  • the methods provided herein further comprise administering a prophylactic treatment for neutropenia to the human before, during, and/or after administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to the human.
  • the prophylactic treatment for neutropenia comprises administration of G-CSF, e.g., in each cycle of treatment.
  • Grade 3 or Grade 4 neutropenia if Grade 3 or Grade 4 neutropenia occurs, treatment with the immunoconjugate (e.g., polatuzumab vedotin-piiq), the anti-CD20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) is held until absolute neutrophil count (ANC) recovers to >1 OOO/ ⁇ L.
  • chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • growth factors e.g., G-CSF
  • G-CSF are administered if necessary to manage neutropenia. See, e.g., G-CSF
  • treatment with the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • the dose of polatuzumab vedotin-piiq is reduced to 1.4 mg/kg if ANC recovers to > 1000/ ⁇ L in the human after Day 7.
  • a prior dose reduction of polatuzumab vedotin-piiq has occurred, treatment with the immunoconjugate (e.g., polatuzumab vedotin-piiq), the anti-CD20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) is discontinued.
  • the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • treatment with the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • the dose of polatuzumab vedotin-piiq is reduced to 1.4 mg/kg if platelets recover to > 75,000/ ⁇ L after Day 7.
  • a prior dose reduction of polatuzumab vedotin-piiq has occurred, treatment with the immunoconjugate (e.g., polatuzumab vedotin-piiq), the anti-CD20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) is discontinued.
  • the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • treatment with the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • treatment with the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • treatment with polatuzumab vedotin-piiq alone is discontinued if the Grade 2 or Grade 3 peripheral neuropathy does not recover to Grade ⁇ 1 on or before Day 14 if the patient previously had Grade 2 peripheral neuropathy and/or if a prior dose reduction to 1.4 mg/kg for polatuzumab vedotin-piiq or 75 mg/m 2 for oxaliplatin occurred.
  • treatment is discontinued if the subject had a previous Grade 3 peripheral neuropathy.
  • oxaliplatin and polatuzumab vedotin-piiq are permanently discontinued if the Grade 2 or Grade 3 peripheral neuropathy does not recover to ⁇ Grade 1 until > 14 days or after the scheduled date for the next cycle.
  • treatment with the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • oxaliplatin infusion is prolonged to 6 hours.
  • infusion is slowed or held.
  • subjects are given supportive treatment.
  • supportive treatment includes acetaminophen/paracetamol and an antihistamine such as diphenhydramine and/or intravenous saline.
  • supportive treatment for bronchospasm, urticaria, or dyspnea includes antihistamines, oxygen, corticosteroids (e.g.,
  • infusion-rate escalation is resumed upon resolution of symptoms.
  • infusion rate escalation after re-initiation upon complete resolution of symptoms the infusion is resumed at 50% of the rate achieved prior to interruption.
  • the rate of infusion is escalated in increments of 50 mg/hour every 30 minutes.
  • polatuzumab vedotin is infused over 90 minutes in the next cycle.
  • polatuzumab vedotin if no infusion-related reaction occurs, subsequent infusions of polatuzumab vedotin are administered over 30 minutes. In some embodiments, premedication is administered for all cycles. In some embodiments, if wheezing or urticaria symptoms recur, treatment with the immunoconjugate (e.g., polatuzumab vedotin-piiq), the anti-CD20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) is discontinued.
  • the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • infusion is discontinued.
  • subjects are given supportive treatmnet.
  • supportive treatment includes acetaminophen/paracetamol and an antihistamine such as diphenhydramine and/or intravenous saline.
  • supportive treatment for bronchospasm, urticaria, or dyspnea includes antihistamines, oxygen, corticosteroids (e.g., 100 mg IV prednisolone or equivalent), and/or bronchodilators.
  • corticosteroids e.g., 100 mg IV prednisolone or equivalent
  • the infusion is resumed at 50% of the rate achieved prior to interruption.
  • the rate of infusion is escalated in increments of 50 mg/hour every 30 minutes.
  • treatment with the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • a Grade 4 IRR occurs, treatment with the immunoconjugate (e.g., polatuzumab vedotin-piiq), the anti-CD20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) is discontinued.
  • the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • treatment with the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • hepatic transaminase > 3 x baseline and an increase in direct bilirubin > 2 x ULN without any findings of cholestasis or jaundice or signs of hepatic dysfunction and in the absence of other contributory factors (e.g., worsening of metastatic disease or concomitant exposure to known hepatotoxic agent or of a documented infectious etiology) are observed, treatment with the immunoconjugate (e.g., polatuzumab vedotin-piiq), the anti-CD20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) is discontinued.
  • the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin does not result in tumor lysis syndrome in the human.
  • the methods provided herein further comprise administering a prophylactic treatment for tumor lysis syndrome to the human before, during, and/or after administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to the human.
  • the prophylactic treatment comprises hydration, e.g., 3 liters of fluids per day, e.g., starting at about 1 or 2 days prior to administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • the prophylactic treatment comprises allopurinol (e.g., 300 mg/day orally) or a suitable alternative treatment (e.g., rasburicase), starting at about 48 to about 72 hours prior to administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • the prophylactic treatment comprises hydration, e.g., 3 liters of fluids per day, e.g., starting at about 1 or 2 days prior to administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin; and allopurinol (e.g., 300 mg/day orally) or a suitable alternative treatment (e.g., rasburicase), starting at about 48 to about 72 hours prior to administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • hydration e.g., 3 liters of fluids per day, e.g., starting at about 1 or 2 days prior to administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin
  • allopurinol e.g., 300 mg/day orally
  • a suitable alternative treatment e.g., r
  • the prophylactic treatment for tumor lysis syndrome is administered to the human if the human has a risk of tumor lysis syndrome, e.g., if the human has a high tumor burden (e.g., lymphocyte count ⁇ 25 x 10 9 /L or bulky lymphadenopathy).
  • the prophylactic treatment for tumor lysis syndrome is administered prior to each administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin.
  • Grade 3 or Grade 4 tumor lysis syndrome occurs, treatment with the immunoconjugate (e.g., polatuzumab vedotin-piiq), the anti-CD20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) is held.
  • the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • the next dose is delayed for up to 14 days.
  • treatment with the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin does not result in an infection in the human.
  • the infection is a pneumocystis infection or a herpesvirus infection.
  • the methods provided herein further comprise administering a prophylactic treatment for infections to the human before, during, and/or after administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to the human.
  • the prophylactic treatment for infections comprises one or more suitable anti-viral medications.
  • the human is administered a prophylactic treatment for hepatitis B reactivation, e.g., as described in Flowers et al., 2013; National Comprehensive Cancer Network (NCCN) 2017.
  • the immunoconjugate e.g. , polatuzumab vedotin- piiq
  • the anti-CD20 antibody e.g. , rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • treatment with the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • treatment with the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • previous doses of treatment with the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin does not result in Hepatitis B reactivation in the human.
  • the methods provided herein further comprise administering a prophylactic treatment for Hepatitis B reactivation to the human before, during, and/or after administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin to the human.
  • the prophylactic treatment for Hepatitis B reactivation comprises an anti-viral medication, e.g., as described in in Flowers et al., 2013; National Comprehensive Cancer Network (NCCN) 2017.
  • the methods provided herein further comprise administering anti-viral medication to the human if Hepatitis B reactivation is detected in the human, e.g., a suitable nucleoside analogue.
  • Hepatitis B reactivation is determiend by new detectable HBV-DNA levels.
  • HBV-DNA levels are between the World Health Organization (WHO) -recommended range of 29 IU/mL and 100 IU/mL, HBV-DNA levels are retested within 2 weeks.
  • WHO World Health Organization
  • treatment with the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • the subject is treated with a nucleoside analogue if HBV-DNA levels are positive.
  • HBV-DNA levels at the WHO-recommended cutoff of > 100 IU/mL are observed, treatment with the immunoconjugate (e.g., polatuzumab vedotin-piiq), the anti-CD20 antibody (e.g., rituximab), and the one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) is held and a nucleoside analogue is administered.
  • the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • the immunoconjugate e.g., polatuzumab vedotin-piiq
  • the anti-CD20 antibody e.g., rituximab
  • the one or more chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • administration of the immunoconjugate, the rituximab, the gemcitabine, and the oxaliplatin does not result in one or more adverse events selected from the group consisting of drug-induced liver injury, progressive multifocal leukoencephalopathy, systemic hypersensitivity reaction, anaphylactic reaction, anaphylactoid reaction, and second malignancy.
  • drug-induced liver injury comprises elevated ALT or AST in combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's Law, in the human.
  • drug-induced liver injury comprises treatment-emergent ALT or AST > 3 x baseline value in combination with total bilirubin > 2 x ULN (of which ⁇ 35% is direct bilirubin) in the human.
  • drug-induced liver injury comprises treatment-emergent ALT or AST > 3 x baseline value in combination with clinical jaundice in the human.
  • systemic hypersensitivity reactions, anaphylactic reactions, and anaphylactoid reactions are assessed using Sampson’s criteria.
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-Hlthat comprises 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 wherein p is between 1 and 8 for use in a method of treating diffuse large B-cell lymphoma (DLBCL, e.g., relapsed/refractory DLBCL), in an individual (a human individual) in need thereof.
  • DLBCL diffuse large B-cell lymphoma
  • the immunoconjugate is for use according to any of the methods provided herein.
  • the immunoconjugate comprises an anti-CD79b antibody comprising (i) a VH comprising the amino acid sequence of SEQ ID NO: 19 and (ii) a VL comprising the amino acid sequence of SEQ ID NO: 20.
  • the immunoconjugate is polatuzumab vedotin-piiq.
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody comprising (i) an HVR-Hlthat comprises 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 wherein p is between 1 and 8 in the manufacture of a medicament for treating diffuse large B-cell lymphoma (DLBCL, e.g., relapsed/refractory DLBCL), in an individual (a human individual) in need thereof, wherein the medicament is for (e.g., formulated for) administration
  • DLBCL diffuse large B
  • the medicament i.e., the medicament comprising the immunoconjugate
  • the immunoconjugate comprises an anti-CD79b antibody comprising (i) a VH comprising the amino acid sequence of SEQ ID NO: 19 and (ii) a VL comprising the amino acid sequence of SEQ ID NO: 20.
  • the immunoconjugate is polatuzumab vedotin-piiq.
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody that comprises (i) a VH comprising the amino acid sequence of SEQ ID NO: 19 and (ii) a VL comprising the amino acid sequence of SEQ ID NO: 20, and wherein p is between 2 and 5, for use in a method of treating diffuse large B-cell lymphoma (DLBCL, e.g., relapsed/reffactory DLBCL), in an individual (a human individual) in need thereof, the method comprising administering to the individual an effective amount of (a) the immunoconjugate, (b) rituximab (c) one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin), wherein the immunoconjugate is administered at a dose between about 1.4 and about 1.8 mg/kg, the rituximab is administered at a dose 375 mg/m 2 , and the one or more chemotherapeutic agents are administered
  • DLBCL
  • the immunoconjugate is for use according to a method described herein. In some embodiments, p is between 3 and 4. In some embodiments, p is 3.5. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 36 and a light chain comprising the amino acid sequence of SEQ ID NO: 35. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody that 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.
  • the immunoconjugate comprises an anti- CD79b antibody that 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.
  • the immunoconjugate is polatuzumab vedotin-piiq.
  • an immunoconjugate comprising the formula wherein Ab is an anti-CD79b antibody that comprises (i) a VH comprising the amino acid sequence of SEQ ID NO: 19 and (ii) a VL comprising the amino acid sequence of SEQ ID NO: 20, and wherein p is between 2 and 5, for use in the manufacture of a medicament for treating diffuse large B-cell lymphoma (DLBCL, e.g., relapsed/refractory DLBCL), in an individual (a human individual) in need thereof, wherein the medicament is for (e.g.
  • DLBCL diffuse large B-cell lymphoma
  • rituximab formulated for administration in combination with rituximab, and one or more chemotherapeutic agents (e.g., gemcitabine and oxaliplatin) wherein the medicament is formulated for administration of the immunoconjugate at a dose between about 1.4 and about 1.8 mg/kg, the rituximab is for administration at a dose of 375 mg/m 2 , and the one or more chemotherapeutic agents are for administration at a dose of 50-2000 mg/m 2 (e.g., gemcitabine administered at a dose of 1000 mg/m 2 and oxaliplatin administered at a dose of 100 mg/m 2 ).
  • chemotherapeutic agents e.g., gemcitabine and oxaliplatin
  • the medicament i.e., the medicament comprising the immunoconjugate
  • p is between 3 and 4. In some embodiments, p is 3.5.
  • the immunoconjugate comprises an anti-CD79b antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 36 and a light chain comprising the amino acid sequence of SEQ ID NO: 35. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody that 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.
  • the immunoconjugate comprises an anti- CD79b antibody that 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.
  • the immunoconjugate is polatuzumab vedotin-piiq.
  • Immunoconjugates Comprising an Anti-CD79b Antibody and a Drug / Cytotoxic Agent (“Anti-CD 79b Immunoconjugates ”)
  • the anti-CD79b immunoconjugate comprises an anti-CD79b antibody (Ab) which targets a cancer cell (such as a diffuse large B-cell lymphoma (DLBCL) cell), a drug moiety (D), and a linker moiety (L) that attaches Ab to D.
  • a cancer cell such as a diffuse large B-cell lymphoma (DLBCL) cell
  • D drug moiety
  • L linker moiety
  • the anti-CD79b antibody is attached to the linker moiety (L) through one or more amino acid residues, such as lysine and/or cysteine.
  • the immunoconjugate comprises the formula Ab-(L-D)p, wherein: (a) Ab is the anti-CD79b antibody; (b) L is a linker; (c) D is a cytotoxic agent; and (d) p ranges from 1-8.
  • An exemplary anti-CD79b immunoconjugate comprises Formula I:
  • the number of drug moieties that can be conjugated to the anti-CD79b antibody is limited by the number of free cysteine residues.
  • free cysteine residues are introduced into the antibody amino acid sequence by the methods described elsewhere herein.
  • Exemplary anti-CD79b immunoconjugates of Formula I comprise, but are not limited to, anti-CD79b antibodies that comprise 1, 2, 3, or 4 engineered cysteine amino acids (Lyon, R. et al (2012) Methods in Enzym. 502:123-138).
  • one or more free cysteine residues are already present in the anti-CD79b antibody, without the use of engineering, in which case the existing free cysteine residues may be used to conjugate the anti-CD79b antibody to the drug / cytotoxic agent.
  • the anti-CD79b antibody is exposed to reducing conditions prior to conjugation of the antibody to the drug / cytotoxic agent in order to generate one or more free cysteine residues.
  • a “linker” (L) is a bifunctional or multifunctional moiety that can be used to link one or more drug moieties (D) to the anti-CD79b antibody (Ab) to form an anti-CD79b immunoconjugate of Formula I.
  • anti-CD79b immunoconjugate can be prepared using a linker having reactive functionalities for covalently attaching to the drug and to the anti-CD79b antibody.
  • a cysteine thiol of the anti-CD79b antibody (Ab) can form a bond with a reactive functional group of a linker or a drug-linker intermediate to make the anti-CD79b immunoconjugate.
  • a linker has a functionality that is capable of reacting with a free cysteine present on the anti-CD79b antibody to form a covalent bond.
  • exemplary reactive functionalities include, without limitation, e.g., maleimide, haloacetamides, ⁇ -haloacetyl, activated esters such as succinimide esters, 4-nitrophenyl esters, pentafluorophenyl esters, tetrafluorophenyl esters, anhydrides, acid chlorides, sulfonyl chlorides, isocyanates, and isothiocyanates.
  • a linker has a functionality that is capable of reacting with an electrophilic group present on the anti-CD79b antibody.
  • electrophilic groups include, without limitation, e.g. , aldehyde and ketone carbonyl groups.
  • a heteroatom of the reactive functionality of the linker can react with an electrophilic group on an antibody and form a covalent bond to an antibody unit.
  • exemplary reactive functionalities include, but are not limited to, e.g. , hydrazide, oxime, amino, hydrazine, thiosemicarbazone, hydrazine carboxylate, and arylhydrazide.
  • the linker comprises one or more linker components.
  • exemplary linker components include, e.g., 6-maleimidocaproyl (“MC”), maleimidopropanoyl (“MP”), valine-citrulline (“val-cit” or “vc”), alanine-phenylalanine (“ala-phe”), p- aminobenzyloxycarbonyl (a “PAB”), N-Succinimidyl 4-(2-pyridylthio) pentanoate (“SPP”), and 4-(N-maleimidomethyl) cyclohexane- 1 carboxylate (“MCC”),
  • MC 6-maleimidocaproyl
  • MP maleimidopropanoyl
  • val-cit valine-citrulline
  • alanine-phenylalanine ala-phe
  • PAB p- aminobenzyloxycarbonyl
  • SPP N-Succinimidyl 4-(2-pyridy
  • the linker is a “cleavable linker,” facilitating release of a drug.
  • Nonlimiting exemplary cleavable linkers include acid-labile linkers (e.g., comprising hydrazone), protease-sensitive (e.g., peptidase-sensitive) linkers, photolabile linkers, or disulfide-containing linkers (Chari et al., Cancer Research 52:127-131 (1992); US 5208020).
  • a linker (L) has the following Formula II:
  • A is a “stretcher unit,” and a is an integer from 0 to 1 ; W is an “amino acid unit,” and w is an integer from 0 to 12; Y is a “spacer unit,” and y is 0, 1, or 2; and Ab, D, and p are defined as above for Formula I.
  • Exemplary embodiments of such linkers are described in U.S. Patent No. 7,498,298, which is expressly incorporated herein by reference.
  • a linker component comprises a “stretcher unit” that links an antibody to another linker component or to a drug moiety.
  • stretcher units are shown below (wherein the wavy line indicates sites of covalent attachment to an antibody, drug, or additional linker components):
  • a linker component comprises an “amino acid unit.”
  • the amino acid unit allows for cleavage of the linker by a protease, thereby facilitating release of the drug /cytotoxic agent from the anti-CD79b immunoconjugate upon exposure to intracellular proteases, such as lysosomal enzymes (Doronina et al. (2003) Nat. Biotechnol. 21:778-784).
  • Exemplary amino acid units include, but are not limited to, dipeptides, tripeptides, tetrapeptides, and pentapeptides.
  • Exemplary dipeptides include, but are not limited to, valine-citrulline (vc or val-cit), alanine-phenylalanine (af or ala-phe); phenylalanine-lysine (fk or phe-lys); phenylalanine-homolysine (phe-homolys); and N -methyl-valine-citmlline (Me-val- cit).
  • Exemplary tripeptides include, but are not limited to, glycine-valine-citmlline (gly-val-cit) and glycine-glycine-glycine (gly-gly-gly).
  • amino acid unit may comprise amino acid residues that occur naturally and/or minor amino acids and/or non-naturally occurring amino acid analogs, such as citrulline.
  • Amino acid units can be designed and optimized for enzymatic cleavage by a particular enzyme, for example, a tumor-associated protease, cathepsin B, C and D, or a plasmin protease.
  • a linker component comprises a “spacer” unit that links the antibody to a drug moiety, either directly or through a stretcher unit and/or an amino acid unit.
  • a spacer unit may be “self-immolative” or a “non-self-immolative.”
  • a “non-self-immolative” spacer unit is one in which part or all of the spacer unit remains bound to the drug moiety upon cleavage of the ADC.
  • non-self-immolative spacer units include, but are not limited to, a glycine spacer unit and a glycine-glycine spacer unit,
  • enzymatic cleavage of an ADC containing a glycine-glycine spacer unit by a tumor-cell associated protease results in release of a glycine-glycine-drug moiety from the remainder of the ADC.
  • the glycine-glycine-drug moiety is subjected to a hydrolysis step in the tumor cell, thus cleaving the glycine-glycine spacer unit from the drug moiety.
  • a “self-immolative” spacer unit allows for release of the drug moiety.
  • a spacer unit of a linker comprises a p-aminobenzyl unit.
  • a p-aminobenzyl alcohol is attached to an amino acid unit via an amide bond, and a carbamate, methylcarbamate, or carbonate is made between the benzyl alcohol and the drug (Hamann et al. (2005) Expert Opin. Ther. Patents (2005) 15:1087-1103).
  • the spacer unit is p-aminobenzyloxycarbonyl (PAB).
  • an anti-CD79b immunoconjugate comprises a self-immolative linker that comprises the structure: wherein Q is -C 1 -C 8 alkyl, -O-(C 1 -C 8 alkyl), -halogen, -nitro, or -cyno; m is an integer ranging from 0 to 4; and p ranges from 1 to about 20. In some embodiments, p ranges from 1 to 10, 1 to 7, 1 to 5, or 1 to 4.
  • self-immolative spacers include, but are not limited to, aromatic compounds that are electronically similar to the PAB group, such as 2-aminoimidazol-5-methanol derivatives (U.S. Patent No. 7,375,078; Hay et al. (1999) Bioorg. Med. Chem. Lett. 9:2237) and ortho- or para-aminobenzylacetals.
  • spacers can be used that undergo cyclization upon amide bond hydrolysis, such as substituted and unsubstituted 4-aminobutyric acid amides (Rodrigues et al (1995) Chemistry Biology 2:223), appropriately substituted bicyclo[2.2.1] and bicyclo[2.2.2] ring systems (Storm et al (1972) J. Amer. Chem. Soc. 94:5815) and 2 -aminophenylpropionic acid amides (Amsberry, et al (1990) J. Org. Chem. 55:5867).
  • Linkage of a drug to the a-carbon of a glycine residue is another example of a self-immolative spacer that may be useful in ADC (Kingsbury et al (1984) J. Med. Chem. 27:1447).
  • linker L may be a dendritic type linker for covalent attachment of more than one drug moiety to an antibody through a branching, multifunctional linker moiety
  • Dendritic linkers can increase the molar ratio of drug to antibody, i.e. loading, which is related to the potency of the ADC.
  • an antibody bears only one reactive cysteine thiol group, a multitude of drug moieties may be attached through a dendritic linker.
  • Nonlimiting exemplary linkers are shown below in the context of an anti-CD79 immunoconjugates of Formulas III, IV, V : wherein (Ab) is an anti-CD79b antibody, (D) is a drug / cytotoxic agent, “Val-Cit” is a valine- citrulline dipeptide, MC is 6-maleimidocaproyl, PAB is p-aminobenzyloxycarbonyl, and p is 1 to about 20 (e.g., 1 to 15, 1 to 10, 1 to 8, 2 to 5, or 3 to 4).
  • the anti-CD79b immunoconjugate comprises a structure of any one of formulas VI-V below :
  • each R is independently H or Ci-C 6 alkyl; and n is 1 to 12.
  • peptide-type linkers can be prepared by forming a peptide bond between two or more amino acids and/or peptide fragments.
  • Such peptide bonds can be prepared, for example, according to a liquid phase synthesis method (e.g., E. Schroder and K. Liibke (1965) “The Peptides”, volume 1, pp 76-136, Academic Press).
  • a linker is substituted with groups that modulate solubility and/or reactivity.
  • a charged substituent such as sulfonate (-SO3-) or ammonium may increase water solubility of the linker reagent and facilitate the coupling reaction of the linker reagent with the antibody and/or the drug moiety, or facilitate the coupling reaction of Ab-L (anti-CD79b antibody-linker intermediate) with D, or D-L (drug / cytotoxic agent-linker intermediate) with Ab, depending on the synthetic route employed to prepare the anti-CD79b immunoconjugate.
  • a charged substituent such as sulfonate (-SO3-) or ammonium may increase water solubility of the linker reagent and facilitate the coupling reaction of the linker reagent with the antibody and/or the drug moiety, or facilitate the coupling reaction of Ab-L (anti-CD79b antibody-linker intermediate) with D, or D-L (drug / cytotoxic agent-linker intermediate)
  • a portion of the linker is coupled to the antibody and a portion of the linker is coupled to the drug, and then the anti-CD79 Ab-(linker portion) 3 is coupled to drug / cytotoxic agent-(linker portion) b to form the anti-CD79b immunoconjugate of Formula I.
  • the anti-CD79b antibody comprises more than one (linker portion) 3 substituents, such that more than one drug / cytotoxic agent is coupled to the anti-CD79b antibody in the anti-CD79b immunoconjugate of Formula I.
  • anti-CD79b immunoconjugates expressly contemplate, but are not limited to, anti-CD79b immunoconjugates prepared with the following linker reagents: bis- maleimido-trioxyethylene glycol (BMPEO), N-( ⁇ -maleimidopropyloxy)-N-hydroxy succinimide ester (BMPS), N-( ⁇ -maleimidocaproyloxy) succinimide ester (EMCS), ⁇ -[ ⁇ - maleimidobutyryloxy] succinimide ester (GMBS), 1,6-hexane-bis-vinylsulfone (HBVS), succinimidyl 4-(N-maleimidomethyl)cyclohexane-l-carboxy-(6-amidocaproate) (LC-SMCC), m- maleimidobenzoyl-N-hydroxysuccinimide ester (MBS), 4-(4-N-Maleimidophenyl)butyric acid hydr
  • BMPEO bis-
  • bis-maleimide reagents allow the attachment of the thiol group of a cysteine in the antibody to a thiol-containing drug moiety, linker, or linker-drug intermediate.
  • Other functional groups that are reactive with thiol groups include, but are not limited to, iodoacetamide, bromoacetamide, vinyl pyridine, disulfide, pyridyl disulfide, isocyanate, and isothiocyanate.
  • Certain useful linker reagents can be obtained from various commercial sources, such as Pierce Biotechnology, Inc. (Rockford, IL), Molecular Biosciences Inc. (Boulder, CO), or synthesized in accordance with procedures described in the art; for example, in Toki et al (2002) J. Org. Chem. 67:1866-1872; Dubowchik, et al. (1997) Tetrahedron Letters, 38:5257-60; Walker, M.A. (1995) J. Org. Chem. 60:5352-5355; Frisch et al (1996) Bioconjugate Chem. 7:180-186;
  • Carbon- 14-labeled l-isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid is an exemplary chelating agent for conjugation of radionucleotide to the antibody. See, e.g., WO94/11026.
  • the immunoconjugate (e.g., anti-CD79b immunoconjugate) comprises an anti-CD79b antibody that comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (d) HVR-L1 comprising an amino acid sequence of SEQ ID NO:
  • the immunoconjugate comprises an anti-CD79b antibody comprising at least one of: (i) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23, and/or (ii) HVR-L1 comprising an amino acid sequence of SEQ ID NO: 24.
  • the immunoconjugate comprises an anti-CD79b antibody comprising at least one of: (i) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23, and/or (ii) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24.
  • the immunoconjugate comprises an anti-CD79b antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23.
  • the immunoconjugate comprises an anti-CD79b antibody that comprises an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23.
  • the immunoconjugate comprises an anti-CD79b antibody that comprises an HVR- H3 comprising the amino acid sequence of SEQ ID NO: 23 and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26.
  • the immunoconjugate comprises an anti-CD79b antibody that comprises an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23, an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26, and an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22.
  • the immunoconjugate comprises an anti-CD79b antibody that comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23.
  • the immunoconjugate comprises an anti-CD79b antibody comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising an amino acid sequence of SEQ ID NO: 24; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26.
  • the immunoconjugate comprises an anti-CD79b antibody that comprises at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26.
  • the immunoconjugate comprises (a) HVR-L1 comprising an amino acid sequence of SEQ ID NO: 24; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26.
  • the immunoconjugate comprises an anti-CD79b antibody that comprises an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24
  • the immunoconjugate comprises an anti-CD79b antibody that comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26.
  • the immunoconjugate comprises an anti-CD79b antibody comprising (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22, and (iii) HVR-H3 comprising an amino acid sequence selected from SEQ ID NO:23; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising an amino acid sequence of SEQ ID NO: 24, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25, and (iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26.
  • the immunoconjugate comprises an anti-CD79b antibody that comprises at least one of: (i) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23, and/or (ii) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24.
  • the immunoconjugate comprises an anti-CD79b antibody that comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (d) HVR-L1 comprising an amino acid sequence of SEQ ID NO: 24; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26 (See, Table A).
  • the immunoconjugate comprises at least one of: HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23 and/or HVR-L1 comprising an amino acid sequence of SEQ ID NO: 24 (See, Table A).
  • the immunoconjugate comprises an anti-CD79b antibody that comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26 (See, Table A).
  • the immunoconjugate comprises an anti-CD79b antibody that comprises, according to numbering in Rabat et al., the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of the anti-CD79b antibody in polatuzumab vedotin-piiq.
  • the anti-CD79b immunoconjugate comprises a humanized anti-CD79b antibody.
  • an anti-CD79b antibody comprises HVRs as in any of the embodiments provided herein, and further comprises a human acceptor framework, e.g., a human immunoglobulin framework or a human consensus framework.
  • the human acceptor framework is the human VL kappa 1 (VL KI ) framework and/or the VH framework VH III .
  • a humanized anti-CD79b antibody comprises (a) HVR- H1 comprising the amino acid sequence of SEQ ID NO: 21; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (d) HVR-L1 comprising an amino acid sequence of SEQ ID NO: 24; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26.
  • the immunoconjugate comprises an anti-CD79b antibody that comprises at least one, two, three, four, five, six, seven, or eight framework regions (FRs) selected from (a) a heavy chain FR (HC FR) 1 comprising the amino acid sequence of SEQ ID NO: 27; (b) an HC FR2 comprising the amino acid sequence of SEQ ID NO: 28; (c) an HC FR3 comprising the amino acid sequence of SEQ ID NO: 29; (d) an HC FR4 comprising an amino acid sequence of SEQ ID NO: 30; (e) a light chain FR (LC FR) 1 comprising the amino acid sequence of SEQ ID NO: 31; (f) an LC FR2 comprising the amino acid sequence of SEQ ID NO: 32; (g) an LC FR3 comprising the amino acid sequence of SEQ ID NO: 33; and (h) an LC FR4 comprising the amino acid sequence of SEQ ID NO: 34 (See, Table B).
  • FRs framework regions
  • the immunoconjugate comprises an anti-CD79b antibody that comprises at least one, at least two, at least three, or all four HC FR sequences selected from (a) an HC FR1 comprising the amino acid sequence of SEQ ID NO: 27; (b) an HC FR2 comprising the amino acid sequence of SEQ ID NO: 28; (c) an HC FR3 comprising the amino acid sequence of SEQ ID NO: 29; and (d) an HC FR4 comprising an amino acid sequence of SEQ ID NO: 30.
  • the immunoconjugate comprises an anti-CD79b antibody that comprises at least one, at least two, at least three, or all four LC FR sequences selected from (a) an LC FR1 comprising the amino acid sequence of SEQ ID NO: 31; (b) an LC FR2 comprising the amino acid sequence of SEQ ID NO: 32; (c) an LC FR3 comprising the amino acid sequence of SEQ ID NO: 33; and (d) an LC FR4 comprising the amino acid sequence of SEQ ID NO: 34.
  • the immunoconjugate comprises an anti-CD79b antibody that comprises (a) an HC FR 1 comprising the amino acid sequence of SEQ ID NO: 27; (b) an HC FR2 comprising the amino acid sequence of SEQ ID NO: 28; (c) an HC FR3 comprising the amino acid sequence of SEQ ID NO: 29; and (d) an HC FR4 comprising the amino acid sequence of SEQ ID NO: 30.
  • the immunoconjugate comprises an anti-CD79b antibody that comprises (a) an LC FR1 comprising the amino acid sequence of SEQ ID NO: 31 ; (b) an LC FR2 comprising the amino acid sequence of SEQ ID NO: 32; (c) an LC FR3 comprising the amino acid sequence of SEQ ID NO: 33; and (d) an LC FR4 comprising the amino acid sequence of SEQ ID NO: 34.
  • the immunoconjugate comprises an anti-CD79b antibody that comprises (a) a VH domain comprising at least one, at least two, at least three, or all four HC FR sequences selected from (i) an HC FR1 comprising the amino acid sequence of SEQ ID NO: 27; (ii) an HC FR2 comprising the amino acid sequence of SEQ ID NO: 28; (iii) an HC FR3 comprising the amino acid sequence of SEQ ID NO: 29; and (iv) an HC FR4 comprising an amino acid sequence of SEQ ID NO: 30; and (b) a VL domain comprising at least one, at least two, at least three, or all four LC FR sequences selected from (i) an LC FR1 comprising the amino acid sequence of SEQ ID NO: 31; (ii) an LC FR2 comprising the amino acid sequence of SEQ ID NO: 32; (iii) an LC FR3 comprising the amino acid sequence of SEQ
  • the immunoconjugate comprises an anti-CD79b antibody that comprises (a) an HC FR1 comprising the amino acid sequence of SEQ ID NO: 27; (b) an HVR- H1 comprising the amino acid sequence of SEQ ID NO: 21; (c) an HC FR2 comprising the amino acid sequence of SEQ ID NO: 28; (d) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22; (e) an HC FR3 comprising the amino acid sequence of SEQ ID NO: 29; (f) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23; (g) an HC FR4 comprising the amino acid sequence of SEQ ID NO: 30; (h) an LC FR1 comprising the amino acid sequence of SEQ ID NO: 31; (i) an HVR-L1 comprising an amino acid sequence of SEQ ID NO: 24; (j) an LC FR2 comprising the amino acid sequence of SEQ ID NO: 32; (k
  • Table B Heavy Chain and Light Chain Framework Region Amino Acid Sequences.
  • the immunoconjugate (e.g., the anti-CD79b immunoconjugate) comprises an anti-CD79b antibody comprising a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 19.
  • VH heavy chain variable domain
  • a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of SEQ ID NO: 19 contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-CD79b immunoconjugate comprising that sequence retains the ability to bind to CD79b.
  • a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO: 19.
  • a total of 1 to 5 amino acids have been substituted, inserted and/or deleted in SEQ ID NO: 19.
  • the immunoconjugate (e.g., the anti-CD79b immunoconjugate) comprises the VH sequence of SEQ ID NO: 19, including post-translational modifications of that sequence.
  • the VH comprises one, two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17 or SEQ ID NO: 23.
  • the immunoconjugate (e.g., the anti-CD79b immunoconjugate) comprises an anti-CD79b antibody that comprises a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 20.
  • VL light chain variable domain
  • a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of SEQ ID NO: 20 contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-CD79b immunoconjugate comprising that sequence retains the ability to bind to CD79b.
  • a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO: 20.
  • a total of 1 to 5 amino acids have been substituted, inserted and/or deleted in SEQ ID NO: 20.
  • the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FRs).
  • the anti- CD79b immunoconjugate comprises an anti-CD79b antibody that comprises the VL sequence of SEQ ID NO: 20, including post-translational modifications of that sequence.
  • the VL comprises one, two or three HVRs selected from (a) HVR-L1 comprising an amino acid sequence of SEQ ID NO: 24; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26.
  • the VL comprises one, two or three HVRs selected from (a) HVR-Ll comprising the amino acid sequence of SEQ ID NO: 24; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26.
  • the immunoconjugate (e.g., the anti-CD79b immunoconjugate) comprises an anti-CD79b antibody that comprises VH as in any of the embodiments provided herein, and a VL as in any of the embodiments provided herein.
  • the immunoconjugate comprises an anti-CD79b antibody that comprises the VH and VL sequences in SEQ ID NO: 19 and SEQ ID NO: 20, respectively, including post- translational modifications of those sequences.
  • the immunoconjugate comprises an anti-CD79b antibody that comprises the VH and the VL of the anti-CD79b antibody in polatuzumab vedotin-piiq.
  • the immunoconjugate (e.g., anti-CD79b immunoconjugate) comprises an anti-CD79b antibody that binds to the same epitope as an anti-CD79b antibody described herein.
  • the immunoconjugate (e.g., anti-CD79b immunoconjugate) comprises an anti-CD79b antibody that binds to the same epitope as an anti- CD79b antibody comprising a VH sequence of SEQ ID NO: 19 and a VL sequence of SEQ ID NO: 20.
  • the immunoconjugate comprises an anti-CD79b antibody that is a monoclonal antibody, a chimeric antibody, humanized antibody, or human antibody.
  • the immunoconjugate comprises an antigen-binding fragment of an anti-CD79b antibody described herein, e.g., a Fv, Fab, Fab’, scFv, diabody, or F(ab’)i fragment.
  • the immunoconjugate comprises a substantially full length anti-CD79b antibody, e.g., an IgGl antibody or other antibody class or isotype as described elsewhere herein.
  • the immunoconjugate comprises an anti-CD79b antibody that comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 36, and/or a light chain comprising the amino acid sequence of SEQ ID NO: 35.
  • the immunoconjugate comprises an anti-CD79b antibody that comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 37 and/or a light chain comprising the amino acid sequence of SEQ ID NO: 35.
  • the immunoconjugate comprises an anti- CD79b antibody that comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 36 and/or a light chain comprising the amino acid sequence of SEQ ID NO: 38.
  • the immunoconjugate comprises an anti-CD79b antibody that comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 36 and a light chain comprising the amino acid sequence of SEQ ID NO: 35. In some embodiments, the immunoconjugate comprises an anti-CD79b antibody that 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 immunoconjugate comprises an anti-CD79b antibody that 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.
  • the immunoconjugate comprises an anti-CD79b antibody that comprises the heavy chain and the light chain of the anti-CD79b antibody in polatuzumab vedotin-piiq.
  • the immunoconjugate comprises an anti-CD79b antibody that comprises the heavy chain and the light chain of the anti-CD79b antibody in iladatuzumab vedotin.
  • 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.
  • Anti-CD79 immunoconjugates comprise an anti-CD79b antibody (e.g., an anti- CD79b antibody described herein) conjugated to one or more drugs / cytotoxic agents, such as chemotherapeutic agents or drugs, growth inhibitory agents, toxins (e.g., protein toxins, enzymatically active toxins of bacterial, fungal, plant, or animal origin, or fragments thereof), or radioactive isotopes (i.e., a radioconjugate).
  • chemotherapeutic agents e.g., an anti- CD79b antibody described herein
  • drugs / cytotoxic agents such as chemotherapeutic agents or drugs, growth inhibitory agents, toxins (e.g., protein toxins, enzymatically active toxins of bacterial, fungal, plant, or animal origin, or fragments thereof), or radioactive isotopes (i.e., a radioconjugate).
  • cytotoxic agents such as chemotherapeutic agents or drugs, growth inhibitory agents,
  • the anti-CD79 immunoconjugates selectively deliver an effective dose of a drug to cancerous cells / tissues whereby greater selectivity, i.e. a lower efficacious dose, may be achieved while increasing the therapeutic index (“therapeutic window”) (Polakis P. (2005) Current Opinion in Pharmacology 5:382-387).
  • Anti-CD79 immunoconjugates used in the methods provided herein include those with anticancer activity,
  • the anti-CD79 immunoconjugate comprises an anti-CD79b antibody conjugated, i.e. covalently attached, to the drug moiety.
  • the anti-CD79b antibody is covalently attached to the drug moiety through a linker.
  • the drug moiety (D) of the anti-CD79 immunoconjugate may include any compound, moiety or group that has a cytotoxic or cytostatic effect.
  • Dmg moieties may impart their cytotoxic and cytostatic effects by mechanisms including but not limited to tubulin binding, DNA binding or intercalation, and inhibition of RNA polymerase, protein synthesis, and/or topoisomerase.
  • Exemplary drug moieties include, but are not limited to, a maytansinoid, dolastatin, auristatin, calicheamicin, anthracycline, duocarmycin, vinca alkaloid, taxane, trichothecene, CC1065, camptothecin, elinafide, and stereoisomers, isosteres, analogs, and derivatives thereof that have cytotoxic activity.
  • an anti-CD79b immunoconjugate comprises an anti-CD79b antibody conjugated to one or more maytansinoid molecules.
  • Maytansinoids are derivatives of maytansine, and are mitotic inhibitors which act by inhibiting tubulin polymerization. Maytansine was first isolated from the east African shrub Maytenus serrata (U.S. Patent No. 3896111). Subsequently, it was discovered that certain microbes also produce maytansinoids, such as maytansinol and C-3 maytansinol esters (U.S. Patent No. 4,151,042). Synthetic maytansinoids are disclosed, for example, in U.S. Patent Nos.
  • Maytansinoid drug moieties are attractive drug moieties in antibody-drug conjugates because they are: (i) relatively accessible to prepare by fermentation or chemical modification or derivatization of fermentation products, (ii) amenable to derivatization with functional groups suitable for conjugation through non-disulfide linkers to antibodies, (iii) stable in plasma, and (iv) effective against a variety of tumor cell lines.
  • Certain maytansinoids suitable for use as maytansinoid drug moieties are known in the art and can be isolated from natural sources according to known methods or produced using genetic engineering techniques (see, e.g., Yu et al (2002) PNAS 99:7968-7973). Maytansinoids may also be prepared synthetically according to known methods.
  • Exemplary maytansinoid drug moieties include, but are not limited to, those having a modified aromatic ring, such as: C-19-dechloro (US Pat. No. 4256746) (prepared, for example, by lithium aluminum hydride reduction of ansamitocin P2); C-20-hydroxy (or C-20-demethyl) +/-C-19-dechloro (US Pat. Nos. 4361650 and 4307016) (prepared, for example, by demethylation using Streptomyces or Actinomyces or dechlorination using LAH); and C-20-demethoxy, C-20- acyloxy (-OCOR), +/-dechloro (U.S. Pat. No. 4,294,757) (prepared, for example, by acylation using acyl chlorides), and those having modifications at other positions of the aromatic ring.
  • Exemplary maytansinoid drug moieties also include those having modifications such as: C-9-SH (US Pat. No. 4424219) (prepared, for example, by the reaction of maytansinol with H 2 S or P2S5); C- 14-alkoxymethyl (demethoxy/GH 2 OR)(US 4331598); C- 14-hydroxymethyl or acyloxymethyl (CH 2 OH or CH 2 OAc) (US Pat. No. 4450254) (prepared, for example, from Nocardia); C- 15 -hydroxy/acyloxy (US 4364866) (prepared, for example, by the conversion of maytansinol by Streptomyces); C-15-methoxy (US Pat. Nos.
  • an ester linkage may be formed by reaction with a hydroxyl group using conventional coupling techniques.
  • the reaction may occur at the C-3 position having a hydroxyl group, the C-14 position modified with hydroxymethyl, the C-15 position modified with a hydroxyl group, and the C-20 position having a hydroxyl group.
  • the linkage is formed at the C-3 position of maytansinol or a maytansinol analogue.
  • Maytansinoid drug moieties include those having the structure: wherein the wavy line indicates the covalent attachment of the sulfur atom of the maytansinoid drug moiety to a linker of an anti-CD79b immunoconjugate.
  • Each R may independently be H or a Ci-Ce alkyl.
  • the alkylene chain attaching the amide group to the sulfur atom may be methanyl, ethanyl, or propyl, i.e., m is 1, 2, or 3 (US 633410; US 5208020; Chari et al (1992) Cancer Res. 52:127-131; Liu et al (1996) Proc. Natl. Acad. Sci USA 93:8618-8623).
  • the maytansinoid drug moiety has the following stereochemistry:
  • Exemplary embodiments of maytansinoid drug moieties include, but are not limited to, DM1; DM3; and DM4, having the structures: wherein the wavy line indicates the covalent attachment of the sulfur atom of the drug to a linker (L) of an anti-CD79b immunoconjugate.
  • exemplary maytansinoid anti-CD79b immunoconjugates have the following structures and abbreviations (wherein Ab is an anti-CD79b antibody and p is 1 to about 20. In some embodiments, p is 1 to 10, p is 1 to 7, p is 1 to 5, or p is 1 to 4):
  • Exemplary antibody-drug conjugates where DM1 is linked through a BMPEO linker to a thiol group of the antibody have the structure and abbreviation: wherein Ab is an anti-CD79b antibody; n is 0, 1, or 2; and p is 1 to about 20. In some embodiments, p is 1 to 10, p is 1 to 7, p is 1 to 5, or p is 1 to 4.
  • Immunoconjugates containing maytansinoids, methods of making the same, and their therapeutic use are disclosed, for example, in U.S. Patent Nos. 5,208,020 and 5,416,064; US 2005/0276812 Al; and European Patent EP 0425235 Bl, the disclosures of which are hereby expressly incorporated by reference. See also Liu et al. Proc. Natl. Acad. Sci. USA 93:8618-8623 (1996); and Chari et al. Cancer Research 52:127-131 (1992).
  • anti-CD79b antibody-maytansinoid conjugates may be prepared by chemically linking an anti-CD79b antibody to a maytansinoid molecule without significantly diminishing the biological activity of either the antibody or the maytansinoid molecule. See, e.g., U.S. Patent No. 5,208,020 (the disclosure of which is hereby expressly incorporated by reference).
  • an anti-CD79b immunoconjugate with an average of 3-4 maytansinoid molecules conjugated per antibody molecule has shown efficacy in enhancing cytotoxicity of target cells without negatively affecting the function or solubility of the antibody. In some instances, even one molecule of toxin/antibody is expected to enhance cytotoxicity over the use of naked anti-CD79b antibody.
  • Exemplary linking groups for making antibody-maytansinoid conjugates include, for example, those described herein and those disclosed in U.S. Patent No. 5208020; EP Patent 0425 235 Bl; Chari et al. Cancer Research 52:127-131 (1992); US 2005/0276812 Al; and US 2005/016993 Al, the disclosures of which are hereby expressly incorporated by reference.
  • Drug moieties include dolastatins, auristatins, and analogs and derivatives thereof (US
  • Auristatins are derivatives of the marine mollusk compound dolastatin-10. While not intending to be bound by any particular theory, dolastatins and auristatins have been shown to interfere with microtubule dynamics, GTP hydrolysis, and nuclear and cellular division (Woyke et al (2001) Antimicrob. Agents and Chemother. 45(12):3580-3584) and have anticancer (US 5663149) and antifungal activity (Pettit et al (1998) Antimicrob. Agents Chemother. 42:2961-2965).
  • the dolastatin/auristatin drug moiety may be attached to the antibody through the N (amino) terminus or the C (carboxyl) terminus of the peptidic drug moiety (WO 02/088172; Doronina et al (2003) Nature Biotechnology 21(7):778-784; Francisco et al (2003) Blood 102(4):1458-1465).
  • Exemplary auristatin embodiments include the N -terminus linked monomethylauristatin drug moieties D E and D F , disclosed in US 7498298 and US 7659241, the disclosures of which are expressly incorporated by reference in their entirety: wherein the wavy line of DE and DF indicates the covalent attachment site to an antibody or antibody-linker component, and independently at each location:
  • R 2 is selected from H and C 1 -C 8 alkyl
  • R 3 is selected from H, C 1 -C 8 alkyl, C 3 -C 8 carbocycle, aryl, C 1 -C 8 alkyl-aryl, C 1 -C 8 alkyl- (C 3 -C 8 carbocycle), C 3 -C 8 heterocycle and C 1 -C 8 alkyl-(C 3 -C8 heterocycle);
  • R 4 is selected from H, C 1 -C 8 alkyl, C 3 -C 8 carbocycle, aryl, C 1 -C 8 alkyl-aryl, C 1 -C 8 alkyl- (C 3 -C 8 carbocycle), C 3 -C 8 heterocycle and C 1 -C 8 alkyl-(C 3 -C 8 heterocycle);
  • R 5 is selected from H and methyl; or R 4 and R 5 jointly form a carbocyclic ring and have the formula -(CR a R b ) n - wherein R a and R b are independently selected from H, C 1 -C 8 alkyl and C 3 -C 8 carbocycle and n is selected from 2, 3, 4, 5 and 6;
  • R 6 is selected from H and C 1 -C 8 alkyl
  • R 7 is selected from H, C 1 -C 8 alkyl, C 3 -C 8 carbocycle, aryl, C 1 -C 8 alkyl-aryl, C 1 -C 8 alkyl- (C 3 -C 8 carbocycle), C 3 -C 8 heterocycle and C 1 -C 8 alkyl-(C 3 -C 8 heterocycle); each R 8 is independently selected from H, OH, C 1 -C 8 alkyl, C 3 -C 8 carbocycle and 0-(C 1 -
  • R 9 is selected from H and C 1 -C 8 alkyl
  • R 10 is selected from aryl or C 3 -C 8 heterocycle
  • Z is O, S, NH, or NR 12 , wherein R 12 is C 1 -C 8 alkyl;
  • R 11 is selected from H, C 1 -C 20 alkyl, aryl, C 3 -C 8 heterocycle, -(R 13 O) m -R 14 , or -(R 13 O) m -
  • m is an integer ranging from 1-1000;
  • R 13 is Ci-C 8 alkyl;
  • R 14 is H or C 1 -C 8 alkyl; each occurrence of R 15 is independently H, COOH, -(CH 2 ) n -N(R 16 ) 2 , -(CH 2 ) n -SO 3 H, or -(CH 2 ) deliberately-SO3- C 1 -C 8 alkyl; each occurrence of R 16 is independently H, C 1 -C 8 alkyl, or -(CH 2 ) n -COOH;
  • R 18 is selected from -C(R 8 )2-C(R 8 )2-aryl, -C(R 8 )2-C(R 8 )2-(C 3 -C 8 heterocycle), and -C(R 8 )2-C(R 8 )2-(C 3 -C 8 carbocycle); and n is an integer ranging from 0 to 6.
  • R 3 , R 4 and R 7 are independently isopropyl or sec-butyl and R 5 is
  • R 3 and R 4 are each isopropyl, R 5 is -H, and R 7 is sec- butyl.
  • R 2 and R 6 are each methyl, and R 9 is -H.
  • each occurrence of R 8 is -OCH 3 .
  • R 3 and R 4 are each isopropyl
  • R 2 and R 6 are each methyl
  • R 5 is -H
  • R 7 is sec-butyl
  • each occurrence of R 8 is -OCH 3
  • R 9 is -H.
  • Z is -O- or -NH-.
  • R 10 is aryl
  • R 10 is -phenyl
  • R 11 is -H, methyl or t-butyl.
  • R 11 when Z is -NH, R 11 is -CH(R 15 )2, wherein R 15 is -(CH 2 ) n -N(R 16 )2, and R 16 is -C 1 -C 8 alkyl or -(CH 2 ) n -COOH.
  • Z when Z is -NH, R 11 is -CH(R 15 ) 2 , wherein R 15 is -(CH 2 ) n -
  • An exemplary auristatin embodiment of formula D E is MMAE, wherein the wavy line indicates the covalent attachment to a linker (L) of an anti-CD79b immunoconjugate: MMAE
  • An exemplary auristatin embodiment of formula DF is MMAF, wherein the wavy line indicates the covalent attachment to a linker (L) of an anti-CD79b immunoconjugate:
  • Other exemplary embodiments include monomethylvaline compounds having phenylalanine carboxy modifications at the C-terminus of the pentapeptide auristatin drug moiety (WO 2007/008848) and monomethylvaline compounds having phenylalanine sidechain modifications at the C-terminus of the pentapeptide auristatin drug moiety (WO 2007/008603).
  • Nonlimiting exemplary embodiments of an anti-CD79b immunoconjugate of Formula I comprising MMAE or MMAF and various linker components have the following structures and abbreviations (wherein “Ab” is an anti-CD79b antibody; p is 1 to about 8, “Val-Cif ’ is a valine- citrulline dipeptide; and “S” is a sulfur atom:
  • the anti-CD79b immunoconjugate comprises the structure of Ab-MC-vc-PAB-MMAE, wherein p is, e.g., about 1 to about 8; about 2 to about 7; about 3 to about 5; about 3 to about 4; or about 3.5.
  • the anti-CD79b immunoconjugate is huMA79bv28-MC-vc-P AB -MM AE, e.g., an anti-CD79b immunoconjugate comprising the structure of Ab-MC-vc-PAB-MMAE, wherein p is, e.g., about 1 to about 8; about 2 to about 7; about 3 to about 5; about 3 to about 4; or about 3.5, wherein the anti-CD79b antibody (Ab) comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 36, and a light chain comprising the amino acid sequence of SEQ ID NO: 35.
  • the anti-CD79b immunoconjugate is polatuzumab vedotin-piiq.
  • Polatuzumab vedotin-piiq has the IUPHAR/BPS Number 8404, the KEGG Number D10761, and can also be referred to as “DCDS4501A,” or “RG7596.”
  • Nonlimiting exemplary embodiments of anti-CD79b immunoconjugates of Formula I comprising MMAF and various linker components further include Ab-MC-PAB-MMAF and Ab- PAB-MMAF.
  • Immunoconjugates comprising MMAF attached to an antibody by a linker that is not proteolytically cleavable have been shown to possess activity comparable to immunoconjugates comprising MMAF attached to an antibody by a proteolytically cleavable linker (Doronina et al. (2006) Bioconjugate Chem. 17:114-124). In some such embodiments, drug release is believed to be effected by antibody degradation in the cell.
  • Nonlimiting exemplary embodiments of anti-CD79b immunoconjugates of Formula I comprising MMAE and various linker components further include Ab-MC-PAB-MMAE and Ab- PAB-MMAE.
  • peptide-based drug moieties can be prepared by forming a peptide bond between two or more amino acids and/or peptide fragments.
  • Such peptide bonds can be prepared, for example, according to a liquid phase synthesis method (see, e.g., E. Schroder and K. Lübke, “The Peptides”, volume 1, pp 76-136, 1965, Academic Press).
  • Auristatin/dolastatin drug moieties may, in some embodiments, be prepared according to the methods of: US 7498298; US 5635483; US 5780588; Pettit et al (1989) J. Am. Chem. Soc.
  • auristatin/dolastatin drug moieties of formulas D E such as MMAE, and DF, such as MMAF, and drug-linker intermediates and derivatives thereof, such as MC-MMAF, MC-MMAE, MC-vc-PAB-MMAF, and MC-vc-PAB-MMAE, may be prepared using methods described in US 7498298; Doronina et al. (2006) Bioconjugate Chem. 17:114-124; and Doronina et al. (2003) Nat. Biotech. 21:778-784and then conjugated to an antibody of interest.
  • the anti-CD79b immunoconjugate comprises an anti-CD79b antibody conjugated to one or more calicheamicin molecules.
  • the calicheamicin family of antibiotics, and analogues thereof, are capable of producing double-stranded DNA breaks at sub- picomolar concentrations (Hinman et al., (1993) Cancer Research 53:3336-3342; Lode et al., (1998) Cancer Research 58:2925-2928).
  • Calicheamicin has intracellular sites of action but, in certain instances, does not readily cross the plasma membrane. Therefore, cellular uptake of these agents through antibody-mediated internalization may, in some embodiments, greatly enhance their cytotoxic effects.
  • Nonlimiting exemplary methods of preparing anti-CD79b antibody immunoconjugates with a calicheamicin drug moiety are described, for example, in US 5712374; US 5714586; US 5739116; and US 5767285.
  • Other Drug Moieties are described, for example, in US 5712374; US 5714586; US 5739116; and US 5767285.
  • an anti-CD79b immunoconjugate comprises geldanamycin
  • enzymatically active toxins and fragments thereof including, but not limited to, diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin and the tricothecenes. See, e.g., WO 93/21232.
  • Drug moieties also include compounds with nucleolytic activity (e.g., a ribonuclease or a DNA endonuclease).
  • nucleolytic activity e.g., a ribonuclease or a DNA endonuclease.
  • an anti-CD79b immunoconjugate comprises a highly radioactive atom.
  • a variety of radioactive isotopes are available for the production of radioconjugated antibodies. Examples include At 211 , 1 131 , 1 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 and radioactive isotopes of Lu.
  • an anti-CD79b immunoconjugate when used for detection, it may comprise a radioactive atom for scintigraphic studies, for example Tc 99 or I 123 , or a spin label for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, MRI), such as zirconium-89, iodine- 123, iodine- 131, indium-111, fluorine- 19, carbon-13, nitrogen- 15, oxygen-17, gadolinium, manganese or iron.
  • NMR nuclear magnetic resonance
  • zirconium-89 may be complexed to various metal chelating agents and conjugated to antibodies, e.g., for PET imaging (WO 2011/056983),
  • radio- or other labels may be incorporated in the anti-CD79b immunoconjugate in known ways.
  • a peptide may be biosynthesized or chemically synthesized using suitable amino acid precursors comprising, for example, one or more fluorine- 19 atoms in place of one or more hydrogens.
  • labels such as Tc 99 , I 123 , Re 186 , Re 188 and In 111 can be attached via a cysteine residue in the anti-CD79b antibody.
  • yttrium-90 can be attached via a lysine residue of the anti-CD79b antibody.
  • the IODOGEN method Frraker et al (1978) Biochem.
  • an anti-CD79b immunoconjugate may comprise an anti- CD79b antibody conjugated to a prodrug-activating enzyme.
  • a prodrug-activating enzyme converts a prodrug (e.g., a peptidyl chemotherapeutic agent, see WO 81/01145) to an active drug, such as an anti-cancer drug.
  • Such immunoconjugates are useful, in some embodiments, in antibody-dependent enzyme-mediated prodrug therapy (“ADEPT”).
  • Enzymes that may be conjugated to an anti-CD79b antibody include, but are not limited to, alkaline phosphatases, which are useful for converting phosphate-containing prodrugs into free drugs; arylsulfatases, which are useful for converting sulfate-containing prodrugs into free drugs; cytosine deaminase, which is useful for converting non-toxic 5-fluorocytosine into the anti-cancer drug, 5-fluorouracil; proteases, such as serratia protease, thermolysin, subtilisin, carboxypeptidases and cathepsins (such as cathepsins B and L), which are useful for converting peptide-containing prodrugs into free drugs; D-alanylcarboxypeptidases, which are useful for converting prodrugs that contain D-amino acid substituents; carbohydrate
  • Drug loading is represented by p, the average number of drug moieties per anti- CD79b antibody in a molecule of Formula I. Drug loading may range from 1 to 20 drug moieties (D) per antibody.
  • Anti-CD79b immunoconjugates of Formula I include collections of anti-CD79b antibodies conjugated with a range of drug moieties, from 1 to 20. The average number of drug moieties per anti-CD79b antibody in preparations of anti-CD79b immunoconjugates from conjugation reactions may be characterized by conventional means such as mass spectroscopy, ELISA assay, and HPLC. The quantitative distribution of anti-CD79b immunoconjugates in terms of p may also be determined.
  • p may be limited by the number of attachment sites on the anti-CD79b antibody.
  • an anti-CD79b antibody may have only one or several cysteine thiol groups, or may have only one or several sufficiently reactive thiol groups through which a linker may be attached.
  • higher drug loading e.g., p >5
  • the average drug loading for an anti-CD79b immunoconjugates ranges from 1 to about 8; from about 2 to about 6; from about 3 to about 5; or from about 3 to about 4.
  • the optimal ratio of drug moieties per antibody may be less than 8, and may be about 2 to about 5 (US 7498298).
  • the optimal ratio of drug moieties per antibody is about 3 to about 4.
  • the optimal ratio of drug moieties per antibody is about
  • an antibody may contain, for example, lysine residues that do not react with the drug-linker intermediate or linker reagent, as discussed below.
  • antibodies do not contain many free and reactive cysteine thiol groups which may be linked to a drug moiety; indeed most cysteine thiol residues in antibodies exist as disulfide bridges.
  • an anti-CD79b antibody may be reduced with a reducing agent such as dithiothreitol (DTT) or tricarbonylethylphosphine (TCEP), under partial or total reducing conditions, to generate reactive cysteine thiol groups.
  • a reducing agent such as dithiothreitol (DTT) or tricarbonylethylphosphine (TCEP)
  • DTT dithiothreitol
  • TCEP tricarbonylethylphosphine
  • an anti-CD79b antibody is subjected to denaturing conditions to reveal reactive nucleophilic groups such as lysine or cysteine.
  • the loading (drug/antibody ratio) of an anti-CD79b immunoconjugate may be controlled in different ways, and for example, by: (i) limiting the molar excess of drug-linker intermediate or linker reagent relative to antibody, (ii) limiting the conjugation reaction time or temperature, and (iii) partial or limiting reductive conditions for cysteine thiol modification.
  • the resulting product is a mixture of anti-CD79b immunoconjugate compounds with a distribution of one or more drug moieties attached to an anti-CD79b antibody.
  • the average number of drugs per antibody may be calculated from the mixture by a dual ELISA antibody assay, which is specific for antibody and specific for the drug.
  • Individual anti-CD79b immunoconjugate molecules may be identified in the mixture by mass spectroscopy and separated by HPLC, e.g., hydrophobic interaction chromatography (see, e.g., McDonagh et al (2006) Prot. Engr.
  • a homogeneous anti-CD79b immunoconjugate with a single loading value may be isolated from the conjugation mixture by electrophoresis or chromatography.
  • An anti-CD79b immunoconjugate of Formula I may be prepared by several routes employing organic chemistry reactions, conditions, and reagents known to those skilled in the art, including, but not limited to, e.g., (1) reaction of a nucleophilic group of an anti-CD79b antibody with a bivalent linker reagent to form Ab-L via a covalent bond, followed by reaction with a drug moiety D; and (2) reaction of a nucleophilic group of a drug moiety with a bivalent linker reagent, to form D-L, via a covalent bond, followed by reaction with a nucleophilic group of an anti-CD79b antibody.
  • Exemplary methods for preparing an anti-CD79b immunoconjugate of Formula I via the latter route are described in US 7498298, which is expressly incorporated herein by reference.
  • Nucleophilic groups on antibodies include, but are not limited to: (i) N-terminal amine groups, (ii) side chain amine groups, e.g., lysine, (iii) side chain thiol groups, e.g., cysteine, and (iv) sugar hydroxyl or amino groups where the antibody is glycosylated.
  • Amine, thiol, and hydroxyl groups are nucleophilic and capable of reacting to form covalent bonds with electrophilic groups on linker moieties and linker reagents including: (i) active esters such as NHS esters, HOBt esters, haloformates, and acid halides; (ii) alkyl and benzyl halides such as haloacetamides; and (iii) aldehydes, ketones, carboxyl, and maleimide groups. Certain antibodies have reducible interchain disulfides, i.e. cysteine bridges.
  • Anti-CD79b antibodies may be made reactive for conjugation with linker reagents by treatment with a reducing agent such as DTT (dithiothreitol) or tricarbonylethylphosphine (TCEP), such that the anti-CD79b antibody is fully or partially reduced.
  • a reducing agent such as DTT (dithiothreitol) or tricarbonylethylphosphine (TCEP)
  • TCEP tricarbonylethylphosphine
  • Each cysteine bridge will thus form, theoretically, two reactive thiol nucleophiles.
  • Additional nucleophilic groups can be introduced into anti-CD79b antibodies through modification of lysine residues, e.g., by reacting lysine residues with 2-iminothiolane (Traut’s reagent), resulting in conversion of an amine into a thiol.
  • Reactive thiol groups may also be introduced into an anti-CD79b antibody by introducing one, two, three, four, or more cysteine residues (e.g., by preparing variant antibodies comprising one or more non-native cysteine amino acid residues).
  • Anti-CD79b immunoconjugates described herein may also be produced by reaction between an electrophilic group on an anti-CD79b antibody, such as an aldehyde or ketone carbonyl group, with a nucleophilic group on a linker reagent or drug.
  • an electrophilic group on an anti-CD79b antibody such as an aldehyde or ketone carbonyl group
  • nucleophilic groups on a linker reagent include, but are not limited to, hydrazide, oxime, amino, hydrazine, thiosemicarbazone, hydrazine carboxylate, and arylhydrazide.
  • an anti-CD79b antibody is modified to introduce electrophilic moieties that are capable of reacting with nucleophilic substituents on the linker reagent or drug.
  • the sugars of glycosylated anti-CD79b antibodies may be oxidized, e.g., with periodate oxidizing reagents, to form aldehyde or ketone groups which may react with the amine group of linker reagents or drug moieties.
  • the resulting imine Schiff base groups may form a stable linkage, or may be reduced, e.g., by borohydride reagents to form stable amine linkages.
  • reaction of the carbohydrate portion of a glycosylated anti-CD79b antibody with either galactose oxidase or sodium meta-periodate may yield carbonyl (aldehyde and ketone) groups in the anti-CD79b antibody that can react with appropriate groups on the drug (Hermanson, Bioconjugate Techniques).
  • anti-CD79b antibodies containing N-terminal serine or threonine residues can react with sodium meta-periodate, resulting in production of an aldehyde in place of the first amino acid (Geoghegan & Stroh, (1992) Bioconjugate Chem. 3:138-146; US 5362852).
  • Such an aldehyde can be reacted with a drug moiety or linker nucleophile.
  • nucleophilic groups on a drug moiety include, but are not limited to: amine, thiol, hydroxyl, hydrazide, oxime, hydrazine, thiosemicarbazone, hydrazine carboxylate, and arylhydrazide groups capable of reacting to form covalent bonds with electrophilic groups on linker moieties and linker reagents including: (i) active esters such as NHS esters, HOBt esters, haloformates, and acid halides; (ii) alkyl and benzyl halides such as haloacetamides; (iii) aldehydes, ketones, carboxyl, and maleimide groups.
  • active esters such as NHS esters, HOBt esters, haloformates, and acid halides
  • alkyl and benzyl halides such as haloacetamides
  • aldehydes ketones, carboxyl, and maleimide groups.
  • Nonlimiting exemplary cross-linker reagents that may be used to prepare anti-CD79b immunoconjugates are described herein in the section titled “Exemplary Linkers.” Methods of using such cross-linker reagents to link two moieties, including a proteinaceous moiety and a chemical moiety, are known in the art.
  • a fusion protein comprising an anti-CD79b antibody and a cytotoxic agent may be made, e.g., by recombinant techniques or peptide synthesis.
  • a recombinant DNA molecule may comprise regions encoding the antibody and cytotoxic portions of the conjugate either adjacent to one another or separated by a region encoding a linker peptide which does not destroy the desired properties of the conjugate.
  • an anti-CD79b antibody may be conjugated to a “receptor” (such as streptavidin) for utilization in tumor pre-targeting wherein the antibody-receptor conjugate is administered to the patient, followed by removal of unbound conjugate from the circulation using a clearing agent and then administration of a “ligand” (e.g., avidin) which is conjugated to a cytotoxic agent (e.g., a drug or radionucleotide).
  • a ligand e.g., avidin
  • cytotoxic agent e.g., a drug or radionucleotide
  • anti-CD20 antibodies Depending on binding properties and biological activities of anti-CD20 antibodies to the CD20 antigen, two types of anti-CD20 antibodies (type I and type II anti-CD20 antibodies) can be distinguished according to Cragg, M.S., et al., Blood 103 (2004) 2738-2743; and Cragg, M.S., et al., Blood 101 (2003) 1045-1052, see Table C.
  • type I anti-CD20 antibodies include e.g., rituximab, HI47 IgG3 (ECACC, hybridoma), 2C6 IgGl (as disclosed in WO 2005/103081), 2F2 IgGl (as disclosed and
  • the anti-CD20 antibody used a method of treatment provided herein is rituximab.
  • the rituximab reference antibody; example of a type I anti-CD20 antibody
  • the rituximab is a genetically engineered chimeric human gamma 1 murine constant domain containing monoclonal antibody directed against the human CD20 antigen.
  • this antibody is not glycoengineered and not afucosylated and thus has an amount of fucose of at least 85%.
  • This chimeric antibody comprises human gamma 1 constant domains and is identified by the name “C2B8” in US 5,736,137 (Andersen, et. al .) issued on April 17, 1998, assigned to IDEC Pharmaceuticals Corporation.
  • Rituximab is approved for the treatment of patients with diffuse large B-cell lymphoma (DLBCL), relapsed or refractory low-grade or follicular, CD20 positive, B-cell non-Hodgkin’s lymphoma.
  • DLBCL diffuse large B-cell lymphoma
  • rituximab exhibits human complement-dependent cytotoxicity (CDC) (Reff, M.E., et. al, Blood 83(2) (1994) 435-445). Additionally, it exhibits activity in assays that measure antibody- dependent cellular cytotoxicity (ADCC).
  • the anti-CD20 antibody used in a method of treatment provided herein comprises, according to numbering in Rabat et al., the CDR-H1, CDR-H2, CDR- H3, CDR-L1, CDR-L2, and CDR-L3 of rituximab.
  • anti-CD20 antibody used in a method of treatment provided herein comprises the VH and the VL of rituximab.
  • anti-CD20 antibody used in a method of treatment provided herein comprises the heavy chain and the light chain of rituximab.
  • the term “rituximab” refers to an anti-CD20 antibody having the CAS Registry Number 174722-31-7.
  • the anti-CD20 antibody used in a method of treatment provided herein is an afucosylated anti-CD20 antibody.
  • type II anti-CD20 antibodies include e.g., humanized B-Lyl antibody
  • IgGl (a chimeric humanized IgGl antibody as disclosed in WO 2005/044859), 11B8 IgGl (as disclosed in WO 2004/035607), and AT80 IgGl .
  • IgGl isotype show characteristic CDC properties.
  • Type II anti-CD20 antibodies have a decreased CDC (if IgGl isotype) compared to type I antibodies of the IgGl isotype.
  • the type II anti-CD20 antibody e.g., a GA101 antibody
  • ADCC antibody dependent cellular cytotoxicity
  • the type II anti-CD20 antibodies more preferably an afucosylated humanized B-Lyl antibody as described in WO 2005/044859 and WO 2007/031875.
  • the anti-CD20 antibody used in a method of treatment provided herein is GA101 antibody.
  • the GA101 antibody as used herein refers to any one of the following antibodies that bind human CD20: (1) an antibody comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO:5, an HVR-H2 comprising the amino acid sequence of SEQ ID NO:6, an HVR-H3 comprising the amino acid sequence of SEQ ID NO:7, an HVR-L1 comprising the amino acid sequence of SEQ ID NO:8, an HVR-L2 comprising the amino acid sequence of SEQ ID NO:9, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 10; (2) an antibody comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 11 and a VL domain comprising the amino acid sequence of SEQ ID NO: 12, (3) an antibody comprising an amino acid sequence of SEQ ID NO: 13 and an amino acid sequence of SEQ ID NO: 14; (4) an antibody known as obinutuzumab, or (5) an antibody that comprises an amino acid sequence that has at least 95%,
  • the anti-CD20 antibody used in a method of treatment provided herein is a humanized B-Lyl antibody.
  • the humanized B-Lyl antibody refers to humanized B-Lyl antibody as disclosed in WO 2005/044859 and WO 2007/031875, which were obtained from the murine monoclonal anti-CD20 antibody B-Lyl (variable region of the murine heavy chain (VH): SEQ ID NO: 3; variable region of the murine light chain (VL): SEQ ID NO: 4- see Poppema, S.
  • the humanized B-Lyl antibody has variable region of the heavy chain (VH) selected from group of SEQ ID NO: 15- 16 and 40-55 (corresponding to B-HH2 to B-HH9 and B-HL8 to B-HL17 of WO 2005/044859 and WO 2007/031875).
  • the variable domain is selected from the group consisting of SEQ ID NO: 15, 16, 42, 44, 46, 48 and 50 (corresponding to B-HH2, BHH-3, B-HH6, B-HH8, B-HL8, B-HL11 and B-HL13 of WO 2005/044859 and WO 2007/031875).
  • the humanized B- Lyl antibody has variable region of the light chain (VL) of SEQ ID NO:55 (corresponding to B- KV1 of WO 2005/044859 and WO 2007/031875).
  • the humanized B-Lyl antibody has a variable region of the heavy chain (VH) of SEQ ID NO:42 (corresponding to B- HH6 of WO 2005/044859 and WO 2007/031875) and a variable region of the light chain (VL) of SEQ ID NO:55 (corresponding to B-KV1 of WO 2005/044859 and WO 2007/031875).
  • the humanized B-Lyl antibody is an IgGl antibody.
  • Such afucosylated humanized B-Lyl antibodies are glycoengineered (GE) in the Fc region according to the procedures described in WO 2005/044859, WO 2004/065540, WO 2007/031875, Umana, P. et al, Nature Biotechnol. 17 (1999) 176-180 and WO 99/154342.
  • the afucosylated glyco-engineered humanized B-Lyl is B-HH6-B-KV1 GE.
  • the anti-CD20 antibody is obinutuzumab (recommended INN, WHO Drug Information, Vol. 26, No. 4, 2012, p. 453).
  • obinutuzumab is synonymous for GA101 or RO5072759. It is commercially available for therapeutic use under the trade name GAZYVA®, and is provided as a 1000 mg/40 mL (25 mg/mL) single-dose vial. This replaces all previous versions (e.g., Vol. 25, No. 1, 2011, p.75-76), and is formerly known as afutuzumab (recommended INN, WHO Drug Information, Vol. 23, No. 2, 2009, p. 176;Vol. 22, No. 2, 2008, p. 124).
  • the humanized B-Lyl antibody is an antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 17 and a light chain comprising the amino acid sequence of SEQ ID NO: 18, or an antigen-binding fragment thereof such antibody.
  • the humanized B-Lyl antibody comprises a heavy chain variable region comprising the three heavy chain CDRs of SEQ ID NO: 17 and a light chain variable region comprising the three light chain CDRs of SEQ ID NO: 18.
  • the anti-CD20 antibody used in a method of treatment provided herein comprises, according to numbering in Rabat et al., the CDR-H1, CDR-H2, CDR- H3, CDR-L1, CDR-L2, and CDR-L3 of obinutuzumab.
  • anti-CD20 antibody used in a method of treatment provided herein comprises the VH and the VL of obinutuzumab.
  • anti-CD20 antibody used in a method of treatment provided herein comprises the heavy chain and the light chain of obinutuzumab.
  • the humanized B-Lyl antibody is an afucosylated glyco- engineered humanized B-Lyl .
  • Such glycoengineered humanized B-Lyl antibodies have an altered pattern of glycosylation in the Fc region, preferably having a reduced level of fucose residues.
  • the amount of fucose is about 60% or less of the total amount of oligosaccharides at Asn297 (in one embodiment the amount of fucose is between about 40% and about 60%, in another embodiment the amount of fucose is about 50% or less, and in still another embodiment the amount of fucose is about 30% or less).
  • the oligosaccharides of the Fc region are bisected.
  • the “ratio of the binding capacities to CD20 on Raji cells (ATCC-No. CCL-86) of an anti-CD20 antibodies compared to rituximab” is determined by direct immunofluorescence measurement (the mean fluorescence intensities (MFI) is measured) using said anti-CD20 antibody conjugated with Cy5 and rituximab conjugated with Cy5 in a FACSArray (Becton Dickinson) with Raji cells (ATCC-No. CCL-86), as described in Example No. 2, and calculated as follows:
  • MFI is the mean fluorescent intensity.
  • Cy5-labeling ratio as used herein means the number of Cy5 -label molecules per molecule antibody.
  • said type II anti-CD20 antibody has a ratio of the binding capacities to CD20 on Raji cells (ATCC-No. CCL-86) of said second anti-CD20 antibody compared to rituximab of 0.3 to 0.6, and in one embodiment, 0.35 to 0.55, and in yet another embodiment, 0.4 to 0.5.
  • antibody having increased antibody dependent cellular cytotoxicity it is meant an antibody, as that term is defined herein, having increased ADCC as determined by any suitable method known to those of ordinary skill in the art.
  • the assay uses target cells that are known to express the target antigen recognized by the antigen-binding region of the antibody;
  • PBMCs peripheral blood mononuclear cells
  • the assay is carried out according to following protocol: i) the PBMCs are isolated using standard density centrifugation procedures and are suspended at 5 x 10 6 cells/ml in RPMI cell culture medium; ii) the target cells are grown by standard tissue culture methods, harvested from the exponential growth phase with a viability higher than 90%, washed in RPMI cell culture medium, labeled with 100 micro-Curies of 51 Cr, washed twice with cell culture medium, and resuspended in cell culture medium at a density of 10 5 cells/ml; iii) 100 microliters of the final target cell suspension above are transferred to each well of a 96-well microtiter plate; iv) the antibody is serially-diluted from 4000 ng/ml to 0.04 ng/ml in cell culture medium and 50 microliters of the resulting antibody solutions are added to the target cells in the 96-well microtiter plate, testing in triplicate various antibody concentrations covering the whole concentration range above; v) for the maximum release (
  • “increased ADCC” is defined as either an increase in the maximum percentage of specific lysis observed within the antibody concentration range tested above, and/or a reduction in the concentration of antibody required to achieve one half of the maximum percentage of specific lysis observed within the antibody concentration range tested above.
  • the increase in ADCC is relative to the ADCC, measured with the above assay, mediated by the same antibody, produced by the same type of host cells, using the same standard production, purification, formulation and storage methods, which are known to those skilled in the art, except that the comparator antibody (lacking increased ADCC) has not been produced by host cells engineered to overexpress GnTIII and/or engineered to have reduced expression from the fucosyltransferase 8 (FUT8) gene (e.g., including, engineered for FUT8 knock out).
  • FUT8 fucosyltransferase 8
  • the “increased ADCC” can be obtained by, for example, mutating and/or glycoengineering of said antibodies.
  • the anti-CD20 antibody is glycoengineered to have a biantennary oligosaccharide attached to the Fc region of the antibody that is bisected by GlcNAc.
  • the anti-CD20 antibody is glycoengineered to lack fucose on the carbohydrate attached to the Fc region by expressing the antibody in a host cell that is deficient in protein fucosylation (e.g., Lee 13 CHO cells or cells having an alpha- 1 ,6-fucosyltransferase gene (FUT8) deleted or the FUT gene expression knocked down).
  • the anti-CD20 antibody sequence has been engineered in its Fc region to enhance ADCC.
  • such engineered anti-CD20 antibody variant comprises an Fc region with one or more amino acid substitutions at positions 298, 333, and/or 334 of the Fc region (EU numbering of residues)).
  • the term “complement-dependent cytotoxicity (CDC)” refers to lysis of human cancer target cells by the antibody according to the invention in the presence of complement.
  • CDC can be measured by the treatment of a preparation of CD20 expressing cells with an anti-CD20 antibody according to the invention in the presence of complement.
  • CDC is found if the antibody induces at a concentration of 100 nM the lysis (cell death) of 20% or more of the tumor cells after 4 hours.
  • the assay is performed with 51 Cr or Eu labeled tumor cells and measurement of released 51 Cr or Eu. Controls include the incubation of the tumor target cells with complement but without the antibody.
  • the anti-CD20 antibody is a monoclonal antibody, e.g., a human antibody.
  • the anti-CD20 antibody is an antibody fragment, e.g., a Fv, Fab, Fab’, scFv, diabody, or F(ab’) 2 fragment.
  • the anti-CD20 antibody is a substantially full length antibody, e.g., an IgGl antibody, IgG2a antibody or other antibody class or isotype as defined herein.
  • the anti-CD20 antibody is any of ABP 798 (Amgen, USA), Zytux (AryoGen Pharmed, Iran), AcellBia/Usmal (Biocad, Russia), BI 695500 (Boehringer Ingelheim, Germany), Truxima (Celltrion, South Korea), Blitzima (Celltrion, South Korea), Ritemvia (Celltrion, South Korea), Rituzena/ Tuxella (Celltrion, South Korea), CT-P10 (Celltrion, South Korea), Reditux (Dr Reddy’s Laboratories, India), Maball (Hetero Group, India), MabTas (Intas Biopharmaceuticals, India), JHL1101 (JHL Biotech, Taiwan),
  • an antibody used in a method of treatment provided herein may incorporate any of the features, singly or in combination, as described in below.
  • an antibody used in a method of treatment provided herein has a dissociation constant (Kd) of ⁇ ⁇ , ⁇ 100 nM, ⁇ 50 nM, ⁇ 10 nM, ⁇ 5 nM, ⁇ 1 nM, ⁇ 0.1 nM, ⁇ 0.01 nM, or ⁇ 0.001 nM, and optionally is ⁇ 10 -13 M. (e.g., 10 -8 M or less, e.g., from 10 -8 M to 10 -13 M, e.g., from 10 -9 M to 10 -13
  • Kd is measured by a radiolabeled antigen binding assay (RIA) performed with the Fab version of an antibody of interest and its antigen as described by the following assay.
  • Solution binding affinity of Fabs for antigen is measured by equilibrating Fab with a minimal concentration of ( 125 I)-labeled antigen in the presence of a titration series of unlabeled antigen, then capturing bound antigen with an anti-Fab antibody-coated plate (see, e.g., Chen et al., J. Mol. Biol. 293:865-881(1999)).
  • MICROTITER ® multi-well plates (Thermo Scientific) are coated overnight with 5 ⁇ g/inl of a capturing anti-Fab antibody (Cappel Labs) in 50 mM sodium carbonate (pH 9.6), and subsequently blocked with 2% (w/v) bovine serum albumin in PBS for two to five hours at room temperature (approximately 23°C).
  • a non-adsorbent plate (Nunc #269620)
  • 100 pM or 26 pM [ 125 I]-antigen are mixed with serial dilutions of a Fab of interest (e.g., consistent with assessment of the anti-VEGF antibody, Fab-12, in Presta et al., Cancer Res.
  • the Fab of interest is then incubated overnight; however, the incubation may continue for a longer period ⁇ e.g., about 65 hours) to ensure that equilibrium is reached. Thereafter, the mixtures are transferred to the capture plate for incubation at room temperature (e.g., for one hour). The solution is then removed and the plate washed eight times with 0.1% polysorbate 20 (TWEEN- 20 ® ) in PBS. When the plates have dried, 150 ⁇ l/well of scintillant (MICRO SCINT-20TM; Packard) is added, and the plates are counted on a TOPCOUNT TM gamma counter (Packard) for ten minutes. Concentrations of each Fab that give less than or equal to 20% of maximal binding are chosen for use in competitive binding assays.
  • Kd is measured using surface plasmon resonance assays using a BIACORE ® -2000 or a BIACORE ® -3000 (BIAcore, Inc., Piscataway, NJ) at 25°C with immobilized antigen CMS chips at -10 response units (RU).
  • CM5 carboxymethylated dextran biosensor chips
  • EDC N-ethyl- N (3- dimethylaminopropyl)-carbodiimide hydrochloride
  • NHS N-hydroxysuccinimide
  • Antigen is diluted with 10 mM sodium acetate, pH 4.8, to 5 ⁇ g/ml ( ⁇ 0.2 ⁇ ) before injection at a flow rate of 5 ⁇ l/minute to achieve approximately 10 response units (RU) of coupled protein.
  • 1 M ethanolamine is injected to block unreacted groups.
  • two-fold serial dilutions of Fab (0.78 nM to 500 nM) are injected in PBS with 0.05% polysorbate 20 (TWEEN-20TM) surfactant (PBST) at 25°C at a flow rate of approximately 25 ⁇ l/min.
  • Association rates (k on ) and dissociation rates (k off ) are calculated using a simple one-to-one Langmuir binding model
  • an antibody used in a method of treatment provided herein is an antibody fragment.
  • Antibody fragments include, but are not limited to, Fab, Fab’, Fab’-SH, F(ab’)2, Fv, and scFv fragments, and other fragments described below.
  • Fab, Fab’, Fab’-SH, F(ab’)2, Fv, and scFv fragments and other fragments described below.
  • Diabodies are antibody fragments with two antigen-binding sites that may be bivalent or bispecific. See, for example, EP 404,097; WO 1993/01161; Hudson et al., Nat. Med. 9:129-134 (2003); and Hollinger et al., Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al., Nat. Med. 9:129-134 (2003).
  • Single-domain antibodies are antibody fragments comprising all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody.
  • a single-domain antibody is a human single-domain antibody (Domantis, Inc., Waltham, MA; see, e.g., U.S. Patent No. 6,248,516 Bl).
  • Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody as well as production by recombinant host cells (e.g., E. coli or phage), as described herein.
  • recombinant host cells e.g., E. coli or phage
  • an antibody a used in a method of treatment provided herein is a chimeric antibody.
  • Certain chimeric antibodies are described, e.g., in U.S. Patent No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)).
  • a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate, such as a monkey) and a human constant region.
  • a chimeric antibody is a “class switched” antibody in which the class or subclass has been changed from that of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof.
  • a chimeric antibody is a humanized antibody.
  • a non-human antibody is humanized to reduce immunogenicity to humans, while retaining the specificity and affinity of the parental non-human antibody.
  • a humanized antibody comprises one or more variable domains in which HVRs, e.g., CDRs, (or portions thereof) are derived from a non-human antibody, and FRs (or portions thereof) are derived from human antibody sequences.
  • HVRs e.g., CDRs, (or portions thereof) are derived from a non-human antibody
  • FRs or portions thereof
  • a humanized antibody optionally will also comprise at least a portion of a human constant region.
  • some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the HVR residues are derived), e.g., to restore or improve antibody specificity or affinity.
  • a non-human antibody e.g., the antibody from which the HVR residues are derived
  • Human framework regions that may be used for humanization include but are not limited to: framework regions selected using the “best-fit” method (see, e.g., Sims et al. J. Immunol. 151:2296 (1993)); framework regions derived from the consensus sequence of human antibodies of a particular subgroup of light or heavy chain variable regions (see, e.g., Carter et al. Proc. Natl. Acad. Sci. USA, 89:4285 (1992); and Presta et al. J. Immunol., 151:2623 (1993)); human mature (somatically mutated) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, Front. Biosci.
  • an antibody used in a method of treatment provided herein is a human antibody.
  • Human antibodies can be produced using various techniques known in the art. Human antibodies are described generally in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5: 368-74 (2001) and Lonberg, Curr. Opin. Immunol. 20:450-459 (2008).
  • Human antibodies may be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigenic challenge.
  • Such animals typically contain all or a portion of the human immunoglobulin loci, which replace the endogenous immunoglobulin loci, or which are present extrachromosomally or integrated randomly into the animal’s chromosomes.
  • the endogenous immunoglobulin loci have generally been inactivated.
  • Human antibodies can also be made by hybridoma-based methods. Human myeloma and mouse-human heteromyeloma cell lines for the production of human monoclonal antibodies have been described. ⁇ See, e.g., Kozbor J. Immunol., 133: 3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987); and Boemer et al., J. Immunol., 147: 86 (1991).) Human antibodies generated via human B-cell hybridoma technology are also described in Li et al., Proc. Natl. Acad. Sci.
  • Human antibodies may also be generated by isolating Fv clone variable domain sequences selected from human-derived phage display libraries. Such variable domain sequences may then be combined with a desired human constant domain. Techniques for selecting human antibodies from antibody libraries are described below.
  • an antibody used in a method of treatment provided herein may be isolated by screening combinatorial libraries for antibodies with the desired activity or activities. For example, a variety of methods are known in the art for generating phage display libraries and screening such libraries for antibodies possessing the desired binding characteristics. Such methods are reviewed, e.g., in Hoogenboom et al.
  • phage display methods repertoires of VH and VL genes are separately cloned by polymerase chain reaction (PCR) and recombined randomly in phage libraries, which can then be screened for antigen-binding phage as described in Winter et al., Ann. Rev. Immunol., 12: 433-455 (1994). Phage typically display antibody fragments, either as single-chain Fv (scFv) fragments or as Fab fragments. Libraries from immunized sources provide high-affinity antibodies to the immunogen without the requirement of constructing hybridomas.
  • PCR polymerase chain reaction
  • naive repertoire can be cloned (e.g., from human) to provide a single source of antibodies to a wide range of non-self and also self antigens without any immunization as described by Griffiths et al., EMBO J, 12 : 725-734 (1993).
  • naive libraries can also be made synthetically by cloning unrearranged V-gene segments from stem cells, and using PCR primers containing random sequence to encode the highly variable CDR3 regions and to accomplish rearrangement in vitro, as described by Hoogenboom and Winter, J. Mol. Biol., 227: 381-388 (1992).
  • Patent publications describing human antibody phage libraries include, for example: US Patent No. 5,750,373, and US Patent Publication Nos. 2005/0079574, 2005/0119455, 2005/0266000, 2007/0117126, 2007/0160598, 2007/0237764, 2007/0292936, and 2009/0002360.
  • Antibodies or antibody fragments isolated from human antibody libraries are considered human antibodies or human antibody fragments herein.
  • an antibody used in a method of treatment provided herein is a multi specific antibody, e.g., a bispecific antibody.
  • Multispecific antibodies are monoclonal antibodies that have binding specificities for at least two different sites.
  • one of the binding specificities is for one antigen (e.g., CD79b or CD20) and the other is for any other antigen.
  • one of the binding specificities is for one antigen (e.g., CD79b or CD20) and the other is for CD3. See, e.g., U.S. Patent No. 5,821,337.
  • bispecific antibodies may bind to two different epitopes of a single antigen (e.g., CD79b or CD20). Bispecific antibodies may also be used to localize cytotoxic agents to cells which express the antigen (e.g., CD79b or CD20). Bispecific antibodies can be prepared as full length antibodies or antibody fragments,
  • Multispecific antibodies include, but are not limited to, recombinant co-expression of two immunoglobulin heavy chain-light chain pairs having different specificities (see Milstein and Cuello, Nature 305: 537 (1983)), WO 93/08829, and Traunecker et al, EMBOJ. 10: 3655 (1991)), and “knob-in-hole” engineering (see, e.g., U.S. Patent No. 5,731,168).
  • Multi-specific antibodies may also be made by engineering electrostatic steering effects for making antibody Fc-heterodimeric molecules (WO 2009/089004A1); cross-linking two or more antibodies or fragments (see, e.g., US Patent No.
  • Optus antibodies are also included herein (see, e.g., US 2006/0025576A1).
  • the antibody or fragment herein also includes a “Dual Acting FAb” or “DAF” comprising an antigen binding site that binds to CD79b as well as another, different antigen (see, US 2008/0069820, for example).
  • DAF Double Acting FAb
  • amino acid sequence variants of an antibody ⁇ e.g., an anti- CD79b antibody or an anti-CD20 antibody
  • an antibody used in a method of treatment provided herein
  • Amino acid sequence variants of an antibody may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions from, and/or insertions into and/or substitutions of residues within the amino acid sequences of the antibody. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final constmct possesses the desired characteristics, e.g., antigen-binding.
  • antibody variants having one or more amino acid substitutions are provided.
  • Sites of interest for substitutional mutagenesis include the HVRs and FRs.
  • Conservative substitutions are shown in Table D under the heading of “preferred substitutions.” More substantial changes are provided in Table D under the heading of “exemplary substitutions,” and as further described below in reference to amino acid side chain classes.
  • Amino acid substitutions may be introduced into an antibody of interest and the products screened for a desired activity, e.g., retained/improved antigen binding, decreased immunogenicity, or improved ADCC or CDC.
  • Amino acids may be grouped according to common side-chain properties:
  • Non-conservative substitutions will entail exchanging a member of one of these classes for another class.
  • substitutional variant involves substituting one or more hypervariable region residues of a parent antibody (e.g., a humanized or human antibody).
  • a parent antibody e.g., a humanized or human antibody.
  • the resulting variant(s) selected for further study will have modifications (e.g., improvements) in certain biological properties (e.g., increased affinity, reduced immunogenicity) relative to the parent antibody and/or will have substantially retained certain biological properties of the parent antibody.
  • An exemplary substitutional variant is an affinity matured antibody, which may be conveniently generated, e.g., using phage display-based affinity maturation techniques such as those described herein. Briefly, one or more HVR residues are mutated and the variant antibodies displayed on phage and screened for a particular biological activity (e.g ., binding affinity).
  • Alterations may be made in HVRs, e.g., to improve antibody affinity. Such alterations may be made in HVR “hotspots,” i. e. , residues encoded by codons that undergo mutation at high frequency during the somatic maturation process (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)), and/or SDRs (a-CDRs), with the resulting variant VH or VL being tested for binding affinity.
  • HVR “hotspots” i. e. , residues encoded by codons that undergo mutation at high frequency during the somatic maturation process (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)), and/or SDRs (a-CDRs), with the resulting variant VH or VL being tested for binding affinity.
  • Affinity maturation by constructing and reselecting from secondary libraries has been described, e.g., in Ho
  • affinity maturation diversity is introduced into the variable genes chosen for maturation by any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis), A secondary library is then created. The library is then screened to identify any antibody variants with the desired affinity.
  • Another method to introduce diversity involves HVR- directed approaches, in which several HVR residues (e.g., 4-6 residues at a time) are randomized. HVR residues involved in antigen binding may be specifically identified, e.g., using alanine scanning mutagenesis or modeling. CDR-H3 and CDR-L3 in particular are often targeted.
  • substitutions, insertions, or deletions may occur within one or more HVRs so long as such alterations do not substantially reduce the ability of the antibody to bind antigen.
  • conservative alterations e.g., conservative substitutions as provided herein
  • Such alterations may be outside of HVR “hotspots” or SDRs.
  • each HVR either is unaltered, or contains no more than one, two or three amino acid substitutions.
  • a useful method for identification of residues or regions of an antibody that may be targeted for mutagenesis is called “alanine scanning mutagenesis” as described by Cunningham and Wells (1989) Science, 244:1081-1085.
  • a residue or group of target residues e.g., charged residues such as Arg, Asp, His, Lys, and Glu
  • a neutral or negatively charged amino acid e.g., alanine or polyalanine
  • a crystal structure of an antigen-antibody complex is used to identify contact points between the antibody and antigen. Such contact residues and neighboring residues may be targeted or eliminated as candidates for substitution. Variants may be screened to determine whether they contain the desired properties.
  • Amino acid sequence insertions include amino- and/or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing a hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues.
  • terminal insertions include an antibody with an N-terminal methionyl residue.
  • Other insertional variants of the antibody molecule include the fusion to the N- or C-terminus of the antibody to an enzyme (e.g., for ADEPT) or a polypeptide which increases the serum half-life of the antibody.
  • an antibody used in a method of treatment provided herein is altered to increase or decrease the extent to which the antibody is glycosylated. Addition or deletion of glycosylation sites to an antibody may be conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites is created or removed.
  • the carbohydrate attached thereto may be altered.
  • Native antibodies produced by mammalian cells typically comprise a branched, biantennary oligosaccharide that is generally attached by an N-linkage to Asn297 of the CH2 domain of the Fc region. See, e.g., Wright et al. TIBTECH 15:26-32 (1997).
  • the oligosaccharide may include various carbohydrates, e.g., mannose, N-acetyl glucosamine (GlcNAc), galactose, and sialic acid, as well as a fucose attached to a GlcNAc in the “stem” of the biantennary oligosaccharide structure.
  • modifications of the oligosaccharide in an antibody of the invention may be made in order to create antibody variants with certain improved properties.
  • antibody variants having a carbohydrate structure that lacks fucose attached (directly or indirectly) to an Fc region.
  • the amount of fucose in such antibody may be from 1 % to 80%, from 1 % to 65%, from 5% to 65% or from 20% to 40%.
  • the amount of fucose is determined by calculating the average amount of fucose within the sugar chain at Asn297, relative to the sum of all glycostructures attached to Asn 297 (e.g., complex, hybrid and high mannose structures) as measured by MALDI-TOF mass spectrometry, as described in WO 2008/077546, for example.
  • Asn297 refers to the asparagine residue located at about position 297 in the Fc region (Eu numbering of Fc region residues); however, Asn297 may also be located about ⁇ 3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to minor sequence variations in antibodies. Such fucosylation variants may have improved ADCC function. See, e.g., US Patent Publication Nos. US 2003/0157108 (Presta, L.); US 2004/0093621 (Kyowa Hakko Kogyo Co., Ltd).
  • Examples of publications related to “defucosylated” or “fucose-deficient” antibody variants include: US 2003/0157108; WO 2000/61739; WO 2001/29246; US 2003/0115614; US 2002/0164328; US 2004/0093621; US 2004/0132140; US 2004/0110704; US 2004/0110282; US 2004/0109865; WO 2003/085119; WO 2003/084570; WO 2005/035586; WO 2005/035778; W02005/053742; W02002/031140; Okazaki et al. J. Mol. Biol. 336:1239-1249 (2004); Yamane-Ohnuki et al. Biotech. Bioeng.
  • Examples of cell lines capable of producing defucosylated antibodies include Lee 13 CHO cells deficient in protein fucosylation (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); US Pat Appl No US 2003/0157108 Al, Presta, L; and WO 2004/056312 Al, Adams et al., especially at Example 11), and knockout cell lines, such as alpha- 1 ,6-fucosyltransferase gene, FUT8, knockout CHO cells (see, e.g., Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94(4):680-688 (2006); and W02003/085107).
  • Antibody variants are further provided with bisected oligosaccharides, e.g., in which a biantennary oligosaccharide attached to the Fc region of the antibody is bisected by GlcNAc.
  • Such antibody variants may have reduced fucosylation and/or improved ADCC function. Examples of such antibody variants are described, e.g., in WO 2003/011878 (Jean-Mairet et al.); US Patent No. 6,602,684 (Umana et al.); and US 2005/0123546 (Umana et al.). Antibody variants with at least one galactose residue in the oligosaccharide attached to the Fc region are also provided. Such antibody variants may have improved CDC function. Such antibody variants are described, e.g., in WO 1997/30087 (Patel et al.); WO 1998/58964 (Raju, S.); and WO 1999/22764 (Raju, S.).
  • one or more amino acid modifications may be introduced into the Fc region of an antibody (e.g., an anti-CD79b antibody or an anti-CD20 antibody) used in a method of treatment provided herein, thereby generating an Fc region variant.
  • the Fc region variant may comprise a human Fc region sequence (e.g., a human IgGl, IgG2, IgG3 or IgG4 Fc region) comprising an amino acid modification (e.g., a substitution) at one or more amino acid positions.
  • the invention contemplates an antibody variant that possesses some but not all effector functions, which make it a desirable candidate for applications in which the half-life of the antibody in vivo is important yet certain effector functions (such as complement and ADCC) are unnecessary or deleterious.
  • In vitro and/or in vivo cytotoxicity assays can be conducted to confirm the reduction/depletion of CDC and/or ADCC activities.
  • Fc receptor (FcR) binding assays can be conducted to ensure that the antibody lacks FcyR binding (hence likely lacking ADCC activity), but retains FcRn binding ability.
  • NK cells express Fc(RIII only, whereas monocytes express Fc(RI, Fc(RII and Fc(RIII.
  • FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991).
  • Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest is described in U.S. Patent No. 5,500,362 (see, e.g., Hellstrom, I. et al. Proc. Nat’l Acad. Sci. USA 83:7059-7063 (1986)) and Hellstrom, I et al., Proc.
  • non-radioactive assays methods may be employed (see, for example, ACTITM non-radioactive cytotoxicity assay for flow cytometry (CellT echnology, Inc. Mountain View, CA; and CytoTox 96 ® non-radioactive cytotoxicity assay (Promega, Madison, WI).
  • Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells.
  • ADCC activity of the molecule of interest may be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al. Proc. Nat’l Acad. Sci. USA 95:652-656 (1998).
  • Clq binding assays may also be carried out to confirm that the antibody is unable to bind Clq and hence lacks CDC activity. See, e.g., Clq and C3c binding ELISA in WO 2006/029879 and WO 2005/100402.
  • a CDC assay may be performed (see, for example, Gazzano- Santoro et al., J. Immunol. Methods 202:163 (1996); Cragg, M.S.
  • FcRn binding and in vivo clearance/half-life determinations can also be performed using methods known in the art (see, e.g., Petkova, S.B. et al., Int’l. Immunol. 18(12): 1759-1769 (2006)).
  • Antibodies with reduced effector function include those with substitution of one or more of Fc region residues 238, 265, 269, 270, 297, 327 and 329 (U.S. Patent No. 6,737,056).
  • Such Fc mutants include Fc mutants with substitutions at two or more of amino acid positions 265, 269, 270, 297 and 327, including the so-called “DANA” Fc mutant with substitution of residues 265 and 297 to alanine (US Patent No. 7,332,581).
  • an antibody variant comprises an Fc region with one or more amino acid substitutions which improve ADCC, e.g., substitutions at positions 298, 333, and/or 334 of the Fc region (EU numbering of residues).
  • alterations are made in the Fc region that result in altered (i.e., either improved or diminished) Cl q binding and/or Complement Dependent Cytotoxicity (CDC), e.g., as described inUS Patent No. 6,194,551, WO 99/51642, and Idusogie et al. J. Immunol. 164: 4178-4184 (2000).
  • CDC Complement Dependent Cytotoxicity

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