WO2023056403A1

WO2023056403A1 - Methods for treatment of hematologic cancers using anti-tigit antibodies, anti-cd38 antibodies, and pd-1 axis binding antagonists

Info

Publication number: WO2023056403A1
Application number: PCT/US2022/077321
Authority: WO
Inventors: Raymond D. MENG; Yann NOUET; Shannon Moore RUPPERT
Original assignee: Genentech, Inc.; F. Hoffmann-La Roche Ag; Hoffmann-La Roche Inc.
Priority date: 2021-09-30
Filing date: 2022-09-30
Publication date: 2023-04-06
Also published as: TW202321308A

Abstract

This invention relates to methods and compositions for use in treating a hematologic cancer (e.g., a myeloma (e.g., a multiple myeloma (MM), e.g., a relapsed or refractory MM) or a lymphoma (e.g., a non- Hodgkin's lymphoma (NHL), e.g., a relapsed or refractory diffuse large B cell lymphoma (DLBCL) or a relapsed or refractory follicular lymphoma (FL))) in a patient, for example, by administering to the patient a treatment regimen that includes an anti-T-cell immunoreceptor with Ig and ITIM domains (TIGIT) antagonist antibody (e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., atezolizumab), and an anti- CD38 antibody (e.g., daratumumab); a treatment regimen that includes an anti-TIGIT antagonist antibody (e.g., tiragolumab) and an anti-CD38 antibody (e.g., daratumumab); or a treatment regimen that includes an anti-TIGIT antagonist antibody (e.g., tiragolumab) and an anti-CD20 antibody (e.g., rituximab).

Description

METHODS FOR TREATMENT OF HEMATOLOGIC CANCERS USING ANTI-TIGIT ANTIBODIES, ANTI-CD38 ANTIBODIES, AND PD-1 AXIS BINDING ANTAGONISTS

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on September 15, 2022, is named 50474-265WO3_Sequence_Listing_9_15_22_ST26 and is 75,006 bytes in size.

FIELD OF THE INVENTION

This invention relates to methods and compositions for use in treating a hematologic cancer (e.g., a myeloma (e.g., a multiple myeloma (MM), e.g., a relapsed or refractory MM) or a lymphoma (e.g., a nonHodgkin’s lymphoma (NHL), e.g., a relapsed or refractory diffuse large B cell lymphoma (DLBCL) or a relapsed or refractory follicular lymphoma (FL))) in a patient, for example, by administering to the patient a treatment regimen that includes an anti-T-cell immunoreceptor with Ig and ITIM domains (TIGIT) antagonist antibody (e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., atezolizumab), and an anti- CD38 antibody (e.g., daratumumab); a treatment regimen that includes an anti-TIGIT antagonist antibody (e.g., tiragolumab) and an anti-CD38 antibody (e.g., daratumumab); or a treatment regimen that includes an anti-TIGIT antagonist antibody (e.g., tiragolumab) and an anti-CD20 antibody (e.g., rituximab).

BACKGROUND OF THE INVENTION

Cancers are characterized by the uncontrolled growth of cell subpopulations. Cancers are the leading cause of death in the developed world and the second leading cause of death in developing countries, with over 14 million new cancer cases diagnosed and over eight million cancer deaths occurring each year. Cancer care thus represents a significant and ever-increasing societal burden.

The most common hematologic cancer in adults is non-Hodgkin’s lymphoma (NHL). Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive NHL, accounting for approximately 30% of all NHLs diagnosed annually, and follicular lymphoma (FL) is the most common subtype of indolent NHL (iNHL), which accounts for approximately one-third of all NHLs. Nearly 40% of patients with DLBCL will eventually die of relapsed disease or disease that is refractory to first-line treatment, and FL remains an incurable disease with the currently available therapies. Another hematologic cancer, multiple myeloma (MM), affects almost 20,000 people every year in the United States, and worldwide, approximately 160,000 people are diagnosed with MM annually. MM remains incurable despite advances in treatment, with an estimated median survival of 8-10 years for standard-risk myeloma and 2-3 years for high-risk disease. Hence, there remains a significant need for novel therapeutic agents in this population.

Thus, there is an unmet need in the field for the development of efficacious immunotherapies and methods of dosing the same which achieve a more favorable benefit-risk profile for the treatment of hematologic cancers, such as myelomas (e.g., MM) and lymphomas (e.g., NHL, e.g., DLBCL or FL). SUMMARY OF THE INVENTION

The present invention involves methods and compositions for use in treating a hematologic cancer (e.g., a myeloma (e.g., a multiple myeloma (MM), e.g., a relapsed or refractory MM) or a lymphoma (e.g., a non-Hodgkin’s lymphoma (NHL), e.g., a relapsed or refractory diffuse large B cell lymphoma (DLBCL) or a relapsed or refractory follicular lymphoma (FL))) in a subject, for example, by administering to the subject a treatment regimen that includes an anti-TIGIT antagonist antibody (e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., atezolizumab), and an anti-CD38 antibody (e.g., daratumumab); a treatment regimen that includes an anti-TIGIT antagonist antibody (e.g., tiragolumab) and an anti-CD38 antibody (e.g., daratumumab); or a treatment regimen that includes an anti-TIGIT antagonist antibody (e.g., tiragolumab) and an anti-CD20 antibody (e.g., rituximab).

In one aspect, the disclosure provides a method for treating a subject having a hematologic cancer, the method comprising administering to the subject an effective amount of an anti-TIGIT antagonist antibody, an anti-CD38 antibody, and a PD-1 axis binding antagonist.

In some aspects, the method comprises administering to the subject the anti-TIGIT antagonist antibody at a fixed dose of between about 30 mg to about 1200 mg, the anti-CD38 antibody at a dose of between about 300 mg to about 3600 mg, and the PD-1 axis binding antagonist at a dose of between about 900 mg to about 1500 mg.

In some aspects, the method comprises administering to the subject the anti-TIGIT antagonist antibody, anti-CD38 antibody, and PD-1 axis binding antagonist in a dosing regimen comprising at least nine dosing cycles, wherein: (a) the anti-TIGIT antagonist antibody is administered once every three weeks; (b) the PD-1 axis binding antagonist is administered once every three weeks; and (c) the anti- CD38 antibody is administered once every week during each of dosing cycles 1-3, once every three weeks during each of dosing cycles 4-8, and once every four weeks during dosing cycle 9.

In another aspect, the disclosure provides a method for treating a subject having a hematologic cancer, the method comprising administering to the subject an anti-TIGIT antagonist antibody at a fixed dose of between about 30 mg to about 1200 mg, an anti-CD38 antibody at a dose of between about 300 mg to about 3600 mg, and a PD-1 axis binding antagonist at a dose of between about 900 mg to about 1500 mg in a dosing regimen comprising at least nine dosing cycles, wherein (a) the anti-TIGIT antagonist antibody is administered once every three weeks; (b) the PD-1 axis binding antagonist is administered once every three weeks; and (c) the anti-CD38 antibody is administered once every week during each of dosing cycles 1 -3, once every three weeks during each of dosing cycles 4-8, and once every four weeks during dosing cycle 9.

In another aspect, the method comprises administering to the subject the anti-TIGIT antagonist antibody, anti-CD38 antibody, and PD-1 axis binding antagonist in a dosing regimen comprising at least 19 dosing cycles, wherein (a) the anti-TIGIT antagonist antibody is administered once every three weeks; (b) the PD-1 axis binding antagonist is administered once every three weeks; and (c) the anti-CD38 antibody is administered once every week during each of dosing cycles 1 and 2, once every three weeks during each of dosing cycles 3-18, and once every four weeks during dosing cycle 19.

In another aspect, the disclosure features a method for treating a subject having a hematologic cancer, the method comprising administering to the subject an anti-TIGIT antagonist antibody at a fixed dose of between about 30 mg to about 1200 mg, an anti-CD38 antibody at a dose of between about 300 mg to about 3600 mg, and a PD-1 axis binding antagonist at a dose of between about 900 mg to about 1500 mg in a dosing regimen comprising at least 19 dosing cycles, wherein (a) the anti-TIGIT antagonist antibody is administered once every three weeks; (b) the PD-1 axis binding antagonist is administered once every three weeks; and (c) the anti-CD38 antibody is administered once every week during each of dosing cycles 1 and 2, once every three weeks during each of dosing cycles 3-18, and once every four weeks during dosing cycle 19.

In some aspects, the length of each dosing cycle is 21 days.

In some aspects, the anti-TIGIT antagonist antibody is administered on or about day 1 of each dosing cycle.

In some aspects, the anti-CD38 antibody is administered on or about days 1 , 8, and 15 of each of dosing cycles 1-3, on or about day 1 of each of dosing cycles 4-8, and on or about day 1 of dosing cycle 9.

In other aspects, the anti-CD38 antibody is administered on or about days 1 , 8, and 15 of each of dosing cycles 1 and 3, on or about day 1 of each of dosing cycles 3-18, and on or about day 1 of dosing cycle 19.

In some aspects, the PD-1 axis binding antagonist is administered on or about day 1 of each dosing cycle.

In some aspects, the anti-TIGIT antagonist antibody, the anti-CD38 antibody, and the PD-1 axis binding antagonist are each administered on or about day 1 of each of dosing cycles 1-9.

In some aspects, the anti-TIGIT antagonist antibody, the anti-CD38 antibody, and the PD-1 axis binding antagonist are each administered on or about day 1 of each of dosing cycles 1-19.

In some aspects, the anti-TIGIT antagonist antibody is administered prior to the anti-CD38 antibody and the PD-1 axis binding antagonist.

In some aspects, the anti-TIGIT antagonist antibody is administered first, the PD-1 axis binding antagonist is administered second, and the anti-CD38 antibody is administered third.

In some aspects, the anti-TIGIT antagonist antibody is administered first, the anti-CD38 antibody is administered second, and the PD-1 axis binding antagonist is administered third.

In some aspects, the method comprises a first observation period following administration of the anti-TIGIT antagonist antibody, a second observation period following administration of the PD-1 axis binding antagonist, and a third observation period following administration of the anti-CD38 antibody.

In some aspects, the first observation period and the second observation period are each between about 30 minutes to about 60 minutes in length.

In some aspects, the third observation period is about 6 hours in length following the first dose of the anti-CD38 antibody and is about 60 minutes in length following subsequent doses of the anti-CD38 antibody.

In some aspects, the method comprises a first observation period following administration of the anti-TIGIT antagonist antibody, a second observation period following administration of the anti-CD38 antibody, and a third observation period following administration of the PD-1 axis binding antagonist.

In some aspects, the first observation period and the third observation period are each between about 30 minutes to about 60 minutes in length. In some aspects, the second observation period is about 6 hours in length following the first dose of the anti-CD38 antibody and is about 60 minutes in length following subsequent doses of the anti-CD38 antibody.

In some aspects, the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are administered simultaneously.

In some aspects, the dosing regimen comprises at least 16 dosing cycles.

In some aspects, the method further comprises administering to the subject a corticosteroid prior to the first, second, and third administrations of the anti-CD38 antibody.

In some aspects, the method further comprises administering to the subject a corticosteroid, an antipyretic, and an antihistamine prior to the first administration of the anti-CD38 antibody.

In some aspects, the method further comprises administering to the subject a leukotriene receptor antagonist prior to the first administration of the anti-CD38 antibody.

In some aspects, the method further comprises administering to the subject a corticosteroid prior to each administration of the anti-CD38 antibody.

In some aspects, the method further comprises administering to the subject an antipyretic prior to each administration of the anti-CD38 antibody.

In some aspects, the method further comprises administering to the subject an antihistamine prior to each administration of the anti-CD38 antibody.

In some aspects, the method further comprises administering to the subject a corticosteroid, an antipyretic, and an antihistamine prior to each administration of the anti-CD38 antibody.

In some aspects, the method comprises administering to the subject a corticosteroid on each of the two days following the first, second, and third administrations of the anti-CD38 antibody.

In some aspects, the corticosteroid is methylprednisolone, the antipyretic is acetaminophen, the antihistamine is diphenhydramine, and/or the leukotriene receptor is montelukast.

In some aspects, the method comprises administering to the subject the anti-TIGIT antagonist antibody at a fixed dose of about 600 mg.

In some aspects, the anti-TIGIT antagonist antibody comprises the following hypervariable regions (HVRs): (a) an HVR-H1 comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1); (b) an HVR-H2 comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3); (d) an HVR-L1 comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4); (e) an HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and (f) an HVR-L3 comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6).

In some aspects, the anti-TIGIT antagonist antibody further comprises the following light chain variable region FRs: (a) an FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7); (b) an FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8); (c) an FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and (d) an FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10).

In some aspects, the anti-TIGIT antagonist antibody further comprises the following heavy chain variable region FRs: (a) an FR-H1 comprising the amino acid sequence of XiVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11), wherein Xi is Q or E; (b) an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12); (c) an FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and (d) an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14). In some aspects, Xi is Q. In some aspects, Xi is E.

In some aspects, the anti-TIGIT antagonist antibody comprises: (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of EVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGKTYYRFKWYSDYAVSVK GRITINPDTSKNQFSLQLNSVTPEDTAVFYCTRESTTYDLLAGPFDYWGQGTLVTVSS (SEQ ID NO: 17) or QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGKTYYRFKWYSDYAVSVK GRITINPDTSKNQFSLQLNSVTPEDTAVFYCTRESTTYDLLAGPFDYWGQGTLVTVSS (SEQ ID NO: 18); (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of DIVMTQSPDSLAVSLGERATINCKSSQTVLYSSNNKKYLAWYQQKPGQPPNLLIYWASTRESGVPDRFSG SGSGTDFTLTISSLQAEDVAVYYCQQYYSTPFTFGPGTKVEIK (SEQ ID NO: 19); or (c) a VH domain as in (a) and a VL domain as in (b).

In some aspects, the anti-TIGIT antagonist antibody comprises: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 19.

In some aspects, the anti-TIGIT antagonist antibody comprises: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 17; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 19.

In some aspects, the anti-TIGIT antagonist antibody is a monoclonal antibody. In some aspects, the anti-TIGIT antagonist antibody is a human antibody. In some aspects, the anti-TIGIT antagonist antibody is a full-length antibody. In some aspects, the anti-TIGIT antagonist antibody exhibits effector function.

In some aspects, the anti-TIGIT antagonist antibody is an IgG class antibody. In some aspects, the IgG class antibody is an IgG 1 subclass antibody.

In some aspects, the anti-TIGIT antagonist antibody is tiragolumab.

In some aspects, the anti-TIGIT antagonist antibody is an antibody fragment that binds TIGIT selected from the group consisting of Fab, Fab’, Fab’-SH, Fv, single chain variable fragment (scFv), and (Fab’)2 fragments.

In some aspects, the anti-TIGIT antagonist antibody is vibostolimab, etigilimab, EQS084448, SGN-TGT, TJ-T6, BGB-A1217, AB308, domvanalimab, BMS-986207, ASP8374, or CQM902.

In some aspects, the anti-TIGIT antagonist antibody is administered intravenously.

In some aspects, the method comprises administering to the subject the anti-CD38 antibody at a dose of about 1800 mg.

In some aspects, the anti-CD38 antibody is an anti-CD38 antagonist antibody.

In some aspects, the anti-CD38 antibody comprises the following hypervariable regions (HVRs): (a) an HVR-H1 comprising the amino acid sequence of SFAMS (SEQ ID NO: 20); (b) an HVR-H2 comprising the amino acid sequence of AISGSGGGTYYADSVKG (SEQ ID NO: 21); (c) an HVR-H3 comprising the amino acid sequence of DKILWFGEPVFDY (SEQ ID NO: 22); (d) an HVR-L1 comprising the amino acid sequence of RASQSVSSYLA (SEQ ID NO: 23); (e) an HVR-L2 comprising the amino acid sequence of DASNRAT (SEQ ID NO: 24); and (f) an HVR-L3 comprising the amino acid sequence of QQRSNWPPTF (SEQ ID NO: 25).

In some aspects, the anti-CD38 antibody further comprises the following light chain variable region framework regions (FRs): (a) an FR-L1 comprising the amino acid sequence of EIVLTQSPATLSLSPGERATLSC (SEQ ID NO: 26); (b) an FR-L2 comprising the amino acid sequence of WYQQKPGQAPRLLIY (SEQ ID NO: 27); (c) an FR-L3 comprising the amino acid sequence of GIPARFSGSGSGTDFTLTISSLEPEDFAVYYC (SEQ ID NO: 28); and (d) an FR-L4 comprising the amino acid sequence of GQGTKVEIK (SEQ ID NO: 29).

In some aspects, the anti-CD38 antibody further comprises the following heavy chain variable region FRs: (a) an FR-H1 comprising the amino acid sequence of EVQLLESGGGLVQPGGSLRLSCAVSGFTFN (SEQ ID NO: 30); (b) an FR-H2 comprising the amino acid sequence of WVRQAPGKGLEWVS (SEQ ID NO: 31); (c) an FR-H3 comprising the amino acid sequence of RFTISRDNSKNTLYLQMNSLRAEDTAVYFCAK (SEQ ID NO: 32); and (d) an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 33).

In some aspects, the anti-CD38 antibody further comprises: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQAPGKGLEWVSAISGSGGGT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCAKDKILWFGEPVFDYWGQGTLVTVSS (SEQ ID NO: 34); (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIP ARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPTFGQGTKVEIK (SEQ ID NO: 35); or (c) a VH domain as in (a) and a VL domain as in (b).

In some aspects, the anti-CD38 antibody comprises: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 34; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 35.

In some aspects, the anti-CD38 antibody is a monoclonal antibody. In some aspects, the anti- CD38 antibody is a human antibody. In some aspects, the anti-CD38 antibody is a full-length antibody. In some aspects, the anti-CD38 antibody is daratumumab.

In some aspects, the anti-CD38 antibody is an antibody fragment that binds CD38 selected from the group consisting of Fab, Fab’, Fab’-SH, Fv, single chain variable fragment (scFv), and (Fab’)2 fragments.

In some aspects, the anti-CD38 antibody is an IgG class antibody. In some aspects, the IgG class antibody is an IgG 1 subclass antibody.

In some aspects, the method comprises administering to the subject the anti-CD38 antibody subcutaneously.

In some aspects, the anti-CD38 antibody is formulated with recombinant human hyaluronidase PH20 (rHuPH20). In some aspects, the anti-CD38 antibody is formulated with rHuPH20 at a dose of 1800 mg of the anti-CD38 antibody per 30,000 U rHuPH20.

In some aspects, the method comprises administering to the subject the anti-CD38 antibody intravenously.

In some aspects, the method comprises administering to the subject the PD-1 axis binding antagonist at a dose of about 1200 mg.

In some aspects, the PD-1 axis binding antagonist is selected from the group consisting of a PD- L1 binding antagonist, a PD-1 binding antagonist, and a PD-L2 binding antagonist. In some aspects, the PD-1 axis binding antagonist is a PD-L1 binding antagonist. In some aspects, the PD-L1 binding antagonist inhibits the binding of PD-L1 to one or more of its ligand binding partners. In some aspects, the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1 , B7-1 , or both PD-1 and B7-1 . In some aspects, the PD-L1 binding antagonist is an anti-PD-L1 antagonist antibody.

In some aspects, the anti-PD-L1 antagonist antibody is atezolizumab, MDX-1105, durvalumab, avelumab, SHR-1316, CS1001 , envafolimab, TQB2450, ZKAB001 , LP-002, CX-072, IMC-001 , KL-A167, APL-502, cosibelimab, lodapolimab, FAZ053, TG-1501 , BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311 , RC98, PDL-GEX, KD036, KY1003, YBL-007, or HS-636.

In some aspects, the anti-PD-L1 antagonist antibody is atezolizumab.

In some aspects, the anti-PD-L1 antagonist antibody comprises the following HVRs: (a) an HVR- H1 sequence comprising the amino acid sequence of GFTFSDSWIH (SEQ ID NO: 60); (b) an HVR-H2 sequence comprising the amino acid sequence of AWISPYGGSTYYADSVKG (SEQ ID NO: 61); (c) an HVR-H3 sequence comprising the amino acid sequence of RHWPGGFDY (SEQ ID NO: 62); (d) an HVR- L1 sequence comprising the amino acid sequence of RASQDVSTAVA (SEQ ID NO: 63); (e) an HVR-L2 sequence comprising the amino acid sequence of SASFLYS (SEQ ID NO: 64); and (f) an HVR-L3 sequence comprising the amino acid sequence of QQYLYHPAT (SEQ ID NO: 65).

In some aspects, the anti-PD-L1 antagonist antibody comprises: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 66; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 67; or (c) a VH domain as in (a) and a VL domain as in (b).

In some aspects, the anti-PD-L1 antagonist antibody comprises: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 66; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 67.

In some aspects, the anti-PD-L1 antagonist antibody comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 58; and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 59.

In some aspects, the anti-PD-L1 antagonist antibody is a monoclonal antibody. In some aspects, the anti-PD-L1 antagonist antibody is a humanized antibody. In some aspects, the anti-PD-L1 antagonist antibody is a humanized antibody. In some aspects, the anti-PD-L1 antagonist antibody is a full-length antibody.

In some aspects, the anti-PD-L1 antagonist antibody is an antibody fragment that binds PD-L1 selected from the group consisting of Fab, Fab’, Fab’-SH, Fv, scFv, and (Fab’)2 fragments. In some aspects, the anti-PD-L1 antagonist antibody is an IgG class antibody. In some aspects, the IgG class antibody is an IgG 1 subclass antibody.

In some aspects, the PD-1 axis binding antagonist is a PD-1 binding antagonist. In some aspects, the PD-1 binding antagonist inhibits the binding of PD-1 to one or more of its ligand binding partners. In some aspects, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 , PD-L2, or both PD-L1 and PD-L2. In some aspects, the PD-1 binding antagonist is an anti-PD-1 antagonist antibody.

In some aspects, the anti-PD-1 antagonist antibody is nivolumab, pembrolizumab, MEDI-0680, spartalizumab, cemiplimab, BGB-108, prolgolimab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, retifanlimab, sasanlimab, penpulimab, CS1003, HLX10, SCT-I10A, zimberelimab, balstilimab, genolimzumab, Bl 754091 , cetrelimab, YBL-006, BAT1306, HX008, budigalimab, AMG 404, CX-188, JTX-4014, 609A, Sym021 , LZM009, F520, SG001 , AM0001 , ENUM 244C8, ENUM 388D4, STI- 1110, AK-103, or hAb21.

In some aspects, the PD-1 binding antagonist is an Fc fusion protein. In some aspects, the Fc fusion protein is AMP-224.

In some aspects, the method comprises administering to the subject the PD-1 axis binding antagonist intravenously.

In some aspects, the hematologic cancer is a myeloma. In some aspects, the myeloma is a multiple myeloma (MM). In some aspects, the MM is a relapsed or refractory MM.

In another aspect, the disclosure provides a method for treating a subject having a relapsed or refractory MM, the method comprising administering to the subject tiragolumab at a fixed dose of 600 mg, daratumumab at a fixed dose of 1800 mg, and atezolizumab at a fixed dose of 1200 mg in a dosing regimen comprising at least nine dosing cycles, wherein the length of each dosing cycle is 21 days, and wherein: (a) tiragolumab is administered on or about day 1 of each dosing cycle; (b) atezolizumab is administered on or about day 1 of each dosing cycle; and (c) daratumumab is administered on or about days 1 , 8, and 15 of each of dosing cycles 1-3, on or about day 1 during each of dosing cycles 4-8, and once every 4 weeks beginning on or about day 1 of dosing cycle 9.

In another aspect, the disclosure provides a method for treating a subject having a relapsed or refractory MM, the method comprising administering to the subject tiragolumab at a fixed dose of 840 mg, daratumumab at a fixed dose of 1800 mg, and atezolizumab at a fixed dose of 1680 mg in a dosing regimen comprising at least nine dosing cycles, wherein the length of each dosing cycle is 21 days, and wherein: (a) the tiragolumab is administered once every 4 weeks; (b) the atezolizumab is administered once every 4 weeks; and (c) the daratumumab is administered on or about days 1 , 8, and 15 of each of dosing cycles 1-3, on or about day 1 during each of dosing cycles 4-8, and once every 4 weeks beginning on or about day 1 of dosing cycle 9.

In another aspect, the disclosure provides a method for treating a subject having a relapsed or refractory MM, the method comprising administering to the subject tiragolumab at a fixed dose of 420 mg, daratumumab at a fixed dose of 1800 mg, and atezolizumab at a fixed dose of 840 mg in a dosing regimen comprising at least nine dosing cycles, wherein the length of each dosing cycle is 21 days and wherein: (a) the tiragolumab is administered once every two weeks; (b) the atezolizumab is administered once every two weeks; and (c) the daratumumab is administered on or about days 1 , 8, and 15 of each of dosing cycles 1-3, on or about day 1 during each of dosing cycles 4-8, and once every 4 weeks beginning on or about day 1 of dosing cycle 9.

In some aspects, the dosing regimen comprises at least 16 dosing cycles.

In another aspect, the disclosure features a method for treating a subject having a relapsed or refractory MM, the method comprising administering to the subject tiragolumab at a fixed dose of 600 mg, daratumumab at a fixed dose of 1800 mg, and atezolizumab at a fixed dose of 1200 mg in a dosing regimen comprising at least 19 dosing cycles, wherein the length of each dosing cycle is 21 days, and wherein (a) tiragolumab is administered on or about day 1 of each dosing cycle; (b) atezolizumab is administered on or about day 1 of each dosing cycle; and (c) daratumumab is administered on or about days 1 , 8, and 15 of each of dosing cycles 1 and 2, on or about day 1 during each of dosing cycles 3-18, and once every 4 weeks beginning on or about day 1 of dosing cycle 19.

In another aspect, the disclosure features a method for treating a subject having a relapsed or refractory MM, the method comprising administering to the subject tiragolumab at a fixed dose of 840 mg, daratumumab at a fixed dose of 1800 mg, and atezolizumab at a fixed dose of 1680 mg in a dosing regimen comprising at least 19 dosing cycles, wherein the length of each dosing cycle is 21 days, and wherein (a) the tiragolumab is administered once every 4 weeks; (b) the atezolizumab is administered once every 4 weeks; and (c) the daratumumab is administered on or about days 1 , 8, and 15 of each of dosing cycles 1 and 2, on or about day 1 during each of dosing cycles 3-18, and once every 4 weeks beginning on or about day 1 of dosing cycle 19.

In another aspect, the disclosure features a method for treating a subject having a relapsed or refractory MM, the method comprising administering to the subject tiragolumab at a fixed dose of 420 mg, daratumumab at a fixed dose of 1800 mg, and atezolizumab at a fixed dose of 840 mg in a dosing regimen comprising at least 19 dosing cycles, wherein the length of each dosing cycle is 21 days and wherein (a) the tiragolumab is administered once every two weeks; (b) the atezolizumab is administered once every two weeks; and (c) the daratumumab is administered on or about days 1 , 8, and 15 of each of dosing cycles 1 and 2, on or about day 1 during each of dosing cycles 3-18, and once every 4 weeks beginning on or about day 1 of dosing cycle 19.

In some aspects, the method comprises administering to the subject the tiragolumab simultaneously with the atezolizumab.

In some aspects, the method comprises administering to the subject the tiragolumab after the atezolizumab.

In some aspects, the method comprises administering to the subject the atezolizumab after the tiragolumab.

In another aspect, the disclosure provides a method for treating a subject having a hematologic cancer, the method comprising administering to the subject an anti-TIGIT antagonist antibody at a fixed dose of about 840 mg, an anti-CD38 antibody at a dose of about 1800 mg, and a PD-1 axis binding antagonist at a dose of about 1680 mg in a dosing regimen comprising at least nine dosing cycles, wherein: (a) the anti-TIGIT antagonist antibody is administered once every four weeks; (b) the PD-1 axis binding antagonist is administered once every four weeks; and (c) the anti-CD38 antibody is administered once every week during each of dosing cycles 1 -3, once every three weeks during each of dosing cycles 4-8, and once every four weeks during dosing cycle 9. In another aspect, the disclosure provides a method for treating a subject having a hematologic cancer, the method comprising administering to the subject an anti-TIGIT antagonist antibody at a fixed dose of about 420 mg, an anti-CD38 antibody at a dose of about 1800 mg, and a PD-1 axis binding antagonist at a dose of about 840 mg in a dosing regimen comprising at least nine dosing cycles, wherein: (a) the anti-TIGIT antagonist antibody is administered once every two weeks; (b) the PD-1 axis binding antagonist is administered once every two weeks; and (c) the anti-CD38 antibody is administered once every week during each of dosing cycles 1 -3, once every three weeks during each of dosing cycles 4-8, and once every four weeks during dosing cycle 9.

In another aspect, the disclosure features a method for treating a subject having a hematologic cancer, the method comprising administering to the subject an anti-TIGIT antagonist antibody at a fixed dose of about 840 mg, an anti-CD38 antibody at a dose of about 1800 mg, and a PD-1 axis binding antagonist at a dose of about 1680 mg in a dosing regimen comprising at least 19 dosing cycles, wherein (a) the anti-TIGIT antagonist antibody is administered once every four weeks; (b) the PD-1 axis binding antagonist is administered once every four weeks; and (c) the anti-CD38 antibody is administered once every week during each of dosing cycles 1 and 2, once every three weeks during each of dosing cycles 3- 18, and once every four weeks during dosing cycle 19.

In another aspect, the disclosure features a method for treating a subject having a hematologic cancer, the method comprising administering to the subject an anti-TIGIT antagonist antibody at a fixed dose of about 420 mg, an anti-CD38 antibody at a dose of about 1800 mg, and a PD-1 axis binding antagonist at a dose of about 840 mg in a dosing regimen comprising at least 19 dosing cycles, wherein (a) the anti-TIGIT antagonist antibody is administered once every two weeks; (b) the PD-1 axis binding antagonist is administered once every two weeks; and (c) the anti-CD38 antibody is administered once every week during each of dosing cycles 1 and 2, once every three weeks during each of dosing cycles 3- 18, and once every four weeks during dosing cycle 19.

In some aspects, the length of each dosing cycle is 21 days.

In another aspect, the disclosure provides a kit comprising an anti-TIGIT antagonist antibody, an PD-1 axis binding antagonist, and an anti-CD38 antibody, and a package insert comprising instructions to administer the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, and the anti-CD38 antibody to a subject having a hematologic cancer. In some aspects, the anti-TIGIT antagonist antibody is tiragolumab, the PD-1 axis binding antagonist is atezolizumab, and the anti-CD38 antibody is daratumumab.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic diagram showing an overview of the tiragolumab plus daratumumab dosing schedule in Arm C of the GO41036 clinical trial. Timing of the administration of the investigational medicinal products is indicated by the arrows at various time points. C = cycle; D = day; Q4W= every 4 weeks.

FIG. 2 is a schematic diagram showing an overview of an exemplary dosing schedule for the tiragolumab plus daratumumab plus atezolizumab arm (Arm E) of the GO41036 clinical trial. Timing of the administration of the investigational medicinal products is indicated by the arrows at various time points. C = cycle; D = day; Q4W = every 4 weeks. DETAILED DESCRIPTION OF THE INVENTION

The present invention provides therapeutic methods and compositions for treatment of hematologic cancer. The invention is based, at least in part, on the discovery that immunotherapies including an anti-TIGIT antibody (e.g., an anti-TIGIT antagonist antibody, such as tiragolumab) in combination with a PD-1 axis binding antagonist (e.g., an anti-programmed death ligand-1 (PD-L1) antibody (e.g., atezolizumab) or an anti-programmed death-1 (PD-1) antibody) and an anti-CD38 antibody (e.g., daratumumab) can be useful in the treatment of cancer. The invention is also based, at least in part, on the discovery that immunotherapies including an anti-TIGIT antibody (e.g., an anti-TIGIT antagonist antibody, such as tiragolumab) in combination with an anti-CD38 antibody (e.g., daratumumab), and immunotherapies including an anti-TIGIT antibody (e.g., an anti-TIGIT antagonist antibody, such as tiragolumab) in combination with an anti-CD20 antibody (e.g., rituximab) can be useful in the treatment of cancer. Compositions, uses, and kits involving such combinations and/or dosing regimens are also provided herein.

I. General Techniques

The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodology by those skilled in the art, such as, for example, the widely utilized methodologies described in Sambrook et al., Molecular Cloning: A Laboratory Manual 3d edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Current Protocols in Molecular Biology (F.M. Ausubel, et al. eds., (2003)); the series Methods in Enzymology (Academic Press, Inc.): PCR 2: A Practical Approach (M.J. MacPherson, B.D. Hames and G.R. Taylor eds. (1995)), Harlow and Lane, eds. (1988) Antibodies, A Laboratory Manual, and Animal Cell Culture (R.l. Freshney, ed. (1987)); Oligonucleotide Synthesis (M.J. Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (J.E. Cellis, ed., 1998) Academic Press; Animal Cell Culture (R.l. Freshney), ed., 1987); Introduction to Cell and Tissue Culture (J.P. Mather and P.E. Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (A. Doyle, J.B. Griffiths, and D.G. Newell, eds., 1993-8) J. Wiley and Sons; Handbook of Experimental Immunology (D.M. Weir and C.C. Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (J.M. Miller and M.P. Calos, eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994); Current Protocols in Immunology (J.E. Coligan et al., eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (C .A. Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: A Practical Approach (D. Catty., ed., IRL Press, 1988-1989); Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and J. D. Capra, eds., Harwood Academic Publishers, 1995); and Cancer: Principles and Practice of Oncology (V.T. DeVita et al., eds.,

J.B. Lippincott Company, 1993).

II. Definitions

The following abbreviations are used herein:

It is to be understood that aspects and embodiments of the invention described herein include “comprising,” “consisting,” and “consisting essentially of’ aspects and embodiments. As used herein, the singular form “a,” “an,” and “the” includes plural references unless indicated otherwise.

The term “about” as used herein refers to the usual error range for the respective value readily known to the skilled person in this technical field. Reference to “about” a value or parameter herein includes (and describes) aspects that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X.”

As used herein, “achieving a clinical response” refers to achieving one or more indicators of therapeutic efficacy for a disease (e.g., a cancer, e.g., a hematologic cancer) in a patient or population of patients during or following treatment with one or more agents intended to treat the disease (e.g., during or following a dosing regimen comprising one or more agents, e.g., during or following a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody, an anti-CD38 antibody, and a PD-1 axis binding antagonist (e.g., tiragolumab, daratumumab, and atezolizumab)); an anti-TIGIT antagonist antibody and an anti-CD38 antibody (e.g., tiragolumab and daratumumab); or an anti-TIGIT antagonist antibody and an anti-CD20 antibody (e.g., tiragolumab and rituximab); wherein the improvement is attributed to the treatment. The indicator of therapeutic efficacy may be, e.g., progression-free survival (PFS) (e.g., a duration of PFS that is at or above a target duration of PFS); overall survival (OS) (e.g., a duration of OS that is at or above a target duration of OS); a partial response (PR); a complete response (CR); an objective response rate (ORR); or a duration of objective response (DOR). The term “TIGIT” or “T-cell immunoreceptor with Ig and ITIM domains” as used herein refers to any native TIGIT from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. TIGIT is also known in the art as DKFZp667A205, FLJ39873, V-set and immunoglobulin domain-containing protein 9, V-set and transmembrane domain-containing protein 3, VSIG9, VSTM3, and WUCAM. The term encompasses “full- length,” unprocessed TIGIT (e.g., full-length human TIGIT having the amino acid sequence of SEQ ID NO: 52), as well as any form of TIGIT that results from processing in the cell (e.g., processed human TIGIT without a signal sequence, having the amino acid sequence of SEQ ID NO: 53). The term also encompasses naturally occurring variants of TIGIT, e.g., splice variants or allelic variants. The amino acid sequence of an exemplary human TIGIT may be found under UniProt Accession Number Q495A1 .

As used herein, “tiragolumab” is a fully human IgGI/kappa MAb-derived in Open Monoclonal Technology (OMT) rats that binds TIGIT and comprises the heavy chain sequence of SEQ ID NO: 69 and the light chain sequence of SEQ ID NO: 70. Tiragolumab comprises two N-linked glycosylation sites (N306) in the Fc domain. Tiragolumab is also described in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Proposed INN: List 117, Vol. 31 , No. 2, published July 7, 2017 (see page 343).

The term “anti-TIGIT antagonist antibody” refers to an antibody or an antigen-binding fragment or variant thereof that is capable of binding TIGIT with sufficient affinity such that it substantially or completely inhibits the biological activity of TIGIT. For example, an anti-TIGIT antagonist antibody may block signaling through PVR, PVRL2, and/or PVRL3 so as to restore a functional response by T-cells (e.g., proliferation, cytokine production, target cell killing) from a dysfunctional state to antigen stimulation. For example, an anti-TIGIT antagonist antibody may block signaling through PVR without impacting PVR- CD226 interaction. It will be understood by one of ordinary skill in the art that in some instances, an anti- TIGIT antagonist antibody may antagonize one TIGIT activity without affecting another TIGIT activity. For example, an anti-TIGIT antagonist antibody for use in certain of the methods or uses described herein is an anti-TIGIT antagonist antibody that antagonizes TIGIT activity in response to one of PVR interaction, PVRL3 interaction, or PVRL2 interaction, e.g., without affecting or minimally affecting any of the other TIGIT interactions. In one aspect, the extent of binding of an anti-TIGIT antagonist antibody to an unrelated, non-TIGIT protein is less than about 10% of the binding of the antibody to TIGIT as measured, e.g., by a radioimmunoassay (RIA). In certain aspects, an anti-TIGIT antagonist antibody that binds to TIGIT has a dissociation constant (KD) of < 1 pM, < 100 nM, < 10 nM, < 1 nM, < 0.1 nM, < 0.01 nM, or < 0.001 nM (e.g., 10⁸ M or less, e.g., from 10⁸ M to 10 ¹³ M, e.g., from 10⁹ M to 10 ¹³ M). In certain aspects, an anti-TIGIT antagonist antibody binds to an epitope of TIGIT that is conserved among TIGIT from different species or an epitope on TIGIT that allows for cross-species reactivity. In some aspects, the anti-TIGIT binding antibody has intact Fc-mediated effector function (e.g., tiragolumab, vibostolimab, etigilimab, EQS084448, or TJ-T6). In some aspects, the anti-TIGIT binding antibody has enhanced Fc- mediated effector function (e.g., SGN-TGT). In other aspects, the anti-TIGIT binding antibody lacks Fc- mediated effector function (e.g., domvanalimab, BMS-986207, ASP8374, or CQM902). In some aspects, the anti-TIGIT binding antibody is an lgG1 class antibody (e.g., tiragolumab, vibostolimab, domvanalimab, BMS-986207, etigilimab, BGB-A1217, SGN-TGT, EQS084448 (EOS-448), TJ-T6, or AB308). In other aspects, the anti-TIGIT binding antibody is an lgG4 class antibody (e.g., ASP8374 or COM902). In one aspect, the anti-TIGIT antagonist antibody is tiragolumab.

The term “PD-1 axis binding antagonist” refers to a molecule that inhibits the interaction of a PD-1 axis binding partner with either one or more of its binding partners, so as to remove T-cell dysfunction resulting from signaling on the PD-1 signaling axis, with a result being to restore or enhance T-cell function (e.g., proliferation, cytokine production, and/or target cell killing). As used herein, a PD-1 axis binding antagonist includes a PD-L1 binding antagonist, a PD-1 binding antagonist, and a PD-L2 binding antagonist. In some instances, the PD-1 axis binding antagonist includes a PD-L1 binding antagonist or a PD-1 binding antagonist. In a preferred aspect, the PD-1 axis binding antagonist is a PD-L1 binding antagonist.

The term “PD-L1 binding antagonist” refers to a molecule that decreases, blocks, inhibits, abrogates, or interferes with signal transduction resulting from the interaction of PD-L1 with either one or more of its binding partners, such as PD-1 and/or B7-1. In some instances, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partners. In a specific aspect, the PD-L1 binding antagonist inhibits binding of PD-L1 to PD-1 and/or B7-1 . In some instances, the PD-L1 binding antagonists include anti-PD-L1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners, such as PD-1 and/or B7-1 . In one instance, a PD-L1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD- L1 so as to render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some instances, the PD-L1 binding antagonist binds to PD-L1 . In some instances, a PD- L1 binding antagonist is an anti-PD-L1 antibody (e.g., an anti-PD-L1 antagonist antibody). Exemplary anti-PD-L1 antagonist antibodies include atezolizumab, MDX-1105, MEDI4736 (durvalumab), MSB0010718C (avelumab), SHR-1316, CS1001 , envafolimab, TQB2450, ZKAB001 , LP-002, CX-072, IMC-001 , KL-A167, APL-502, cosibelimab, lodapolimab, FAZ053, TG-1501 , BGB-A333, BCD-135, AK- 106, LDP, GR1405, HLX20, MSB2311 , RC98, PDL-GEX, KD036, KY1003, YBL-007, and HS-636. In some aspects, the anti-PD-L1 antibody is atezolizumab, MDX-1105, MEDI4736 (durvalumab), or MSB0010718C (avelumab). In one specific aspect, the PD-L1 binding antagonist is MDX-1105. In another specific aspect, the PD-L1 binding antagonist is MEDI4736 (durvalumab). In another specific aspect, the PD-L1 binding antagonist is MSB0010718C (avelumab). In other aspects, the PD-L1 binding antagonist may be a small molecule, e.g., GS-4224, INCB086550, MAX-10181 , INCB090244, CA-170, or ABSK041 , which in some instances may be administered orally. Other exemplary PD-L1 binding antagonists include AVA-004, MT-6035, VXM10, LYN192, GB7003, and JS-003. In a preferred aspect, the PD-L1 binding antagonist is atezolizumab.

The term “PD-1 binding antagonist” refers to a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-1 with one or more of its binding partners, such as PD-L1 and/or PD-L2. PD-1 (programmed death 1) is also referred to in the art as “programmed cell death 1 ,” “PDCD1 ,” “CD279,” and “SLEB2.” An exemplary human PD-1 is shown in UniProtKB/Swiss-Prot Accession No. Q15116. In some instances, the PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to one or more of its binding partners. In a specific aspect, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 and/or PD-L2. For example, PD-1 binding antagonists include anti-PD-1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-1 with PD-L1 and/or PD-L2. In one instance, a PD-1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-1 so as render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some instances, the PD-1 binding antagonist binds to PD-1 . In some instances, the PD-1 binding antagonist is an anti-PD-1 antibody (e.g., an anti-PD-1 antagonist antibody). Exemplary anti-PD-1 antagonist antibodies include nivolumab, pembrolizumab, MEDI-0680, PDR001 (spartalizumab), REGN2810 (cemiplimab), BGB-108, prolgolimab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, retifanlimab, sasanlimab, penpulimab, CS1003, HLX10, SCT-I10A, zimberelimab, balstilimab, genolimzumab, Bl 754091 , cetrelimab, YBL-006, BAT1306, HX008, budigalimab, AMG 404, CX-188, JTX-4014, 609A, Sym021 , LZM009, F520, SG001 , AM0001 , ENUM 244C8, ENUM 388D4, STI-1110, AK-103, and hAb21 . In a specific aspect, a PD-1 binding antagonist is MDX-1106 (nivolumab). In another specific aspect, a PD-1 binding antagonist is MK-3475 (pembrolizumab). In another specific aspect, a PD-1 binding antagonist is a PD-L2 Fc fusion protein, e.g., AMP-224. In another specific aspect, a PD-1 binding antagonist is MEDI- 0680. In another specific aspect, a PD-1 binding antagonist is PDR001 (spartalizumab). In another specific aspect, a PD-1 binding antagonist is REGN2810 (cemiplimab). In another specific aspect, a PD-1 binding antagonist is BGB-108. In another specific aspect, a PD-1 binding antagonist is prolgolimab. In another specific aspect, a PD-1 binding antagonist is camrelizumab. In another specific aspect, a PD-1 binding antagonist is sintilimab. In another specific aspect, a PD-1 binding antagonist is tislelizumab. In another specific aspect, a PD-1 binding antagonist is toripalimab. Other additonal exemplary PD-1 binding antagonists include BION-004, CB201 , AUNP-012, ADG104, and LBL-006.

The term “PD-L2 binding antagonist” refers to a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-L2 with either one or more of its binding partners, such as PD-1 . PD-L2 (programmed death ligand 2) is also referred to in the art as “programmed cell death 1 ligand 2,” “PDCD1 LG2,” “CD273,” “B7-DC,” “Btdc,” and “PDL2.” An exemplary human PD-L2 is shown in UniProtKB/Swiss-Prot Accession No. Q9BQ51. In some instances, a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to one or more of its binding partners. In a specific aspect, the PD-L2 binding antagonist inhibits binding of PD-L2 to PD-1 . Exemplary PD-L2 antagonists include anti-PD-L2 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L2 with either one or more of its binding partners, such as PD-1 . In one aspect, a PD-L2 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-L2 so as render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some aspects, the PD-L2 binding antagonist binds to PD-L2. In some aspects, a PD-L2 binding antagonist is an immunoadhesin. In other aspects, a PD-L2 binding antagonist is an anti- PD-L2 antagonist antibody. The terms “programmed death ligand 1” and “PD-L1” refer herein to native sequence human PD- L1 polypeptide. Native sequence PD-L1 polypeptides are provided under Uniprot Accesion No. Q9NZQ7. For example, the native sequence PD-L1 may have the amino acid sequence as set forth in Uniprot Accesion No. Q9NZQ7-1 (isoform 1) (SEQ ID NO: 68). In another example, the native sequence PD-L1 may have the amino acid sequence as set forth in Uniprot Accesion No. Q9NZQ7-2 (isoform 2). In yet another example, the native sequence PD-L1 may have the amino acid sequence as set forth in Uniprot Accesion No. Q9NZQ7-3 (isoform 3). PD-L1 is also referred to in the art as “programmed cell death 1 ligand 1 ,” “PDCD1 LG1 ,” “CD274,” “B7-H,” and “PDL1 .”

The Kabat numbering system is generally used when referring to a residue in the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain) (e.g., Kabat et al., Sequences of Immunological Interest. 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)). The “EU numbering system” or“EU index” is generally used when referring to a residue in an immunoglobulin heavy chain constant region (e.g., the EU index reported in Kabat et al., supra). The “EU index as in Kabat” refers to the residue numbering of the human IgG 1 EU antibody.

For the purposes herein, “atezolizumab” is an Fc-engineered, humanized, non-glycosylated lgG1 kappa immunoglobulin that binds PD-L1 and comprises the heavy chain sequence of SEQ ID NO: 58 and the light chain sequence of SEQ ID NO: 59. Atezolizumab comprises a single amino acid substitution (asparagine to alanine) at position 297 on the heavy chain (N297A) using EU numbering of Fc region amino acid residues, which results in a non-glycosylated antibody that has minimal binding to Fc receptors. Atezolizumab is also described in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Proposed INN: List 112, Vol. 28, No. 4, published January 16, 2015 (see page 485).

“CD20” and “CD20 antigen” are used interchangeably herein and refer to a transmembrane phosphoprotein with a molecular weight of approximately 35 kD that is found on the surface of greater than 90% of B cells from peripheral blood or lymphoid organs. CD20 is expressed during early pre-B cell development and remains until plasma cell differentiation; it is not found on human stem cells, lymphoid progenitor cells, or normal plasma cells. CD20 is present on both normal B cells as well as malignant B cells, and is expressed in > 90% of B cell NHLs. CD20 includes any native CD20 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. The term encompasses “full-length,” unprocessed CD20, as well as any form of CD20 that results from processing in the cell. The term also encompasses naturally occurring variants of CD20, e.g., splice variants or allelic variants. Other names for CD20 in the literature include “B- lymphocyte- restricted differentiation antigen” and “Bp35”. The CD20 antigen is encoded by the MS4A1 gene. The nucleic acid sequence of an exemplary human MS4A1 is shown under NCBI Reference Sequence: NM_152866.2 or in SEQ ID NO: 54. The amino acid sequence of an exemplary CD20 protein encoded by MS4A1 is shown under UniProt Accession No. P11836 or in SEQ ID NO: 55. The CD20 antigen is described in, for example, Clark and Ledbetter, Adv. Can. Res. 52:81-149, 1989 and Valentine et al. J. Biol. Chem. 264(19):11282-11287, 1989.

“Anti-CD20 antibody” and “CD20 binding antibody” are used interchangeably herein and encompass all antibodies that bind CD20 with sufficient affinity such that the antibody is useful as a therapeutic agent in targeting a cell expressing the antigen, and do not significantly cross-react with other proteins such as a negative control protein in the assays described below. For example, an anti-CD20 antibody may bind to CD20 on the surface of a malignant B cell and mediate B cell lysis through the activation of complement-dependent lysis, antibody-dependent cellular cytotoxicity (ADCC), and apoptosis mediated by Fc cross-linking, leading to the depletion of circulating B lymphocytes. In certain aspects, an anti-CD20 antibody that binds to CD20 has a dissociation constant (KD) of < 1 pM, < 100 nM, < 10 nM, < 1 nM, < 0.1 nM, < 0.01 nM, or < 0.001 nM (e.g., 10 ⁸ M or less, e.g., from 10⁸ M to 10 ¹³ M, e.g., from 10 ⁹ M to 10 ¹³ M). In certain aspects, an anti-CD20 antibody that binds to CD20 has a KD of < 10 nM. In certain aspects, the binding is at a KD of < 7.5 nM, < 5 nM, between 1-5 nM, or <1 nM. In certain aspects, the anti-CD20 antibody may bind to both human CD20 and cyno CD20. Anti-CD20 antibodies also include anti-CD20 antagonist antibodies. Bispecific antibodies wherein one arm of the antibody binds CD20 are also contemplated. Also encompassed by this definition of anti-CD20 antibody are functional fragments of the preceding antibodies.

Examples of antibodies which bind the CD20 antigen include: “C2B8” which is now called “rituximab” (“RITUXAN®”) (US Patent No. 5,736,137, expressly incorporated herein by reference); the yttrium-[90]-labeled 2B8 murine antibody designated “Y2B8” or “Ibritumomab Tiuxetan” ZEVALIN® (US Patent No. 5,736,137, expressly incorporated herein by reference); murine lgG2a “B1 ,” also called “tositumomab,” (Beckman Coulter) optionally labeled with ¹³¹1 to generate the “131 I-B1 ” antibody (iodine 1131 tositumomab, BEXXAR™) (US Patent No. 5,595,721 , expressly incorporated herein by reference); murine monoclonal antibody “1 F5” (Press et al. Blood 69(2):584-591 , 1987 and variants thereof including “framework patched” or humanized 1 F5 (W003/002607, Leung, S.); ATCC deposit HB-96450); murine 2H7 and chimeric 2H7 antibody (US Patent No. 5,677,180, expressly incorporated herein by reference); humanized 2H7; huMax-CD20 or “ofatumumab” ARZERRA® (Genmab, Denmark); AME-133 (Applied Molecular Evolution); A20 antibody or variants thereof such as chimeric or humanized A20 antibody (cA20, hA20, respectively) (US 2003/0219433, Immunomedics); and monoclonal antibodies L27, G28-2, 93-1 B3, B-C1 or NU-B2 available from the International Leukocyte Typing Workshop (Valentine et al., In: Leukocyte Typing III (McMichael, Ed., p. 440, Oxford University Press, 1987).

The terms “rituximab” or “RITUXAN®” herein refer to the genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen and designated “C2B8” in US Patent No. 5,736,137, expressly incorporated herein by reference, including fragments thereof which retain the ability to bind CD20. Rituximab is also described in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Proposed INN: List 77, Vol. 11 , No. 2, published June 9, 1997 (see page 99).

The term “rituximab and hyaluronidase human” or “RITUXAN HYCELA®” herein refers to a formulation of rituximab comprising recombinant human hyaluronidase (rHuPH20).

“CD38” as used herein, refers to a CD38 glycoprotein found on the surface of many immune cells, including CD4+, CD8+, B lymphocytes, and natural killer (NK) cells, and includes any native CD38 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. CD38 is expressed at a higher level and more uniformly on myeloma cells as compared to normal lymphoid and myeloid cells. The term encompasses “full-length,” unprocessed CD38, as well as any form of CD38 that results from processing in the cell. The term also encompasses naturally occurring variants of CD38, e.g., splice variants or allelic variants. CD38 is also referred to in the art as cluster of differentiation 38, ADP-ribosyl cyclase 1 , cADPr hydrolase 1 , and cyclic ADP-ribose hydrolase 1 . CD38 is encoded by the CD38 gene. The nucleic acid sequence of an exemplary human CD38 is shown under NCBI Reference Sequence: NM_001775.4 or in SEQ ID NO: 56. The amino acid sequence of an exemplary human CD38 protein encoded by CD38 is shown under UniProt Accession No. P28907 or in SEQ ID NO: 57.

The term “anti-CD38 antibody” encompass all antibodies that bind CD38 with sufficient affinity such that the antibody is useful as a therapeutic agent in targeting a cell expressing the antigen, and do not significantly cross-react with other proteins such as a negative control protein in the assays described below. For example, an anti-CD38 antibody may bind to CD38 on the surface of a MM cell and mediate cell lysis through the activation of complement-dependent cytotoxicity, ADCC, antibody-dependent cellular phagocytosis (ADCP), and apoptosis mediated by Fc cross-linking, leading to the depletion of malignant cells and reduction of the overall cancer burden. An anti-CD38 antibody may also modulate CD38 enzyme activity through inhibition of ribosyl cyclase enzyme activity and stimulation of the cyclic adenosine diphosphate ribose (cADPR) hydrolase activity of CD38. In certain aspects, an anti-CD38 antibody that binds to CD38 has a dissociation constant (KD) of < 1 pM, < 100 nM, < 10 nM, < 1 nM, < 0.1 nM, < 0.01 nM, or < 0.001 nM (e.g., 10⁸ M or less, e.g., from 10⁸ M to 10¹³ M, e.g., from 10⁹ M to 10¹³ M). In certain aspects, the anti-CD38 antibody may bind to both human CD38 and chimpanzee CD38. Anti-CD38 antibodies also include anti-CD38 antagonist antibodies. Bispecific antibodies wherein one arm of the antibody binds CD38 are also contemplated. Also encompassed by this definition of anti-CD38 antibody are functional fragments of the preceding antibodies. Examples of antibodies which bind CD38 include: daratumumab (DARZALEX®) (U.S. Patent No: 7,829,673 and U.S. Pub. No: 20160067205 A1 , expressly incorporated herein by reference); “MOR202” (U.S. Patent No: 8,263,746, expressly incorporated herein by reference); and isatuximab (SAR-650984) (U.S. Patent No: 8,153,765, expressly incorporated herein by reference).

For the purposes herein, “daratumumab” is an immunoglobulin G1 kappa (IgGl K) human monoclonal antibody that binds to the CD38 antigen and comprises the heavy chain sequence of SEQ ID NO: 34 and the light chain sequence of SEQ ID NO: 35. Daratumumab is also described in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Proposed INN: List 101 , Vol. 23, No. 2, published July 15, 2009 (see page 138-139).

The term “daratumumab and hyaluronidase-fihj” or “DARZALEX FASPRO®” herein refers to a formulation of daratumumab comprising recombinant human hyaluronidase (rHuPH20).

The term “cancer” refers to a disease caused by an uncontrolled division of abnormal cells in a part of the body. In one instance, the cancer is a hematologic cancer. The cancer may be advanced or metastatic. The cancer may be relapsed or refractory. Examples of cancer include, but are not limited to, lymphoma, blastoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include, but are not limited to, hematologic cancers including myeloma and B cell lymphoma (including multiple myeloma (MM) (e.g., relapsed or refractory MM); diffuse large B-cell lymphoma (DLBCL) (e.g., relapsed or refractory DLBCL); follicular lymphoma (FL) (e.g., relapsed or refractory FL); non-Hodgkin lymphoma (NHL) (e.g., relapsed or refractory NHL); low grade/follicular 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); acute myologenous leukemia (AML); hairy cell leukemia; and chronic myeloblastic leukemia (CML).

The term “tumor” refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. The terms “cancer,” “cancerous,” “cell proliferative disorder,” “proliferative disorder,” and “tumor” are not mutually exclusive as referred to herein.

A “tumor cell” as used herein, refers to any tumor cell present in a tumor or a sample thereof. Tumor cells may be distinguished from other cells that may be present in a tumor sample, for example, stromal cells and tumor-infiltrating immune cells, using methods known in the art and/or described herein.

“Tumor immunity” refers to the process in which tumors evade immune recognition and clearance. Thus, as a therapeutic concept, tumor immunity is “treated” when such evasion is attenuated, and the tumors are recognized and attacked by the immune system. Examples of tumor recognition include tumor binding, tumor shrinkage, and tumor clearance.

As used herein, “metastasis” is meant the spread of cancer from its primary site to other places in the body. Cancer cells can break away from a primary tumor, penetrate into lymphatic and blood vessels, circulate through the bloodstream, and grow in a distant focus (metastasize) in normal tissues elsewhere in the body. Metastasis can be local or distant. Metastasis is a sequential process, contingent on tumor cells breaking off from the primary tumor, traveling through the bloodstream, and stopping at a distant site. At the new site, the cells establish a blood supply and can grow to form a life-threatening mass. Both stimulatory and inhibitory molecular pathways within the tumor cell regulate this behavior, and interactions between the tumor cell and host cells in the distant site are also significant.

As used herein, “treating” comprises effective cancer treatment with an effective amount of a therapeutic agent (e.g., an anti-TIGIT antagonist antibody (e.g., tiragolumab) or combination of therapeutic agents (e.g., a PD-1 axis binding antagonist, an anti-CD38 antibody, and an anti-TIGIT antagonist antibody, e.g., atezolizumab, daratumumab, and tiragolumab). Treating herein includes, inter alia, adjuvant therapy, neoadjuvant therapy, non-metastatic cancer therapy (e.g., locally advanced cancer therapy), and metastatic cancer therapy. The treatment may be first-line treatment (e.g., the patient may be previously untreated or not have received prior systemic therapy), or second line or later treatment.

Herein, an “effective amount” refers to the amount of a therapeutic agent (e.g., an anti-TIGIT antagonist antibody (e.g., tiragolumab) or a combination of therapeutic agents (e.g., a PD-1 axis binding antagonist, an anti-CD38 antibody, and an anti-TIGIT antagonist antibody, e.g., atezolizumab, daratumumab, and tiragolumab)), that achieves a therapeutic result. In some examples, the effective amount of a therapeutic agent or a combination of therapeutic agents is the amount of the agent or of the combination of agents that achieves a clinical endpoint of improved objective response rate (ORR), a complete response (CR), a partial response (PR), improved survival (e.g., progression-free survival (PFS) and/or overall survival (OS)), and/or improved duration of response (DOR).

“Individual response” or “response” can be assessed using any endpoint indicating a benefit to the subject, including, without limitation, (1) inhibition, to some extent, of disease progression (e.g., progression of cancer, e.g., a hematologic cancer, e.g., a myeloma (e.g., MM, e.g., a relapsed or refractory MM) or a lymphoma (e.g., a NHL, e.g., a relapsed or refractory DLBCL or a relapsed or refractory FL)), including slowing down and complete arrest; (2) a reduction in tumor size; (3) inhibition (i.e., reduction, slowing down or complete stopping) of cancer cell infiltration into adjacent peripheral organs and/or tissues; (4) inhibition (i.e. reduction, slowing down or complete stopping) of metastasis; (5) relief, to some extent, of one or more symptoms associated with the disease or disorder (e.g., cancer, e.g., a hematologic cancer, e.g., a myeloma (e.g., MM, e.g., a relapsed or refractory MM) or a lymphoma (e.g., a NHL, e.g., a relapsed or refractory DLBCL or a relapsed or refractory FL)); (6) increase or extend in the length of survival, including overall survival and progression-free survival; and/or (7) decreased mortality at a given point of time following treatment.

An “objective response” refers to a measurable response including complete response (CR) or partial response (PR). In some aspects, “objective response rate” (ORR) refers to the sum of complete response (CR) rate and partial response (PR) rate. For MM, ORR may be defined as the proportion of patients with best overall response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) (see, e.g., Table 4, below), as defined by the International Myeloma Working Group Uniform Response (IMWG) criteria, as disclosed in Durie et al. Leukemia. 20(9):1467-1473, 2006; Durie et al. Leukemia. 29:2416-2417, 2015; and Kumar et al. Lancet Oncol. 17:e328-46, 2016; which are incorporated herein by reference in their entireties. For NHL, ORR may be defined as the proportion of patients with a CR or PR on two consecutive occasions > 4 weeks apart, according to the Lugano Response Criteria for Malignant Lymphoma (Lugano) classification (see, e.g., Table 6, below), as described in Cheson et al. J. Clin. Oncol. 32(27):3059-3067, 2014, which is incorporated herein by reference in its entirety.

As used herein, “duration of objective response” (DOR) is defined as the time from the first occurrence of a documented objective response to disease progression (e.g., according to IMWG criteria for MM (see, e.g., Tables 4 and 5, below) or according to the Lugano classification for NHL (see, e.g., Table 6, below)), or death from any cause within 30 days of the last dose of a treatment, whichever occurs first.

As used herein, “survival” refers to the patient remaining alive, and includes overall survival as well as progression-free survival.

As used herein, “overall survival” (OS) refers to the percentage of subjects in a group who are alive after a particular duration of time, e.g., 1 year or 5 years from the time of diagnosis or treatment. In some aspects, OS may be defined as the time from enrollment to death from any cause. OS may be defined as the time from the first study treatment to death from any cause.

As used herein, “progression-free survival” (PFS) refers to the length of time during and after treatment during which the disease being treated (e.g., cancer, e.g., a hematologic cancer, e.g., a myeloma (e.g., MM, e.g., a relapsed or refractory MM) or a lymphoma (e.g., a NHL, e.g., a relapsed or refractory DLBCL or a relapsed or refractory FL)) does not get worse, i.e., does not progress (e.g., according to IMWG criteria for MM (see, e.g., Tables 4 and 5, below) or according to the Lugano classification for NHL (see, e.g., Table 6, below). Progression-free survival may include the amount of time patients have experienced a complete response or a partial response, as well as the amount of time patients have experienced stable disease. As the skilled person will appreciate, a patients’ progression- free survival is improved or enhanced if the patient experiences a longer length of time during which the disease does not progress as compared to the average or mean progression-free survival time of a control group of similarly situated patients. As used herein, “complete response” or “CR” refers to disappearance of all signs of cancer (e.g., disappearance of target lesions). This does not always mean the cancer has been cured. For MM, CR is further defined according to the IMWG criteria (e.g., as described in Table 4, below). For NHL, CR is further defined according to the Lugano classification (e.g., as described in Table 6, below).

As used herein, “stringent complete response” or “sCR” refers to a complete response as defined by the IMWG criteria (e.g., as described in Table 4, below) plus normal free light chain (FLC) ratio and absence of clonal cells in bone marrow by immunohistochemistry (kappa/lambda ratio < 4:1 or > 1 :2 for kappa and lambda patients, respectively after counting > 100 plasma cells).

As used herein, “partial response” or “PR” refers to a decrease in the size of one or more lesions or tumors, or in the extent of cancer in the body, in response to treatment. With respect to MM, PR refers to at least a 50% reduction of serum M-protein and at least a 90% reduction in 24 hr urinary M-protein or to a level of less than 200 mg/24 hr. For MM, PR is further defined according to the IMWG criteria (e.g., as described in Table 4, below). Partial response, with respect to NHL, refers to at least a 50% decrease in the sum of the product of the perpendicular diameters for multiple lesions (SPD) of up to six target measurable nodes and extranodal sites; a score of 4 or 5 with reduced uptake compared to baseline and residual masses of the lymph nodes and extralymphatic sites; spleen enlargement regression of at least 50% in length beyond normal; residual uptake of higher than normal bone marrow, but reduced compared with baseline; a non-measured lesion that is absent, normal, or regressed (i.e., that has not increased); and/or an absence of new lesions. For NHL, PR is further defined according to the Lugano classification (e.g., as described in Table 6, below).

As used herein, “very good partial response” or “VGPR” refers to serum and urine M-protein detectable by immunofixation but not on electrophoresis; or > 90% reduction in serum M-protein-plus urine M-protein level < 100 mg/24 hr, as defined by the IMWG criteria (see, e.g., Table 4, below).

As used herein, “minimal response” or “MR” is defined per the IMWG criteria (see, e.g., Table 4, below) and refers to >25% but < 49% reductions of serum M-protein and reduction in 24-hour urine M- protein by 50%-89%, and additionally, if present at baseline, 25%-49% reduction in the size (SPD) ^c of soft tissue plasmacytomas.

As used herein, “stable disease” or “SD” refers to neither sufficient shrinkage of target lesions and/or a decrease in the extent of cancer in the body to qualify for PR, nor sufficient increase to qualify for PD. For MM, SD refers to a response otherwise not meeting the criteria for MR, CR, VGPR, PR, or PD as defined according to the IMWG criteria (e.g., as described in Tables 4 and 5, below). SD, with respect to NHL, refers to (a) less than a 50% decrease from baseline in SPD of up to 6 dominant, measurable nodes and extranodal sites, without meeting criteria for progressive disease, (b) a score of 4 or 5 with no significant change in fluorodeoxyglucose (FDG) uptake from baseline at interim or end of treatment in the target nodes/nodal masses, and/or extranodal lesions, (c) no change from baseline for the bone marrow, (d) the absence of increases consistent with progression in the non-measured lesion or with respect to organ enlargement, and/or (e) the absence of the formation of new lesions. SD for NHL is further defined according to the Lugano classification (e.g., as described in Table 6, below).

As used herein, “progressive disease” or “PD” refers to an increase in the size of one or more lesions or tumors, or in the extent of cancer in the body, in response to treatment. PD, with respect to MM, refers to an increase of at least 25% from the lowest response value in at least one of the following: (a) serum M-protein, (b) urine M-protein, (c) the difference between involved and uninvolved FLC levels, (d) bone marrow plasma cell percentage irrespective of baseline status, (e) the appearance of new lesion(s), or (f) at least a 50% increase in circulating plasma cells. For MM, PD is further defined according to the IMWG criteria (e.g., as described in Table 5, below). For NHL, PD refers to one or more of (a) cross product of the longest transverse diameter of a lesion (LDi) and perpendicular diameter (PPD) progression, (b) abnormalities of the individual target nodes/nodal masses or extranodal lesions, (c) a score of 4 or 5 with an increase in the intensity of uptake from baseline, (d) new FDG-avid foci, (e) new or recurrent splenomegaly, (f) new or clear progression of preexisting non-measured lesions), (g) regrowth of previously resolved lesions, (h) a new node, extranodal site, or assessable disease of any size attributable to lymphoma (e.g., new FDG-avid foci consistent with lymphoma), and (i) new or recurrent FDG avid-foci or new or recurrent involvement of the bone marrow. For NHL, PD is further defined according to the Lugano classification (e.g., as described in Table 6, below).

“Clinical relapse,” as used herein refers to direct indications of increasing disease and/or end organ dysfunction relating to the underlying clonal plasma cell proliferative disorder. For MM, clinical relapse is defined according to the IMWG criteria (see, e.g., Table 5, below) and includes one or more of (a) development of new soft tissue plasmacytomas or bone lesions, (b) definite increase in the size of existing plasmacytomas or bone lesions, defined as a 50% (and > 1 cm) increase as measured serially by the sum of the products of the cross-diameters of the measurable lesion, (c) hypercalcemia > 11 mg/dL (2.65 mm/L), (d) decrease in in hemoglobin of > 2 g/dL (1 .25 mmol/L) not related to therapy or other nonmyeloma related conditions, (e) a rise in serum creatinine by 2 mg/dL or more (177 pmol/L or more) from the start of therapy and attributable to myeloma, and/or (f) hyperviscosity related to serum paraprotein.

As used herein, “delaying progression” of a disorder or disease means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease or disorder (e.g., cancer, e.g., a hematologic cancer, e.g., a myeloma (e.g., MM, e.g., a relapsed or refractory MM) or a lymphoma (e.g., a NHL, e.g., a relapsed or refractory DLBCL or a relapsed or refractory FL)). This delay can be of varying lengths of time, depending on the history of the disease and/or subject being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the subject does not develop the disease. For example, in a late-stage cancer, development of central nervous system (CNS) metastasis, may be delayed.

As used herein, the term “reducing or inhibiting cancer relapse” means to reduce or inhibit tumor or cancer relapse, or tumor or cancer progression.

By “reduce or inhibit” is meant the ability to cause an overall decrease of 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or greater. Reduce or inhibit can refer to the symptoms of the disorder being treated (e.g., cancer, e.g., a hematologic cancer, e.g., a myeloma (e.g., MM, e.g., a relapsed or refractory MM) or a lymphoma (e.g., a NHL, e.g., a relapsed or refractory DLBCL or a relapsed or refractory FL)), the presence or size of metastases, or the size of the primary tumor.

By “extending survival” is meant increasing overall or progression-free survival in a treated patient relative to an untreated patient (e.g., relative to a patient not treated with the medicament), or relative to a patient who does not express a biomarker at the designated level, and/or relative to a patient treated with an approved anti-tumor agent. An objective response refers to a measurable response, including stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), and minimal response (MR).

As used herein, “complete response” and “CR” refers to disappearance of all target lesions. For example, complete response may be defined as no evidence of initial monoclonal protein isotype(s) on immunofixation of the serum and urine, disappearance of any soft tissue plasmacytomas, and < 5% plasma cells in bone marrow, according to the International Myeloma Working Group (IMWG) criteria (see Durie et al. Leukemia. 29: 2416-2417, 2015; Kumar et al. Lancet Oncol. 17: e328-46, 2016).

As used herein, “stringent complete response” and “sCR” refers to a complete response with additional criteria. For example, stringent complete response may defined as normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry (kappa/lambda ratio < 4:1 or > 1 :2 for kappa and lambda patients, respectively after counting > 100 plasma cells), according to the IMWG criteria (see Durie et al. Leukemia. 29: 2416-2417, 2015; Kumar et al. Lancet Oncol. 17: e328-46, 2016).

As used herein, the term “chemotherapeutic agent” refers to a compound useful in the treatment of cancer, such as hematologic cancer. Examples of chemotherapeutic agents include EGFR inhibitors (including small molecule inhibitors (e.g., erlotinib (TARCEVA®, Genentech/OSI Pharm.); PD 183805 (Cl 1033, 2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSA®) 4-(3’-Chloro-4’-fluoroanilino)-7-methoxy-6-(3- morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)- quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimido[5,4- d]pyrimidine-2,8-diamine, Boehringer Ingelheim); PKI-166 ((R)-4-[4-[(1-phenylethyl)amino]-1 H-pyrrolo[2,3- d]pyrimidin-6-yl]-phenol); (R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine); CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide); EKB-569 (N-[4-[(3-chloro-4- fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide) (Wyeth); AG1478 (Pfizer); AG1571 (SU 5271 ; Pfizer); and dual EGFR/HER2 tyrosine kinase inhibitors such as lapatinib (TYKERB®, GSK572016 or N-[3-chloro-4-[(3 fluorophenyl)methoxy]phenyl]- 6[5[[[2methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine)); a tyrosine kinase inhibitor (e.g., an EGFR inhibitor; a small molecule HER2 tyrosine kinase inhibitor such as TAK165 (Takeda); CP- 724,714, an oral selective inhibitor of the ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual-HER inhibitors such as EKB-569 (available from Wyeth) which preferentially binds EGFR but inhibits both HER2 and EGFR-overexpressing cells; PKI-166 (Novartis); pan-HER inhibitors such as canertinib (CI- 1033; Pharmacia); Raf-1 inhibitors such as antisense agent ISIS-5132 (ISIS Pharmaceuticals) which inhibit Raf-1 signaling; non-HER-targeted tyrosine kinase inhibitors such as imatinib mesylate (GLEEVEC®, Glaxo SmithKline); multi-targeted tyrosine kinase inhibitors such as sunitinib (SUTENT®, Pfizer); VEGF receptor tyrosine kinase inhibitors such as vatalanib (PTK787/ZK222584, Novartis/Schering AG); MAPK extracellular regulated kinase I inhibitor CI-1040 (Pharmacia); quinazolines, such as PD 153035, 4-(3-chloroanilino) quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines, such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d] pyrimidines; curcumin (diferuloyl methane, 4,5-bis (4-fluoroanilino)phthalimide); tyrphostines containing nitrothiophene moieties; PD-0183805 (Warner-Lamber); antisense molecules (e.g., those that bind to HER-encoding nucleic acid); quinoxalines (U.S. Patent No. 5,804,396); tryphostins (U.S. Patent No. 5,804,396); ZD6474 (Astra Zeneca); PTK-787 (Novartis/Schering AG); pan-HER inhibitors such as Cl- 1033 (Pfizer); Affinitac (ISIS 3521 ; Isis/Lilly); PKI 166 (Novartis); GW2016 (Glaxo SmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis/Schering AG); INC-1 C11 (Imclone); and rapamycin (sirolimus, RAPAMUNE®)); proteasome inhibitors such as bortezomib (VELCADE®, Millennium Pharm.); disulfiram; epigallocatechin gallate; salinosporamide A; carfilzomib; 17-AAG (geldanamycin); radicicol; lactate dehydrogenase A (LDH-A); fulvestrant (FASLODEX®, AstraZeneca); letrozole (FEMARA®, Novartis), finasunate (VATALANIB®, Novartis); oxaliplatin (ELOXATIN®, Sanofi); 5-FU (5-fluorouracil); leucovorin; lonafamib (SCH 66336); sorafenib (NEXAVAR®, Bayer Labs); AG1478, alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including topotecan and irinotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); adrenocorticosteroids (including prednisone and prednisolone); cyproterone acetate; 5a-reductases including finasteride and dutasteride); vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat dolastatin; aldesleukin, talc duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin y1 and calicheamicin w1); 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, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, detorubicin, 6-diazo-5-oxo-L-norleucine, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5- fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamnol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2’,2”-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; chloranmbucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; etoposide (VP-16); ifosfamide; mitoxantrone; novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11 ; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids, prodrugs, and derivatives of any of the above.

Chemotherapeutic agents also include (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all transretionic acid, fenretinide, as well as troxacitabine (a 1 ,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, such as, for example, PKC-alpha, Ralf and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®, LEUVECTIN®, and VAXID®; (ix) growth inhibitory agents including vincas (e.g., vincristine and vinblastine), NAVELBINE® (vinorelbine), taxanes (e.g., paclitaxel, nab-paclitaxel, and docetaxel), topoisomerase II inhibitors (e.g., doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin), and DNA alkylating agents (e.g., tamoxigen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, and ara-C); and (x) pharmaceutically acceptable salts, acids, prodrugs, and derivatives of any of the above.

The term “cytotoxic agent” as used herein refers to any agent that is detrimental to cells (e.g., causes cell death, inhibits proliferation, or otherwise hinders a cellular function). Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., At²¹¹, I¹³¹ , 1¹²⁵, Y⁹⁰, Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi²¹², P³², Pb²¹² and radioactive isotopes of Lu); chemotherapeutic agents; enzymes and fragments thereof such as nucleolytic enzymes; and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof. Exemplary cytotoxic agents can be selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, inhibitors of LDH-A, inhibitors of fatty acid biosynthesis, cell cycle signaling inhibitors, HDAC inhibitors, proteasome inhibitors, and inhibitors of cancer metabolism. In one instance, the cytotoxic agent is a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin). In one instance, the cytotoxic agent is an antagonist of EGFR, e.g., N-(3- ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (e.g., erlotinib). In one instance the cytotoxic agent is a RAF inhibitor, e.g., a BRAF and/or CRAF inhibitor. In one instance the RAF inhibitor is vemurafenib. In one instance, the cytotoxic agent is a PI3K inhibitor.

The term “patient” refers to a human patient. For example, the patient may be an adult.

The term “antibody” herein specifically covers monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired biological activity. In one instance, the antibody is a full-length monoclonal antibody.

The term IgG “isotype” or “subclass” as used herein is meant any of the subclasses of immunoglobulins defined by the chemical and antigenic characteristics of their constant regions.

Depending on the amino acid sequences of the constant domains of their heavy chains, antibodies (immunoglobulins) can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., lgG1 , lgG2, lgG3, lgG4, lgA1 , and lgA2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called a, y, £, y, and p, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known and described generally in, for example, Abbas et al. Cellular and Mol. Immunology, 4th ed. (W.B. Saunders, Co., 2000). An antibody may be part of a larger fusion molecule, formed by covalent or non- covalent association of the antibody with one or more other proteins or peptides.

The terms “full-length antibody,” “intact antibody,” and “whole antibody” are used herein interchangeably to refer to an antibody in its substantially intact form, not antibody fragments as defined below. The terms refer to an antibody comprising an Fc region.

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. In one aspect, a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl-terminus of the heavy chain. However, antibodies produced by host cells may undergo post-translational cleavage of one or more, particularly one or two, amino acids from the C- terminus of the heavy chain. Therefore, an antibody produced by a host cell by expression of a specific nucleic acid molecule encoding a full-length heavy chain may include the full-length heavy chain, or it may include a cleaved variant of the full-length heavy chain. This may be the case where the final two C- terminal amino acids of the heavy chain are glycine (G446) and lysine (K447). Therefore, the C-terminal lysine (Lys447), or the C-terminal glycine (Gly446) and lysine (Lys447), of the Fc region may or may not be present. Amino acid sequences of heavy chains including an Fc region are denoted herein without the C-terminal lysine (Lys447) if not indicated otherwise. In one aspect, a heavy chain including an Fc region as specified herein, comprised in an antibody disclosed herein, comprises an additional C-terminal glycine-lysine dipeptide (G446 and K447). In one aspect, a heavy chain including an Fc region as specified herein, comprised in an antibody disclosed herein, comprises an additional C-terminal glycine residue (G446). In one aspect, a heavy chain including an Fc region as specified herein, comprised in an antibody disclosed herein, comprises an additional C-terminal lysine residue (K447). In one embodiment, the Fc region contains a single amino acid substitution N297A of the heavy chain. Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

A “naked antibody” refers to an antibody that is not conjugated to a heterologous moiety (e.g., a cytotoxic moiety) or radiolabel. The naked antibody may be present in a pharmaceutical composition.

“Antibody fragments” comprise a portion of an intact antibody, preferably comprising the antigen-binding region thereof. In some instances, the antibody fragment described herein is an antigenbinding fragment. Examples of antibody fragments include Fab, Fab’, Fab’-SH, F(ab’)2, and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFvs); and multispecific antibodies formed from antibody fragments.

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. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies 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.

The term “hypervariable region” or“HVR” as used herein refers to each of the regions of an antibody variable domain which are hypervariable in sequence and which determine antigen binding specificity, for example “complementarity determining regions” (“CDRs”).

Generally, antibodies comprise six CDRs: three in the VH (CDR-H1 , CDR-H2, CDR-H3), and three in the VL (CDR-L1 , CDR-L2, CDR-L3). Exemplary CDRs herein include:

(a) hypervariable loops occurring at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987));

(b) CDRs occurring at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31 -35b (H1), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)); and

(c) antigen contacts occurring at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J. Mol. Biol. 262: 732-745 (1996)).

Unless otherwise indicated, the CDRs are determined according to Kabat et al., supra. One of skill in the art will understand that the CDR designations can also be determined according to Chothia, supra, McCallum, supra, or any other scientifically accepted nomenclature system.

“Framework” or “FR” refers to variable domain residues other than complementary determining regions (CDRs). The FR of a variable domain generally consists of four FR domains: FR1 , FR2, FR3, and FR4. Accordingly, the CDR and FR sequences generally appear in the following sequence in VH (or VL): FR1-CDR-H1 (CDR-L1)-FR2- CDR-H2(CDR-L2)-FR3- CDR-H3(CDR-L3)-FR4. The term “variable domain residue numbering as in Kabat” or “amino acid position numbering as in Kabat,” and variations thereof, refers to the numbering system used for heavy chain variable domains or light chain variable domains of the compilation of antibodies in Kabat et al., supra. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening of, or insertion into, a FR or HVR of the variable domain. For example, a heavy chain variable domain may include a single amino acid insert (residue 52a according to Kabat) after residue 52 of H2 and inserted residues (e.g., residues 82a, 82b, and 82c, etc., according to Kabat) after heavy chain FR residue 82. The Kabat numbering of residues may be determined for a given antibody by alignment at regions of homology of the sequence of the antibody with a “standard” Kabat numbered sequence.

As used herein, a “PD-L1 -positive tumor cell fraction” is the percentage of viable tumor cells showing partial or complete membrane staining (exclusive of cytoplasmic staining) at any intensity relative to all viable tumor cells present in a sample, following staining of the sample in the context of an immunohistochemical (IHC) assay, e.g., an IHC assay staining for PD-L1 using the antibody SP142, SP263, 22C3, or 28-8. Accordingly, a PD-L1 -positive tumor cell fraction may be calculated using the PD- L1 IHC SP142 (Ventana) assay, for example, by the formula PD-L1 -positive tumor cell fraction = (number of PD-L1 -positive tumor cells)/(total number of PD-L1 -positive and PD-L1 negative tumor cells), wherein PD-L1 cytoplasmic staining of tumor cells and all non-tumor cells (e.g., tumor-infiltrating immune cells, normal cells, necrotic cells, and debris) are excluded from evaluation and scoring. It will be appreciated that any given diagnostic PD-L1 antibody may correspond with a particular IHC assay protocol and/or scoring terminology that can be used to derive a PD-L1 -positive tumor cell fraction. For example, a PD- L1 -positive tumor cell fraction can be derived from a tumor cell sample stained with SP263, 22C3, SP142, or 28-8 using OPTIVIEW® detection on Benchmark ULTRA, EnVision Flex on AutostainerLink 48, OPTIVIEW® detection and amplification on Benchmark ULTRA, or EnVision Flex on AutostainerLink 48, respectively.

The term “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.

As used herein, “in combination with” refers to administration of one treatment modality in addition to another treatment modality, for example, a treatment regimen that includes administration of a PD-1 axis binding antagonist (e.g., atezolizumab), an anti-CD38 antibody (e.g., daratumumab), and an anti- TIGIT antagonist antibody (e.g., tiragolumab). As such, “in combination with” refers to administration of one treatment modality before, during, or after administration of the other treatment modality to the patient.

A drug that is administered “concurrently” with one or more other drugs is administered during the same treatment cycle, on the same day of treatment, as the one or more other drugs, and, optionally, at the same time as the one or more other drugs. For instance, for cancer therapies given every 3 weeks, the concurrently administered drugs are each administered on day 1 of a 3-week cycle.

As used herein, the term “adverse event” or “AE” refers to any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure. Adverse events may be classified by “grade,” as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 or v5.0 (NIH CTCAE). In some aspects, the AE is a low-grade AE, e.g., a Grade 1 or Grade 2 AE. Grade 1 includes AEs that are asymptomatic or have mild symptoms. Grade 2 includes AEs that are moderate and limit age-appropriate instrumental activities of daily living (e.g., preparing meals, shopping for groceries or clothes) and that indicate local or noninvasive intervention. In other instances, the AE is a high-grade AE, e.g., a Grade 3, Grade 4, or Grade 5 AE. In some instances, the AE is a Grade 3 or a Grade 4 AE. Grade 3 includes AEs that are severe or medically significant, but not immediately life-threatening, and that indicate hospitalization or prolongation of hospitalization. Grade 4 includes AEs that have life-threatening consequences and indicate urgent intervention. Grade 5 includes AEs that result in or relate to death.

As used herein, the term “treatment-related AE” refers to an AE that is judged by an investigator to have occurred as a result of a treatment, e.g., a PD-1 axis binding antagonist therapy (e.g., atezolizumab therapy) and/or an anti-TIGIT antagonist antibody therapy (e.g., tiragolumab therapy).

III. Therapeutic Methods and Compositions for Cancer

Provided herein are methods and uses for treating a hematologic cancer (e.g., a myeloma (e.g., a multiple myeloma (MM), e.g., a relapsed or refractory MM)) comprising administering to a subject or population of subjects (a) an effective amount of an anti-TIGIT antagonist antibody (e.g., tiragolumab), an anti-CD38 antibody (e.g., daratumumab), and a PD-1 axis binding antagonist (e.g., atezolizumab).

Also provided are methods and uses for treating a hematologic cancer (e.g., a myeloma (e.g., a multiple myeloma (MM), e.g., a relapsed or refractory MM)) comprising administering to a subject or population of subjects an effective amount of an anti-TIGIT antagonist antibody (e.g., tiragolumab) and an anti-CD38 antibody (e.g., daratumumab), wherein at least one dose of the anti-CD38 antibody is administered subcutaneously.

Further provided are methods and uses for treating a hematologic cancer (e.g., a lymphoma (e.g., a non-Hodgkin’s lymphoma (NHL), e.g., a relapsed or refractory diffuse large B cell lymphoma (DLBCL) or a relapsed or refractory follicular lymphoma (FL))) in a subject or population of subjects comprising administering to the subject or population of subjects an effective amount of an anti-TIGIT antagonist antibody (e.g., tiragolumab) and an anti-CD20 antibody (e.g., rituximab), wherein at least one dose of the anti-CD20 antibody is administered subcutaneously.

A. Treatment of hematologic cancer using an anti-TIGIT antagonist antibody, an anti-CD38 antibody, and a PD-1 axis binding antagonist

Monotherapy with the PD-1 axis binding antagonist atezolizumab has been observed to have limited clinical activity in multiple myeloma (MM), despite showing pharmacodynamic (PD) activity; it is hypothesized that this limited outcome is related to an immune-suppressive tumor microenvironment (TME). Combination therapy comprising atezolizumab and daratumumab shows an improved overall response rate (ORR) as compared to daratumumab monotherapy. This result may be driven by daratumumab making the TME more permissive for atezolizumab, e.g., due to tumor debulking and immunomodulatory activities of daratumumab. Given the anti-myeloma activity and immunomodulatory properties of daratumumab and solid tumor studies suggesting that inhibition of both of the PD-1/PD-L1 and TIGIT/PVR axes may contribute to optimal T cell activation in MM patients whose T cells express both PD-1 and TIGIT, the disclosure provides a triplet therapy combining an anti-TIGIT antagonist antibody, an anti-CD38 antibody, and a PD-1 axis binding antagonist (e.g., tiragolumab, daratumumab, and atezolizumab) for the treatment of hematological cancers (e.g., multiple myeloma (MM)).

In one aspect, the disclosure provides a method for treating a subject having a hematologic cancer, e.g., a myeloma (e.g., a multiple myeloma (MM), e.g., a relapsed or refractory MM), the method comprising administering to the subject an effective amount of an anti-TIGIT antagonist antibody (e.g., tiragolumab), an anti-CD38 antibody (e.g., daratumumab), and a PD-1 axis binding antagonist (e.g., atezolizumab).

In another aspect, the disclosure features a method for treating a subject having a hematologic cancer, e.g., a myeloma (e.g., a multiple myeloma (MM), e.g., a relapsed or refractory MM), the method comprising administering to the subject an anti-TIGIT antagonist antibody (e.g., tiragolumab) at a fixed dose of between about 30 mg to about 1200 mg, an anti-CD38 antibody (e.g., daratumumab) at a dose of between about 300 mg to about 3600 mg and a PD-1 axis binding antagonist (e.g., atezolizumab) at a dose of between about 900 mg to about 1500 mg in a dosing regimen comprising at least nine dosing cycles, wherein: (a) the anti-TIGIT antagonist antibody is administered once every three weeks; (b) the PD-1 axis binding antagonist is administered once every three weeks; and (c) the anti-CD38 antibody is administered once every week during each of dosing cycles 1 -3, once every three weeks during each of dosing cycles 4-8, and once every four weeks during dosing cycle 9. In other aspects, the anti-CD38 antibody is administered once every week during each of dosing cycles 1 and 2 and once every three weeks during each of the subsequent dosing cycles, e.g., once every three weeks during cycles 3-19 of a dosing regimen comprising at least 19 dosing cycles.

For example, in another aspect, the disclosure features a method for treating a subject having a hematologic cancer, the method comprising administering to the subject an anti-TIGIT antagonist antibody at a fixed dose of between about 30 mg to about 1200 mg, an anti-CD38 antibody at a dose of between about 300 mg to about 3600 mg, and a PD-1 axis binding antagonist at a dose of between about 900 mg to about 1500 mg in a dosing regimen comprising at least 19 dosing cycles, wherein: (a) the anti-TIGIT antagonist antibody is administered once every three weeks; (b) the PD-1 axis binding antagonist is administered once every three weeks; and (c) the anti-CD38 antibody is administered once every week during each of dosing cycles 1 and 2, once every three weeks during each of dosing cycles 3-18, and once every four weeks during dosing cycle 19.

In some aspects, the hematologic cancer is a myeloma. In some aspects, the myeloma is a multiple myeloma (MM). In some aspects, the MM is a relapsed or refractory MM. In some aspects, the patient has received at least three prior lines of treatment for the MM, e.g., is 4L+, e.g., has received three, four, five, six, or more than six prior lines of treatment. For example, the patient may have been exposed to a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), an autologous stem cell transplant (ASCT), an anti-CD38 therapy, a CAR-T therapy, or a therapy comprising a bispecific antibody. In some instances, the patient has been exposed to all three of PI, IMiD, and anti-CD38 therapy. In some aspects, the patient is refractory to a proteasome inhibitor and/or an immunomodulatory drug (IMiD). Exemplary anti-TIGIT antagonist antibodies are provided in Section VI. Exemplary PD-1 axis binding antagonists are provided in Section VII. Exemplary anti-CD38 antibodies are provided in Section VIII.

/. Effective amounts

In some aspects, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a fixed dose of between about 30 mg to about 1200 mg (e.g., between about 30 mg to about 1100 mg, e.g., between about 60 mg to about 1000 mg, e.g., between about 100 mg to about 900 mg, e.g., between about 200 mg to about 800 mg, e.g., between about 300 mg to about 800 mg, e.g., between about 400 mg to about 800 mg, e.g., between about 400 mg to about 750 mg, e.g., between about 450 mg to about 750 mg, e.g., between about 500 mg to about 700 mg, e.g., between about 550 mg to about 650 mg, e.g., 600 mg ± 10 mg, e.g., 600 ± 6 mg, e.g., 600 ± 5 mg, e.g., 600 ± 3 mg, e.g., 600 ± 1 mg, e.g., 600 ± 0.5 mg, e.g., 600 mg) every three weeks. In some aspects, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a fixed dose of between about 30 mg to about 600 mg (e.g., between about 50 mg to between 600 mg, e.g., between about 60 mg to about 600 mg, e.g., between about 100 mg to about 600 mg, e.g., between about 200 mg to about 600 mg, e.g., between about 200 mg to about 550 mg, e.g., between about 250 mg to about 500 mg, e.g., between about 300 mg to about 450 mg, e.g., between about 350 mg to about 400 mg, e.g., about 375 mg) every three weeks. In some aspects, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti- TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a fixed dose of about 600 mg every three weeks. In some aspects, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti- TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a fixed dose of 600 mg. In some aspects, the anti-TIGIT antagonist antibody (e.g., tiragolumab) is administered intravenously.

In some aspects, the effective amount of the anti-CD38 antibody (e.g., an anti-CD38 antibody as disclosed herein, e.g., daratumumab) is a fixed dose of between about 300 mg to about 3600 mg (e.g., between about 400 mg to about 3200 mg, e.g., between about 600 mg to about 3000 mg, e.g., between about 1200 mg to about 2600 mg, e.g., between about 1650 mg to about 1950 mg, e.g., between about 1700 mg to about 1900 mg, e.g., between about 1750 mg to about 1850 mg, e.g., 1800 mg ± 10 mg, e.g., 1800 ± 6 mg, e.g., 1800 ± 5 mg, e.g., 1800 ± 3 mg, e.g., 1800 ± 1 mg, e.g., 1800 ± 0.5 mg, e.g., 1800 mg). In some aspects, the effective amount of the anti-CD38 antibody (e.g., an anti-CD38 antibody as disclosed herein, e.g., daratumumab) is a fixed dose of 1800 mg. The anti-CD38 antibody may be administered subcutaneously for all doses; may be administered intravenously for all doses; or may be administered subcutaneously for some doses and intravenously for other doses.

In some aspects, the anti-CD38 antibody (e.g., daratumumab) is administered subcutaneously (e.g., administered subcutaneously in a formulation with human hyaluronidase PH20 (rHuPH20)) and the effective amount of the anti-CD38 antibody (e.g., daratumumab) is a fixed dose of about 1800 mg. In some aspects, the anti-CD38 antibody (e.g., daratumumab) is administered subcutaneously and the effective amount of the anti-CD38 antibody (e.g., daratumumab) is a dose of 1800 mg of the anti-CD38 antibody formulated in 30,000 U rHuPH20 (e.g., at a volume of 15 mL). In some aspects, the subcutaneous administration is by manual push, e.g., for about 3-5 minutes. In some aspects, the subcutaneous administration comprises injection into abdominal subcutaneous tissues. In some aspects, the anti-CD38 antibody (e.g., daratumumab) is administered intravenously and the effective amount of the anti-CD38 antibody (e.g., daratumumab) is a dose of between about 8 mg/kg to about 24 mg/kg of the subject’s body weight (e.g., between about 8 mg/kg to about 22 mg/kg, e.g., between about 10 mg/kg to about 20 mg/kg, e.g., between about 10 mg/kg to about 18 mg/kg, e.g., between about 12 mg/kg to about 16 mg/kg, e.g., about 16 ± 2 mg/kg, about 16 ± 1 mg/kg, about 16 ± 0.5 mg/kg, about 16 ± 0.2 mg/kg, or about 16 ± 0.1 mg/kg, e.g., about 16 mg/kg). In some aspects, the anti- CD38 antibody (e.g., daratumumab) is administered intravenously, the effective amount of the anti-CD38 antibody (e.g., daratumumab) is a dose of about 16 mg/kg.

In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of between about 80 mg to about 2000 mg (e.g., between about 100 mg to about 1600 mg, e.g., between about 200 mg to about 1600 mg, e.g., between about 300 mg to about 1600 mg, e.g., between about 400 mg to about 1600 mg, e.g., between about 500 mg to about 1600 mg, e.g., between about 600 mg to about 1600 mg, e.g., between about 700 mg to about 1600 mg, e.g., between about 800 mg to about 1600 mg, e.g., between about 900 mg to about 1500 mg, e.g., between about 1000 mg to about 1400 mg, e.g., between about 1050 mg to about 1350 mg, e.g., between about 1100 mg to about 1300 mg, e.g., between about 1150 mg to about 1250 mg, e.g., between about 1175 mg to about 1225 mg, e.g., between about 1190 mg to about 1210 mg, e.g., 1200 mg ± 5 mg, e.g., 1200 ± 2.5 mg, e.g., 1200 ± 1 .0 mg, e.g., 1200 ± 0.5 mg, e.g., 1200 mg) every three weeks (Q3W). In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of about 1200 mg every three weeks (e.g., 1200 mg ± 10 mg, e.g., 1200 ± 6 mg, e.g., 1200 ± 5 mg, e.g., 1200 ± 3 mg, e.g., 1200 ± 1 mg, e.g., 1200 ± 0.5 mg, e.g., 1200 mg every three weeks). In some instances, the effective amount of atezolizumab is a dose of 1200 mg every three weeks. In some aspects, the PD-1 axis binding antagonist (e.g., atezolizumab) is administered intravenously.

In some aspects, the method comprises administering to the subject the anti-TIGIT antagonist antibody (e.g., tiragolumab) at a fixed dose of between about 30 mg to about 1200 mg, the anti-CD38 antibody (e.g., daratumumab) at a dose of between about 300 mg to about 3600 mg, and the PD-1 axis binding antagonist (e.g., atezolizumab) at a dose of between about 900 mg to about 1500 mg.

In some aspects, the method comprises administering to the subject the anti-TIGIT antagonist antibody (e.g., tiragolumab) at a fixed dose of between 30 mg to 1200 mg, the anti-CD38 antibody (e.g., daratumumab) at a dose of between 300 mg to 3600 mg, and the PD-1 axis binding antagonist (e.g., atezolizumab) at a dose of between 900 mg to 1500 mg.

In some aspects, the method comprises administering to the subject the anti-TIGIT antagonist antibody at a fixed dose of about 600 mg. In some aspects, the method comprises administering to the subject the anti-TIGIT antagonist antibody at a fixed dose of 600 mg.

In some aspects, the method comprises administering to the subject the anti-CD38 antibody at a dose of about 1800 mg. In some aspects, the method comprises administering to the subject the anti- CD38 antibody at a dose of 1800 mg.

In some aspects, the method comprises administering to the subject the PD-1 axis binding antagonist at a dose of about 1200 mg. In some aspects, the method comprises administering to the subject the PD-1 axis binding antagonist at a dose of 1200 mg. In some instances, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a fixed dose of between about 10 mg to about 1000 mg (e.g., between about 20 mg to about 1000 mg, e.g., between about 50 mg to about 900 mg, e.g., between about 100 mg to about 850 mg, e.g., between about 200 mg to about 800 mg, e.g., between about 300 mg to about 600 mg, e.g., between about 400 mg to about 500 mg, e.g., between about 405 mg to about 450 mg, e.g., between about 410 mg to about 430 mg, e.g., about 420 mg) every two weeks (Q2W). In some instances, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a fixed dose of about 420 mg every two weeks (e.g., 420 mg ± 10 mg, e.g., 420 ± 6 mg, e.g., 420 ± 5 mg, e.g., 420 ± 3 mg, e.g., 420 ± 1 mg, e.g., 420 ± 0.5 mg, e.g., 420 mg every two weeks).

In some instances, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a fixed dose of between about 200 mg to about 2000 mg (e.g., between about 200 mg to about 1600 mg, e.g., between about 250 mg to about 1600 mg, e.g., between about 300 mg to about 1600 mg, e.g., between about 400 mg to about 1500 mg, e.g., between about 500 mg to about 1400 mg, e.g., between about 600 mg to about 1200 mg, e.g., between about 700 mg to about 1100 mg, e.g., between about 800 mg to about 1000 mg, e.g., between about 800 mg to about 900 mg, e.g., about 800, about 810, about 820, about 830, about 840, about 850, about 860, about 870, about 880, about 890, or about 900 mg) every four weeks (Q4W). In some instances, the effective amount of anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a fixed dose of about 840 mg every four weeks (e.g., 840 mg ± 10 mg, e.g., 840 ± 6 mg, e.g., 840 ± 5 mg, e.g., 840 ± 3 mg, e.g., 840 ± 1 mg, e.g., 840 ± 0.5 mg, e.g., 840 mg every four weeks).

In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a fixed dose of between about 20 mg to about 1600 mg (e.g., between about 40 mg to about 1500 mg, e.g., between about 200 mg to about 1400 mg, e.g., between about 300 mg to about 1400 mg, e.g., between about 400 mg to about 1400 mg, e.g., between about 500 mg to about 1300 mg, e.g., between about 600 mg to about 1200 mg, e.g., between about 700 mg to about 1100 mg, e.g., between about 800 mg to about 1000 mg, e.g., between about 800 mg to about 900 mg, e.g., about 800, about 810, about 820, about 830, about 840, about 850, about 860, about 870, about 880, about 890, or about 900 mg) every two weeks (Q2W). In some instances, the effective amount of the PD-1 axis binding antagonist is atezolizumab at a fixed dose of about 840 mg every two weeks (e.g., 840 mg ± 10 mg, e.g., 840 ± 6 mg, e.g., 840 ± 5 mg, e.g., 840 ± 3 mg, e.g., 840 ± 1 mg, e.g., 840 ± 0.5 mg, e.g., 840 mg every two weeks). In some embodiments, the effective amount of the PD-1 axis binding antagonist is avelumab at a fixed dose of about 800 mg every two weeks. In some embodiments, the effective amount of the PD-1 axis binding antagonist is nivolumab at a fixed dose of about 240 mg every two weeks.

In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a fixed dose of between about 500 mg to about 3000 mg (e.g., between about 500 mg to about 2800 mg, e.g., between about 600 mg to about 2700 mg, e.g., between about 650 mg to about 2600 mg, e.g., between about 700 mg to about 2500 mg, e.g., between about 1000 mg to about 2400 mg, e.g., between about 1100 mg to about 2300 mg, e.g., between about 1200 mg to about 2200 mg, e.g., between about 1300 mg to about 2100 mg, e.g., between about 1400 mg to about 2000 mg, e.g., between about 1500 mg to about 1900 mg, e.g., between about 1600 mg to about 1800 mg, e.g., between about 1620 mg to about 1700 mg, e.g., between about 1640 mg to about 1690 mg, e.g., between about 1660 mg to about 1680 mg, about 1680 mg, e.g., about 1600 mg, about 1610 mg, about 1620 mg, about 1630 mg, about 1640 mg, about 1650 mg, about 1660 mg, about 1670 mg, about 1680 mg, about 1690 mg, or about 1700 mg) every four weeks (Q4W). In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a fixed dose of 1680 mg every four weeks (e.g., 1680 mg ± 10 mg, e.g., 1680 ± 6 mg, e.g., 1680 ± 5 mg, e.g., 1680 ± 3 mg, e.g., 1680 ± 1 mg, e.g., 1680 ± 0.5 mg, e.g., 1680 mg every four weeks). In some embodiments, the effective amount of the PD-1 axis binding antagonist is nivolumab at a fixed dose of about 480 mg every four weeks.

//. Timing and number of cycles

In some aspects, the method comprises administering to the subject the anti-TIGIT antagonist antibody (e.g., tiragolumab), anti-CD38 antibody (e.g., daratumumab), and PD-1 axis binding antagonist (e.g., atezolizumab) in a dosing regimen comprising at least nine dosing cycles, wherein: (a) the anti- TIGIT antagonist antibody is administered once every three weeks; (b) the PD-1 axis binding antagonist is administered once every three weeks; and (c) the anti-CD38 antibody is administered once every week during each of dosing cycles 1-3, once every three weeks during each of dosing cycles 4-8, and once every four weeks during dosing cycle 9.

In other aspects, the method comprises administering to the subject the anti-TIGIT antagonist antibody (e.g., tiragolumab), anti-CD38 antibody (e.g., daratumumab), and PD-1 axis binding antagonist (e.g., atezolizumab) in a dosing regimen comprising at least 19 dosing cycles, wherein: (a) the anti-TIGIT antagonist antibody is administered once every three weeks; (b) the PD-1 axis binding antagonist is administered once every three weeks; and (c) the anti-CD38 antibody is administered once every week during each of dosing cycles 1 and 2, once every three weeks during each of dosing cycles 3-18, and once every four weeks during dosing cycle 19.

In any of the methods and uses of the invention, the anti-TIGIT antagonist antibody (e.g., an anti- TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the anti-CD38 antibody (e.g., daratumumab), and the PD-1 axis binding antagonist (e.g., atezolizumab) may be administered in a dosing regimen that includes at least nine dosing cycles (e.g., 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, or 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60 or more dosing cycles). In some aspects, the dosing regimen includes at least 12 dosing cycles. In some aspects, the dosing regimen includes at least 16 dosing cycles. In some aspects, the dosing regimen includes at least 19 dosing cycles. In some aspects, the dosing cycles of the anti-TIGIT antagonist antibody (e.g., tiragolumab), anti-CD38 antibody (e.g., daratumumab), and PD-1 axis binding antagonist (e.g., atezolizumab) continue until there is a loss of clinical benefit (e.g., confirmed disease progression, drug resistance, death, or unacceptable toxicity).

In some aspects, the length of each dosing cycle is about 18 to 24 days (e.g., 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, or 24 days). In some aspects, the length of each dosing cycle is about 21 days. In some aspects, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered on about day 1 (e.g., day 1 ± 1 day) of each dosing cycle. For example, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) may be administered intravenously at a fixed dose of about 600 mg on day 1 of each 21 -day dosing cycle (i.e., at a fixed dose of about 600 mg every three weeks).

In some aspects in which the length of each dosing cycle is about 21 days, the anti-CD38 antibody (e.g., daratumumab) is administered on or about day 1 (e.g., day 1 ± 1 day), day 8 (e.g., day 8 ± 1 day), and day 15 (e.g., day 15 ± 1 day) of each of dosing cycles 1-3, on or about day 1 (e.g., day 1 ± 1 day) of each of dosing cycles 4-8, and on or about day 1 (e.g., day 1 ± 1 day) of dosing cycle 9. For example, the anti-CD38 antibody (e.g., daratumumab) may be administered (e.g., administered subcutaneously or intravenously) at a fixed dose of about 1800 mg on days 1 , 8, and 15 of each of dosing cycles 1 , 2, and 3, and on day 1 of each of dosing cycles 4, 5, 6, 7, 8, and 9. In some aspects, the anti- CD38 antibody may be administered intravenously at a dose of 16 mg/kg on days 1 , 8, and 15 of each of dosing cycles 1 , 2, and 3, and on day 1 of each of dosing cycles 4, 5, 6, 7, 8, and 9.

In other aspects in which the length of each dosing cycle is about 21 days, the anti-CD38 antibody (e.g., daratumumab) is administered on or about day 1 (e.g., day 1 ± 1 day), day 8 (e.g., day 8 ± 1 day), and day 15 (e.g., day 15 ± 1 day) of each of dosing cycles 1 and 2, on or about day 1 (e.g., day 1 ± 1 day) of each of dosing cycles 3-18, and on or about day 1 (e.g., day 1 ± 1 day) of dosing cycle 19. For example, the anti-CD38 antibody (e.g., daratumumab) may be administered (e.g., administered subcutaneously or intravenously) at a fixed dose of about 1800 mg on days 1 , 8, and 15 of each of dosing cycles 1 and 2, and on day 1 of each of dosing cycles 3-19. In some aspects, the anti-CD38 antibody may be administered intravenously at a dose of 16 mg/kg on days 1 , 8, and 15 of each of dosing cycles 1 and 2, and on day 1 of each of dosing cycles 3-19.

In other aspects in which the length of each dosing cycle is about 21 days, the anti-CD38 antibody (e.g., daratumumab) is administered on or about day 2 (e.g., day 2 ± 1 day), day 8 (e.g., day 8 ± 1 day), and day 15 (e.g., day 15 ± 1 day) of each of dosing cycles 1-3, on or about day 1 (e.g., day 1 ± 1 day) of each of dosing cycles 4-8, and on or about day 1 (e.g., day 1 ± 1 day) of dosing cycle 9. For example, the anti-CD38 antibody (e.g., daratumumab) may be administered (e.g., administered subcutaneously or intravenously) at a fixed dose of about 1800 mg on days 2, 8, and 15 of each of dosing cycles 1 , 2, and 3, and on day 1 of each of dosing cycles 4, 5, 6, 7, 8, and 9. In some aspects, the anti- CD38 antibody is administered intravenously at a dose of 16 mg/kg on days 1 , 8, and 15 of each of dosing cycles 1 , 2, and 3, and on day 1 of each of dosing cycles 4, 5, 6, 7, 8, and 9.

In other aspects in which the length of each dosing cycle is about 21 days, the anti-CD38 antibody (e.g., daratumumab) is administered on or about day 2 (e.g., day 2 ± 1 day), day 8 (e.g., day 8 ± 1 day), and day 15 (e.g., day 15 ± 1 day) of each of dosing cycles 1 and 2, on or about day 1 (e.g., day 1 ± 1 day) of each of dosing cycles 3-18, and on or about day 1 (e.g., day 1 ± 1 day) of dosing cycle 19. For example, the anti-CD38 antibody (e.g., daratumumab) may be administered (e.g., administered subcutaneously or intravenously) at a fixed dose of about 1800 mg on days 2, 8, and 15 of each of dosing cycles 1 and 2, and on day 1 of each of dosing cycles 4, 5, 6, 7, 8, and 9. In some aspects, the anti-CD38 antibody is administered intravenously at a dose of 16 mg/kg on days 1 , 8, and 15 of each of dosing cycles 1 and 2, and on day 1 of each of dosing cycles 3-19. In some aspects in which the length of each dosing cycle is about 21 days, the anti-CD38 antibody (e.g., daratumumab) is administered once every four weeks beginning on or about day 1 of dosing cycle 9. For example, the anti-CD38 antibody (e.g., daratumumab) may be administered (e.g., administered subcutaneously or intravenously) at a fixed dose of about 1800 mg on day 1 of dosing cycle 9, on day 8 of dosing cycle 10, on day 15 of dosing cycle 11 , on day 1 of dosing cycle 13, on day 8 of dosing cycle 14, on day 15 of dosing cycle 15, on day 1 of dosing cycle 17, and once every four weeks thereafter. In some aspects, the anti-CD38 antibody is administered intravenously at a dose of 16 mg/kg on day 1 of dosing cycle 9, on day 8 of dosing cycle 10, on day 15 of dosing cycle 11 , on day 1 of dosing cycle 13, on day 8 of dosing cycle 14, on day 15 of dosing cycle 15, on day 1 of dosing cycle 17, and once every four weeks thereafter.

Alternatively, in some aspects in which the length of each dosing cycle is about 21 days, the anti- CD38 antibody (e.g., daratumumab) is administered once every four weeks beginning on or about day 1 of dosing cycle 19. For example, the anti-CD38 antibody (e.g., daratumumab) may be administered (e.g., administered subcutaneously or intravenously) at a fixed dose of about 1800 mg on day 1 of dosing cycle 19, on day 8 of dosing cycle 20, on day 15 of dosing cycle 21 , on day 1 of dosing cycle 23, on day 8 of dosing cycle 24, on day 15 of dosing cycle 25, on day 1 of dosing cycle 27, and once every four weeks thereafter. In some aspects, the anti-CD38 antibody is administered intravenously at a dose of 16 mg/kg on day 1 of dosing cycle 19, on day 8 of dosing cycle 20, on day 15 of dosing cycle 21 , on day 1 of dosing cycle 23, on day 8 of dosing cycle 24, on day 15 of dosing cycle 25, on day 1 of dosing cycle 27, and once every four weeks thereafter.

In some aspects, any of the doses of the anti-CD38 antibody (e.g., daratumumab) may be split into two doses and administered to the subject over the course of two consecutive days. In some aspects, the first dose of the anti-CD38 antibody (e.g., daratumumab) is administered over days 1 and 2 of dosing cycle 1 .

In some aspects, the PD-1 axis binding antagonist (e.g., atezolizumab) is administered on about day 1 (e.g., day 1 ± 1 day) of each dosing cycle. For example, the PD-1 axis binding antagonist (e.g., atezolizumab) may be administered intravenously at a fixed dose of about 1200 mg on day 1 of each 21- day dosing cycle (i.e., at a fixed dose of about 1200 mg every three weeks).

In some aspects, the method comprises administering to the subject the anti-TIGIT antagonist antibody (e.g., tiragolumab), anti-CD38 antibody (e.g., daratumumab), and PD-1 axis binding antagonist (e.g., atezolizumab) in a dosing regimen comprising at least nine dosing cycles, wherein: (a) the anti- TIGIT antagonist antibody is administered intravenously once every three weeks at a fixed dose of about 600 mg on day 1 of each dosing cycle; (b) the PD-1 axis binding antagonist is administered intravenously once every three weeks at a fixed dose of about 1200 mg on day 1 of each dosing cycle; and (c) the anti- CD38 antibody is administered subcutaneously (e.g., administered subcutaneously in a formulation with 30,000 U rHuPH20) once every week at a fixed dose of about 1800 mg on days 1 , 8, and 15 of each of dosing cycles 1 , 2, and 3; once every three weeks at a fixed dose of about 1800 mg on day 1 of each of dosing cycles 4, 5, 6, 7, 8, and 9; and once every four weeks thereafter (e.g., the anti-CD38 antibody is administered subcutaneously at a fixed dose of about 1800 mg on day 8 of dosing cycle 10, on day 15 of dosing cycle 11 , on day 1 of dosing cycle 13, on day 8 of dosing cycle 14, on day 15 of dosing cycle 15, on day 1 of dosing cycle 17, and once every four weeks thereafter), wherein each dosing cycle of the dosing regimen is 21 days.

In other aspects, the method comprises administering to the subject the anti-TIGIT antagonist antibody (e.g., tiragolumab), anti-CD38 antibody (e.g., daratumumab), and PD-1 axis binding antagonist (e.g., atezolizumab) in a dosing regimen comprising at least 19 dosing cycles, wherein: (a) the anti-TIGIT antagonist antibody is administered intravenously once every three weeks at a fixed dose of about 600 mg on day 1 of each dosing cycle; (b) the PD-1 axis binding antagonist is administered intravenously once every three weeks at a fixed dose of about 1200 mg on day 1 of each dosing cycle; and (c) the anti-CD38 antibody is administered subcutaneously (e.g., administered subcutaneously in a formulation with 30,000 U rHuPH20) once every week at a fixed dose of about 1800 mg on days 1 , 8, and 15 of each of dosing cycles 1 and 2; once every three weeks at a fixed dose of about 1800 mg on day 1 of each of dosing cycles 3-18; and once every four weeks thereafter (e.g., the anti-CD38 antibody is administered subcutaneously at a fixed dose of about 1800 mg on day 8 of dosing cycle 20, on day 15 of dosing cycle 21 , on day 1 of dosing cycle 23, on day 8 of dosing cycle 24, on day 15 of dosing cycle 25, on day 1 of dosing cycle 27, and once every four weeks thereafter), wherein each dosing cycle of the dosing regimen is 21 days.

In some aspects, the method comprises administering to the subject the anti-TIGIT antagonist antibody (e.g., tiragolumab), anti-CD38 antibody (e.g., daratumumab), and PD-1 axis binding antagonist (e.g., atezolizumab) in a dosing regimen comprising at least nine dosing cycles, wherein: (a) the anti- TIGIT antagonist antibody is administered intravenously once every three weeks at a fixed dose of 600 mg on day 1 of each dosing cycle; (b) the PD-1 axis binding antagonist is administered intravenously once every three weeks at a fixed dose of 1200 mg on day 1 of each dosing cycle; and (c) the anti-CD38 antibody is administered subcutaneously (e.g., administered subcutaneously in a formulation with 30,000 U rHuPH20) once every week at a fixed dose of 1800 mg on days 1 , 8, and 15 of each of dosing cycles 1 , 2, and 3; once every three weeks at a fixed dose of 1800 mg on day 1 of each of dosing cycles 4, 5, 6, 7, 8, and 9; and once every four weeks thereafter (e.g., the anti-CD38 antibody is administered subcutaneously at a fixed dose of 1800 mg on day 8 of dosing cycle 10, on day 15 of dosing cycle 11 , on day 1 of dosing cycle 13, on day 8 of dosing cycle 14, on day 15 of dosing cycle 15, on day 1 of dosing cycle 17, and once every four weeks thereafter), wherein each dosing cycle of the dosing regimen is 21 days.

In other aspects, the method comprises administering to the subject the anti-TIGIT antagonist antibody (e.g., tiragolumab), anti-CD38 antibody (e.g., daratumumab), and PD-1 axis binding antagonist (e.g., atezolizumab) in a dosing regimen comprising at least 19 dosing cycles, wherein: (a) the anti-TIGIT antagonist antibody is administered intravenously once every three weeks at a fixed dose of 600 mg on day 1 of each dosing cycle; (b) the PD-1 axis binding antagonist is administered intravenously once every three weeks at a fixed dose of 1200 mg on day 1 of each dosing cycle; and (c) the anti-CD38 antibody is administered subcutaneously (e.g., administered subcutaneously in a formulation with 30,000 U rHuPH20) once every week at a fixed dose of 1800 mg on days 1 , 8, and 15 of each of dosing cycles 1 and 2; once every three weeks at a fixed dose of 1800 mg on day 1 of each of dosing cycles 3-19; and once every four weeks thereafter (e.g., the anti-CD38 antibody is administered subcutaneously at a fixed dose of 1800 mg on day 8 of dosing cycle 20, on day 15 of dosing cycle 21 , on day 1 of dosing cycle 23, on day 8 of dosing cycle 24, on day 15 of dosing cycle 25, on day 1 of dosing cycle 27, and once every four weeks thereafter), wherein each dosing cycle of the dosing regimen is 21 days.

In some aspects, the method comprises administering to the subject tiragolumab, daratumumab, and atezolizumab in a dosing regimen comprising at least nine dosing cycles, wherein: (a) tiragolumab is administered intravenously once every three weeks at a fixed dose of 600 mg on day 1 of each dosing cycle; (b) atezolizumab is administered intravenously once every three weeks at a fixed dose of 1200 mg on day 1 of each dosing cycle; and (c) daratumumab is administered subcutaneously once every week at a fixed dose of 1800 mg in a formulation with 30,000 U rHuPH20 on days 1 , 8, and 15 of each of dosing cycles 1 , 2, and 3; once every three weeks at a fixed dose of 1800 mg in a formulation with 30,000 U rHuPH20 on day 1 of each of dosing cycles 4, 5, 6, 7, 8, and 9; and once every four weeks thereafter (e.g., daratumumab is administered subcutaneously at a fixed dose of 1800 mg in a formulation with 30,000 U rHuPH20 on day 8 of dosing cycle 10, on day 15 of dosing cycle 11 , on day 1 of dosing cycle 13, on day 8 of dosing cycle 14, on day 15 of dosing cycle 15, on day 1 of dosing cycle 17, and once every four weeks thereafter), wherein each dosing cycle of the dosing regimen is 21 days.

In some aspects, the method comprises administering to the subject tiragolumab, daratumumab, and atezolizumab in a dosing regimen comprising at least 19 dosing cycles, wherein: (a) tiragolumab is administered intravenously once every three weeks at a fixed dose of 600 mg on day 1 of each dosing cycle; (b) atezolizumab is administered intravenously once every three weeks at a fixed dose of 1200 mg on day 1 of each dosing cycle; and (c) daratumumab is administered subcutaneously once every week at a fixed dose of 1800 mg in a formulation with 30,000 U rHuPH20 on days 1 , 8, and 15 of each of dosing cycles 1 and 2; once every three weeks at a fixed dose of 1800 mg in a formulation with 30,000 U rHuPH20 on day 1 of each of dosing cycles 3-19; and once every four weeks thereafter (e.g., daratumumab is administered subcutaneously at a fixed dose of 1800 mg in a formulation with 30,000 U rHuPH20 on day 8 of dosing cycle 20, on day 15 of dosing cycle 21 , on day 1 of dosing cycle 23, on day 8 of dosing cycle 24, on day 15 of dosing cycle 25, on day 1 of dosing cycle 27, and once every four weeks thereafter), wherein each dosing cycle of the dosing regimen is 21 days.

In another aspect, the disclosure features a method for treating a subject having a hematologic cancer, the method comprising administering to the subject an anti-TIGIT antagonist antibody at a fixed dose of about 10 mg to about 1000 mg (e.g., a fixed dose of about 420 mg), an anti-CD38 antibody at a dose of between about 300 mg to about 3600 mg (e.g., a dose of about 1800 mg), and a PD-1 axis binding antagonist at a fixed dose of between about 20 mg to about 1600 mg (e.g., a dose of about 840 mg) in a dosing regimen comprising at least nine dosing cycles, wherein (a) the anti-TIGIT antagonist antibody is administered once every two weeks; (b) the PD-1 axis binding antagonist is administered once every two weeks; and (c) the anti-CD38 antibody is administered once every week during each of dosing cycles 1-3, once every three weeks during each of dosing cycles 4-8, and once every four weeks during dosing cycle 9. In some aspects, the length of each dosing cycle is 21 days. In some aspects, the dosing regimen comprises at least 16 dosing cycles.

In another aspect, the disclosure features a method for treating a subject having a hematologic cancer, the method comprising administering to the subject an anti-TIGIT antagonist antibody at a fixed dose of about 10 mg to about 1000 mg (e.g., a fixed dose of about 420 mg), an anti-CD38 antibody at a dose of between about 300 mg to about 3600 mg (e.g., a dose of about 1800 mg), and a PD-1 axis binding antagonist at a fixed dose of between about 20 mg to about 1600 mg (e.g., a dose of about 840 mg) in a dosing regimen comprising at least nine dosing cycles, wherein (a) the anti-TIGIT antagonist antibody is administered once every two weeks; (b) the PD-1 axis binding antagonist is administered once every two weeks; and (c) the anti-CD38 antibody is administered once every week during each of dosing cycles 1 and 2, once every three weeks during each of dosing cycles 3018, and once every four weeks during dosing cycle 19. In some aspects, the length of each dosing cycle is 21 days.

In another aspect, the disclosure features a method for treating a subject having a relapsed or refractory MM, the method comprising administering to the subject tiragolumab at a fixed dose of 420 mg, daratumumab at a fixed dose of 1800 mg, and atezolizumab at a fixed dose of 840 mg in a dosing regimen comprising at least nine dosing cycles, wherein the length of each dosing cycle is 21 days and wherein (a) the tiragolumab is administered once every two weeks; (b) the atezolizumab is administered once every two weeks; and (c) the daratumumab is administered on or about days 1 , 8, and 15 of each of dosing cycles 1-3, on or about day 1 during each of dosing cycles 4-8, and once every 4 weeks beginning on or about day 1 of dosing cycle 9. In some aspects, the dosing regimen comprises at least 16 dosing cycles.

In another aspect, the disclosure features a method for treating a subject having a hematologic cancer, the method comprising administering to the subject an anti-TIGIT antagonist antibody at a fixed dose of between about 200 mg to about 2000 mg (e.g., a fixed dose of about 840 mg), an anti-CD38 antibody at a dose of between about 300 mg to about 3600 mg (e.g., a dose of about 1800 mg), and a PD-1 axis binding antagonist at a fixed dose of between about 500 mg to about 3000 mg (e.g., a dose of about 1680 mg) in a dosing regimen comprising at least nine dosing cycles, wherein (a) the anti-TIGIT antagonist antibody is administered once every four weeks; (b) the PD-1 axis binding antagonist is administered once every four weeks; and (c) the anti-CD38 antibody is administered once every week during each of dosing cycles 1-3, once every three weeks during each of dosing cycles 4-8, and once every four weeks during dosing cycle 9. In some aspects, the length of each dosing cycle is 21 days. In some aspects, the dosing regimen comprises at least 16 dosing cycles.

In another aspect, the disclosure features a method for treating a subject having a relapsed or refractory MM, the method comprising administering to the subject tiragolumab at a fixed dose of 840 mg, daratumumab at a fixed dose of 1800 mg, and atezolizumab at a fixed dose of 1680 mg in a dosing regimen comprising at least nine dosing cycles, wherein the length of each dosing cycle is 21 days, and wherein (a) the tiragolumab is administered once every 4 weeks; (b) the atezolizumab is administered once every 4 weeks; and (c) the daratumumab is administered on or about days 1 , 8, and 15 of each of dosing cycles 1-3, on or about day 1 during each of dosing cycles 4-8, and once every 4 weeks beginning on or about day 1 of dosing cycle 9. In some aspects, the dosing regimen comprises at least 16 dosing cycles.

In some aspects, when the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the anti-CD38 antibody (e.g., daratumumab) are scheduled to be administered on the same day, the anti-CD38 antibody may be administered either on that day, or on the next consecutive day. Accordingly, in some aspects, the anti-TIGIT antagonist antibody (e.g., an anti- TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered to the subject on day 1 of the dosing cycle and the anti-CD38 antibody (e.g. daratumumab) is administered to the subject on day 2 of the dosing cycle. In other aspects, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the anti-CD38 antibody (e.g. daratumumab) are both administered to the subject on day 1 of the dosing cycle.

In some aspects, the anti-TIGIT antagonist antibody, the anti-CD38 antibody, and the PD-1 axis binding antagonist are each administered on or about day 1 of each of dosing cycles 1-9. In some aspects, the anti-TIGIT antagonist antibody, the anti-CD38 antibody, and the PD-1 axis binding antagonist are each administered on or about day 1 of each of dosing cycles 1-19.

In some aspects, the method comprises administering to the subject the tiragolumab after the atezolizumab. In other aspects, the method comprises administering to the subject the atezolizumab after the tiragolumab. In some aspects in which the anti-TIGIT antagonist antibody, the anti-CD38 antibody, and the PD-1 axis binding antagonist are administered on the same day, in some aspects, the anti-TIGIT antagonist antibody is administered prior to the anti-CD38 antibody and the PD-1 axis binding antagonist. In some aspects, the anti-TIGIT antagonist antibody is administered first, the PD-1 axis binding antagonist is administered second, and the anti-CD38 antibody is administered third. In other aspects, the anti-TIGIT antagonist antibody is administered first, the anti-CD38 antibody is administered second, and the PD-1 axis binding antagonist is administered third. In some aspects, the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are administered simultaneously. In some aspects, the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist (e.g., tiragolumab and atezolizumab) are combined in an IV bag prior to administration.

Hi. Observation periods

In some aspects in which the anti-TIGIT antagonist antibody is administered first, the PD-1 axis binding antagonist is administered second, and the anti-CD38 antibody is administered third, the method comprises a first observation period following administration of the anti-TIGIT antagonist antibody, a second observation period following administration of the PD-1 axis binding antagonist, and a third observation period following administration of the anti-CD38 antibody. In some aspects, the first observation period and the second observation period are each between about 30 minutes to about 60 minutes in length. In some aspects, the third observation period is about 6 hours in length following the first dose of the anti-CD38 antibody and is about 60 minutes in length following subsequent doses of the anti-CD38 antibody.

In some aspects in which the anti-TIGIT antagonist antibody is administered first, the anti-CD38 antibody is administered second, and the PD-1 axis binding antagonist is administered third, the method comprises a first observation period following administration of the anti-TIGIT antagonist antibody, a second observation period following administration of the anti-CD38 antibody, and a third observation period following administration of the PD-1 axis binding antagonist. In some aspects, the first observation period and the third observation period are each between about 30 minutes to about 60 minutes in length. In some aspects, the second observation period is about 6 hours in length following the first dose of the anti-CD38 antibody and is about 60 minutes in length following subsequent doses of the anti-CD38 antibody. iv. Premedication and post-medication

In some aspects, the method comprises administering to the subject a corticosteroid (e.g., methylprednisolone) prior to the first, second, and third administrations of the anti-CD38 antibody. In some aspects, the corticosteroid is methylprednisolone. In some aspects, the corticosteroid (e.g., methylprednisolone) is administered orally at 100 mg prior to the first administration of the anti-CD38 antibody, at 60 mg prior to the second administration of the anti-CD38 antibody, and at 40 mg prior to the third administration of the anti-CD38 antibody.

In some aspects, the method comprises administering to the subject a corticosteroid, an antipyretic, and an antihistamine prior to the first administration of the anti-CD38 antibody. In some aspects, the corticosteroid is methylprednisolone, the antipyretic is acetaminophen, and the antihistamine is diphenhydramine.

In some aspects, the method further comprises administering to the subject a leukotriene receptor antagonist (e.g., montelukast) prior to the first administration of the anti-CD38 antibody.

In some aspects, the corticosteroid is administered prior to additional administrations of the anti- 038 antibody, e.g., prior to each administration of the anti-CD38 antibody.

In some aspects, the method comprises administering to the subject an antipyretic (e.g., acetaminophen) prior to each administration of the anti-CD38 antibody. In some aspects, the method comprises administering to the subject an antihistamine (e.g., diphenhydramine) prior to each administration of the anti-CD38 antibody.

In some aspects, the method comprises administering to the subject a corticosteroid, an antipyretic, and an antihistamine (e.g., methylprednisolone, acetaminophen, and diphenhydramine) prior to each administration of the anti-CD38 antibody.

In some aspects, the method comprises administering to the subject a corticosteroid (e.g., methylprednisolone) on each of the two days following the first, second, and third administrations of the anti-CD38 antibody. For example, 20 mg methylprednisolone may be administered to the subject on days 1 and 2 following administration of the anti-CD38 antibody.

In some examples, the corticosteroid (e.g., methylprednisolone) may be administered orally at a dose of 20-100 mg (e.g., at a dose of 40-100 mg 1 hour prior to the administration of the anti-CD38 antibody and/or at a dose of about 20 mg on each of the two days following the administration of the anti- CD38 antibody), the antipyretic (e.g., acetaminophen) may be administered orally at a dose of 650-1000 mg (e.g., at least 30 minutes prior to the administration of the anti-CD38 antibody), the antihistamine (e.g., diphenhydramine) may be administered orally or by IV at a dose of 25-50 mg (e.g., about one to three hours prior to the administration of the anti-CD38 antibody), and/or the leukotriene receptor antagonist (e.g., montelukast) may be administered orally at a dose of about 10 mg (e.g., 1-3 hours priorto the administration of the anti-CD38 antibody).

In another aspect, the disclosure features a method for treating a subject having a relapsed or refractory MM, the method comprising administering to the subject tiragolumab at a fixed dose of 600 mg, daratumumab at a fixed dose of 1800 mg, and atezolizumab at a fixed dose of 1200 mg in a dosing regimen comprising at least nine dosing cycles, wherein the length of each dosing cycle is 21 days, and wherein: (a) tiragolumab is administered on or about day 1 of each dosing cycle; (b) atezolizumab is administered on or about day 1 of each dosing cycle; and (c) daratumumab is administered on or about days 1 , 8, and 15 of each of dosing cycles 1-3, on or about day 1 during each of dosing cycles 4-8, and once every 4 weeks beginning on or about day 1 of dosing cycle 9. In some aspects, the dosing regimen comprises at least 16 dosing cycles.

In another aspect, the disclosure features a method for treating a subject having a relapsed or refractory MM, the method comprising administering to the subject tiragolumab at a fixed dose of 600 mg, daratumumab at a fixed dose of 1800 mg, and atezolizumab at a fixed dose of 1200 mg in a dosing regimen comprising at least 19 dosing cycles, wherein the length of each dosing cycle is 21 days, and wherein: (a) tiragolumab is administered on or about day 1 of each dosing cycle; (b) atezolizumab is administered on or about day 1 of each dosing cycle; and (c) daratumumab is administered on or about days 1 , 8, and 15 of each of dosing cycles 1 and 2, on or about day 1 during each of dosing cycles 3-18, and once every 4 weeks beginning on or about day 1 of dosing cycle 19.

B. Treatment of hematologic cancer using an anti-TIGIT antagonist antibody and an anti- CD38 antibody

In another aspect, provided herein is a method for treating a hematologic cancer (e.g., a myeloma (e.g., a multiple myeloma (MM), e.g., a relapsed or refractory MM)) comprising administering to a subject or population of subjects an effective amount of an anti-TIGIT antagonist antibody (e.g., tiragolumab) and an anti-CD38 antibody (e.g., daratumumab), wherein at least one dose of the anti-CD38 antibody is administered subcutaneously. In some aspects, all doses of the anti-CD38 antibody are administered subcutaneously.

In some aspects, the hematologic cancer is a myeloma. In some aspects, the myeloma is a multiple myeloma (MM). In some aspects, the MM is a relapsed or refractory MM. In some aspects, the patient has received at least three prior lines of treatment for the MM, e.g., is 4L+, e.g., has received three, four, five, six, or more than six prior lines of treatment. For example, the patient may have been exposed to a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), an autologous stem cell transplant (ASCT), an anti-CD38 therapy, a CAR-T therapy, or a therapy comprising a bispecific antibody. In some instances, the patient has been exposed to all three of PI, IMiD, and anti-CD38 therapy. In some aspects, the patient is refractory to a proteasome inhibitor and/or an immunomodulatory drug (IMiD).

Exemplary anti-TIGIT antagonist antibodies are provided in Section VI. Exemplary anti-CD38 antibodies are provided in Section VIII.

/. Effective amounts

In some aspects, the effective amount of the anti-CD38 antibody (e.g., an anti-CD38 antibody as disclosed herein, e.g., daratumumab) is a fixed dose of between about 300 mg to about 3600 mg (e.g., between about 400 mg to about 3200 mg, e.g., between about 600 mg to about 3000 mg, e.g., between about 1200 mg to about 2600 mg, e.g., between about 1650 mg to about 1950 mg, e.g., between about 1700 mg to about 1900 mg, e.g., between about 1750 mg to about 1850 mg, e.g., 1800 mg ± 10 mg, e.g., 1800 ± 6 mg, e.g., 1800 ± 5 mg, e.g., 1800 ± 3 mg, e.g., 1800 ± 1 mg, e.g., 1800 ± 0.5 mg, e.g., 1800 mg). In some aspects, the effective amount of the anti-CD38 antibody (e.g., an anti-CD38 antibody as disclosed herein, e.g., daratumumab) is a fixed dose of 1800 mg. The anti-CD38 antibody may be administered subcutaneously for all doses or may be administered subcutaneously for some doses and intravenously for other doses (e.g., administered subcutaneously for at least one, at least two, at least three, or more than three doses). In some aspects, the anti-CD38 antibody (e.g., daratumumab) is administered subcutaneously (e.g., administered subcutaneously in a formulation with human hyaluronidase PH20 (rHuPH20)) and the effective amount of the anti-CD38 antibody (e.g., daratumumab) is a fixed dose of about 1800 mg. In some aspects, the anti-CD38 antibody (e.g., daratumumab) is administered subcutaneously and the effective amount of the anti-CD38 antibody (e.g., daratumumab) is a dose of 1800 mg of the anti-CD38 antibody formulated in 30,000 U rHuPH20 (e.g., at a volume of 15 mL). In some aspects, the subcutaneous administration is by manual push, e.g., for about 3-5 minutes. In some aspects, the subcutaneous administration comprises injection into abdominal subcutaneous tissues.

In some aspects in which the anti-CD38 antibody (e.g., daratumumab) is administered intravenously, the effective amount of the anti-CD38 antibody (e.g., daratumumab) is a dose of between about 8 mg/kg to about 24 mg/kg of the subject’s body weight (e.g., between about 8 mg/kg to about 22 mg/kg, e.g., between about 10 mg/kg to about 20 mg/kg, e.g., between about 10 mg/kg to about 18 mg/kg, e.g., between about 12 mg/kg to about 16 mg/kg, e.g., about 16 ± 2 mg/kg, about 16 ± 1 mg/kg, about 16 ± 0.5 mg/kg, about 16 ± 0.2 mg/kg, or about 16 ± 0.1 mg/kg, e.g., about 16 mg/kg). In some aspects in which the anti-CD38 antibody (e.g., daratumumab) is administered intravenously, the effective amount of the anti-CD38 antibody (e.g., daratumumab) is a dose of about 16 mg/kg.

In some aspects, the method comprises administering to the subject the anti-TIGIT antagonist antibody (e.g., tiragolumab) at a fixed dose of between about 30 mg to about 1200 mg and the anti-CD38 antibody (e.g., daratumumab) at a dose of between about 300 mg to about 3600 mg.

In some aspects, the method comprises administering to the subject the anti-TIGIT antagonist antibody (e.g., tiragolumab) at a fixed dose of between 30 mg to 1200 mg and the anti-CD38 antibody (e.g., daratumumab) at a dose of between 300 mg to 3600 mg.

//. Timing and number of cycles

In some aspects, the method comprises administering to the subject the anti-TIGIT antagonist antibody (e.g., tiragolumab) and anti-CD38 antibody (e.g., daratumumab) in a dosing regimen comprising at least at least nine dosing cycles, wherein: (a) the anti-TIGIT antagonist antibody is administered once every three weeks; (b) the PD-1 axis binding antagonist is administered once every three weeks; and (c) the anti-CD38 antibody is administered once every week during each of dosing cycles 1-3, once every three weeks during each of dosing cycles 4-8, and once every four weeks during dosing cycle 9. In other aspects, the anti-CD38 antibody is administered once every week during each of dosing cycles 1 and 2, once every three weeks during each of cycles 3-19, and once every four weeks thereafter.

In any of the methods and uses of the invention, the anti-TIGIT antagonist antibody (e.g., an anti- TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the anti-CD38 antibody (e.g., daratumumab) may be administered in a dosing regimen that includes at least nine dosing cycles (e.g., 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, or 50 or more dosing cycles). In some aspects, the dosing regimen includes at least 12 dosing cycles. In some aspects, the dosing regimen includes at least 16 dosing cycles. In some aspects, the dosing regimen includes at least 19 dosing cycles. In some aspects, the dosing cycles of the anti-TIGIT antagonist antibody (e.g., tiragolumab) and anti-CD38 antibody (e.g., daratumumab) continue until there is a loss of clinical benefit (e.g., confirmed disease progression, drug resistance, death, or unacceptable toxicity).

In some aspects, the length of each dosing cycle is about 18 to 24 days (e.g., 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, or 24 days). In some aspects, the length of each dosing cycle is about 21 days.

In some aspects, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered on about day 1 (e.g., day 1 ± 1 day) of each dosing cycle. For example, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) may be administered intravenously at a fixed dose of about 600 mg on day 1 of each 21 -day dosing cycle (i.e., at a fixed dose of about 600 mg every three weeks).

In other aspects in which the length of each dosing cycle is about 21 days, the anti-CD38 antibody (e.g., daratumumab) is administered on or about day 2 (e.g., day 2 ± 1 day), day 8 (e.g., day 8 ± 1 day), and day 15 (e.g., day 15 ± 1 day) of each of dosing cycles 1-3, on or about day 1 (e.g., day 1 ± 1 day) of each of dosing cycles 4-8, and on or about day 1 (e.g., day 1 ± 1 day) of dosing cycle 9. For example, the anti-CD38 antibody (e.g., daratumumab) may be administered (e.g., administered subcutaneously or intravenously) at a fixed dose of about 1800 mg on days 2, 8, and 15 of each of dosing cycles 1 , 2, and 3 and on day 1 of each of dosing cycles 4, 5, 6, 7, 8, and 9.

In other aspects in which the length of each dosing cycle is about 21 days, the anti-CD38 antibody (e.g., daratumumab) is administered on or about day 2 (e.g., day 2 ± 1 day), day 8 (e.g., day 8 ± 1 day), and day 15 (e.g., day 15 ± 1 day) of each of dosing cycles 1 and 2, on or about day 1 (e.g., day 1 ± 1 day) of each of dosing cycles 3-18, and on or about day 1 (e.g., day 1 ± 1 day) of dosing cycle 19. For example, the anti-CD38 antibody (e.g., daratumumab) may be administered (e.g., administered subcutaneously or intravenously) at a fixed dose of about 1800 mg on days 2, 8, and 15 of each of dosing cycles 1 and 2 and on day 1 of each of dosing cycles 3-19,

In some aspects in which the length of each dosing cycle is about 21 days, the anti-CD38 antibody (e.g., daratumumab) is administered once every four weeks beginning on or about day 1 of dosing cycle 9. For example, the anti-CD38 antibody (e.g., daratumumab) may be administered (e.g., administered subcutaneously or intravenously) at a fixed dose of about 1800 mg on day 1 of dosing cycle 9, on day 8 of dosing cycle 10, on day 15 of dosing cycle 11 , on day 1 of dosing cycle 13, on day 8 of dosing cycle 14, on day 15 of dosing cycle 15, on day 1 of dosing cycle 17, and once every four weeks thereafter.

In other aspects in which the length of each dosing cycle is about 21 days, the anti-CD38 antibody (e.g., daratumumab) is administered once every four weeks beginning on or about day 1 of dosing cycle 19. For example, the anti-CD38 antibody (e.g., daratumumab) may be administered (e.g., administered subcutaneously or intravenously) at a fixed dose of about 1800 mg on day 1 of dosing cycle 19, on day 8 of dosing cycle 20, on day 15 of dosing cycle 21 , on day 1 of dosing cycle 23, on day 8 of dosing cycle 24, on day 15 of dosing cycle 25, on day 1 of dosing cycle 27, and once every four weeks thereafter.

In some aspects, the method comprises administering to the subject the anti-TIGIT antagonist antibody (e.g., tiragolumab) and the anti-CD38 antibody (e.g., daratumumab) in a dosing regimen comprising at least nine dosing cycles, wherein: (a) the anti-TIGIT antagonist antibody is administered intravenously once every three weeks at a fixed dose of about 600 mg on day 1 of each dosing cycle and (b) the anti-CD38 antibody is administered subcutaneously (e.g., administered subcutaneously in a formulation with 30,000 U rHuPH20) once every week at a fixed dose of about 1800 mg on days 1 , 8, and 15 of each of dosing cycles 1 , 2, and 3; once every three weeks at a fixed dose of about 1800 mg on day 1 of each of dosing cycles 4, 5, 6, 7, 8, and 9; and once every four weeks thereafter (e.g., the anti-CD38 antibody is administered subcutaneously at a fixed dose of about 1800 mg on day 8 of dosing cycle 10, on day 15 of dosing cycle 11 , on day 1 of dosing cycle 13, on day 8 of dosing cycle 14, on day 15 of dosing cycle 15, on day 1 of dosing cycle 17, and once every four weeks thereafter), wherein each dosing cycle of the dosing regimen is 21 days.

In some aspects, the method comprises administering to the subject the anti-TIGIT antagonist antibody (e.g., tiragolumab) and the anti-CD38 antibody (e.g., daratumumab) in a dosing regimen comprising at least 19 dosing cycles, wherein: (a) the anti-TIGIT antagonist antibody is administered intravenously once every three weeks at a fixed dose of about 600 mg on day 1 of each dosing cycle and (b) the anti-CD38 antibody is administered subcutaneously (e.g., administered subcutaneously in a formulation with 30,000 U rHuPH20) once every week at a fixed dose of about 1800 mg on days 1 , 8, and 15 of each of dosing cycles 1 and 2; once every three weeks at a fixed dose of about 1800 mg on day 1 of each of dosing cycles 3-19; and once every four weeks thereafter (e.g., the anti-CD38 antibody is administered subcutaneously at a fixed dose of about 1800 mg on day 8 of dosing cycle 20, on day 15 of dosing cycle 21 , on day 1 of dosing cycle 23, on day 8 of dosing cycle 24, on day 15 of dosing cycle 25, on day 1 of dosing cycle 27, and once every four weeks thereafter), wherein each dosing cycle of the dosing regimen is 21 days.

In some aspects, the method comprises administering to the subject tiragolumab and daratumumab in a dosing regimen comprising at least nine dosing cycles, wherein: (a) tiragolumab is administered intravenously once every three weeks at a fixed dose of 600 mg on day 1 of each dosing cycle; and (b) daratumumab is administered subcutaneously once every week at a fixed dose of 1800 mg in a formulation with 30,000 U rHuPH20 on days 1 , 8, and 15 of each of dosing cycles 1 , 2, and 3; once every three weeks at a fixed dose of 1800 mg in a formulation with 30,000 U rHuPH20 on day 1 of each of dosing cycles 4, 5, 6, 7, 8, and 9; and once every four weeks thereafter (e.g., daratumumab is administered subcutaneously at a fixed dose of 1800 mg in a formulation with 30,000 U rHuPH20 on day 8 of dosing cycle 10, on day 15 of dosing cycle 11 , on day 1 of dosing cycle 13, on day 8 of dosing cycle 14, on day 15 of dosing cycle 15, on day 1 of dosing cycle 17, and once every four weeks thereafter), wherein each dosing cycle of the dosing regimen is 21 days.

In some aspects, the method comprises administering to the subject tiragolumab and daratumumab in a dosing regimen comprising at least 19 dosing cycles, wherein: (a) tiragolumab is administered intravenously once every three weeks at a fixed dose of 600 mg on day 1 of each dosing cycle; and (b) daratumumab is administered subcutaneously once every week at a fixed dose of 1800 mg in a formulation with 30,000 U rHuPH20 on days 1 , 8, and 15 of each of dosing cycles 1 and 2; once every three weeks at a fixed dose of 1800 mg in a formulation with 30,000 U rHuPH20 on day 1 of each of dosing cycles 3-19; and once every four weeks thereafter (e.g., daratumumab is administered subcutaneously at a fixed dose of 1800 mg in a formulation with 30,000 U rHuPH20 on day 8 of dosing cycle 20, on day 15 of dosing cycle 21 , on day 1 of dosing cycle 23, on day 8 of dosing cycle 24, on day 15 of dosing cycle 25, on day 1 of dosing cycle 27, and once every four weeks thereafter), wherein each dosing cycle of the dosing regimen is 21 days.

In some aspects, the anti-TIGIT antagonist antibody and the anti-CD38 antibody are each administered on or about day 1 of each of dosing cycles 1-9. In some aspects, the anti-TIGIT antagonist antibody and the anti-CD38 antibody are each administered on or about day 1 of each of dosing cycles 1- 19.

In some aspects in which the anti-TIGIT antagonist antibody and the anti-CD38 antibody are administered on the same day, the anti-TIGIT antagonist antibody is administered prior to the anti-CD38 antibody. Hi. Observation periods

In some aspects in which the anti-TIGIT antagonist antibody is administered first and the anti- CD38 antibody is administered second, the method comprises a first observation period following administration of the anti-TIGIT antagonist antibody and a second observation period following administration of the anti-CD38 antibody. In some aspects, the first observation period and the second observation period are each between about 30 minutes to about 60 minutes in length. In some aspects, the second observation period is about 6 hours in length following the first dose of the anti-CD38 antibody and is about 60 minutes in length following subsequent doses of the anti-CD38 antibody. iv. Premedication and post-medication

In some aspects, the method comprises administering to the subject an antipyretic (e.g., acetaminophen) prior to each administration of the anti-CD38 antibody.

In some aspects, the method comprises administering to the subject an antihistamine (e.g., diphenhydramine) prior to each administration of the anti-CD38 antibody.

In some examples, the corticosteroid (e.g., methylprednisolone) may be administered orally at a dose of 20-100 mg (e.g., at a dose of 40-100 mg 1 hour priorto the administration of the anti-CD38 antibody and/or at a dose of about 20 mg on each of the two days following the administration of the anti- CD38 antibody), the antipyretic (e.g., acetaminophen) may be administered orally at a dose of 650-1000 mg (e.g., at least 30 minutes prior to the administration of the anti-CD38 antibody), the antihistamine (e.g., diphenhydramine) may be administered orally or by IV at a dose of 25-50 mg (e.g., about one to three hours prior to the administration of the anti-CD38 antibody), and/or the leukotriene receptor antagonist (e.g., montelukast) may be administered orally at a dose of about 10 mg (e.g., 1-3 hours priorto the administration of the anti-CD38 antibody).

In another aspect, the disclosure features a method for treating a subject having a relapsed or refractory MM, the method comprising administering to the subject tiragolumab at a fixed dose of 600 mg and daratumumab at a fixed dose of 1800 mg in a dosing regimen comprising at least nine dosing cycles, wherein the length of each dosing cycle is 21 days, and wherein: (a) tiragolumab is administered on or about day 1 of each dosing cycle; and (b) daratumumab is administered on or about days 1 , 8, and 15 of each of dosing cycles 1 -3, on or about day 1 during each of dosing cycles 4-8, and once every 4 weeks beginning on or about day 1 of dosing cycle 9, and wherein at least one dose of the anti-CD38 antibody is administered subcutaneously. Alternatively, the dosing regimen comprises at least 19 dosing cycles, and the anti-CD38 antibody is administered once every week during each of dosing cycles 1 and 2, once every three weeks during each of dosing cycles 3-18, and once every four weeks during dosing cycle 19. In some aspects, all doses of the anti-CD38 antibody are administered subcutaneously. In some aspects, the dosing regimen comprises at least 12 dosing cycles. In some aspects, the dosing regimen comprises at least 16 dosing cycles.

C. Treatment of hematologic cancer using an anti-TIGIT antagonist antibody and an anti- CD20 antibody

In another aspect, provided herein is a method for treating a hematologic cancer (e.g., a lymphoma (e.g., a non-Hodgkin’s lymphoma (NHL), e.g., a relapsed or refractory diffuse large B cell lymphoma (DLBCL) or a relapsed or refractory follicular lymphoma (FL))) comprising administering to a subject or population of subjects an effective amount of an anti-TIGIT antagonist antibody (e.g., tiragolumab) and an anti-CD20 antibody (e.g., rituximab), wherein the first dose of the anti-CD20 antibody is administered intravenously and at least one subsequent dose of the anti-CD20 antibody is administered subcutaneously (e.g., is administered subcutaneously in a formulation with rHuPH20, e.g., is RITUXAN HYCELA®). In some aspects, all subsequent doses of the anti-CD20 antibody are administered subcutaneously.

In some aspects, the hematologic cancer is a lymphoma (e.g., a non-Hodgkin’s lymphoma (NHL), e.g., a relapsed or refractory diffuse large B cell lymphoma (DLBCL) or a relapsed or refractory follicular lymphoma (FL)).

Exemplary anti-TIGIT antagonist antibodies are provided in Section VI. Exemplary anti-CD20 antibodies are provided in Section IX.

/. Effective amounts

In aspects in which the anti-CD20 antibody (e.g., rituximab) is delivered intravenously (e.g., the first dose), the effective amount of the anti-CD20 antibody may be a dose of between about 250 mg/m² to about 500 mg/m² (e.g., between about 250 mg/m² to about 450 mg/m², e.g., between about 250 mg/m² to about 400 mg/m², e.g., between about 300 mg/m² to about 400 mg/m², e.g., between about 325 mg/m² to about 400 mg/m², e.g., between about 350 mg/m² to about 400 mg/m², e.g., between about 350 mg/m² to about 375 mg/m², e.g., about 375 ± 2 mg/m², about 375 ± 1 mg/m², about 375 ± 0.5 mg/m², about 375 ± 0.2 mg/m², or about 375 ± 0.1 mg/m², e.g., about 375 mg/m²). In some aspects, the effective amount of the anti-CD20 antibody (e.g., rituximab) is a dose of about 375 mg/m². In some aspects, the first dose of the anti-CD20 antibody (e.g., rituximab) is a dose of about 375 mg/m².

In aspects, in which the anti-CD20 antibody (e.g., rituximab) is delivered subcutaneously, the effective amount of the anti-CD20 antibody may be a fixed dose of between about 200 mg to about 2800 mg (e.g., between about 400 mg to about 2400 mg, e.g., between about 800 mg to about 2000 mg, e.g., between about 1000 mg to about 1800 mg, e.g., between about 1250 mg to about 1650 mg, e.g., between about 1300 mg to about 1500 mg, e.g., between about 1350 mg to about 1450 mg, e.g., 1400 mg ± 10 mg, e.g., 1400 ± 6 mg, e.g., 1400 ± 5 mg, e.g., 1400 ± 3 mg, e.g., 1400 ± 1 mg, e.g., 1400 ± 0.5 mg, e.g., 1400 mg). In some aspects, the effective amount of the anti-CD20 antibody (e.g., an anti-CD20 antibody as disclosed herein, e.g., rituximab) is a fixed dose of 1400 mg. In some aspects, the anti-CD20 antibody (e.g., rituximab) is administered subcutaneously (e.g., administered subcutaneously in a formulation with human hyaluronidase PH20 (rHuPH20)) and the effective amount of the anti-CD20 antibody (e.g., rituximab) is a fixed dose of about 1400 mg. In some aspects, the anti-CD20 antibody (e.g., rituximab) is administered subcutaneously and the effective amount of the anti-CD20 antibody (e.g., rituximab) is a dose of 1400 mg of the anti-CD20 antibody formulated in 23,400 U rHuPH20 (e.g., at a volume of 11 .7 mL). In some aspects, the subcutaneous administration is with the anti-CD20 antibody (e.g., rituximab) formulated for subcutaneous administration with rHuPH20, e.g., is RITUXAN HYCELA®. In some aspects, the subcutaneous administration is by manual push, e.g., for about 3-5 minutes. In some aspects, the subcutaneous administration comprises injection into abdominal subcutaneous tissues. In some aspects, the method comprises administering to the subject the anti-TIGIT antagonist antibody (e.g., tiragolumab) at a fixed dose of between about 30 mg to about 1200 mg, and the anti-CD20 antibody (e.g., rituximab) at (a) a first dose of between about 250 mg/m² to about 500 mg/m², wherein the first dose is delivered intravenously, and (b) at least one subsequent dose of between about 200 mg to about 2800 mg, wherein the at least one subsequent dose is administered subcutaneously. In some aspects, the method comprises administering to the subject the anti-TIGIT antagonist antibody (e.g., tiragolumab) at a fixed dose of between 30 mg to 1200 mg, and the anti-CD20 antibody (e.g., rituximab) at

(a) a first dose of between 250 mg/m² to 500 mg/m², wherein the first dose is delivered intravenously, and

(b) at least one subsequent dose of between 200 mg to 2800 mg, wherein the at least one subsequent dose is administered subcutaneously.

In some aspects, the method comprises administering to the subject the anti-CD20 antibody at (a) a first dose of about 375 mg/m², wherein the first dose is delivered intravenously, and (b) at least one subsequent dose of about 1400 mg, wherein the at least one subsequent dose is administered subcutaneously. In some aspects, the method comprises administering to the subject the anti-CD20 antibody at (a) a first dose of 375 mg/m², wherein the first dose is delivered intravenously, and (b) at least one subsequent dose of 1400 mg, wherein the at least one subsequent dose is administered subcutaneously.

//. Timing and number of cycles

In some aspects, the method comprises administering to the subject the anti-TIGIT antagonist antibody (e.g., tiragolumab) and anti-CD20 antibody (e.g., rituximab) in a dosing regimen comprising at least a first, a second, and a third dosing cycle, wherein: (a) the anti-TIGIT antagonist antibody is administered once every three weeks; and (b) the anti-CD20 antibody is administered once every week, wherein the first dose of the anti-CD20 antibody is administered intravenously and at least one subsequent dose of the anti-CD20 antibody is administered subcutaneously.

In any of the methods and uses of the invention, the anti-TIGIT antagonist antibody (e.g., an anti- TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the anti-CD20 antibody (e.g., rituximab) may be administered in a dosing regimen that includes at least a first and a second dosing cycle (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, or 50 or more dosing cycles). In other aspects, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the anti-CD20 antibody (e.g., rituximab) may be administered in a dosing regimen that includes at least a first, a second, and a third dosing cycle (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, or 50 or more dosing cycles). In other aspects, the dosing regimen includes at least 12 dosing cycles. In other aspects, the dosing regimen includes at least 16 dosing cycles. In some aspects, the dosing cycles of the anti-TIGIT antagonist antibody (e.g., an anti- TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the anti-CD20 antibody (e.g., rituximab) continue until there is a loss of clinical benefit (e.g., confirmed disease progression, drug resistance, death, or unacceptable toxicity).

In some aspects, each dosing cycle of the dosing regimen comprises a single dose of the anti- TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab). In some aspects, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered on about day 1 (e.g., day 1 ± 1 day) of each dosing cycle. For example, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered intravenously at a fixed dose of about 600 mg on day 1 of each 21-day dosing cycle (i.e., at a fixed dose of about 600 mg every three weeks). In another aspect, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered intravenously at a fixed dose of about 600 mg on day 2 of each 21-day dosing cycle (i.e., at a fixed dose of about 600 mg every three weeks). Similarly in other aspects, the first dosing cycle comprises a first dose (C1 D1), a second dose (C1 D2), and a third dose (C1 D3) of the anti-CD20 antibody; and the second dosing cycle comprises at least a first dose (C2D1) of the anti-CD20 antibody (e.g., rituximab). In some aspects, the dosing regimen comprises a total of four doses of the anti-CD20 antibody (e.g., rituximab). In some aspects in which the length of each dosing cycle is about 21 days, the method comprises administering the C1 D1 of the anti-CD20 antibody on or about day 1 (e.g., day 1 ± 1 day) of the first dosing cycle, the C1 D2 of the anti-CD20 antibody on or about day 8 (e.g., day 8 ± 1 day) of the first dosing cycle, and the C1 D3 of the anti-CD20 antibody on or about day 15 (e.g., day 15 ± 1 day) of the first dosing cycle, wherein the C1 D1 is administered intravenously and one or both of the C1 D2 and the C1 D3 are administered subcutaneously. For example, the C1 D1 of the anti-CD20 antibody is administered intravenously to the subject at a dose of 375 mg/m² on day 1 of the first dosing cycle, the C1 D2 of the anti-CD20 antibody is administered subcutaneously to the subject at a dose of 1400 mg on day 8 of the first dosing cycle, and the C1 D3 of the anti-CD20 antibody is administered subcutaneously to the subject at a dose of 1400 mg on day 15 of the first dosing cycle. In some aspects, the method comprises administering to the subject the C2D1 of the anti-CD20 antibody on or about day 1 (e.g., day 1 ± 1 day) of the second dosing cycle. For example, the C2D1 of the anti-CD20 antibody (e.g., rituximab) is administered subcutaneously to the subject at a dose of 1400 mg on day 1 of the second dosing cycle. In some aspects, any of the C1 D1 , C1 D2, C1 D3, and C2D1 of the anti-CD20 antibody (e.g., rituximab) may be split into two doses and administered to the subject over the course of two consecutive days.

In other aspects, the first dosing cycle comprises a first dose (C1 D1), a second dose (C1 D2), and a third dose (C1 D3) of the anti-CD20 antibody; the second dosing cycle comprises a first dose (C2D1), a second dose (C2D2), and a third dose (C2D3) of the anti-CD20 antibody; and the third dosing cycle comprises at least a first dose (C3D1) and a second dose (C3D2) of the anti-CD20 antibody (e.g., rituximab). In some aspects, the dosing regimen comprises a total of eight doses of the anti-CD20 antibody (e.g., rituximab), wherein the first dose of the antibody is administered intravenously and one, two, three, four, five, six, or all seven of the subsequent doses are administered subcutaneously. In some aspects in which the length of each dosing cycle is about 21 days, the method comprises administering the C1 D1 of the anti-CD20 antibody on or about day 1 (e.g., day 1 ± 1 day) of the first dosing cycle, the C1 D2 of the anti-CD20 antibody on or about day 8 (e.g., day 8 ± 1 day) of the first dosing cycle, and the C1 D3 of the anti-CD20 antibody on or about day 15 (e.g., day 15 ± 1 day) of the first dosing cycle. For example, the C1 D1 of the anti-CD20 antibody is administered intravenously to the subject at a dose of 375 mg/m² on day 1 of the first dosing cycle, the C1 D2 of the anti-CD20 antibody is administered subcutaneously to the subject at a dose of 1400 mg on day 8 of the first dosing cycle, and the C1 D3 of the anti-CD20 antibody is administered subcutaneously to the subject at a dose of 1400 mg on day 15 of the first dosing cycle. In some aspects, the method comprises administering to the subject the C2D1 of the anti-CD20 antibody on or about day 1 (e.g., day 1 ± 1 day) of the second dosing cycle, the C2D2 of the anti-CD20 antibody on or about day 8 (e.g., day 8 ± 1 day) of the second dosing cycle, and the C2D3 of the anti-CD20 antibody on or about day 15 (e.g., day 15 ± 1 day) of the second dosing cycle. For example, the C2D1 of the anti-CD20 antibody (e.g., rituximab) is administered subcutaneously to the subject at a dose of 1400 mg on day 1 of the second dosing cycle, the C2D2 is administered subcutaneously to the subject at a dose of 1400 mg on day 8 of the second dosing cycle, and the C2D3 is administered subcutaneously to the subject at a dose of 1400 mg on day 15 of the second dosing cycle. In some aspects, the method comprises administering to the subject the C3D1 of the anti-CD20 antibody on or about day 1 (e.g., day 1 ± 1 day) of the third dosing cycle and the C3D2 of the anti-CD20 antibody on or about day 8 (e.g., day 8 ± 1 day) of the third dosing cycle. For example, the C3D1 of the anti-CD20 antibody (e.g., rituximab) is administered subcutaneously to the subject at a dose of 1400 mg on day 1 of the third dosing cycle and the C3D2 is administered subcutaneously to the subject at a dose of 1400 mg on day 8 of the third dosing cycle. In some aspects, any of the C1 D1 , C1 D2, C1 D3, C2D1 , C2D2, C2D3, C3D1 , and C3D2 of the anti-CD20 antibody (e.g., rituximab) may be split into two doses and administered to the subject over the course of two consecutive days.

In aspects in which the anti-CD20 antibody (e.g., rituximab) is administered subcutaneously, the anti-CD20 antibody (e.g., rituximab) may be formulated with human hyaluronidase PH20 (rHuPH20). In some aspects, the anti-CD20 antibody (e.g., rituximab) for subcutaneous administration is formulated as a dose of 1400 mg of the anti-CD20 antibody in 23,400 U rHuPH20 (e.g., at a volume of 11 .7 mL). In some aspects, the anti-CD20 antibody is administered subcutaneously as RITUXAN HYCELA®.

In some aspects, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the anti-CD20 antibody (e.g., rituximab) are both administered on the same day. For example, in some aspects, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the anti-CD20 antibody are both administered on or about day 1 (e.g., day 1 ± 1 day) of each of dosing cycles 1 and 2. In other aspects, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the anti-CD20 antibody are both administered on or about day 1 (e.g., day 1 ± 1 day) of each of dosing cycles 1 , 2, and 3. In some aspects, the anti-TIGIT antagonist antibody (e.g., an anti- TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered to the subject before the anti-CD20 antibody (e.g., rituximab).

Hi. Observation periods

In some aspects, for example, following administration of the anti-TIGIT antagonist antibody and before administration of the anti-CD20 antibody, the method includes an intervening first observation period. In some aspects, the method further includes a second observation period following administration of the anti-CD20 antibody. In some aspects, the method includes both a first observation period following administration of the anti-TIGIT antagonist antibody and second observation period following administration of the anti-CD20 antibody. In some aspects, the first and second observation periods are each between about 30 minutes to about 60 minutes in length. In aspects in which the first and second observation periods are each about 60 minutes in length, the method may include recording the subject’s vital signs (e.g., pulse rate, respiratory rate, blood pressure, and temperature) at about 30 ± 10 minutes after administration of the anti-TIGIT antagonist antibody and anti-CD20 antibody during the first and second observation periods, respectively. In aspects in which the first and second observation periods are each about 30 minutes in length, the method may include recording the subject’s vital signs (e.g., pulse rate, respiratory rate, blood pressure, and temperature) at about 15 ± 10 minutes after administration of the anti-TIGIT antagonist antibody and anti-CD20 antibody during the first and second observation periods, respectively.

In some aspects, when the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the anti-CD20 antibody (e.g., rituximab) are scheduled to be administered on the same day, the anti-CD20 antibody is administered on one day, and the anti-TIGIT antagonist antibody is administered on the next consecutive day. Accordingly, in some aspects, the anti- CD20 antibody (e.g. rituximab) is administered to the subject before the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab). For example, the anti- CD20 antibody may be administered on day 1 , and the anti-TIGIT antagonist antibody may be administered on day 2. In some aspects, following administration of the anti-CD20 antibody and before administration of the anti-TIGIT antagonist antibody, the method includes an intervening first observation period. In some aspects, the method includes a second observation period following administration of the anti-TIGIT antagonist antibody. In some aspects, the method includes both a first observation period following administration of the anti-CD20 antibody and second observation period following administration of the anti-TIGIT antagonist antibody. In some aspects, the first and second observation periods are each between about 30 minutes to about 60 minutes in length. In aspects in which the first and second observation periods are each about 60 minutes in length, the method may include recording the subject’s vital signs (e.g., pulse rate, respiratory rate, blood pressure, and temperature) at about 30 ± 10 minutes after administration of the anti-CD20 antibody and anti-TIGIT antagonist antibody during the first and second observation periods, respectively. In aspects in which the first and second observation periods are each about 30 minutes in length, the method may include recording the subject’s vital signs (e.g., pulse rate, respiratory rate, blood pressure, and temperature) at about 15 ± 10 minutes after administration of the anti-CD20 antibody and anti-TIGIT antagonist antibody during the first and second observation periods, respectively. iv. Premedication and post-medication In some aspects, the method further comprises administering to the subject an antipyretic and an antihistamine prior to each administration of the anti-CD20 antibody. In some aspects the antipyretic is acetaminophen and the antihistamine is diphenhydramine. In some aspects, the method further comprises administering to the subject a glucocorticoid prior to each administration of the anti-CD20 antibody.

In another aspect, the invention provides for a method of treating a subject having relapsed or refractory NHL by administering to the subject tiragolumab at a fixed dose of 600 mg and rituximab in a dosing regimen comprising at least a first and a second dosing cycle, wherein the length of each dosing cycle is 21 days, and wherein (a) each dosing cycle comprises a single dose of tiragolumab administered on or about day 1 of each dosing cycle; (b) the first dosing cycle comprises a first dose (C1 D 1 ) , a second dose (C1 D2), and a third dose (C1 D3) of rituximab, wherein the C1 D1 , the C1 D2, and the C1 D3 are administered on or about days 1 , 8, and 15, respectively, of the first dosing cycle and wherein the C1 D1 is administered intravenously at a dose of 375 mg/m² and at least one subsequent dose is administered subcutaneously at a dose of 1400 mg; and (c) the second dosing cycle further comprises a single dose of rituximab administered on or about day 1 of the second dosing cycle, and wherein the dosing regimen comprises a total of four doses of rituximab.

In another aspect, the invention provides for a method of treating a subject having relapsed or refractory NHL by administering to the subject tiragolumab at a fixed dose of 600 mg and rituximab at a dose of 375 mg/m² in a dosing regimen comprising a first, a second, and a third dosing cycle, wherein the length of each dosing cycle is 21 days, and wherein: (a) each dosing cycle comprises a single dose of tiragolumab administered on or about day 1 of each dosing cycle; (b) the first dosing cycle comprises a first dose (C1 D1), a second dose (C1 D2), and a third dose (C1 D3) of rituximab, wherein the C1 D1 , the C1 D2, and the C1 D3 are administered on or about days 1 , 8, and 15, respectively, of the first dosing cycle and wherein the C1 D1 is administered intravenously at a dose of 375 mg/m² and at least one subsequent dose is administered subcutaneously at a dose of 1400 mg; (c) the second dosing cycle further comprises a first dose (C2D1), a second dose (C2D2), and a third dose (C2D3) of rituximab administered on or about days 1 , 8, and 15 of the second dosing cycle; and (d) the third dosing cycle further comprises a first dose (C3D1) and a second dose (C3D2) of rituximab, wherein the C3D1 and the C3D2 are administered on or about days 1 and 8, respectively, of the third dosing cycle, and wherein the dosing regimen comprises a total of eight doses of rituximab.

IV. Assessment of PD-L1 Expression

The expression of PD-L1 may be assessed in a patient treated according to any of the methods and compositions for use described herein. The methods and compositions for use may include determining the expression level of PD-L1 in a biological sample (e.g., a tumor sample, bone marrow sample, or blood sample) obtained from the patient having a cancer (e.g., a hematologic cancer, e.g., a myeloma (e.g., a MM, e.g., a relapsed or refractory MM) or a lymphoma (e.g., a NHL, e.g., a relapsed or refractory DLBCL or a relapsed or refractory FL)). In other examples, the expression level of PD-L1 in a biological sample (e.g., a tumor sample, bone marrow sample, or blood sample) obtained from the patient has been determined prior to initiation of treatment or after initiation of treatment. PD-L1 expression may be determined using any suitable approach. For example, PD-L1 expression may be determined as described in U.S. Patent Application Nos. 15/787,988 and 15/790,680. Any suitable tumor sample may be used, e.g., a formalin-fixed and paraffin-embedded (FFPE) tumor sample, an archival tumor sample, a fresh tumor sample, or a frozen tumor sample.

For example, PD-L1 expression may be determined in terms of the percentage of a tumor sample comprised by tumor-infiltrating immune cells expressing a detectable expression level of PD-L1 , as the percentage of tumor-infiltrating immune cells in a tumor sample expressing a detectable expression level of PD-L1 , and/or as the percentage of tumor cells in a tumor sample expressing a detectable expression level of PD-L1 . It is to be understood that in any of the preceding examples, the percentage of the tumor sample comprised by tumor-infiltrating immune cells may be in terms of the percentage of tumor area covered by tumor-infiltrating immune cells in a section of the tumor sample obtained from the patient, for example, as assessed by IHC using an anti-PD-L1 antibody (e.g., the SP142 antibody). Any suitable anti- PD-L1 antibody may be used, including, e.g., SP142 (Ventana), SP263 (Ventana), 22C3 (Dako), 28-8 (Dako), E1 L3N (Cell Signaling Technology), 4059 (ProSci, Inc.), h5H1 (Advanced Cell Diagnostics), and 9A11 . In some examples, the anti-PD-L1 antibody is SP142. In other examples, the anti-PD-L1 antibody is SP263.

In some examples, a tumor sample obtained from the patient has a detectable expression level of PD-L1 in less than 1% of the tumor cells in the tumor sample, in 1% or more of the tumor cells in the tumor sample, in from 1 % to less than 5% of the tumor cells in the tumor sample, in 5% or more of the tumor cells in the tumor sample, in from 5% to less than 50% of the tumor cells in the tumor sample, or in 50% or more of the tumor cells in the tumor sample.

In some examples, a tumor sample obtained from the patient has a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise less than 1% of the tumor sample, more than 1% of the tumor sample, from 1 % to less than 5% of the tumor sample, more than 5% of the tumor sample, from 5% to less than 10% of the tumor sample, or more than 10% of the tumor sample.

In some aspects, the hematologic cancer of a patient treated according to any of the methods provided herein has a PD-L1 -positive tumor cell (TC) fraction or tumor-infiltrating immune cell (IC) fraction of < 5%. In some aspects, the hematologic cancer has a PD-L1 -positive TC fraction of <1%. In other aspects, the hematologic cancer of a patient treated according to any of the methods provided herein has a PD-L1 -positive TC fraction or IC fraction of > 5%. In some aspects, PD-L1 is detected using a Ventana SP142 IHC assay, a Ventana SP263 IHC assay, a pharmDx 22C3 IHC assay, or a pharmDx 28-8 IHC assay.

In some examples, tumor samples may be scored for PD-L1 positivity in tumor-infiltrating immune cells and/or in tumor cells according to the criteria for diagnostic assessment shown in Table 1 and/or Table 2, respectively. Table 1. Tumor-infiltrating immune cell (IC) IHC diagnostic criteria

Table 2. Tumor cell (TC) IHC diagnostic criteria

V. Assessment of TIGIT Expression

The expression level of TIGIT may be assessed in a patient having a cancer (e.g., a hematologic cancer, e.g., a myeloma (e.g., a MM, e.g., a relapsed or refractory MM) or a lymphoma (e.g., a NHL, e.g., a relapsed or refractory DLBCL or a relapsed or refractory FL)) who has been treated according to any of the methods, uses, and compositions for use described herein. The methods, uses, and compositions for use may include determining the expression level of TIGIT in a biological sample (e.g., a tumor sample, bone marrow sample, or blood sample) obtained from the patient. In other examples, the expression level of TIGIT in a biological sample (e.g., a tumor sample, bone marrow sample, or blood sample) obtained from the patient has been determined prior to initiation of treatment or after initiation of treatment. TIGIT expression may be determined using any suitable approach. Any suitable tumor sample may be used, e.g., a formalin-fixed and paraffin-embedded (FFPE) tumor sample, an archival tumor sample, a fresh tumor sample, or a frozen tumor sample.

For example, TIGIT expression may be determined in terms of the percentage of a tumor sample comprised by tumor-infiltrating immune cells expressing a detectable expression level of TIGIT, as the percentage of tumor-infiltrating immune cells in a tumor sample expressing a detectable expression level of TIGIT, and/or as the percentage of tumor cells in a tumor sample expressing a detectable expression level of TIGIT. It is to be understood that in any of the preceding examples, the percentage of the tumor sample comprised by tumor-infiltrating immune cells may be in terms of the percentage of tumor area covered by tumor-infiltrating immune cells in a section of the tumor sample obtained from the patient, for example, as assessed by IHC using an anti-TIGIT antagonist antibody. Any suitable anti-TIGIT antagonist antibody may be used. In some examples, the anti-TIGIT antagonist antibody is 10A7 (WO 2009/126688A3; U.S. Patent No: 9,499,596).

VI. Anti-TIGIT Antagonist Antibodies

The invention provides anti-TIGIT antagonist antibodies useful for treating cancer in a subject (e.g., a human) having a cancer (e.g., a hematologic cancer, e.g., a myeloma (e.g., a MM, e.g., a relapsed or refractory MM) or a lymphoma (e.g., a NHL, e.g., a relapsed or refractory DLBCL or a relapsed or refractory FL)).

In some instances, the anti-TIGIT antagonist antibody is tiragolumab (CAS Registry Number: 1918185-84-8). Tiragolumab (Genentech) is also known as MTIG7192A.

In certain instances, the anti-TIGIT antagonist antibody includes at least one, two, three, four, five, or six HVRs selected from: (a) an HVR-H1 comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1); (b) an HVR-H2 comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3); (d) an HVR-L1 comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4), (e) an HVR- L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and/or (f) an HVR-L3 comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6), or a combination of one or more of the above HVRs and one or more variants thereof having at least about 90% sequence identity (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 1-6.

In some instances, anti-TIGIT antagonist antibodies may include (a) an HVR-H1 comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1); (b) an HVR-H2 comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3); (d) an HVR-L1 comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4); (e) an HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and (f) an HVR-L3 comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6). In some instances, the anti-TIGIT antagonist antibody has a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, EVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGKTYYRFKWYSDYAVSVK GRITINPDTSKNQFSLQLNSVTPEDTAVFYCTRESTTYDLLAGPFDYWGQGTLVTVSS (SEQ ID NO: 17) or an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGKTYYRFKWYSDYAVSVK GRITINPDTSKNQFSLQLNSVTPEDTAVFYCTRESTTYDLLAGPFDYWGQGTLVTVSS (SEQ ID NO: 18); and/or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, DIVMTQSPDSLAVSLGERATINCKSSQTVLYSSNNKKYLAWYQQKPGQPPNLLIYWASTRESGVPDRFSG SGSGTDFTLTISSLQAEDVAVYYCQQYYSTPFTFGPGTKVEIK (SEQ ID NO: 19). In some instances, the anti-TIGIT antagonist antibody has a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 17 and/or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 19. In some instances, the anti-TIGIT antagonist antibody has a VH domain comprising the amino acid sequence of SEQ ID NO: 17 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19. In some instances, the anti-TIGIT antagonist antibody has a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 18 and/or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 19. In some instances, the anti-TIGIT antagonist antibody has a VH domain comprising the amino acid sequence of SEQ ID NO: 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19.

In some instances, the anti-TIGIT antagonist antibody includes a heavy chain and a light chain sequence, wherein: (a) the heavy chain comprises the amino acid sequence: EVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGKTYYRFKWYSDYAVSVK GRITINPDTSKNQFSLQLNSVTPEDTAVFYCTRESTTYDLLAGPFDYWGQGTLVTVSSASTKGPSVFPLAP SSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 69); and (b) the light chain comprises the amino acid sequence: DIVMTQSPDSLAVSLGERATINCKSSQTVLYSSNNKKYLAWYQQKPGQPPNLLIYWASTRESGVPDRFSG SGSGTDFTLTISSLQAEDVAVYYCQQYYSTPFTFGPGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLL NNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPV TKSFNRGEC (SEQ ID NO: 70).

In some instances, the anti-TIGIT antagonist antibody further comprises at least one, two, three, or four of the following light chain variable region framework regions (FRs): an FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7); an FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8); an FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and/or an FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10), or a combination of one or more of the above FRs and one or more variants thereof having at least about 90% sequence identity (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 7-10. In some instances, for example, the antibody further comprises an FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7); an FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8); an FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and an FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10).

In some instances, the anti-TIGIT antagonist antibody further comprises at least one, two, three, or four of the following heavy chain variable region FRs: an FR-H1 comprising the amino acid sequence of XiVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11), wherein Xi is E or Q; an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12); an FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and/or an FR- H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14), or a combination of one or more of the above FRs and one or more variants thereof having at least about 90% sequence identity (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 11- 14. The anti-TIGIT antagonist antibody may further include, for example, at least one, two, three, or four of the following heavy chain variable region FRs: an FR-H1 comprising the amino acid sequence of EVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 15); an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12); an FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and/or an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14), or a combination of one or more of the above FRs and one or more variants thereof having at least about 90% sequence identity (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 12-15. In some instances, the anti-TIGIT antagonist antibody includes an FR-H1 comprising the amino acid sequence of EVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 15); an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12); an FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14). In another instance, for example, the anti-TIGIT antagonist antibody may further include at least one, two, three, or four of the following heavy chain variable region FRs: an FR-H1 comprising the amino acid sequence of QVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 16); an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12); an FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and/or an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14), or a combination of one or more of the above FRs and one or more variants thereof having at least about 90% sequence identity (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 12-14 and 26. In some instances, the anti-TIGIT antagonist antibody includes an FR-H1 comprising the amino acid sequence of QVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 16); an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12); an FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14).

In another aspect, an anti-TIGIT antagonist antibody is provided, wherein the antibody comprises a VH as in any of the instances provided above, and a VL as in any of the instances provided above, wherein one or both of the variable domain sequences include post-translational modifications. In some instances, any one of the anti-TIGIT antagonist antibodies described above is capable of binding to rabbit TIGIT, in addition to human TIGIT. In some instances, any one of the anti-TIGIT antagonist antibodies described above is capable of binding to both human TIGIT and cynomolgus monkey (cyno) TIGIT. In some instances, any one of the anti-TIGIT antagonist antibodies described above is capable of binding to human TIGIT, cyno TIGIT, and rabbit TIGIT. In some instances, any one of the anti-TIGIT antagonist antibodies described above is capable of binding to human TIGIT, cyno TIGIT, and rabbit TIGIT, but not murine TIGIT.

In some instances, the anti-TIGIT antagonist antibody binds human TIGIT with a KD of about 10 nM or lower and cyno TIGIT with a KD of about 10 nM or lower (e.g., binds human TIGIT with a KD of about 0.1 nM to about 1 nM and cyno TIGIT with a KD of about 0.5 nM to about 1 nM, e.g., binds human TIGIT with a KD of about 0.1 nM or lower and cyno TIGIT with a KD of about 0.5 nM or lower).

In some instances, the anti-TIGIT antagonist antibody specifically binds TIGIT and inhibits or blocks TIGIT interaction with poliovirus receptor (PVR) (e.g., the antagonist antibody inhibits intracellular signaling mediated by TIGIT binding to PVR). In some instances, the antagonist antibody inhibits or blocks binding of human TIGIT to human PVR with an IC50 value of 10 nM or lower (e.g., 1 nM to about 10 nM). In some instances, the anti-TIGIT antagonist antibody specifically binds TIGIT and inhibits or blocks TIGIT interaction with PVR, without impacting PVR-CD226 interaction. In some instances, the antagonist antibody inhibits or blocks binding of cyno TIGIT to cyno PVR with an IC50 value of 50 nM or lower (e.g., 1 nM to about 50 nM, e.g., 1 nM to about 5 nM). In some instances, the anti-TIGIT antagonist antibody inhibits and/or blocks the interaction of CD226 with TIGIT. In some instances, the anti-TIGIT antagonist antibody inhibits and/or blocks the ability of TIGIT to disrupt CD226 homodimerization.

In some instances, the methods or uses described herein may include using or administering an isolated anti-TIGIT antagonist antibody that competes for binding to TIGIT with any of the anti-TIGIT antagonist antibodies described above. For example, the method may include administering an isolated anti-TIGIT antagonist antibody that competes for binding to TIGIT with an anti-TIGIT antagonist antibody having the following six HVRs: (a) an HVR-H1 comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1); (b) an HVR-H2 comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3); (d) an HVR-L1 comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4), (e) an HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and (f) an HVR-L3 comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6). The methods described herein may also include administering an isolated anti-TIGIT antagonist antibody that binds to the same epitope as an anti-TIGIT antagonist antibody described above.

In some aspects, the anti-TIGIT antagonist antibody exhibits effector function. In some aspects, the anti-TIGIT antagonist antibody is an antibody having intact Fc-mediated effector function (e.g., tiragolumab, vibostolimab, etigilimab, EOS084448, or TJ-T6) or enhanced effector function (e.g., SGN- TGT).

In other aspects, the anti-TIGIT antagonist antibody is an antibody that lacks Fc-mediated effector function (e.g., domvanalimab, BMS-986207, ASP8374, or CQM902).

In some aspects, the anti-TIGIT antagonist antibody is an IgG class antibody. In some aspects, the anti-TIGIT antagonist antibody is an lgG1 subclass antibody, e.g., tiragolumab, vibostolimab, domvanalimab, BMS-986207, etigilimab, BGB-A1217, SGN-TGT, EOS084448 (EOS-448), TJ-T6, or AB308.

In other aspects, the anti-TIGIT antagonist antibody is an lgG4 subclass antibody, e.g., ASP8374 or COM902.

The anti-TIGIT antagonist antibodies (e.g., tiragolumab) useful in this invention, including compositions containing such antibodies, may be used in combination with a PD-1 axis binding antagonist (e.g., PD-L1 binding antagonists (e.g., anti-PD-L1 antagonist antibodies, e.g., atezolizumab), PD-1 binding antagonists (e.g., anti-PD-1 antagonist antibodies, e.g., pembrolizumab), and PD-L2 binding antagonists (e.g., anti-PD-L2 antagonist antibodies)).

In some embodiments, the anti-TIGIT antagonist antibody functions to inhibit TIGIT signaling. In some embodiments, the anti-TIGIT antagonist antibody inhibits the binding of TIGIT to its binding partners. Exemplary TIGIT binding partners include CD155 (PVR), CD112 (PVRL2 or Nectin-2), and CD113 (PVRL3 or Nectin-3). In some embodiments, the anti-TIGIT antagonist antibody is capable of inhibiting binding between TIGIT and CD155. In some embodiments, the anti-TIGIT antagonist antibody may inhibit binding between TIGIT and CD112. In some embodiments, the anti-TIGIT antagonist antibody inhibits binding between TIGIT and CD113. In some embodiments, the anti-TIGIT antagonist antibody inhibits TIGIT-mediated cellular signaling in immune cells. In some embodiments, the anti-TIGIT antagonist antibody inhibits TIGIT by depleting regulatory T cells (e.g., when engaging a FcyR).

In some embodiments, the anti-TIGIT antagonist antibody is a monoclonal antibody. In some embodiments, the anti-TIGIT antagonist antibody is an antibody fragment selected from the group consisting of Fab, Fab’, Fab’-SH, Fv, scFv, and (Fab’)2 fragments. In some embodiments, the anti-TIGIT antagonist antibody is a humanized antibody. In some embodiments, the anti-TIGIT antagonist antibody is a humanized antibody. In some embodiments, the anti-TIGIT antagonist antibody is a human antibody. In some embodiments, the anti-TIGIT antagonist antibody described herein binds to human TIGIT. In some embodiments, the anti-TIGIT antagonist antibody is an Fc fusion protein.

In some embodiments, the anti-TIGIT antibody is selected from the group consisting of tiragolumab (MTIG7192A, RG6058 or RO7092284), vibostolimab (MK-7684), ASP8374 (PTZ-201), EOS884448 (EOS-448), SEA-TGT (SGN-TGT)), BGB-A1217, BMS-986207 (ONO-4686), COM902 (CGEN-15137), IBI939, domvanalimab (AB154), M6223, AB308, AB154, TJ-T6, MG1131 , NB6253, HLX301 , HLX53, SL-9258 (TIGIT-Fc-LIGHT), STW264, and YBL-012. In some embodiments, the anti- TIGIT antibody is selected from the group consisting of tiragolumab (MTIG7192A, RG6058 or RO7092284), vibostolimab (MK-7684), ASP8374 (PTZ-201), EOS-448, and SEA-TGT (SGN-TGT). The anti-TIGIT antibody may be tiragolumab (MTIG7192A, RG6058 or RO7092284).

Non-limiting examples of anti-TIGIT antibodies that are useful for the methods disclosed herein, and methods for making thereof are described in PCT Pub. Nos. WO2018183889A1 , WO2019129261 A1 , W02016106302A9, WO2018033798A1 , W02020020281A1 , W02019023504A1 , WO2017152088A1 , WO2016028656A1 , W02017030823A2, W02018204405A1 , WO2019152574A1 , and W02020041541A2; U.S. Pat. Nos. US 10,189,902, US 10,213,505, US 10,124,061 , US 10,537,633, and US 10,618,958; and U.S. Pub. Nos. 2020/0095324, 2019/0112375, 2018/0371083, and 2020/0062859, each of which is incorporated herein by reference in its entirety. Additional non-limiting examples of anti- TIGIT antibodies, useful for the methods of disclosed herein, and methods for making thereof are described in PCT Pub. Nos. WO2018204363A1 , WO2018047139A1 , WO2019175799A2, WO2018022946A1 , WO2015143343A2, WO2018218056A1 , WO2019232484A1 , WO2019079777A1 , WO2018128939A1 , WO2017196867A1 , WO2019154415A1 , WO2019062832A1 , WO2018234793A3, WO2018102536A1 , WO2019137548A1 , WO2019129221A1 , WO2018102746A1 , W02018160704A9, WG2020041541A2, WO2019094637A9, W02017037707A1 , WO2019168382A1 , WO2006124667A3, WO2017021526A1 , WO2017184619A2, WO2017048824A1 , WO2019032619A9, WO2018157162A1 , WO2020176718A1 , W02020047329A1 , W02020047329A1 , WO2018220446 A9; U.S. Pat. Nos. US 9,617,338, US 9,567,399, US 10,604,576, and US 9,994,637; and Pub. Nos. US 2018/0355040, US 2019/0175654, US 2019/0040154, US 2019/0382477, US 2019/0010246, US 2020/0164071 , US

2020/0131267, US 2019/0338032, US 2019/0330351 , US 2019/0202917, US 2019/0284269, US

2018/0155422, US 2020/0040082, US 2019/0263909, US 2018/0185480, US 2019/0375843, US

2017/0037133, US 2019/0077869, US 2019/0367579, US 2020/0222503, US 2020/0283496,

CN109734806A, and CN110818795A, each of which is incorporated herein by reference in its entirety.

The anti-TIGIT antibodies useful in the methods disclosed herein include ASP8374 (PTZ-201), BGB-A1217, BMS-986207 (ONO-4686), COM902 (CGEN-15137), M6223, IBI939, EOS-448, domvanalimab (AB154), vibostolimab (MK-7684), and SEA-TGT (SGN-TGT). Additional anti-TIGIT antibodies useful in the methods disclosed herein include AGEN1307; AGEN1777; antibody clones pab2197 and pab2196 (Agenus Inc.); antibody clones TBB8, TDC8, 3TB3, 5TB10, and D1Y1A (Anhui Anke Biotechnology Group Co. Ltd.), antibody clones MAB1 , MAB2, MAB3, MAB4, MAB5, MAB6, MAB 7, MAB8, MAB9, MAB 10, MAB 11 , MAB 12, MAB13, MAB 14, MAB 15, MAB 16, MAB 17, MAB 18, MAB19, MAB20, MAB21 (Astellas Pharma/Potenza Therapeutics), antibody clones hu1217-1-1 and hu1217-2-2 (BeiGene), antibody clones 4D4 and 19G (Brigham & Women’s Hospital), antibody clones 11 G11 , 10D7, 15A6, 22G2, TIGIT G2a, and TIGIT G1 D265A, including such antibodies with modified heavy chain constant regions (Bristol-Myers Squibb); antibody clones 10A7, CPA.9.086, CPA.9.083.H4(S241 P), CPA.9.086.H4(S241 P), CHA.9.547.7.H4(S241 P) and CHA.9.547.13.H4(S241 P) (Compugen); anti- PVRIG/anti-TIGIT bispecific antibodies (Compugen), antibody clones 315293, 328189, 350426, 326504, and 331672 (Fred Hutchinson Cancer Research Center); antibody clones T-01 , T-02, T-03, T-04, T-05, T- 06, T-07, T-08, T-09, and T-10 (Gensun BioPharma Inc.); antibody clones 1 H6, 2B11 , 3A10, 4A5, 4A9, 4H5, 6A2, 6B7, 7F4, 8E1 , 8G3, 9F4, 9G6, 10C1 , 10F10, 11G4, 12B7, 12C8, 15E9, 16C11 , 16D6, and 16E10 (Hefei Ruida Immunological Drugs Research Institute Co. Ltd.); antibody clones h3C5H1 , h3C5H2, h3C5H3, h3C5H4, h3C5H3-1 , h3C5H3-2, h3C5H3-3, h3C5L1 , and h3C5L2 (IGM Biosciences Inc.); antibody clones 90D9, 101 E1 , 116H8, 118A12, 131A12, 143B6, 167F7, 221 F11 , 222H4, 327C9, 342A9, 344F2, 349H6, and 350D10 (l-Mab Biopharma); antibody clones ADI-27238, ADI-30263, ADI-30267, ADI- 30268, ADI-27243, ADI-30302, ADI-30336, ADI-27278, ADI-30193, ADI-30296, ADI-27291 , ADI-30283, ADI-30286, ADI-30288, ADI27297, ADI-30272, ADI-30278, ADI-27301 , ADI-30306, and ADI-30311 (Innovent Biologies, Inc.); antibody clones 26518, 29478, 26452, 29487, 29489, 31282, 26486, 29494, 29499, 26521 , 29513, 26493, 29520, 29523, 29527, 31288, 32919, 32931 , 26432, and 32959 (iTeos Therapeutics); antibody clones m1707, m1708, m1709, m1710, m1711 , h1707, h1708, h1709, hi 710, and hi 711 (Jiangsu Hengrui Medicine Co. Ltd.); antibody clones TIG1 , TIG2, and TIG3 (JN Biosciences LLC); antibody clones (e.g., KY01 , KY02, KY03, KY04, KY05, KY06, KY07, KY08, KY09, KY10, K11 , K12, K13, K14, K15, K16, K17, K18, K19, K20, K21 , K22, K23 Kymab TIGIT (Antibody 2), and Tool TIGIT (Antibody 4) (Kymab Limited); bispecific antibodies 1 D05/in-house anti-TIGIT with 1 D05 (anti-PD-L1) Native variable domain and Kymab TIGIT antigen binding site (ABS) domain (Bispecific 1), In-house anti- TIGIT/1 D05 with Kymab TIGIT Native variable domain and 1 D05 ABS domain (Bispecific 2), Tool anti- TIGIT/Tool anti-PD-L1 with Toon anti-TIGIT Native variable domain and Tool anti-PD-L1 ABS domain (Bispecific 3), Tool anti-PD-L1/Tool anti-TIGIT with Tool anti-PD-L1 Native variable domain and Tool anti- TIGIT ABS domain (Bispecific 4) (Kymab Limited); antibody clones and clone variants 14D7, 26B10, Hu14D7, Hu26B10, 14A6, Hu14A6, 28H5, 31C6, Hu31C6, 25G10, MBS43, 37D10, 18G10, 11A11 , C18G10, and LB155.14A6.G2.A8 (Merck); etigilimab (OMP-313M32) (Mereo BioPharma); antibody clones 64G1 E9B4, 100C4E7D11 , 83G5H11C12, 92E9D4B4, 104G12E12G2, 121C2F10B5, 128E3F10F3F2, 70A11A8E6, 11 D8E124A, 16F10H12C11 , 8F2D8E7, 48B5G4E12, 139E2C2D2, 128E3G7F5, AS19584, AS19852, AS19858, AS19886, AS19887, AS19888, AS20160, AS19584VH26, AS19584VH29, AS19584VH30, AS19584VH31 , AS19886VH5, AS19886VH8, AS19886VH9, AS19886VH10, AS19886VH19, AS19886VH20, AS19584VH28-FC, AS19886VH5-FC, AS19886VH8-FC, AS19584-Fc, and AS19886-Fc (Nanjing Legend Biotechnology Co. Ltd.); antibody clones ARE clones: Ab58, Ab69, Ab75, Ab133, Ab177, Ab122, Ab86, Ab180, Ab83, Ab26, Ab20, Ab147, Ab12, Ab66, Ab176, Ab96, Ab123, Ab109, Ab149, Ab34, Ab61 , Ab64, Ab105, Ab108, Ab178, Ab166, Ab29, Ab135, Ab171 , Ab194, Ab184, Ab164, Ab183, Ab158, Ab55, Ab136, Ab39, Ab159, Ab151 , Ab139, Ab107, Ab36, Ab193, Ab115, Ab106, Ab13f8, Ab127, Ab165, Ab155, Ab19, Ab6, Ab187, Ab179, Ab65, Ab114, Ab102, Ab94, Ab163, Ab110, Ab80, Ab92, Ab117, Ab162, Ab121 , Ab195, Ab84, Ab161 , Ab198, Ab24, Ab98, Ab116, Ab174, Ab196, Ab51 , Ab91 , Ab185, Ab23, Ab7, Ab95, Ab100, Ab140, Ab145, Ab150, Ab168, Ab54, Ab77, Ab43, Ab160, Ab82, Ab189, Ab17, Ab103, Ab18, Ab130, Ab132, Ab134, Ab144; ARG Clones: Ab2, Ab47, Ab49, Ab31 , Ab53, Ab40, Ab5, Ab9, Ab48, Ab4, Ab10, Ab37, Ab33, Ab42, Ab45; ARV Clones: Ab44, Ab97, Ab81 , Ab188, Ab186, Ab62, Ab57, Ab192, Ab73, Ab60, Ab28, Ab32, Ab78, Ab14, Ab152, Ab72, Ab137, Ab128, Ab169, Ab87, Ab74, Ab172, Ab153, Ab120, Ab13, Ab113, Ab16, Ab56, Ab129, Ab50, Ab90, Ab99, Ab3, Ab148, Ab124, Ab22, Ab41 , Ab119, Ab157, Ab27, Ab15, Ab191 , Ab190, Ab79, Ab181 , Ab146, Ab167, Ab88, Ab199, Ab71 , Ab85, Ab59, Ab141 , Ab68, Ab143, Ab46, Ab197, Ab175, Ab156, Ab63, Ab11 , Ab182, Ab89, Ab8, Ab101 , Ab25, Ab154, Ab21 , Ab111 , Ab118, Ab173, Ab38, Ab76, Ab131 , Ab1 , Ab67, Ab70, Ab170, Ab30, Ab93, Ab142, Ab104, Ab112, Ab35, Ab126, and Ab125 (Rigel Pharmaceuticals, Inc.); CASC-674 (Seattle Genetics); antibody clones 2, 2C, 3, 5, 13, 13A, 13B, 13C, 13D, 14, 16, 16C, 16D, 16E, 18, 21 , 22, 25, 25A, 25B, 25C, 25D, 25E, 27, 54, 13 lgG2a afucosylated, 13 hlgG1 wild-type, and 13 LALA-PG (Seattle Genetics); JS006 (Shanghai Junshi Biosciences Ltd.); anti- TIGIT Fc antibody and bispecific antibody PD1 x TIGIT (Xencor), antibody clone VSIG9#1 (Vsig9.01) and 258-CS1#4 (#4) (Yissum Research Development Company of The Hebrew University Of Jerusalem Ltd.); YH29143 (Yuhan Co, Ltd.);antibody clones S02, S03, S04, S05, S06, S11 , S12, S14, S19, S32, S39, S43, S62, S64, F01 , F02, F03, F04, 32D7, 101 H3, 10A7, and 1 F4 (Yuhan Co, Ltd.); anti-zB7R1 clones 318.4.1.1 (E9310), 318.28.2.1 (E9296), 318.39.1 .1 (E9311), 318.59.3.1 (E9400), and 318.77.1 .10 (ZymoGenetics, Inc).

In some embodiments, the anti-TIGIT antibody is selected from the group consisting of tiragolumab, ASP8374 (PTZ-201), BGB-A1217, BMS-986207 (ONO-4686), COM902 (CGEN-15137), M6223, IBI939, EOS884448 (EOS-448), domvanalimab (AB154), vibostolimab (MK-7684), and SEA-TGT (SGN-TGT). ASP874 (PTZ-201) is an anti-TIGIT monoclonal antibody described in PCT Pub. No. WO2018183889A1 and US Pub. No. 2020/0095324. BGB-A1217 is an anti-TIGIT antibody as described in PCT Pub. No. WO2019129261A1 . BMS-986207 (ONO-4686) is an anti-TIGIT antibody as described in PCT Pub. No. W02016106302A9, US Pat. No. 10,189,902 and US Pub. No. 2019/0112375. COM902 (CGEN-15137) is an anti-TIGIT antibody as described in PCT Pub. No. WO2018033798A1 and US Pat. Nos. 10,213,505 and 10,124,061. IBI939 is an anti-TIGIT antibody as described in PCT Pub. No. W02020020281 A1 . EOS884448 (EOS-448) is an anti-TIGIT antibody described in PCT Pub. No. W02019023504A1 . Domvanalimab (AB154) is an anti-TIGIT monoclonal antibody as described in PCT Pub. No. WO2017152088A1 and US Pat. No. 10,537,633. Vibostolimab (MK-7684) is an anti-TIGIT antibody described in PCT Pub. Nos. WO2016028656A1 , W02017030823A2, W02018204405A1 , and/or WO2019152574A1 , US Pat. No. 10,618,958, and US Pub. No. 2018/0371083. SEA-TGT (SGN-TGT) is an anti-TIGIT antibody as described in PCT Pub. No. W02020041541 A2 and US Pub. No. 2020/0062859.

In some embodiments, the anti-TIGIT antagonist antibody is tiragolumab (CAS Registry Number: 1918185-84-8). Tiragolumab (Genentech) is also known as MTIG7192A, RG6058 or RO7092284. Tiragolumab is an anti-TIGIT antagonistic monoclonal antibody described in PCT Pub. No. WG2003072305A8, WG2004024068A3, WG2004024072A3, WO2009126688A2, WG2015009856A2, WG2016011264A1 , WO2016109546A2, WO2017053748A2, and WO2019165434A1 , and US Pub. Nos. 2017/0044256, 2017/0037127, 2017/0145093, 2017/260594, 2017/0088613, 2018/0186875, 2019/0119376 and US Pat. Nos. US9873740B2, US10626174B2, US10611836B2, US9499596B2, US8431350B2, US10047158B2, and US10017572B2.

In some embodiments, the anti-TIGIT antibody comprises at least one, two, three, four, five, or six complementarity determining regions (CDRs) of any of the anti-TIGIT antibodies disclosed herein. In some embodiments, the anti-TIGIT antibody comprises the six CDRs of any of the anti-TIGIT antibodies disclosed herein. In some embodiments, the anti-TIGIT antibody comprises the six CDRs of any one of the antibodies selected from the group consisting of tiragolumab, ASP8374 (PTZ-201), BGB-A1217, BMS- 986207 (ONO-4686), COM902 (CGEN-15137), M6223, IBI939, EOS884448 (EOS-448), domvanalimab (AB154), vibostolimab (MK-7684), and SEA-TGT (SGN-TGT).

In some embodiments, the anti-TIGIT antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region (VH) sequence of any one of the anti- TIGIT antibodies disclosed herein and the light chain comprises a light chain variable region (VL) of the same antibody. In some embodiments, the anti-TIGIT antibody comprises the VH and VL of an anti-TIGIT antibody selected from the group consisting of tiragolumab, ASP8374 (PTZ-201), BGB-A1217, BMS- 986207 (ONO-4686), COM902 (CGEN-15137), M6223, IBI939, EOS884448 (EOS-448), domvanalimab (AB154), vibostolimab (MK-7684), and SEA-TGT (SGN-TGT).

In some embodiments, the anti-TIGIT antibody comprises the heavy chain and the light chain of any of the anti-TIGIT antibodies disclosed herein. In some embodiments, the anti-TIGIT antibody comprises the heavy chain and the light chain of an anti-TIGIT antibody selected from the group consisting of tiragolumab, ASP8374 (PTZ-201), BGB-A1217, BMS-986207 (ONO-4686), COM902 (CGEN-15137), M6223, IBI939, EOS884448 (EOS-448), domvanalimab (AB154), vibostolimab (MK- 7684), and SEA-TGT (SGN-TGT).

In a further aspect, an anti-TIGIT antagonist antibody according to any of the above aspects may incorporate any of the features, singly or in combination, as described in Sections 1-6 below. VII. PD-1 Axis Binding Antagonists

PD-1 axis binding antagonists may include PD-L1 binding antagonists, PD-1 binding antagonists, and PD-L2 binding antagonists. Any suitable PD-1 axis binding antagonist may be used for treating a subject having a cancer (e.g., a hematologic cancer, e.g., a myeloma (e.g., a MM, e.g., a relapsed or refractory MM)).

A. PD-L1 Binding Antagonists

In some instances, the PD-L1 binding antagonist inhibits the binding of PD-L1 to one or more of its ligand binding partners. In other instances, the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1 . In yet other instances, the PD-L1 binding antagonist inhibits the binding of PD-L1 to B7-1 . In some instances, the PD-L1 binding antagonist inhibits the binding of PD-L1 to both PD-1 and B7-1. The PD-L1 binding antagonist may be, without limitation, an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, or a small molecule. In some instances, the PD-L1 binding antagonist is a small molecule that inhibits PD-L1 (e.g., GS-4224, INCB086550, MAX-10181 , INCB090244, CA-170, or ABSK041). In some instances, the PD-L1 binding antagonist is a small molecule that inhibits PD-L1 and VISTA. In some instances, the PD-L1 binding antagonist is CA-170 (also known as AUPM-170). In some instances, the PD-L1 binding antagonist is a small molecule that inhibits PD-L1 and TIM3. In some instances, the small molecule is a compound described in WO 2015/033301 and/or WO 2015/033299.

In some instances, the PD-L1 binding antagonist is an anti-PD-L1 antibody. A variety of anti-PD- L1 antibodies are contemplated and described herein. In any of the instances herein, the isolated anti- PD-L1 antibody can bind to a human PD-L1 , for example a human PD-L1 as shown in UniProtKB/Swiss- Prot Accession No. Q9NZQ7-1 , or a variant thereof. In some instances, the anti-PD-L1 antibody is capable of inhibiting binding between PD-L1 and PD-1 and/or between PD-L1 and B7-1. In some instances, the anti-PD-L1 antibody is a monoclonal antibody. In some instances, the anti-PD-L1 antibody is an antibody fragment selected from the group consisting of Fab, Fab’-SH, Fv, scFv, and (Fab’)2 fragments. In some instances, the anti-PD-L1 antibody is a humanized antibody. In some instances, the anti-PD-L1 antibody is a human antibody. Exemplary anti-PD-L1 antibodies include atezolizumab, MDX- 1105, MEDI4736 (durvalumab), MSB0010718C (avelumab), SHR-1316, CS1001 , envafolimab, TQB2450, ZKAB001 , LP-002, CX-072, IMC-001 , KL-A167, APL-502, cosibelimab, lodapolimab, FAZ053, TG-1501 , BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311 , RC98, PDL-GEX, KD036, KY1003, YBL-007, and HS-636. Examples of anti-PD-L1 antibodies useful in the methods of this invention and methods of making them are described in International Patent Application Publication No. WO 2010/077634 and U.S. Patent No. 8,217,149, each of which is incorporated herein by reference in its entirety.

In some instances, the anti-PD-L1 antibody comprises:

(a) an HVR-H1 , HVR-H2, and HVR-H3 sequence of GFTFSDSWIH (SEQ ID NO: 60), AWISPYGGSTYYADSVKG (SEQ ID NO: 61) and RHWPGGFDY (SEQ ID NO: 62), respectively, and

(b) an HVR-L1 , HVR-L2, and HVR-L3 sequence of RASQDVSTAVA (SEQ ID NO: 63), SASFLYS (SEQ ID NO: 64) and QQYLYHPAT (SEQ ID NO: 65), respectively. In one embodiment, the anti-PD-L1 antibody comprises:

(a) a heavy chain variable region (VH) comprising the amino acid sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRF TISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS (SEQ ID NO: 66), and

(b) the light chain variable region (VL) comprising the amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO: 67).

In some instances, the anti-PD-L1 antibody comprises (a) a VH comprising an amino acid sequence comprising having at least 95% sequence identity (e.g., at least 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of SEQ ID NO: 66; (b) a VL comprising an amino acid sequence comprising having at least 95% sequence identity (e.g., at least 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of SEQ ID NO: 67; or (c) a VH as in (a) and a VL as in (b).

In one embodiment, the anti-PD-L1 antibody comprises atezolizumab, which comprises:

(a) the heavy chain amino acid sequence:

EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRF TISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTS GGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 58), and

(b) the light chain amino acid sequence:

DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC (SEQ ID NO: 59).

In some instances, the anti-PD-L1 antibody is avelumab (CAS Registry Number: 1537032-82-8). Avelumab, also known as MSB0010718C, is a human monoclonal lgG1 anti-PD-L1 antibody (Merck KGaA, Pfizer).

In some instances, the anti-PD-L1 antibody is durvalumab (CAS Registry Number: 1428935-60- 7). Durvalumab, also known as MEDI4736, is an Fc-optimized human monoclonal lgG1 kappa anti-PD-L1 antibody (Medlmmune, AstraZeneca) described in WO 2011/066389 and US 2013/034559.

In some instances, the anti-PD-L1 antibody is MDX-1105 (Bristol Myers Squibb). MDX-1105, also known as BMS-936559, is an anti-PD-L1 antibody described in WO 2007/005874.

In some instances, the anti-PD-L1 antibody is LY3300054 (Eli Lilly).

In some instances, the anti-PD-L1 antibody is STI-A1014 (Sorrento). STI-A1014 is a human anti- PD-L1 antibody.

In some instances, the anti-PD-L1 antibody is KN035 (Suzhou Alphamab). KN035 is singledomain antibody (dAB) generated from a camel phage display library.

In some instances, the anti-PD-L1 antibody comprises a cleavable moiety or linker that, when cleaved (e.g., by a protease in the tumor microenvironment), activates an antibody antigen-binding domain to allow it to bind its antigen, e.g., by removing a non-binding steric moiety. In some instances, the anti-PD-L1 antibody is CX-072 (CytomX Therapeutics).

In some instances, the anti-PD-L1 antibody comprises the six HVR sequences (e.g., the three heavy chain HVRs and the three light chain HVRs) and/or the heavy chain variable domain and light chain variable domain from an anti-PD-L1 antibody described in US 20160108123, WO 2016/000619, WO 2012/145493, U.S. Pat. No. 9,205,148, WO 2013/181634, or WO 2016/061142.

In a still further specific aspect, the anti-PD-L1 antibody has reduced or minimal effector function. In a still further specific aspect, the minimal effector function results from an “effector-less Fc mutation” or aglycosylation mutation. In still a further instance, the effector-less Fc mutation is an N297A or D265A/N297A substitution in the constant region. In still a further instance, the effector-less Fc mutation is an N297A substitution in the constant region. In some instances, the isolated anti-PD-L1 antibody is aglycosylated. Glycosylation of antibodies is typically either N-linked or O- linked. N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline, are the recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain. Thus, the presence of either of these tripeptide sequences in a polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the attachment of one of the sugars N- acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used. Removal of glycosylation sites from an antibody is conveniently accomplished by altering the amino acid sequence such that one of the abovedescribed tripeptide sequences (for N-linked glycosylation sites) is removed. The alteration may be made by substitution of an asparagine, serine or threonine residue within the glycosylation site with another amino acid residue (e.g., glycine, alanine, or a conservative substitution).

In a further aspect, an anti-PD-L1 antibody according to any of the above aspects may incorporate any of the features, singly or in combination, as described in Sections 1-6 below.

B. PD-1 Binding Antagonists

In some instances, the PD-1 axis binding antagonist is a PD-1 binding antagonist. For example, in some instances, the PD-1 binding antagonist inhibits the binding of PD-1 to one or more of its ligand binding partners. In some instances, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 . In other instances, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L2. In yet other instances, the PD-1 binding antagonist inhibits the binding of PD-1 to both PD-L1 and PD-L2. The PD-1 binding antagonist may be, without limitation, an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, or a small molecule. In some instances, the PD-1 binding antagonist is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., an Fc region of an immunoglobulin sequence). For example, in some instances, the PD-1 binding antagonist is an Fc-fusion protein. In some instances, the PD-1 binding antagonist is AMP-224. AMP-224, also known as B7-DCIg, is a PD-L2- Fc fusion soluble receptor described in WO 2010/027827 and WO 2011/066342. In some instances, the PD-1 binding antagonist is a peptide or small molecule compound. In some instances, the PD-1 binding antagonist is AUNP-12 (PierreFabre/Aurigene). See, e.g., WO 2012/168944, WO 2015/036927, WO 2015/044900, WO 2015/033303, WO 2013/144704, WO 2013/132317, and WO 2011/161699. In some instances, the PD-1 binding antagonist is a small molecule that inhibits PD-1.

In some instances, the PD-1 binding antagonist is an anti-PD-1 antibody. A variety of anti-PD-1 antibodies can be utilized in the methods and uses disclosed herein. In any of the instances herein, the PD-1 antibody can bind to a human PD-1 or a variant thereof. In some instances the anti-PD-1 antibody is a monoclonal antibody. In some instances, the anti-PD-1 antibody is an antibody fragment selected from the group consisting of Fab, Fab’, Fab’-SH, Fv, scFv, and (Fab’)2 fragments. In some instances, the anti-PD-1 antibody is a humanized antibody. In other instances, the anti-PD-1 antibody is a human antibody. Exemplary anti-PD-1 antagonist antibodies include nivolumab, pembrolizumab, MEDI-0680, PDR001 (spartalizumab), REGN2810 (cemiplimab), BGB-108, prolgolimab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, retifanlimab, sasanlimab, penpulimab, CS1003, HLX10, SCT-I10A, zimberelimab, balstilimab, genolimzumab, Bl 754091 , cetrelimab, YBL-006, BAT1306, HX008, budigalimab, AMG 404, CX-188, JTX-4014, 609A, Sym021 , LZM009, F520, SG001 , AM0001 , ENUM 244C8, ENUM 388D4, STI-1110, AK-103, and hAb21 .

In some instances, the anti-PD-1 antibody is nivolumab (CAS Registry Number: 946414-94-4). Nivolumab (Bristol-Myers Squibb/Ono), also known as MDX-1106-04, MDX-1106, ONO-4538, BMS- 936558, and OPDIVO®, is an anti-PD-1 antibody described in WO 2006/121168.

In some instances, the anti-PD-1 antibody is pembrolizumab (CAS Registry Number: 1374853- 91-4). Pembrolizumab (Merck), also known as MK-3475, Merck 3475, lambrolizumab, SCH-900475, and KEYTRUDA®, is an anti-PD-1 antibody described in WO 2009/114335.

In some instances, the anti-PD-1 antibody is MEDI-0680 (AMP-514; AstraZeneca). MEDI-0680 is a humanized lgG4 anti-PD-1 antibody.

In some instances, the anti-PD-1 antibody is PDR001 (CAS Registry No. 1859072-53-9; Novartis). PDR001 is a humanized lgG4 anti-PD-1 antibody that blocks the binding of PD-L1 and PD-L2 to PD-1.

In some instances, the anti-PD-1 antibody is REGN2810 (Regeneron). REGN2810 is a human anti-PD-1 antibody.

In some instances, the anti-PD-1 antibody is BGB-108 (BeiGene).

In some instances, the anti-PD-1 antibody is BGB-A317 (BeiGene).

In some instances, the anti-PD-1 antibody is JS-001 (Shanghai Junshi). JS-001 is a humanized anti-PD-1 antibody.

In some instances, the anti-PD-1 antibody is STI-A1110 (Sorrento). STI-A1110 is a human anti- PD-1 antibody.

In some instances, the anti-PD-1 antibody is INCSHR-1210 (Incyte). INCSHR-1210 is a human lgG4 anti-PD-1 antibody.

In some instances, the anti-PD-1 antibody is PF-06801591 (Pfizer).

In some instances, the anti-PD-1 antibody is TSR-042 (also known as ANB011 ; T esaro/AnaptysBio) .

In some instances, the anti-PD-1 antibody is AM0001 (ARMO Biosciences). In some instances, the anti-PD-1 antibody is ENUM 244C8 (Enumeral Biomedical Holdings). ENUM 244C8 is an anti-PD-1 antibody that inhibits PD-1 function without blocking binding of PD-L1 to PD-1.

In some instances, the anti-PD-1 antibody is ENUM 388D4 (Enumeral Biomedical Holdings). ENUM 388D4 is an anti-PD-1 antibody that competitively inhibits binding of PD-L1 to PD-1.

In some instances, the anti-PD-1 antibody comprises the six HVR sequences (e.g., the three heavy chain HVRs and the three light chain HVRs) and/or the heavy chain variable domain and light chain variable domain from an anti-PD-1 antibody described in WO 2015/112800, WO 2015/112805, WO 2015/112900, US 20150210769 , WO2016/089873, WO 2015/035606, WO 2015/085847, WO 2014/206107, WO 2012/145493, US 9,205,148, WO 2015/119930, WO 2015/119923, WO 2016/032927, WO 2014/179664, WO 2016/106160, and WO 2014/194302.

In a still further specific aspect, the anti-PD-1 antibody has reduced or minimal effector function. In a still further specific aspect, the minimal effector function results from an “effector-less Fc mutation” or aglycosylation mutation. In still a further instance, the effector-less Fc mutation is an N297A or D265A/N297A substitution in the constant region. In some instances, the isolated anti-PD-1 antibody is aglycosylated.

In a further aspect, an anti-PD-1 antibody according to any of the above aspects may incorporate any of the features, singly or in combination, as described in Sections 1-6 below.

C. PD-L2 Binding Antagonists

In some instances, the PD-1 axis binding antagonist is a PD-L2 binding antagonist. In some instances, the PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to its ligand binding partners. In a specific aspect, the PD-L2 binding ligand partner is PD-1 . The PD-L2 binding antagonist may be, without limitation, an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, or a small molecule.

In some instances, the PD-L2 binding antagonist is an anti-PD-L2 antibody. In any of the instances herein, the anti-PD-L2 antibody can bind to a human PD-L2 or a variant thereof. In some instances, the anti-PD-L2 antibody is a monoclonal antibody. In some instances, the anti-PD-L2 antibody is an antibody fragment selected from the group consisting of Fab, Fab’, Fab’-SH, Fv, scFv, and (Fab’)2 fragments. In some instances, the anti-PD-L2 antibody is a humanized antibody. In other instances, the anti-PD-L2 antibody is a human antibody. In a still further specific aspect, the anti-PD-L2 antibody has reduced or minimal effector function. In a still further specific aspect, the minimal effector function results from an “effector-less Fc mutation” or aglycosylation mutation. In still a further instance, the effector-less Fc mutation is an N297A or D265A/N297A substitution in the constant region. In some instances, the isolated anti-PD-L2 antibody is aglycosylated.

In a further aspect, an anti-PD-L2 antibody according to any of the above aspects may incorporate any of the features, singly or in combination, as described in Sections 1-6 below. VIII. Anti-CD38 Antibodies

The invention provides anti-CD38 antibodies useful for treating cancer in a subject (e.g., a human) having a cancer (e.g., a hematologic cancer, e.g., a myeloma (e.g., a MM, e.g., a relapsed or refractory MM)).

In some aspects, the anti-CD38 antibody is an anti-CD38 antagonist antibody.

In certain aspects, the anti-CD38 antibodies includes at least one, two, three, four, five, or six HVRs selected from: (a) an HVR-H1 comprising the amino acid sequence of SFAMS (SEQ ID NO: 20); (b) an HVR-H2 comprising the amino acid sequence of AISGSGGGTYYADSVKG (SEQ ID NO: 21); (c) an HVR-H3 comprising the amino acid sequence of DKILWFGEPVFDY (SEQ ID NO: 22); (d) an HVR-L1 comprising the amino acid sequence of RASQSVSSYLA (SEQ ID NO: 23), (e) an HVR-L2 comprising the amino acid sequence of DASNRAT (SEQ ID NO: 24); and/or (f) an HVR-L3 comprising the amino acid sequence of QQRSNWPPTF (SEQ ID NO: 25), or a combination of one or more of the above HVRs and one or more variants thereof having at least about 90% sequence identity (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 20-25.

In some aspects, any of the above anti-CD38 antibodies includes (a) an HVR-H1 comprising the amino acid sequence of SFAMS (SEQ ID NO: 20); (b) an HVR-H2 comprising the amino acid sequence of AISGSGGGTYYADSVKG (SEQ ID NO: 21); (c) an HVR-H3 comprising the amino acid sequence of DKILWFGEPVFDY (SEQ ID NO: 22); (d) an HVR-L1 comprising the amino acid sequence of RASQSVSSYLA (SEQ ID NO: 23); (e) an HVR-L2 comprising the amino acid sequence of DASNRAT (SEQ ID NO: 24); and (f) an HVR-L3 comprising the amino acid sequence of QQRSNWPPTF (SEQ ID NO: 25).

In some aspects, the anti-CD38 antibody further comprises at least one, two, three, or four of the following light chain variable region framework regions (FRs): an FR-L1 comprising the amino acid sequence of EIVLTQSPATLSLSPGERATLSC (SEQ ID NO: 26); an FR-L2 comprising the amino acid sequence of WYQQKPGQAPRLLIY (SEQ ID NO: 27); an FR-L3 comprising the amino acid sequence of GIPARFSGSGSGTDFTLTISSLEPEDFAVYYC (SEQ ID NO: 28); and/or an FR-L4 comprising the amino acid sequence of GQGTKVEIK (SEQ ID NO: 29), or a combination of one or more of the above FRs and one or more variants thereof having at least about 90% sequence identity (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 26-29. In some aspects, for example, the antibody further comprises an FR-L1 comprising the amino acid sequence of EIVLTQSPATLSLSPGERATLSC (SEQ ID NO: 26); an FR-L2 comprising the amino acid sequence of WYQQKPGQAPRLLIY (SEQ ID NO: 27); an FR-L3 comprising the amino acid sequence of GIPARFSGSGSGTDFTLTISSLEPEDFAVYYC (SEQ ID NO: 28); and an FR-L4 comprising the amino acid sequence of GQGTKVEIK (SEQ ID NO: 29).

In some aspects, the anti-CD38 antibody further comprises at least one, two, three, or four of the following heavy chain variable region FRs: an FR-H1 comprising the amino acid sequence of EVQLLESGGGLVQPGGSLRLSCAVSGFTFN (SEQ ID NO: 30); an FR-H2 comprising the amino acid sequence of WVRQAPGKGLEWVS (SEQ ID NO: 31); an FR-H3 comprising the amino acid sequence of RFTISRDNSKNTLYLQMNSLRAEDTAVYFCAK (SEQ ID NO: 32); and/or an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 33), or a combination of one or more of the above FRs and one or more variants thereof having at least about 90% sequence identity (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 30-33. In some aspects, the anti-CD38 antibody includes an FR-H1 comprising the amino acid sequence of EVQLLESGGGLVQPGGSLRLSCAVSGFTFN (SEQ ID NO: 30); an FR-H2 comprising the amino acid sequence of WVRQAPGKGLEWVS (SEQ ID NO: 31); an FR-H3 comprising the amino acid sequence of RFTISRDNSKNTLYLQMNSLRAEDTAVYFCAK (SEQ ID NO: 32); and an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 33).

In some aspects, the anti-CD38 antibody has a VH domain comprising an amino acid sequence having at least at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQAPGKGLEWVSAISGSGGGTYYADSVKGRF TISRDNSKNTLYLQMNSLRAEDTAVYFCAKDKILWFGEPVFDYWGQGTLVTVSS (SEQ ID NO: 34) and/or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIP ARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPTFGQGTKVEIK (SEQ ID NO: 35).

In another aspect, an anti-CD38 antibody is provided, wherein the antibody comprises a VH as in any of the aspects provided above, and a VL as in any of the aspects provided above, wherein one or both of the variable domain sequences include post-translational modifications.

In some aspects, an anti-CD38 antibody may bind to CD38 on the surface of a MM cell and mediate cell lysis through the activation of complement-dependent cytotoxicity, ADCC, antibodydependent cellular phagocytosis (ADCP), and apoptosis mediated by Fc cross-linking, leading to the depletion of malignant cells and reduction of the overall cancer burden. In some aspects, an anti-CD38 antibody may also modulate CD38 enzyme activity through inhibition of ribosyl cyclase enzyme activity and stimulation of the cyclic adenosine diphosphate ribose (cADPR) hydrolase activity of CD38. In certain aspects, an anti-CD38 antibody that binds to CD38 has a dissociation constant (KD) of < 1 pM, < 100 nM, < 10 nM, < 1 nM, < 0.1 nM, < 0.01 nM, or < 0.001 nM (e.g., 10⁸ M or less, e.g. from 10⁸ M to 10¹³ M, e.g., from 10⁹ M to 10¹³ M). In certain aspects, the anti-CD38 antibody may bind to both human CD38 and chimpanzee CD38.

In some aspects, the methods or uses described herein may include using or administering an isolated anti-CD38 antibody that competes for binding to CD38 with any of the anti-CD38 antibodies described above. For example, the method may include administering an isolated anti-CD38 antibody that competes for binding to CD38 with an anti-CD38 antibody having the following six HVRs: (a) an HVR- H1 comprising the amino acid sequence of SFAMS (SEQ ID NO: 20); (b) an HVR-H2 comprising the amino acid sequence of AISGSGGGTYYADSVKG (SEQ ID NO:21); (c) an HVR-H3 comprising the amino acid sequence of DKILWFGEPVFDY (SEQ ID NO: 22); (d) an HVR-L1 comprising the amino acid sequence of RASQSVSSYLA (SEQ ID NO:23), (e) an HVR-L2 comprising the amino acid sequence of DASNRAT (SEQ ID NO: 24); and (f) an HVR-L3 comprising the amino acid sequence of QQRSNWPPTF (SEQ ID NO: 25). The methods described herein may also include administering an isolated anti-CD38 antibody that binds to the same epitope as an anti-CD38 antibody described above.

In some aspects, the anti-CD38 antibody is daratumumab and hyaluronidase-fihj (DARZALEX FASPRO®). In certain aspects, the anti-CD38 antibody is daratumumab (DARZALEX®). In other aspects, the anti-CD38 antibody is MOR202 or isatuximab (SAR-650984). Examples of anti-CD38 antibodies useful for the methods of this invention and methods for making thereof are described in U.S. Patent No: 7,829,673; 8,263,746; and 8,153,765; and U.S. Pub. No: 20160067205 A1. The anti-CD38 antibodies (e.g., daratumumab) useful in this invention, including compositions containing such antibodies, may be used in combination with an anti-TIGIT antagonist antibody to treat a hematologic cancer (e.g., a myeloma (e.g., MM, e.g., a relapsed or refractory MM)).

An anti-CD38 antibody according to any of the above aspects may be a monoclonal antibody, comprising a chimeric, humanized, or human antibody. In some aspects, the anti-CD38 antibody is a monoclonal antibody. In some aspects, the anti-CD38 antibody is a human antibody. In one aspect, an anti-CD38 antibody is an antibody fragment, for example, a Fv, Fab, Fab’, Fab’-SH, scFv, diabody, or F(ab’)2 fragment. In another aspect, the anti-CD38 antibody is a full-length antibody, e.g., an intact IgG antibody (e.g., an intact lgG1 antibody) or other antibody class or isotype as defined herein. In some aspects, the anti-CD38 antibody is an IgG class antibody. In some aspects, the anti-CD38 antibody is an IgG 1 subclass antibody.

In a further aspect, an anti-CD38 antibody according to any of the above aspects may incorporate any of the features, singly or in combination, as described in Sections 1-6 below.

IX. Anti-CD20 Antibodies

The invention provides anti-CD20 antibodies useful for treating cancer in a subject (e.g., a human) having a cancer (e.g., a hematologic cancer, e.g., a lymphoma (e.g., a NHL, e.g., a relapsed or refractory DLBCL or a relapsed or refractory FL)).

In certain aspects, the anti-CD20 antibodies includes at least one, two, three, four, five, or six HVRs selected from: (a) an HVR-H1 comprising the amino acid sequence of SYNMH (SEQ ID NO: 36); (b) an HVR-H2 comprising the amino acid sequence of AIYPGNGDTSYNQKFKG (SEQ ID NO: 37); (c) an HVR-H3 comprising the amino acid sequence of STYYGGDWYFNV (SEQ ID NO: 38); (d) an HVR-L1 comprising the amino acid sequence of RASSSVSYIH (SEQ ID NO: 39), (e) an HVR-L2 comprising the amino acid sequence of ATSNLAS (SEQ ID NO: 40); and/or (f) an HVR-L3 comprising the amino acid sequence of QQWTSNPPT (SEQ ID NO: 41), or a combination of one or more of the above HVRs and one or more variants thereof having at least about 90% sequence identity (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 36-41 .

In some aspects, any of the above anti-CD20 antibodies includes (a) an HVR-H1 comprising the amino acid sequence of SYNMH (SEQ ID NO: 36); (b) an HVR-H2 comprising the amino acid sequence of AIYPGNGDTSYNQKFKG (SEQ ID NO: 37); (c) an HVR-H3 comprising the amino acid sequence of STYYGGDWYFNV (SEQ ID NO: 38); (d) an HVR-L1 comprising the amino acid sequence of RASSSVSYIH (SEQ ID NO: 39); (e) an HVR-L2 comprising the amino acid sequence of ATSNLAS (SEQ ID NO: 40); and (f) an HVR-L3 comprising the amino acid sequence of QQWTSNPPT (SEQ ID NO: 41).

In some aspects, the anti-CD20 antibody further comprises at least one, two, three, or four of the following light chain variable region framework regions (FRs): an FR-L1 comprising the amino acid sequence of QIVLSQSPAILSASPGEKVTMTC (SEQ ID NO: 42); an FR-L2 comprising the amino acid sequence of WFQQKPGSSPKPWIY (SEQ ID NO: 43); an FR-L3 comprising the amino acid sequence of GVPVRFSGSGSGTSYSLTISRVEAEDAATYYC (SEQ ID NO: 44); and/or an FR-L4 comprising the amino acid sequence of FGGGTKLEIK (SEQ ID NO: 45), or a combination of one or more of the above FRs and one or more variants thereof having at least about 90% sequence identity (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 42-45. In some aspects, for example, the antibody further comprises an FR-L1 comprising the amino acid sequence of QIVLSQSPAILSASPGEKVTMTC (SEQ ID NO: 42); an FR-L2 comprising the amino acid sequence of WFQQKPGSSPKPWIY (SEQ ID NO: 43); an FR-L3 comprising the amino acid sequence of GVPVRFSGSGSGTSYSLTISRVEAEDAATYYC (SEQ ID NO: 44); and an FR-L4 comprising the amino acid sequence of FGGGTKLEIK (SEQ ID NO: 45).

In some aspects, the anti-CD20 antibody further comprises at least one, two, three, or four of the following heavy chain variable region FRs: an FR-H1 comprising the amino acid sequence of QVQLQQPGAELVKPGASVKMSCKASGYTFT (SEQ ID NO: 46); an FR-H2 comprising the amino acid sequence of WVKQTPGRGLEWIG (SEQ ID NO: 47); an FR-H3 comprising the amino acid sequence of KATLTADKSSSTAYMQLSSLTSEDSAVYYCAR (SEQ ID NO: 48); and/or an FR-H4 comprising the amino acid sequence of WGAGTTVTVS (SEQ ID NO: 49), or a combination of one or more of the above FRs and one or more variants thereof having at least about 90% sequence identity (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 46-49. In some aspects, the anti-CD20 antibody includes an FR-H1 comprising the amino acid sequence of QVQLQQPGAELVKPGASVKMSCKASGYTFT (SEQ ID NO: 46); an FR-H2 comprising the amino acid sequence of WVKQTPGRGLEWIG (SEQ ID NO: 47); an FR-H3 comprising the amino acid sequence of KATLTADKSSSTAYMQLSSLTSEDSAVYYCAR (SEQ ID NO: 48); and an FR-H4 comprising the amino acid sequence of WGAGTTVTVS (SEQ ID NO: 49).

In some aspects, the anti-CD20 antibody has a VH domain comprising an amino acid sequence having at least at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKA TLTADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVS (SEQ ID NO: 50) and/or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of QIVLSQSPAILSASPGEKVTMTCRASSSVSYIHWFQQKPGSSPKPWIYATSNLASGVPVRFSGSGSGTSY SLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEIK (SEQ ID NO: 51).

In another aspect, an anti-CD20 antibody is provided, wherein the antibody comprises a VH as in any of the aspects provided above, and a VL as in any of the aspects provided above, wherein one or both of the variable domain sequences include post-translational modifications.

In certain aspects, an anti-CD20 antibody may bind to CD20 on the surface of a malignant B cell and mediate B cell lysis through the activation of complement-dependent lysis, antibody-dependent cellular cytotoxicity (ADCC), and apoptosis mediated by Fc cross-linking, leading to the depletion of circulating B lymphocytes. In certain aspects, an anti-CD20 antibody that binds to CD20 has a dissociation constant (KD) of < 1 pM, < 100 nM, < 10 nM, < 1 nM, < 0.1 nM, < 0.01 nM, or < 0.001 nM (e.g., IO ⁸ M or less, e.g. from 10⁸ M to 10¹³ M, e.g., from 10⁹ M to 10¹³ M). In certain aspects, an anti-CD20 antibody that binds to CD20 has a KD of < 10 nM. In certain aspects, the binding is at a KD of < 7.5 nM, < 5 nM, between 1-5 nM, or <1 nM. In certain aspects, the anti-CD20 antibody may bind to both human CD20 and cyno CD20.

In some aspects, the methods or uses described herein may include using or administering an isolated anti-CD20 antibody that competes for binding to CD20 with any of the anti-CD20 antibodies described above. For example, the method may include administering an isolated anti-CD20 antibody that competes for binding to CD20 with an anti-CD20 antibody having the following six HVRs: (a) an HVR- H1 comprising the amino acid sequence of SYNMH (SEQ ID NO: 36); (b) an HVR-H2 comprising the amino acid sequence of AIYPGNGDTSYNQKFKG (SEQ ID NO: 37); (c) an HVR-H3 comprising the amino acid sequence of STYYGGDWYFNV (SEQ ID NO: 38); (d) an HVR-L1 comprising the amino acid sequence of RASSSVSYIH (SEQ ID NO: 39), (e) an HVR-L2 comprising the amino acid sequence of ATSNLAS (SEQ ID NO: 40); and (f) an HVR-L3 comprising the amino acid sequence of QQWTSNPPT (SEQ ID NO: 41). The methods described herein may also include administering an isolated anti-CD20 antibody that binds to the same epitope as an anti-CD20 antibody described above.

In certain aspects, the anti-CD20 antibody is rituximab (RITUXAN®). In other aspects, the anti- CD20 antibody is Y2B8 or Ibritumomab Tiuxetan (ZEVALIN®). In other aspects, the anti-CD20 antibody is tositumomab, (BEXXAR™). In other aspects, the anti-CD20 antibody is huMax-CD20 or ofatumumab (ARZERRA®). Examples of anti-CD20 antibodies useful for the methods of this invention and methods for making thereof are described in U.S. Patent Nos: 5,736,137; 5,595,721 ; 5,677,180; in U.S. Pub. Nos: US 2003/0219433 and US 2003/0219433; and in PCT Pub. No: WQ03/002607, expressly incorporated herein by reference. The anti-CD20 antibodies (e.g., rituximab) useful in this invention, including compositions containing such antibodies, may be used in combination with an anti-TIGIT antagonist antibody to treat a hematologic cancer (e.g., a lymphoma (e.g., a NHL, e.g., a relapsed or refractory DLBCL or a relapsed or refractory FL)).

An anti-CD20 antibody according to any of the above aspects may be a monoclonal antibody, comprising a chimeric, humanized, or human antibody. In one aspect, an anti-CD20 antibody is an antibody fragment, for example, a Fv, Fab, Fab’, scFv, diabody, or F(ab’)2 fragment. In another aspect, the antibody is a full-length antibody, e.g., an intact IgG antibody (e.g., an intact lgG1 antibody) or other antibody class or isotype as defined herein.

In a further aspect, an anti-CD20 antibody according to any of the above aspects may incorporate any of the features, singly or in combination, as described in Sections 1-6 below.

1. Antibody Affinity

In certain aspects, an anti-TIGIT antagonist antibody, anti-CD20 antibody, and/or anti-CD38 antibody provided herein has a dissociation constant (KD) of < 1 pM, < 100 nM, < 10 nM, < 1 nM, < 0.1 nM, < 0.01 nM, or < 0.001 nM (e.g., 10⁸ M or less, e.g., from 10⁸ M to 10 ¹³ M, e.g., from 10⁹ M to 10 ¹³ M).

In one aspect, KD is measured by a radiolabeled antigen binding assay (RIA). In one aspect, an RIA is performed with the Fab version of an antibody of interest and its antigen. For example, solution binding affinity of Fabs for antigen is measured by equilibrating Fab with a minimal concentration of (¹²⁵l)-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)). To establish conditions for the assay, MICROTITER® multi-well plates (Thermo Scientific) are coated overnight with 5 pg/ml 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). In a non-adsorbent plate (Nunc #269620), 100 pM or 26 pM [¹²⁵l]- 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. 57:4593-4599 (1997)). 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 pl/well of scintillant (MICROSCINT-20 ™; Packard) is added, and the plates are counted on a TOPCOUNT ™ 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.

According to another aspect, KD is measured using a BIACORE® surface plasmon resonance assay. For example, an assay using a BIACORE®-2000 or a BIACORE ®-3000 (BIAcore, Inc., Piscataway, NJ) is performed at 25°C with immobilized antigen CM5 chips at ~10 response units (RU). In one aspect, carboxymethylated dextran biosensor chips (CM5, BIACORE, Inc.) are activated with N-ethyl- N’- (3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) according to the supplier’s instructions. Antigen is diluted with 10 mM sodium acetate, pH 4.8, to 5 pg/ml (~0.2 pM) before injection at a flow rate of 5 pl/minute to achieve approximately 10 response units (RU) of coupled protein. Following the injection of antigen, 1 M ethanolamine is injected to block unreacted groups. For kinetics measurements, two-fold serial dilutions of Fab (0.78 nM to 500 nM) are injected in PBS with 0.05% polysorbate 20 (TWEEN-20™) surfactant (PBST) at 25°C at a flow rate of approximately 25 pl/min. Association rates (k_on) and dissociation rates (k_Off) are calculated using a simple one-to-one Langmuir binding model (BIACORE ® Evaluation Software version 3.2) by simultaneously fitting the association and dissociation sensorgrams. The equilibrium dissociation constant (KD) is calculated as the ratio koff/kon. See, for example, Chen et al., J. Mol. Biol. 293:865-881 (1999). If the on-rate exceeds 10⁶M-¹s-¹ by the surface plasmon resonance assay above, then the on-rate can be determined by using a fluorescent quenching technique that measures the increase or decrease in fluorescence emission intensity (excitation = 295 nm; emission = 340 nm, 16 nm band-pass) at 25°C of a 20 nM anti-antigen antibody (Fab form) in PBS, pH 7.2, in the presence of increasing concentrations of antigen as measured in a spectrometer, such as a stop-flow equipped spectrophometer (Aviv Instruments) or a 8000-series SLM-AMINCO ™ spectrophotometer (ThermoSpectronic) with a stirred cuvette.

2. Antibody Fragments

In certain aspects, an anti-TIGIT antagonist antibody, anti-CD20 antibody, and/or anti- CD38 antibody 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. For a review of certain antibody fragments, see Hudson et al. Nat. Med. 9:129-134 (2003). For a review of scFv fragments, see, e.g., Pluckthun, in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., (Springer-Verlag, New York), pp. 269-315 (1994); see also WO 93/16185; and U.S. Patent Nos. 5,571 ,894 and 5,587,458. For discussion of Fab and F(ab’)2 fragments comprising salvage receptor binding epitope residues and having increased in vivo half-life, see U.S. Patent No. 5,869,046.

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. In certain aspects, a single-domain antibody is a human single-domain antibody (Domantis, Inc., Waltham, MA; see, e.g., U.S. Patent No. 6,248,516 B1).

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. coll or phage), as described herein.

3. Chimeric and Humanized Antibodies

In certain aspects, an anti-TIGIT antagonist antibody, anti-CD20 antibody, and/or anti- CD38 antibody 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)). In one example, 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. In a further example, 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.

In certain aspects, a chimeric antibody is a humanized antibody. Typically, a non-human antibody is humanized to reduce immunogenicity to humans, while retaining the specificity and affinity of the parental non-human antibody. Generally, 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. A humanized antibody optionally will also comprise at least a portion of a human constant region. In some aspects, 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.

Humanized antibodies and methods of making them are reviewed, e.g., in Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008), and are further described, e.g., in Riechmann et al., Nature 332:323- 329 (1988); Queen et al., Proc. Nat’l Acad. Sci. USA 86:10029-10033 (1989); US Patent Nos. 5, 821 ,337, 7,527,791 , 6,982,321 , and 7,087,409; Kashmiri et al., Methods 36:25-34 (2005) (describing specificity determining region (SDR) grafting); Padlan, Mol. Immunol. 28:489-498 (1991) (describing “resurfacing”); Dall’Acqua et al., Methods 36:43-60 (2005) (describing “FR shuffling”); and Osbourn et al., Methods 36:61-68 (2005) and Klimka et al., Br. J. Cancer, 83:252-260 (2000) (describing the “guided selection” approach to FR shuffling). 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. 13:1619-1633 (2008)); and framework regions derived from screening FR libraries (see, e.g., Baca et al., J. Biol. Chem. 272:10678-10684 (1997) and Rosok et al., J. Biol. Chem. 271 :22611-22618 (1996)).

4. Human Antibodies

In certain aspects, an anti-TIGIT antagonist antibody, anti-CD20 antibody, and/or anti-CD38 antibody 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. In such transgenic mice, the endogenous immunoglobulin loci have generally been inactivated. For review of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23:1117-1125 (2005). See also, e.g., U.S. Patent Nos. 6,075,181 and 6,150,584 describing XENOMOUSE™ technology; U.S. Patent No. 5,770,429 describing HUMAB® technology; U.S. Patent No. 7,041 ,870 describing K-M MOUSE® technology, and U.S. Patent Application Publication No. US 2007/0061900, describing VELOCIMOUSE® technology). Human variable regions from intact antibodies generated by such animals may be further modified, e.g., by combining with a different human constant region.

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 Boerner 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. USA, 103:3557-3562 (2006). Additional methods include those described, for example, in U.S. Patent No. 7,189,826 (describing production of monoclonal human IgM antibodies from hybridoma cell lines) and Ni, Xiandai Mianyixue, 26(4):265-268 (2006) (describing human-human hybridomas). Human hybridoma technology (Trioma technology) is also described in Vollmers and Brandlein, Histology and Histopathology, 20(3y.927-937 (2005) and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology, 27(3):185-91 (2005).

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. 5. Library-Derived Antibodies

Anti-TIGIT antagonist antibody, anti-CD20 antibodies, and/or anti-CD38 antibodies of the invention 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. in Methods in Molecular Biology 178:1-37 (O’Brien et al., ed., Human Press, Totowa, NJ, 2001) and further described, e.g., in the McCafferty et al., Nature 348:552- 554; Clackson et al., Nature 352: 624-628 (1991); Marks et al., J. Mol. Biol. 222: 581-597 (1992); Marks and Bradbury, in Methods in Molecular Biology 248:161-175 (Lo, ed., Human Press, Totowa, NJ, 2003); Sidhu et al., J. Mol. Biol. 338(2): 299-310 (2004); Lee et al., J. Mol. Biol. 340(5): 1073-1093 (2004); Fellouse, Proc. Natl. Acad. Sci. USA 101 (34): 12467-12472 (2004); and Lee et al., J. Immunol. Methods 284(1-2): 119-132(2004).

In certain 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. Alternatively, the 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). Finally, 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.

Anti-TIGIT antagonist antibody, anti-CD20 antibodies, and/or anti-CD38 antibodies or antibody fragments isolated from human antibody libraries are considered human antibodies or human antibody fragments herein.

6. Antibody Variants

In certain aspects, amino acid sequence variants of the anti-TIGIT antagonist antibodies, anti- CD20 antibodies, and/or anti-CD38 antibodies of the invention are contemplated. As described in detail herein, anti-TIGIT antagonist antibodies, anti-CD20 antibodies, and/or anti-CD38 antibodies may be optimized based on desired structural and functional properties. For example, it may be desirable to improve the binding affinity and/or other biological properties of the antibody. 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 construct possesses the desired characteristics, for example, antigenbinding. a. Substitution, Insertion, and Deletion Variants In certain aspects, anti-TIGIT antagonist antibody, anti-CD20 antibody, and/or anti-CD38 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 3 under the heading of “preferred substitutions.” More substantial changes are provided in Table 3 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, for example, retained/improved antigen binding, decreased immunogenicity, or improved ADCC or CDC.

Table 3. Exemplary and Preferred Amino Acid Substitutions

Amino acids may be grouped according to common side-chain properties: (1) hydrophobic: Norleucine, Met, Ala, Vai, Leu, He;

(2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gin; (3) acidic: Asp, Glu;

(4) basic: His, Lys, Arg;

(5) residues that influence chain orientation: Gly, Pro;

(6) aromatic: Trp, Tyr, Phe.

Non-conservative substitutions will entail exchanging a member of one of these classes for another class.

One type of substitutional variant involves substituting one or more hypervariable region residues of a parent antibody (e.g., a humanized or human antibody). Generally, 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 (e.g., substitutions) 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. 207:1 TOWS (2008)), and/or residues that contact antigen, 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 Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O’Brien et al., ed., Human Press, Totowa, NJ, (2001).) In some aspects of 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.

In certain aspects, 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. For example, conservative alterations (e.g., conservative substitutions as provided herein) that do not substantially reduce binding affinity may be made in HVRs. Such alterations may, for example, be outside of antigen contacting residues in the HVRs. In certain aspects of the variant VH and VL sequences provided above, each HVR either is unaltered, or includes 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. In this method, a residue or group of target residues (e.g., charged residues such as Arg, Asp, His, Lys, and Glu) are identified and replaced by a neutral or negatively charged amino acid (e.g., alanine or polyalanine) to determine whetherthe interaction of the antibody with antigen is affected. Further substitutions may be introduced at the amino acid locations demonstrating functional sensitivity to the initial substitutions. Alternatively, or additionally, a crystal structure of an antigenantibody complex 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. Examples of 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. b. Glycosylation variants

In certain aspects, anti-TIGIT antagonist antibodies, anti-CD20 antibodies, and/or anti-CD38 antibodies of the invention can be altered to increase or decrease the extent to which the antibody is glycosylated. Addition or deletion of glycosylation sites to anti-TIGIT antagonist antibody, anti-CD20 antibody, and/or anti-CD38 antibody of the invention may be conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites is created or removed.

Where the antibody comprises an Fc region, 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 (GIcNAc), galactose, and sialic acid, as well as a fucose attached to a GIcNAc in the “stem” of the biantennary oligosaccharide structure. In some aspects, modifications of the oligosaccharide in an antibody of the invention are made in order to create antibody variants with certain improved properties.

In one aspect, anti-TIGIT antagonist antibody, anti-CD20 antibody, and/or anti-CD38 antibody variants are provided having a carbohydrate structure that lacks fucose attached (directly or indirectly) to an Fc region. For example, 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. 87: 614 (2004). Examples of cell lines capable of producing defucosylated antibodies include Led 3 CHO cells deficient in protein fucosylation (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); US Pat Appl No US 2003/0157108 A1 , Presta, L; and WO 2004/056312 A1 , 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).

In view of the above, in some aspects, the methods of the invention involve administering to the subject in the context of a fractionated, dose-escalation dosing regimen an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein (e.g., tiragolumab)) and/or anti-CD20 antibody (e.g., rituximab) or anti-CD38 antibody (e.g., daratumumab) variant that comprises an aglycosylation site mutation. In some aspects, the aglycosylation site mutation reduces effector function of the antibody. In some aspects, the aglycosylation site mutation is a substitution mutation. In some aspects, the antibody comprises a substitution mutation in the Fc region that reduces effector function. In some aspects, the substitution mutation is at amino acid residue N297, L234, L235, and/or D265 (EU numbering). In some aspects, the substitution mutation is selected from the group consisting of N297G, N297A, L234A, L235A, D265A, and P329G. In some aspects, the substitution mutation is at amino acid residue N297. In a preferred aspect, the substitution mutation is N297A.

Anti-TIGIT antagonist antibody, anti-CD20 antibody, and/or anti-CD38 antibody variants are further provided with bisected oligosaccharides, for example, in which a biantennary oligosaccharide attached to the Fc region of the antibody is bisected by GIcNAc. 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.). c. Fc region variants

In certain aspects, one or more amino acid modifications are introduced into the Fc region of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein (e.g., tiragolumab)), anti-CD20 antibody (e.g., rituximab), and/or anti-CD38 antibody (e.g., daratumumab) of the invention, thereby generating an Fc region variant (see e.g., US 2012/0251531). The Fc region variant may comprise a human Fc region sequence (e.g., a human lgG1 , lgG2, lgG3 or lgG4 Fc region) comprising an amino acid modification (e.g., a substitution) at one or more amino acid positions.

In certain aspects, the invention contemplates an anti-TIGIT antagonist antibody, anti-CD20 antibody, or antibody anti-CD38 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. For example, 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. The primary cells for mediating ADCC, NK cells, express Fc(RII I only, whereas monocytes express Fc(RI, Fc(RI I and Fc(RII I. 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. Nat’l Acad. Sci. USA 82:1499-1502 (1985); 5,821 ,337 (see Bruggemann, M. et al., J. Exp. Med. 166:1351-1361 (1987)). Alternatively, non-radioactive assays methods may be employed (see, for example, ACTI™ nonradioactive cytotoxicity assay for flow cytometry (CellTechnology, Inc. Mountain View, CA; and CYTOTOX96® non-radioactive cytotoxicity assay (Promega, Madison, Wl). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells. Alternatively, or additionally, 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). C1q binding assays may also be carried out to confirm that the antibody is unable to bind C1q and hence lacks CDC activity. See, e.g., C1q and C3c binding ELISA in WO 2006/029879 and WO 2005/100402. To assess complement activation, a CDC assay may be performed (see, for example, Gazzano-Santoro et al. J. Immunol. Methods 202:163 (1996); Cragg, M.S. et al. Blood. 101 :1045-1052 (2003); and Cragg, M.S. and M.J. Glennie Blood. 103:2738-2743 (2004)). 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 Nos. 6,737,056 and 8,219,149). 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 and 8,219,149).

In certain aspects, the proline at position 329 of a wild-type human Fc region in the antibody is substituted with glycine or arginine or an amino acid residue large enough to destroy the proline sandwich within the Fc/Fc.gamma receptor interface that is formed between the proline 329 of the Fc and tryptophan residues Trp 87 and Trp 110 of FcgRIII (Sondermann et al.: Nature 406, 267-273 (20 Jul. 2000)). In certain aspects, the antibody comprises at least one further amino acid substitution. In one aspect, the further amino acid substitution is S228P, E233P, L234A, L235A, L235E, N297A, N297D, or P331S, and still in another aspect the at least one further amino acid substitution is L234A and L235A of the human lgG1 Fc region or S228P and L235E of the human lgG4 Fc region (see e.g., US 2012/0251531), and still in another aspect the at least one further amino acid substitution is L234A and L235A and P329G of the human lgG1 Fc region.

Certain antibody variants with improved or diminished binding to FcRs are described. (See, e.g., U.S. Patent No. 6,737,056; WO 2004/056312, and Shields et al., J. Biol. Chem. 9(2): 6591-6604 (2001).) In certain aspect, 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). In some aspects, alterations are made in the Fc region that result in altered (/.e., either improved or diminished) C1q binding and/or Complement Dependent Cytotoxicity (CDC), e.g., as described in US Patent No. 6,194,551 , WO 99/51642, and Idusogie et al. J. Immunol. 164: 4178-4184 (2000).

Antibodies with increased half-lives and improved binding to the neonatal Fc receptor (FcRn), which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)), are described in US2005/0014934A1 (Hinton et al.). Those antibodies comprise an Fc region with one or more substitutions therein which improve binding of the Fc region to FcRn. Such Fc variants include those with substitutions at one or more of Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307, 311 , 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424, or 434, e.g., substitution of Fc region residue 434 (US Patent No. 7,371 ,826).

See also Duncan & Winter, Nature 322:738-40 (1988); U.S. Patent No. 5,648,260; U.S. Patent No. 5,624,821 ; and WO 94/29351 concerning other examples of Fc region variants.

In some aspects the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein (e.g., tiragolumab)), anti-CD20 antibody (e.g., rituximab), and/or anti-CD38 antibody (e.g., daratumumab) comprises an Fc region comprising an N297G mutation.

In some aspects, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein (e.g., tiragolumab)), anti-CD20 antibody (e.g,. rituximab), and/or anti-CD38 antibody (e.g., daratumumab) comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH1 (CH1₇) domain, a first CH2 (CH2₇) domain, a first CH3 (CH3₇) domain, a second CH1 (CH1₂) domain, second CH2 (CH2₂) domain, and a second CH3 (CH3₂) domain. In some aspects, at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain. In some aspects, the CH3₇ and CH3₂ domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH3₇ domain is positionable in the cavity or protuberance, respectively, in the CH3₂ domain. In some aspects, the CH3₇ and CH3₂ domains meet at an interface between said protuberance and cavity. In some aspects, the CH2₇ and CH2₂ domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH2₇ domain is positionable in the cavity or protuberance, respectively, in the CH2₂ domain. In other aspects, the CH2₇ and CH2₂ domains meet at an interface between said protuberance and cavity. In some aspects, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein (e.g., tiragolumab)), anti-CD20 antibody (e.g., rituximab), and/or anti-CD38 antibody (e.g., daratumumab) is an lgG1 antibody. d. Cysteine engineered antibody variants

In certain aspects, it is desirable to create cysteine engineered anti-TIGIT antagonist antibodies, anti-CD20 antibodies, and/or anti-CD38 antibodies, e.g., “thioMAbs,” in which one or more residues of an antibody are substituted with cysteine residues. In particular aspects, the substituted residues occur at accessible sites of the antibody. By substituting those residues with cysteine, reactive thiol groups are thereby positioned at accessible sites of the antibody and may be used to conjugate the antibody to other moieties, such as drug moieties or linker-drug moieties, to create an immunoconjugate, as described further herein. In certain aspects, any one or more of the following residues are substituted with cysteine: V205 (Kabat numbering) of the light chain; A118 (EU numbering) of the heavy chain; and S400 (EU numbering) of the heavy chain Fc region. Cysteine engineered antibodies may be generated as described, for example, in U.S. Patent No. 7,521 ,541. e. Antibody derivatives

In certain aspects, an anti-TIGIT antagonist antibody of the invention (e.g., an anti-TIGIT antagonist antibody or a variant thereof (e.g., tiragolumab)), anti-CD20 antibody of the invention (e.g., rituximab), and/or anti-CD38 antibody of the invention (e.g., daratumumab or a variant thereof) provided herein are further modified to contain additional nonproteinaceous moieties that are known in the art and readily available. The moieties suitable for derivatization of the antibody include but are not limited to water soluble polymers. Non-limiting examples of water soluble polymers include, but are not limited to, polyethylene glycol (PEG), copolymers of ethylene glycol/propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly-1 , 3-dioxolane, poly-1 ,3, 6-trioxane, ethylene/maleic anhydride copolymer, polyaminoacids (either homopolymers or random copolymers), and dextran or poly(n-vinyl pyrrolidone)polyethylene glycol, propropylene glycol homopolymers, prolypropylene oxide/ethylene oxide co-polymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may have advantages in manufacturing due to its stability in water. The polymer may be of any molecular weight, and may be branched or unbranched. The number of polymers attached to the antibody may vary, and if more than one polymer are attached, they can be the same or different molecules. In general, the number and/or type of polymers used for derivatization can be determined based on considerations including, but not limited to, the particular properties or functions of the antibody to be improved, whether the antibody derivative will be used in a therapy under defined conditions, etc.

In another aspect, conjugates of an antibody and nonproteinaceous moiety that may be selectively heated by exposure to radiation are provided. In one aspect, the nonproteinaceous moiety is a carbon nanotube (Kam et al., Proc. Natl. Acad. Sci. USA 102: 1 1600-11605 (2005)). The radiation may be of any wavelength, and includes, but is not limited to, wavelengths that do not harm ordinary cells, but which heat the nonproteinaceous moiety to a temperature at which cells proximal to the antibody- nonproteinaceous moiety are killed.

Recombinant Production Methods

Anti-TIGIT antagonist antibodies (e.g., an anti-TIGIT antagonist antibody disclosed herein (e.g., tiragolumab)), anti-CD20 antibodies (e.g., rituximab), and/or anti-CD38 antibodies (e.g., daratumumab) of the invention may be produced using recombinant methods and compositions, for example, as described in U.S. Patent No. 4,816,567, which is incorporated herein by reference in its entirety.

For recombinant production of an anti-TIGIT antagonist antibody, anti-CD20 antibody, and/or anti- CD38 antibody, nucleic acid encoding an antibody, is isolated and inserted into one or more vectors for further cloning and/or expression in a host cell. Such nucleic acid may be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the antibody).

Suitable host cells for cloning or expression of antibody-encoding vectors include prokaryotic or eukaryotic cells described herein. For example, antibodies may be produced in bacteria, in particular when glycosylation and Fc effector function are not needed. For expression of antibody fragments and polypeptides in bacteria, see, e.g., U.S. Patent Nos. 5,648,237, 5,789,199, and 5,840,523. (See also Charlton, Methods in Molecular Biology, Vol. 248 (B.K.C. Lo, ed., Humana Press, Totowa, NJ, 2003), pp. 245-254, describing expression of antibody fragments in E. coll.) After expression, the antibody may be isolated from the bacterial cell paste in a soluble fraction and can be further purified.

In addition to prokaryotes, eukaryotic microbes such as filamentous fungi or yeast are suitable cloning or expression hosts for antibody-encoding vectors, including fungi and yeast strains whose glycosylation pathways have been “humanized,” resulting in the production of an antibody with a partially or fully human glycosylation pattern. See Gerngross, Nat. Biotech. 22:1409-1414 (2004), and Li et al., Nat. Biotech. 24:210-215 (2006).

Suitable host cells for the expression of glycosylated antibody are also derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant and insect cells. Numerous baculoviral strains have been identified which may be used in conjunction with insect cells, particularly for transfection of Spodoptera frugiperda cells.

Plant cell cultures can also be utilized as hosts. See, e.g., US Patent Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (describing PLANTIBODIES™ technology for producing antibodies in transgenic plants).

Vertebrate cells may also be used as hosts. For example, mammalian cell lines that are adapted to grow in suspension may be useful. Other examples of useful mammalian host cell lines are monkey kidney CV1 line transformed by SV40 (COS-7); human embryonic kidney line (293 or 293 cells as described, e.g., in Graham et al., J. Gen Virol. 36:59 (1977)); baby hamster kidney cells (BHK); mouse sertoli cells (TM4 cells as described, e.g., in Mather, Biol. Reprod. 23:243-251 (1980)); monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical carcinoma cells (HELA); canine kidney cells (MDCK; buffalo rat liver cells (BRL 3A); human lung cells (W138); human liver cells (Hep G2); mouse mammary tumor (MMT 060562); TRI cells, as described, e.g., in Mather et al., Annals N.Y. Acad. Sci. 383:44-68 (1982); MRC 5 cells; and FS4 cells. Other useful mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR- CHO cells (Urlaub et al., Proc. Natl. Acad. Sci. USA 77:4216 (1980)); and myeloma cell lines such as Y0, NS0, and Sp2/0. For a review of certain mammalian host cell lines suitable for antibody production, see, e.g., Yazaki and Wu, Methods in Molecular Biology, Vol. 248 (B.K.C. Lo, ed., Humana Press, Totowa, NJ), pp. 255-268 (2003).

Immunoconjugates

The invention also provides immunoconjugates comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein (e.g., tiragolumab)), anti-CD20 antibody (e.g., rituximab), and/or anti-CD38 antibody (e.g., daratumumab) of the invention conjugated to one or more 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.

In some aspects, an immunoconjugate is an antibody-drug conjugate (ADC) in which an antibody is conjugated to one or more drugs, including but not limited to a maytansinoid (see U.S. Patent Nos. 5,208,020, 5,416,064 and European Patent EP 0 425 235 B1); an auristatin such as monomethylauristatin drug moieties DE and DF (MMAE and MMAF) (see U.S. Patent Nos. 5,635,483 and 5,780,588, and 7,498,298); a dolastatin; a calicheamicin or derivative thereof (see U.S. Patent Nos. 5,712,374, 5,714,586, 5,739,116, 5,767,285, 5,770,701 , 5,770,710, 5,773,001 , and 5,877,296; Hinman et al., Cancer Res. 53:3336-3342 (1993); and Lode et al., Cancer Res. 58:2925-2928 (1998)); an anthracycline such as daunomycin or doxorubicin (see Kratz et al., Current Med. Chem. 13:477-523 (2006); Jeffrey et al., Bioorganic & Med. Chem. Letters 16:358-362 (2006); Torgov et al., Bioconj. Chem. 16:717-721 (2005); Nagy et al., Proc. Natl. Acad. Sci. USA 97:829-834 (2000); Dubowchik et al., Bioorg. & Med. Chem. Letters 12:1529-1532 (2002); King et al., J. Med. Chem. 45:4336-4343 (2002); and U.S. Patent No. 6,630,579); methotrexate; vindesine; a taxane such as docetaxel, paclitaxel, larotaxel, tesetaxel, and ortataxel; a trichothecene; and CC1065.

In another aspect, an immunoconjugate comprises an anti-TIGIT antagonist antibody as described herein (e.g., tiragolumab), anti-CD20 antibody (e.g., rituximab), and/or anti-CD38 antibody (e.g., daratumumab) conjugated to an enzymatically active toxin or fragment 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.

In another aspect, an immunoconjugate comprises an anti-TIGIT antagonist antibody as described herein (e.g., tiragolumab), an anti-CD20 antibody as described herein (e.g., rituximab), and/or an anti-CD38 antibody as described herein (e.g., daratumumab) conjugated to a radioactive atom to form a radioconjugate. A variety of radioactive isotopes are available for the production of radioconjugates. Examples include At²¹¹ , 1¹³¹ , 1¹²⁵, Y⁹⁰, Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi²¹², P³², Pb²¹² and radioactive isotopes of Lu. When the radioconjugate is used for detection, it may comprise a radioactive atom for scintigraphic studies, for example tc99m or 1123, or a spin label for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, mri), such as iodine-123 again, iodine-131 , indium-111 , fluorine- 19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese or iron.

Conjugates of an antibody and cytotoxic agent may be made using a variety of bifunctional protein coupling agents such as N-succinimidyl-3-(2-pyridyld ith io) propionate (SPDP), succinimidyl-4-(N- maleimidomethyl) cyclohexane-1 -carboxylate (SMCC), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCI), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1 ,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin can be prepared as described in Vitetta et al., Science 238:1098 (1987). Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. See WO94/11026. The linker may be a “cleavable linker” facilitating release of a cytotoxic drug in the cell. For example, an acid- labile linker, peptidase-sensitive linker, photolabile linker, dimethyl linker, or disulfide-containing linker (Chari et al., Cancer Res. 52:127-131 (1992); U.S. Patent No. 5,208,020) may be used. The immunuoconjugates or ADCs herein expressly contemplate, but are not limited to such conjugates prepared with cross-linker reagents including, but not limited to, BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfo-EMCS, sulfo-GMBS, sulfo- KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC, and sulfo-SMPB, and SVSB (succinimidyl-(4- vinylsulfone)benzoate) which are commercially available (e.g., from Pierce Biotechnology, Inc., Rockford, IL., U.S.A).

X. Pharmaceutical Compositions and Formulations

Any of the anti-TIGIT antagonist antibodies, PD-1 axis binding antagonists, anti-CD20 antibodies, or anti-CD38 antibodies described herein can be used in pharmaceutical compositions and formulations. Pharmaceutical compositions and formulations of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, and/or anti-CD38 antibody or an anti-CD20 antibody can be prepared by mixing such antibodies having the desired degree of purity with one or more optional pharmaceutically acceptable carriers (Remington’s Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of lyophilized formulations or aqueous solutions. Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn-protein complexes); and/or non-ionic surfactants such as polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers herein further include insterstitial drug dispersion agents such as soluble neutral-active hyaluronidase glycoproteins (sHASEGP), for example, human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20 (HYLENEX®, Baxter International, Inc.). For example, daratumumab and hyaluronidase-fihj (DARZALEX FASPRO®) is daratumumab formulated with rHuPH20 and is administered by subcutaneous injection into the tissue of the abdomen. In another example, rituximab and human hyaluronidase (RITUXAN HYCELA®) is rituximab formulated with rHuPH20 and is administered by subcutaneous injection into the tissue of the abdomen. Certain exemplary sHASEGPs and methods of use, including rHuPH20, are described in US Patent Publication Nos. 2005/0260186 and 2006/0104968. In one aspect, a sHASEGP is combined with one or more additional glycosaminoglycanases such as chondroitinases.

Exemplary lyophilized antibody formulations are described in US Patent No. 6,267,958. Aqueous antibody formulations include those described in US Patent No. 6,171 ,586 and W02006/044908, the latter formulations including a histidine-acetate buffer.

The formulation herein may also contain more than one active ingredients as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. For example, it may be desirable to further provide an additional therapeutic agent (e.g., a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, and/or an anti-hormonal agent, such as those recited herein above). Such active ingredients are suitably present in combination in amounts that are effective for the purpose intended.

Active ingredients may be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington’s Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, for example, films, or microcapsules. The formulations to be used for in vivo administration are generally sterile. Sterility may be readily accomplished, e.g., by filtration through sterile filtration membranes.

Also provided herein are pharmaceutical compositions and formulations comprising a PD-1 axis binding antagonist (e.g., atezolizumab) and, optionally, a pharmaceutically acceptable carrier. Further provided herein are pharmaceutical compositions and formulations comprising an anti-TIGIT antagonist antibody (e.g., tiragolumab) and, optionally, a pharmaceutically acceptable carrier. Further provided herein are pharmaceutical compositions and formulations comprising an anti-CD38 antibody (e.g., daratumumab) and, optionally, a pharmaceutically acceptable carrier. Further provided herein are pharmaceutical compositions and formulations comprising an anti-CD20 antibody (e.g., rituximab) and, optionally, a pharmaceutically acceptable carrier. The disclosure also provides pharmaceutical compositions and formulations comprising a PD-1 axis binding antagonist (e.g., atezolizumab), an anti- CD38 antibody (e.g., daratumumab), and/or an anti-TIGIT antagonist antibody (e.g., tiragolumab), and optionally, a pharmaceutically acceptable carrier.

Pharmaceutical compositions and formulations as described herein can be prepared by mixing the active ingredients (e.g., a PD-1 axis binding antagonist, an anti-TIGIT antagonist antibody, and an anti-CD38 antibody) having the desired degree of purity with one or more optional pharmaceutically acceptable carriers (see, e.g., Remington’s Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), e.g., in the form of lyophilized formulations or aqueous solutions.

An exemplary tiragolumab formulation comprises a histidine solution containing polysorbate 20, sucrose, L-methionine, and water for injection. Tiragolumab may be provided in a 15-mL vial containing 10 mL of tiragolumab drug product at an approximate concentration of tiragolumab antibody of 60 mg/mL.

An exemplary atezolizumab formulation comprises glacial acetic acid, L-histidine, polysorbate 20, and sucrose, with a pH of 5.8. For example, atezolizumab may be provided in a 20-mL vial containing 1200 mg of atezolizumab that is formulated in glacial acetic acid (16.5 mg), L-histidine (62 mg), polysorbate 20 (8 mg), and sucrose (821 .6 mg), with a pH of 5.8. In another example, atezolizumab may be provided in a 14-mL vial containing 840 mg of atezolizumab that is formulated in glacial acetic acid (11.5 mg), L-histidine (43.4 mg), polysorbate 20 (5.6 mg), and sucrose (575.1 mg) with a pH of 5.8. An exemplary daratumumab formulation suitable for intravenous administration comprises glacial acetic acid (3.7 mg), mannitol (510 mg), polysorbate 20 (8 mg), sodium acetate trihydrate (59.3 mg), sodium chloride (70.1 mg), and water for injection, USP, with a pH of 5.5. For example, daratumumab may be provided in a 20-mL single-dose vial containing 400 mg daratumumab, glacial acetic acid (3.7 mg), mannitol (510 mg), polysorbate 20 (8 mg), sodium acetate trihydrate (59.3 mg), sodium chloride (70.1 mg), and water for injection, USP, with a pH of 5.5. In another example, daratumumab may be provided in a 5-mL single-dose vial containing 100 mg daratumumab, glacial acetic acid (0.9 mg), mannitol (127.5 mg), polysorbate 20 (2 mg), sodium acetate trihydrate (14.8 mg), sodium chloride (17.5 mg), and water for injection, USP, with a pH of 5.5.

Another exemplary daratumumab formulation suitable for subcutaneous administration comprises hyaluronidase, L-histidine, L-histidine hydrochloride monohydrate, L-methionine, polysorbate 20, sorbitol, and water for injection, USP. For example, daratumumab may be provided in a 15-mL single-dose vial containing 1800 mg of daratumumab and 30,000 units of rHuPH20, L-histidine (4.9 mg), L-histidine hydrochloride monohydrate (18.4 mg), L-methionine (13.5 mg), polysorbate 20 (6 mg), sorbitol (735.1 mg), and water for injection, USP.

An exemplary rituximab formulation suitable for intravenous administration comprises polysorbate 80, sodium chloride, sodium citrate dihydrate, and water for injection. For example, rituximab may be provided at a concentration of 10 mg/mL in either 100 mg/10 mL or 500 mg/50 mL single-use vials, containing polysorbate 80 (0.7 mg/mL), sodium chloride (9 mg/mL), sodium citrate dihydrate (7.35 mg/mL), and water for injection, with a pH is 6.5.

Another exemplary rituximab formulation suitable for subcutaneous administration comprises hyaluronidase human, L-histidine, L-histidine hydrochloride monohydrate, L-methionine, polysorbate 80, a,a-trehalose dihydrate, and water for injection. For example, rituximab may be provided in a single-dose vial with 1 ,400 mg rituximab and 23,400 Units hyaluronidase human per 11 .7 mL, with each mL of solution containing rituximab (120 mg), hyaluronidase human (2,000 Units), L-histidine (0.53 mg), L-histidine hydrochloride monohydrate (3.47 mg), L-methionine (1.49 mg), polysorbate 80 (0.6 mg), a,a-trehalose dihydrate (79.45 mg), and water for injection. In another example, rituximab may be provided in a singledose vial with 1 ,600 mg rituximab and 26,800 Units rHuPH20per 13.4 mL, with each mL of solution containing rituximab (120 mg), hyaluronidase human (2,000 Units), L-histidine (0.53 mg), L-histidine hydrochloride monohydrate (3.47 mg), L-methionine (1.49 mg), polysorbate 80 (0.6 mg), a,a-trehalose dihydrate (79.45 mg), and water for injection.

XI. Articles of Manufacture or Kits

In another aspect of the invention, an article of manufacture or a kit containing materials useful for the treatment, prevention, and/or diagnosis of the disorders described above is provided. The article of manufacture comprises a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, etc. The containers may be formed from a variety of materials such as glass or plastic. The container holds a composition which is by itself or combined with another composition effective for treating, preventing, and/or diagnosing the condition and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is an anti-TIGIT antagonist antibody of the invention. The label or package insert indicates that the composition is used for treating the condition of choice (e.g., cancer, e.g., a hematologic cancer, e.g., a myeloma (e.g., MM, e.g., a relapsed or refractory MM) or a lymphoma (e.g., a NHL, e.g., a relapsed or refractory DLBCL or a relapsed or refractory FL)). Moreover, the article of manufacture may comprise (a) a first container with a composition contained therein, wherein the composition comprises an antibody of the invention; and (b) a second container with a composition contained therein, wherein the composition comprises a further cytotoxic or otherwise therapeutic agent. The article of manufacture in this aspect of the invention may further comprise a package insert indicating that the compositions can be used to treat a particular condition. Alternatively, or additionally, the article of manufacture may further comprise a second (or third) container comprising a pharmaceutically- acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer’s solution, and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

In one aspect, provided herein is an article of manufacture or a kit comprising an anti-TIGIT antagonist antibody (e.g., tiragolumab) and one or both of an anti-CD38 antibody (e.g., daratumumab) and a PD-1 axis binding antagonist (e.g., atezolizumab). In some instances, the article of manufacture or kit further comprises a package insert comprising instructions for using the anti-TIGIT antagonist antibody in combination with the PD-1 axis binding antagonist and the anti-CD38 antibody to treat or delay progression of a hematologic cancer (e.g., a myeloma (e.g., a MM, e.g., a relapsed or refractory MM) in a subject. In some instances, the anti-CD38 antibody (e.g., daratumumab) is formulated for subcutaneous administration. In some instances, the anti-CD38 antibody formulated for subcutaneous administration is daratumumab formulated with human hyaluronidase PH20 (rHuPH20). In other instances, the anti-CD38 antibody (e.g., daratumumab) is formulated for intravenous administration.

In another aspect, provided herein is an article of manufacture or a kit comprising an anti-TIGIT antagonist antibody (e.g., tiragolumab) and an anti-CD38 antibody (e.g., daratumumab), wherein the anti- CD38 antibody (e.g., daratumumab) is formulated for subcutaneous administration. In some instances, the article of manufacture or kit further comprises a package insert comprising instructions for using the anti-TIGIT antagonist antibody in combination with anti-CD38 antibody (e.g., daratumumab) to treat or delay progression of a hematologic cancer (e.g., a myeloma (e.g., a MM, e.g., a relapsed or refractory MM) in a subject. In some instances, the anti-CD38 antibody formulated for subcutaneous administration is daratumumab formulated with human hyaluronidase PH20 (rHuPH20).

In another aspect, provided herein is an article of manufacture or a kit comprising an anti-TIGIT antagonist antibody (e.g., tiragolumab) and an anti-CD20 antibody (e.g., rituximab), wherein at least one dose of the anti-CD20 antibody (e.g., rituximab) is formulated for subcutaneous administration. In some instances, the article of manufacture or kit further comprises a package insert comprising instructions for using the anti-TIGIT antagonist antibody in combination with the anti-CD20 antibody to treat or delay progression of a hematologic cancer (e.g., a lymphoma (e.g., a NHL, e.g., a relapsed or refractory DLBCL or a relapsed or refractory FL)) in a subject. In some instances, the anti-CD20 antibody formulated for subcutaneous administration is rituximab formulated with rHuPH20, e.g., is RITUXAN HYCELA ®.

In some instances, anti-TIGIT antagonist antibody, anti-CD38 antibody, and PD-1 axis binding antagonist; anti-TIGIT antagonist antibody and anti-CD38 antibody; or anti-TIGIT antagonist antibody and anti-CD20 antibody are in the same container or separate containers.

The subject may, for example, be a human. It is specifically contemplated that any of the anti- TIGIT antagonist antibodies, anti-CD38 antibodies, anti-CD20 antibodies, and PD-1 axis binding antagonists described herein may be included in the article of manufacture or kit. Any of the articles of manufacture or kits may include instructions to administer a PD-1 axis binding antagonist, an anti-CD38 anitbody, an anti-CD20 antibody, and/or an anti-TIGIT antagonist antibody to a subject in accordance with any of the methods described herein, e.g., any of the methods set forth in Section II above.

EXAMPLES

Example 1 : A Phase la/lb open-label, multicenter study evaluating the safety and pharmacokinetics of tiragolumab plus daratumumub, tiragolumab plus rituximab, and tiragolumab plus daratumumab plus atezolizumab in patients with relapsed or refractory multiple myeloma or relapsed or refractory B cell non-Hodgkin lymphoma

GO41036 is a Phase I open-label, multicenter study designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary activity of tiragolumab when administered in combination with daratumumab in patients with relapsed or refractory (R/R) multiple myeloma (MM) (Arm C), with rituximab in patients with R/R non-Hodgkin lymphoma (NHL) (Arm D), and with daratumumab and atezolizumab in patients with R/R MM (Arm E). Example 1 provides study information applicable to all three combinations.

A. Overview of Study Design

The Phase lb study is designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of tiragolumab in combination with daratumumab in patients with R/R MM, tiragolumab in combination with rituximab in patients with R/R NHL, and tiragolumab in combination with daratumumab and atezolizumab in patients with R/R MM.

The Phase lb study is activated after an assessment of the corresponding Phase la safety run-in data (Arm A for patients with R/R MM; Arm B for patients with R/R NHL) has been completed and all relevant single-agent tiragolumab safety data have been thoroughly reviewed. Data from a minimum of 6 patients in each Phase la safety run-in are assessed before the safety run-in for the corresponding Phase lb portion is activated. If appropriate, the Phase lb safety run-in portion is then initiated at a dose level no higher than the initial tiragolumab dose level in Phase la, using the same comprehensive safety monitoring plan as in the corresponding Phase la safety run-in.

Both the Phase la and Phase lb portions of the study consist of a screening period of up to 28 days, a treatment period, and a follow-up period. Approximately 12-160 patients are expected to be enrolled in the study, at approximately 16 investigative sites.

To characterize the PK properties, immunogenic response, and PD effects of tiragolumab in combination with daratumumab (Arm C), or with rituximab (Arm D), or in combination with daratumumab and atezolizumab (Arm E), blood samples are taken at various timepoints before and after dosing.

Patients undergo tumor assessments during the study. In the absence of unacceptable toxicities and disease progression as determined by the investigator using the International Myeloma Working Group (IMWG) criteria (for MM) or Lugano classification (for NHL), treatment with tiragolumab administered as a single agent or in combination with atezolizumab and/or daratumumab or with rituximab may continue beyond Cycle 1 based on a favorable assessment of benefit and risk by the investigator. Patients may be permitted to continue study treatment even if they meet the criteria for progressive disease in the Phase lb portion of the study provided that they meet the following criteria for continued treatment:

• There is an absence of symptoms and signs indicating unequivocal progression of disease.

• There is no decline in Eastern Cooperative Oncology Group (ECOG) Performance Status.

• There is an absence of tumor progression at critical anatomical sites that cannot be readily managed and stabilized by protocol-allowed medical interventions prior to repeat dosing. Critical anatomical sites include the central nervous system (CNS), the central airway, the great vessels, and other organs or tissues where compromised function secondary to tumor progression would be expected to result acutely in severe and/or irreversible disability or death.

All patients are closely monitored for adverse events throughout the study and for at least 90 days after the final dose of study treatment. Adverse events are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0 (v5.0).

Patients who permanently discontinue tiragolumab and daratumumab (Arm C), tiragolumab and rituximab (Arm D), or tiragolumab, daratumumab, and atezolizumab (Arm E) return to the clinic for a treatment discontinuation visit within 30 days after the final dose of study treatment. Monitoring and recording of adverse events occurs for up to 90 days after the final dose of study treatment or until initiation of another systemic anti-cancer therapy, whichever occurs first. All patients in the study are followed for survival and subsequent anti-cancer therapy information approximately every 3 months until death, loss to follow-up, or study termination, unless the patient requests to be withdrawn from follow-up.

Study Design for Phase la (Arms A and B)

During the Phase la portion of the study, tiragolumab is administered as a single agent by IV infusion on Day 1 of each 21-day cycle (every 3 weeks; Q3W) in patients with R/R MM (Arm A) or R/R NHL (Arm B). The starting dose of tiragolumab is 600 mg Q3W, which is the recommended Phase II dose (RP2D) determined from the Phase I study in solid tumors (G030103).

Study Design for Phase lb (Arms C, D, and E)

Arm C

During the Phase lb portion of the study, patients with R/R MM (Arm C) receive tiragolumab by IV infusion plus daratumumab administered by SC injection (Fig. 1). The dose of daratumumab is 1800 mg according to the dosing schedule described in Example 2 and Fig. 1 .

Arm D

During the Phase lb portion of the study, patients with R/R NHL (Arm D) receive tiragolumab plus rituximab. Patients in Arm D receive a total of 8 doses of rituximab. Rituximab is administered by IV infusion for the first dose at a dose of 375 mg/m². After administration of at least one full infusion of IV rituximab, the SC formulation of rituximab (rituximab and recombinant human hyaluronidase PH20 enzyme (rHuPH20)) may be used for the remaining doses. SC rituximab is administered subcutaneously at a dose of 1400 mg rituximab/23400 U rHuPH20 QW.

Arm E

In Arm E, patients with R/R MM receive tiragolumab and atezolizumab by IV infusion plus daratumumab administered by SC injection. Daratumumab is administered by SC injection at a dose of 1800 mg/30,000 U rHuPH20 weekly for a total of 6 doses, then every 3 weeks for a total of 16 doses (first dose given at week 7), then every 4 weeks from week 55 onward until disease progression. Alternatively, daratumumab may be administered according to the dosing regimen shown in Fig. 2, i.e., at a dose of 1800 mg once every week during each of dosing cycles 1-3, once every three weeks during each of dosing cycles 4-8, and once every four weeks during dosing cycle 9 onward until disease progression. The dose of atezolizumab is 1200 mg Q3W.

For Arms C, D, and E, the starting dose of tiragolumab is 600 mg Q3W, which is the RP2D determined from the Phase I study in solid tumors (G030103).

The Phase lb portion of the study includes a safety run-in that enrolls approximately 3-6 patients in each arm. Enrollment of the first 3 patients in each arm is staggered such that their respective Cycle 1 , Day 1 treatments are administered > 7 days apart. After the first 3 patients in each arm have completed 21 days of study treatment (Days 1-21 of Cycle 1), the IMC reviews all safety data (including all Grade > 4 hematologic adverse events, all Grade > 3 non-hematologic adverse events including Grade > 3 immune- mediated adverse events, and the frequency of all Grade 5 adverse events, if any).

Approximately 3 additional patients are enrolled in the safety run-in to further assess safety and tolerability of tiragolumab. Any patient who does not complete the first 21 days of treatment for a reason other than treatment-related toxicity may be replaced by an additional patient at the same dose level. If study treatment is deemed tolerable in the safety run-in in each arm after a minimum of 6 patients have enrolled and have completed 21 days of study treatment, enrollment may continue at the same dose of tiragolumab in each arm until a total of approximately 20 patients are enrolled, including patients in the safety run-in.

In addition, the enrollment of the first 3 patients in the safety run-in for the tiragolumab in combination daratumumab arm (Arm C) may commence in patients with R/R MM. Next, the enrollment of the first 3 patients in the safety run-in for tiragolumab in combination with atezolizumab and daratumumab (Arm E) may commence in patients with R/R. Similarly, the enrollment of the first 3 patients in the safety run-in for tiragolumab in combination with rituximab may commence in patients with R/R NHL.

If the 600-mg dose of tiragolumab is not tolerated during the safety run-in in any arm, a safety run-in at a lower dose of tiragolumab may be initiated for 3 more patients enrolled in that arm. The safety data for this lower dose group is evaluated after the first 3 patients in that arm have completed 21 days of study treatment (Days 1-21 of Cycle 1). Approximately 3 additional patients are then enrolled in the safety run-in to further assess safety and tolerability of tiragolumab at this lower dose. In the Phase lb portion of the study, only the dose of tiragolumab may be reduced; the dose of daratumumab (Arm C), rituximab (Arm D), or daratumumab and atezolizumab (Arm E) does not change. If study treatment at this lower dose of tiragolumab is tolerated, enrollment continues at the lower dose until a total of approximately 20 patients are enrolled in each arm, including patients in the lower dose safety run-in. A dose of tiragolumab higher than 600 mg may be assessed in the Phase lb study. This higher dose does not exceed 1200 mg Q3W, which is the maximum assessed dose in Study G030103, and does not have a maximum concentration observed (Cmax) or area under the concentration-time curve (AUC)o-2i greater than what was observed at the 1200-mg Q3Wdose level in Study G030103.

Up to a total of approximately 40 patients may be enrolled in each arm.

In Arms B and D, the Sponsor may choose to restrict enrollment to a certain NHL subtype (such as diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL)).

B. Objectives and Endpoints

Specific objectives and corresponding endpoints for the study are outlined below.

Safety Objective (Primary Study Objective)

The primary objective for the study is to evaluate the safety and tolerability of tiragolumab when administered as a single agent in R/R MM (Arm A) or in R/R NHL (Arm B) or in combination with daratumumab in R/R MM (Arm C), in combination with rituximab in R/R NHL (Arm D), or in combination with atezolizumab and daratumumab in R/R MM (Arm E), including the estimation of the RP2D, on the basis of the following endpoints:

• Incidence and severity of adverse events, with severity determined according to the NCI CTCAE, Version 5.0 (v5.0).

• Change from baseline in targeted vital signs.

• Change from baseline in targeted clinical laboratory test results.

• Change from baseline in physical examination findings.

Pharmacokinetic Objectives

The PK objective for the study is to characterize the PK profile of tiragolumab when administered as a single agent in R/R MM (Arm A) or in R/R NHL (Arm B) or in combination with daratumumab in R/R MM (Arm C) or with rituximab in R/R NHL (Arm D). The PK profiles of tiragolumab and atezolizumab are characterized in Arm E when they are given in combination with daratumumab. Characterization is made based on the following endpoints:

• Serum concentration of tiragolumab at specified timepoints.

• Serum concentration of atezolizumab at specified timepoints.

The exploratory PK objectives for the study are to characterize the PK profiles of daratumumab and rituximab when administered in combination with atezolizumab and/or tiragolumab (Arms C, D, and E) based on the following endpoints:

• Serum concentration of daratumumab at specified timepoints.

• Serum concentration of rituximab at specified timepoints. Activity Objectives

The activity objective for the study is to make a preliminary assessment of the activity of tiragolumab as a single agent in R/R MM (Arm A) or in R/R NHL (Arm B) or in combination with daratumumab in R/R MM (Arm C), in combination with rituximab in R/R NHL (Arm D), or in combination with atezolizumab and daratumumab in R/R MM (Arm E) based on the following endpoint:

• Objective response rate (ORR), as determined by the investigator.

- For R/R MM, ORR is defined as the proportion of patients with a best overall response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR), as defined by the International Myeloma Working Group (IMWG) criteria (Durie et al. Leukemia. 29: 2416-2417, 2015; Kumar et al. Lancet Oncol. 17: e328-46, 2016).

- For R/R NHL, ORR is defined as the proportion of patients with a CR or PR on two consecutive occasions > 4 weeks apart, according to the Lugano classification (Cheson et al. J Clin Oncol. 32: 3059-3068, 2014).

The exploratory activity objective for the study is to make a preliminary assessment of the activity of tiragolumab as a single agent in R/R MM (Arm A) or in R/R NHL (Arm B) or in combination with daratumumab in R/R MM (Arm C), with rituximab in R/R NHL (Arm D), or with atezolizumab and daratumumab in R/R MM (Arm E) based on the following endpoints:

• Duration of objective response (DOR), as determined by the investigator.

- For R/R MM, DOR is defined as the time from the first observation that a patient achieved a response (sCR, CR, VGPR, or PR), until the date of first recorded progression or death from any cause during the study (defined as within 30 days after the final dose of study drug), whichever occurs first.

- For R/R NHL, DOR is defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause during the study (defined as within 30 days after the final dose of study drug) (whichever occurs first), according to the Lugano classification (Cheson et al. J Clin Oncol. 32: 3059-3068, 2014).

• Progression-free survival (PFS), as determined by the investigator.

- For R/R MM, PFS is defined as the time from the first study treatment to the first occurrence of disease progression (per IMWG criteria, see Durie et al. Leukemia. 29: 2416-2417, 2015; Kumar et al. Lancet Oncol. 17: e328-46, 2016) or death from any cause during the study (defined as within 30 days after the final dose of study drug), whichever occurs first.

- For R/R NHL, PFS is defined as the time from the first study treatment to the first occurrence of disease progression or death from any cause during the study (defined as within 30 days after the final dose of study drug) (whichever occurs first), according to the Lugano classification (Cheson et al. J Clin Oncol. 32: 3059-3068, 2014).

• Overall survival (OS), defined as the time from the first study treatment to death from any cause. Immunogenicity Objectives

The immunogenicity objective for the study is to evaluate the immune response to tiragolumab as a single agent in R/R MM (Arm A) or in R/R NHL (Arm B) or in combination with daratumumab in R/R MM (Arm C), with rituximab in R/R NHL (Arm D), or with atezolizumab and daratumumab in R/R MM (Arm E) based on the following endpoints:

• Prevalence of anti-drug antibodies (ADAs) to tiragolumab at baseline and incidence of ADAs to tiragolumab during the study.

• Prevalence of ADAs to atezolizumab at baseline and incidence of ADAs to atezolizumab during the study.

The exploratory immunogenicity objectives for the study are as follows:

• To characterize the immunogenicity of daratumumab or rituximab when administered in combination with tiragolumab (Arms C and D respectively) based on the following endpoints:

- For R/R MM (Arm C), prevalence of daratumumab ADAs at baseline and incidence of daratumumab ADAs during the study.

- For R/R NHL (Arm D), prevalence of rituximab ADAs at baseline and incidence of rituximab ADAs during the study.

• To evaluate potential effects of ADAs based on the following endpoint:

- Relationship between ADA status and safety, PK, or activity endpoints.

Biomarker Objective

The exploratory biomarker objective for the study is to identify and/or evaluate biomarkers that may be predictive of response to tiragolumab in combination with daratumumab in R/R MM, with rituximab in R/R NHL, or with atezolizumab and daratumumab in R/R MM (i.e., predictive biomarkers); are early surrogates of activity; are associated with progression to a more severe disease state (i.e., prognostic biomarkers); are associated with acquired resistance to tiragolumab as a single agent or in combination with atezolizumab and/or daratumumab or rituximab; are associated with susceptibility to developing adverse events or can lead to improved adverse event monitoring or investigation (i.e., safety biomarkers); can provide evidence of activity of tiragolumab as a single agent or in combination with atezolizumab and/or daratumumab or rituximab (i.e., pharmacodynamic (PD) biomarkers); and/or can increase the knowledge and understanding of disease biology and drug safety, on the basis of the following endpoint:

• Relationship between biomarkers in blood, bone marrow, and tumor tissue, and safety, PK, activity, immunogenicity, or other biomarker endpoints

C. End of Study and Length of Study

The end of the study is defined as the date when the last patient, last visit occurs or the date at which the last data point required for statistical analysis or safety follow-up is received from the last patient, whichever occurs later. The end of the study is expected to occur approximately 12 months after the last patient is enrolled.

In addition, the Sponsor may decide to terminate the study at any time. D. Rationale for Study Design

Rationale for Patient Population

This study enrolls patients with a history of a hematologic malignancy that is expected to express high levels of TIGIT, including R/R MM and R/R NHL. This patient population is based on the rationale that there is high TIGIT expression in hematologic malignancies, including TIGIT RNA expression in R/R NHL and TIGIT protein on CD8+ T cells, CD4+ T cells, and NK cells in R/R MM.

Despite advances in the treatment of patients with R/R MM with the introduction of novel agents, such as lenalidomide and proteasome inhibitors added to an autologous stem cell transplantation (ASCT) for a subset of patients who are eligible, many patients fail to achieve an optimal response, and all patients eventually relapse. Treatment of refractory patients remains challenging because of disease heterogeneity and the lack of clear understanding of the mechanisms that lead to resistance. With the approval of daratumumab, and other anti-CD38 monoclonal antibodies in development, there is a growing need for treatment options for patients who fail these therapies. This study explores the feasibility and tolerability of administering tiragolumab in combination with daratumumab and in combination with daratumumab and atezolizumab in the R/R MM patient population, including patients that were refractory to, or relapsed during, prior daratumumab therapy.

R/R NHL remains an area of critical unmet medical need. Despite advances in treatment, indolent B-cell malignancies remain incurable, as do approximately half of aggressive NHLs. Response rate and duration of response of these patients are further decreased in subsequent lines of therapy. This study assesses the clinical benefit of tiragolumab combined with rituximab in the area of critical unmet medical need for patients who have R/R NHL. Data from this group not only provide an assessment of the individual contribution of tiragolumab clinical activity but may also inform future clinical studies comparing these regimens to existing standard therapies.

Rationale for Treatment after Disease Progression

Cancer immunotherapies may result in early apparent radiographic progression (pseudoprogression or tumor immune infiltration), including the appearance of new lesions followed by delayed response (Wolchok et al. Clin Cancer Res. 15: 7412-7420, 2009). Additionally, responding tumors may appear to increase in size because of the influx of immune cells (Hoos et al. Semin Oncol. 37: 533-546, 2010; Pennock et al. Am J Clin Oncl. 35: 606-611 , 2012). Unconventional response patterns have been described in patients treated with checkpoint inhibitors such as anti-CTLA-4 (Wolchok et al. Clin Cancer Res. 15: 7412-7420, 2009) and have been observed in solid tumor studies with atezolizumab in Study PCD4989g. Patients with NHL treated with the Bruton tyrosine kinase inhibitor ibrutinib (Imbruvica®) or the PI3K inhibitor idelaisib (Zydelig®) have demonstrated reduction in adenopathy and clinical responses accompanied by transient lymphocytosis (Davids and Letai. J Clin Oncol. 30: 3127-3135, 2012; de Rooij et al. Blood. 119: 2590-2594, 2012; Fiorcari et al. PLoS ONE. 8(12): e83830, 2013). Tumor flare in lymphoma has been described in patients treated with lenalidomide (Eve and Rule. Br J Haematol. 151 : 410-412, 2010; Chanan-Khan et al. Br J Haematol. 155: 457-467, 2011). A similar tumor flare syndrome has not been described in the context of MM, but due to the immunomodulatory properties of daratumumab (Krejcik et al. Blood. 126: 3037, 2015); the combination of tiragolumab and daratumumab may have similar effects. This could manifest as a transient increase in circulating myeloma cells or a transient increase in circulating M-protein, similar to rituximab monotherapy for Waldentstrom’s macroglobulinemia (Ghobrial et al. Cancer. 101 : 2593-2598, 2004). Current response criteria for MM do not account for such observations, which is a phenomenon somewhat similar to the pseudoprogression described above in solid tumors.

For patients with MM plasmacytomas or with NHL, it is possible that tiragolumab as a single agent or in combination with daratumumab, rituximab, or daratumumab and atezolizumab therapy, respectively, may initially increase tumor size and metabolic activity by inducing the influx of T cells into the tumor. Given this, if the study investigator believes that a patient is deriving clinical benefit despite evidence of progressive disease as defined by the IMWG criteria (R/R MM) or the Lugano classification (R/R NHL), that patient may continue study treatment.

Rationale for Tiragolumab Dose and Schedule

The proposed dose of tiragolumab is 600 mg administered by IV infusion on Day 1 of each 21- day cycle (Q3W). Tiragolumab administration continues until disease progression, loss of clinical benefit, or development of unacceptable toxicity. The fixed dose of 600 mg IV Q3W is the RP2D in solid tumors and was selected based on available clinical PK, PD, safety, and preliminary efficacy data from the combined Phase la/Phase lb study (Study G030103), with single-agent tiragolumab or tiragolumab combined with atezolizumab in solid tumors. In both the Phase la portion of Study G030103 with tiragolumab as a single agent and in the Phase lb portion with tiragolumab in combination with atezolizumab, the MTD was not reached, and no DLTs were observed in dose escalation at doses of tiragolumab ranging from 2 mg to 1200 mg. Complete occupancy of peripheral TIGIT receptors on CD4+, CD8+, and NK cells was observed beginning at 30 mg of tiragolumab in both the Phase la and Phase lb portions of the study and remained sustained at all higher doses (Roche unpublished data). Prolonged stable disease was observed in patients in the Phase la portion of the study at tiragolumab doses beginning at 400 mg. In the Phase lb portion of the study with tiragolumab plus atezolizumab, anti-tumor activity, as measured by radiographic PRs, was observed across doses for tiragolumab beginning at 30 mg and ranging up to 600 mg in combination with atezolizumab 1200 mg Q3W.

Alternative doses of tiragolumab may be evaluated in this study based on new nonclinical efficacy, clinical safety, clinical PK and/or PD (including receptor occupancy) data from this current study or from the other ongoing Phase I and/or Phase II studies with tiragolumab, but do not exceed 1200 mg Q3W, the maximum assessed dose in Study G030103, and do not have a Cmax or AUC0-21 greater than what was observed at the 1200-mg Q3Wdose level in Study G030103. Evaluation of dose levels exceeding tiragolumab 1200 mg may be evaluated with supporting rationale.

Rationale for Daratumumab Dose and Schedule

Daratumumab is administered by SC injection at a dose of 1800 mg/30,000 U rHuPH20 once weekly for a total of 6 doses, then every 3 weeks for a total of 16 doses from Week 7 through Week 54, then every 4 weeks from Week 55 onward until disease progression. This dosing schedule has been used in with IV daratumumab in combination with VELCADE® + melphalan + prednisone in patients with newly diagnosed multiple myeloma who are transplant-ineligible. A study with the same regimen using SC daratumumab is currently underway (NCT03412565). This dosing schedule was selected to align more closely with the tiragolumab schedule to minimize risk of missed doses and additional visits for patients.

This SC dose of daratumumab has been reported to be non-inferior in clinical studies to the approved IV dose of 16 mg/kg for patients with R/R MM who have received at least three prior lines of therapy (Mateos et al. J Clin Oncol. 37, no. 15_suppl, 8005, 2019). SC daratumumab also significantly reduced administration time and decreased IRR rates with comparable safety profile to daratumumab IV (Mateos et al. J Clin Oncol. 37, no. 15_suppl, 8005, 2019).

Initial data for SC daratumumab, including clinical PK and safety, was obtained from the Phase lb PAVO study (Usmani et al. Blood. 134: 668-677, 2019). This study evaluated daratumumab in combination with rHuPH20 at 1200 mg and 1800 mg. The PAVO study showed that SC formulations have acceptable tolerability with no new safety signals and a safety profile that was consistent with IV daratumumab. Subsequent data was collected from the Phase III COLUMBA study in which 522 R/R MM patients were randomized to receive a concentrated 1800 mg daratumumab with rHuPH20 SC formulation or 16 mg/kg IV daratumumab (Mateos et al. J Clin Oncol. 37, no. 15_suppl, 8005, 2019). The SC daratumumab formulation was found to be non-inferior to the approved IV formulation for both efficacy and PK endpoints. This study also confirmed that the safety profile was comparable between daratumumab IV and SC but with a significantly reduced rate of IRRs with SC daratumumab.

Routine administration of corticosteroids for prevention of IRRs with daratumumab may reduce the efficacy of T cells. Due to the marked reduction in IRRs with SC daratumumab, further reduction of corticosteroids may be possible. Corticosteroid tapering is being evaluated in daratumumab the PAVO studied mentioned above. In 7 evaluable subjects treated with SC daratumumab who had corticosteroids tapered after 3 weeks, none had IRRs after discontinuation of predose and postdose corticosteroids. Given the initially favorable safety of the 3-week taper in the PAVO study, this protocol uses a similar 3- week steroid taper. Different daratumumab administration schedules may be evaluated based on new nonclinical efficacy, clinical safety, clinical PK, and/or PD data.

Rationale for Rituximab Dose and Schedule

Patients receive a total of 8 doses of rituximab. Rituximab is administered by IV infusion for the first dose at a dose of 375 mg/m². After administration of at least one full infusion of IV rituximab, the subcutaneous formulation of rituximab (rituximab and rHuPH20) may be used for the remaining doses. SC rituximab is administered subcutaneously at a dose of 1400 mg rituximab/23400 U rHuPH20 QW. This is an approved dosage for patients with R/R, low-grade or follicular, CD20-positive, B-cell NHL (Rituxan Hycela USPI) and recommended by the National Comprehensive Cancer Network (NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): B-Cell Lymphomas, Version 2, 2018). Different rituximab administration schedules from the approved dosing regimens (RITUXAN® USPI; RITUXAN HYCELA® USPI) may be evaluated based on new nonclinical efficacy, clinical safety, clinical PK, and/or PD data.

E. Inclusion Criteria

General Inclusion Criteria (All Patients)

All patients must meet the following criteria to qualify for study entry: • Age > 18 years at the time of signing Informed Consent Form.

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 .

• Life expectancy of > 12 weeks.

• Adequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to the first study treatment (Cycle 1 , Day 1):

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x upper limit of normal (ULN).

- Total serum bilirubin < 1 .5 x ULN.

- Alkaline phosphatase < 2.5 x ULN with the following exceptions:

■ Patients with documented liver or bone metastases may have alkaline phosphatase < 5 x ULN.

■ Platelet count > 75,000/pL without transfusion in the 14 days prior to first dose of study treatment.

■ For patients with MM who have > 50% myeloma involvement in the marrow, a platelet count of > 50,000/pL prior to first dose of study treatment is allowed. Patients may not have received a platelet transfusion within 72 hours prior to the platelet count used for eligibility.

- Absolute neutrophil count (ANC) > 1000/pL.

■ For patients with MM, growth factor support may be used to achieve ANC eligibility criteria. Patients may not have received growth factor within the previous 7 days prior to the ANC used for eligibility.

■ Patients with NHL or MM who do not meet criteria for hematologic function because of extensive marrow involvement of NHL, MM, and/or disease-related cytopenias (e.g., immune thrombocytopenia) may be enrolled into the study.

F. Exclusion Criteria

General Exclusion Criteria (All Patients)

Patients who meet any of the following criteria are excluded from study entry:

• Any anti-cancer therapy, whether investigational or approved, including chemotherapy, monoclonal antibody, radioimmunoconjugate, antibody-drug conjugate, hormonal therapy, and/or radiotherapy, within 4 weeks or 5 half-lives of the drug, whichever is shorter, prior to initiation of study treatment, with the following exceptions:

- Prior treatment with cytokine therapy and/or cancer vaccines within 6 weeks or 5 half-lives of the drug, whichever is shorter, before first study drug administration.

- Prior treatment with immune checkpoint inhibitors, including but not limited to anti-CTLA4, anti-PD-1 and/or anti-PD-L1 therapeutic antibodies, within 12 weeks or 5 half-lives of the drug, whichever is shorter, before first study drug administration.

- Prior cancer immunotherapy not explicitly described in the study protocol should be discussed with the Medical Monitor to determine potential eligibility.

- Hormone-replacement therapy or oral contraceptives.

- Herbal therapy within 7 days before first study drug administration. - Palliative radiotherapy for painful metastases or metastases in potentially sensitive locations (e.g., epidural space) within 14 days prior to first study drug administration.

• Prior treatment with any anti-TIGIT agent.

• Prior treatment with CAR-T therapy within 12 weeks before first study drug administration.

• ASCT within 100 days prior to first study drug administration.

• Prior allogeneic SOT.

• Prior solid organ transplantation.

• Adverse events from prior anti-cancer therapy that have not resolved to Grade < 1 , with the following exceptions:

- Grade 2 peripheral sensory or motor neuropathy.

- Any grade alopecia or vitiligo.

- Endocrinopathy managed with replacement therapy.

• Treatment-emergent immune-mediated adverse events associated with prior immunotherapeutic agents as follows:

- Any history of an immune-mediated Grade 4 adverse event attributed to prior cancer immunotherapy (other than endocrinopathy managed with replacement therapy or asymptomatic elevation of serum amylase or lipase).

- Any history of an immune-mediated Grade 3 adverse event attributed to prior cancer immunotherapy (other than endocrinopathy managed with replacement therapy or asymptomatic elevation of serum amylase or lipase) that resulted in permanent discontinuation of the prior immunotherapeutic agent and/or occurred < 6 months prior to Cycle 1 , Day 1 .

- All immune-mediated adverse events related to prior cancer immunotherapy (other than endocrinopathy managed with replacement therapy or stable vitiligo) must have resolved completely to baseline.

Patients treated with corticosteroids for immune-mediated adverse events must demonstrate absence of related symptoms or signs for > 4 weeks following discontinuation of corticosteroids.

• Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogren syndrome, Guillain-Barre syndrome, or multiple sclerosis, with the following exceptions:

- Patients with a history of autoimmune-mediated hypothyroidism who are on a stable dose of thyroid-replacement hormone are eligible for the study.

- Patients with controlled Type 1 diabetes mellitus who are on a stable insulin regimen are eligible for the study.

- Patients with a history of disease-related immune thrombocytopenic purpura or autoimmune hemolytic anemia may be eligible for the study after consultation with the Medical Monitor.

• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug- induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan

- History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

• History of confirmed progressive multifocal leukoencephalopathy (PML).

• Spinal cord compression not definitively treated with surgery and/or radiation or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for > 2 weeks prior to screening.

• Malignancies other than disease under study within 5 years prior to first study drug administration, with the exception of those with a negligible risk of metastasis or death (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer, or ductal carcinoma in situ).

• Leptomeningeal disease.

• Significant cardiovascular disease such as New York Heart Association Class II or higher cardiac disease, myocardial infarction within the last 3 months, unstable arrhythmias, and/or unstable angina.

• Significant active pulmonary disease (e.g., bronchospasm and/or obstructive pulmonary disease).

• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently).

- Patients with indwelling catheters (e.g., PleurX catheters) are allowed.

• Recent major surgery within 4 weeks prior to first study drug administration, or anticipation of need for a major surgical procedure during the course of the study.

- Protocol-mandated procedures (e.g., tumor biopsies and bone marrow biopsies) and superficial lymph node biopsies for diagnosis are permitted.

• Uncontrolled tumor-related pain.

- Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or metastases causing nerve impingement) should be treated prior to enrollment.

- Asymptomatic metastatic lesions whose further growth would likely cause functional deficits or intractable pain (e.g., epidural metastasis that is not currently associated with spinal cord compression) should be considered for loco-regional therapy if appropriate prior to enrollment.

• Known active bacterial, viral (including SARS-CoV-2), fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 4 weeks prior to first study drug administration

• Recent infections not meeting the above criteria for severe infections, including the following:

- Signs or symptoms of infection within 2 weeks prior to first study drug administration.

- Received oral or IV antibiotics within 2 weeks prior to first study drug administration.

■ Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible.

• Active tuberculosis.

• Active Epstein-Barr virus (EBV) infection and known or suspected chronic active EBV infection at screening. - Patients positive for EBV IgG and/or Epstein Barr nuclear antigen (EBNA) are eligible only if EBV IgM and/or EBV polymerase chain reaction (PCR) are negative.

• Active hepatitis B (defined as having a positive hepatitis B surface antigen (HBsAg) test at screening).

- Patients with past or resolved hepatitis B infection (defined as having a negative HBsAg test and a positive IgG antibody to hepatitis B core antigen (anti-HBc) are eligible. Hepatitis B virus (HBV) DNA must be obtained in these patients prior to first study drug administration and must demonstrate no active infection.

• Acute or chronic hepatitis C virus (HCV) infection.

- Patients who are positive for HCV antibody must be negative for HCV by PCR to be eligible for study participation.

• Known history of HIV seropositivity.

• Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during study treatment or within 5 months after the final dose of study treatment.

- Influenza vaccination should be given during influenza season only. Patients must not receive live, attenuated influenza vaccine (e.g., FluMist) within 4 weeks prior to first study drug administration or at any time during the study, and for 5 months after the last study treatment.

• Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone > 10 mg/day, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) within 2 weeks prior to first dose of study treatment.

- Patients who received acute, low-dose, systemic immunosuppressant medications (e.g., single dose of dexamethasone for nausea or B symptoms) may be enrolled in the study.

- The use of inhaled corticosteroids is permitted.

- The use of oral mineralocorticoids (e.g., fludrocortisone for patients with orthostatic hypotension) is permitted.

- The use of physiologic doses of corticosteroids for management of adrenal insufficiency is permitted.

• History of illicit drug or alcohol abuse within 12 months prior to screening, in the investigator’s judgment.

• Any serious medical condition, metabolic dysfunction, physical examination finding, and/or abnormality in clinical laboratory tests that, in the investigator’s judgment, precludes the patient’s safe participation in and completion of the study, or which could affect compliance with the protocol or interpretation of results, or which may render the patient at high risk from treatment complications.

• History of severe allergic or anaphylactic reactions to monoclonal antibody therapy (or recombinant antibody-related fusion proteins).

• Known hypersensitivity to CHO-cell products. G. Study Treatment

The investigational medicinal products (IMPs) for the study are tiragolumab, daratumumab/rHuPH20, rituximab, rituximab/rHuPH20, and atezolizumab. See Example 2 for dosing and administration of the tiragolumab plus daratumumab study treatment. See Example 3 for dosing and administration of the tiragolumab plus rituximab study treatment. See Example 4 for dosing and administration of the tiragolumab plus daratumumab plus atezolizumab study treatment.

H. Concomitant Therapy

Concomitant therapy consists of any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a patient in addition to protocol-mandated study treatment from 7 days prior to initiation of study treatment to the treatment discontinuation visit.

In general, investigators should manage a patient's care (including preexisting conditions) with supportive therapies other than those defined as prohibited therapies as clinically indicated, per local standard practice. Patients who experience infusion-associated symptoms may be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or F receptor antagonists (e.g., famotidine, cimetidine), or equivalent medications per local standard practice. Serious infusion- associated events manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen and/or p2-adrenergic agonists).

Permitted Therapy Patients are permitted to use the following therapies during the study:

• Oral contraceptives

• Hormone-replacement therapy

• Concomitant use of hematopoietic growth factors such as erythropoietin, granulocyte colonystimulating factor (G-CSF; filgrastim, pegfilgrastim), granulocyte/macrophage colony-stimulating factor (sargramostim), orthrombopoietin (oprelvekin, eltrombopag) is permitted. Initiation or dose and schedule modifications of hematopoietic growth factors are allowed in accordance with instructions provided in the package inserts, institutional practice, and/or published guidelines.

• Systemic corticosteroids and other immune-modulating medications may, in theory, attenuate the potential beneficial immunologic effects of treatment with tiragolumab but should be administered at the discretion of the treating physician in line with the management guidelines, or after consultation with the Medical Monitor. For patients who receive rituximab, in addition to premedication with antihistamines and antipyretics, an additional glucocorticoid (e.g., 100 mg IV prednisone or prednisolone or equivalent) is allowed at the investigator’s discretion. The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed. Physiologic doses of corticosteroids for adrenal insufficiency are allowed. Megestrol administered as an appetite stimulant is acceptable while the patient is enrolled in the study. • Anti-infective prophylaxis for viral, fungal, bacterial, or pneumocystis infections is permitted and should be instituted per institutional practice.

• Premedication with an antihistamine and acetaminophen is required for all patients receiving tiragolumab in combination with atezolizumab and/or daratumumab, ortiragolumab in combination with rituximab. Refer to the Study Treatment sections of Example 2, 3, and 4 for more details.

• Immunosuppressive medications, including, but not limited to, cyclophosphamide, azathioprine, methotrexate, and thalidomide. Must be used with caution. These agents could potentially alter the activity and the safety of tiragolumab.

• Vaccinations (such as influenza, SARS-CoV-2).

- Live attenuated vaccines are not permitted.

• Cannabinoids are permitted only if obtained in accordance with local regulations.

I. Assessments

All patients are closely monitored for adverse events throughout the study and for at least 90 days after the final dose of study treatment. Adverse events are graded according to the NCI CTCAE, v5.0.

Tumor and Response Evaluations

All measurable disease must be documented at screening and re-assessed at each subsequent tumor evaluation. Response assessments are assessed by the investigator on the basis of physical examinations, blood or urine samples, CT scans, fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT scans, and/or magnetic resonance imaging (MRI) scans, and bone marrow examinations, according to the IMWG response criteria for MM and the Lugano classification for NHL (Cheson et al. J Clin Oncol. 32: 3059-3068, 2014).

Biomarker Assessments

Biomarker research may include, but are not limited to, analysis of genes or gene signatures associated with tumor molecular subtype and tumor immunobiology, PD-L1 , expression of targets specific to each drug combination, EBV, tumor mutation load, MSI status, lymphocyte subpopulations, T cellreceptor repertoire, or cytokines associated with T-cell activation. Research may involve DNA or RNA extraction, analysis of somatic mutations, and use of next-generation sequencing (NGS) (including whole exome sequencing (WES)).

J. Analysis

The final study analysis is based on patient data collected through study discontinuation. In general, data are summarized as warranted, and listings are used in place of tables when the samples sizes are small. Continuous variables are summarized using means, standard deviations, median, and ranges; categorical variables are summarized using counts and percentages. Summaries are presented by assigned treatment and tumor type. Determination of Sample Size

The study is intended to obtain preliminary safety, PK, PD, and preliminary activity information in the treated populations, and the sample sizes do not reflect explicit power and type I error considerations.

The planned enrollment for the study (both Phase la and Phase lb) is approximately 12-160 patients. For the safety run-in stage in both Phase la and Phase lb, approximately 12-24 patients may be enrolled.

Initial planned enrollment is approximately 20 patients in each arm. Up to approximately 40 patients, including patients in the safety run-in, may be enrolled in each arm. Following the enrollment of 20 patients, including patients in the corresponding safety run-in, the IMC meets to conduct an interim analysis to determine if there is evidence of anti-tumor activity and/or clinical benefit as assessed by the investigators in order to continue enrollment to approximately 40 patients, including patients in the safety run-in.

The larger number of patients enrolled in each indication-specific arm in Phase lb allows for a better opportunity of seeing a given adverse event in at least 1 patient, particularly when the incidence of the adverse event is low.

Safety Analyses

Safety is assessed through summaries of adverse events, exposure to study treatment, and changes from baseline in laboratory test results, vital signs, and physical findings. All patients who receive any amount of study treatment (tiragolumab, atezolizumab, daratumumab, and/or rituximab) is included in the safety analyses.

Verbatim descriptions of adverse events are mapped to thesaurus terms. Adverse event data are listed by study site, dose group or tumor type as appropriate, patient number, and study day. Events occurring on or after treatment on Day 1 are summarized by mapped term, appropriate thesaurus level, and NCI CTCAE v5.0 grade. In addition, serious adverse events, including deaths, are listed separately, and summarized. Adverse events leading to treatment discontinuation are listed.

Relevant laboratory and vital signs data are displayed by time, with NCI CTCAE Grade 3 and Grade 4 values identified, where appropriate. Incidence of ADA response (presence of serum or anti- tiragolumab, anti-atezolizumab, anti-daratumumab, and/or anti-rituximab) and the potential correlation with PK, PD, and safety parameters may be assessed.

Activity Analyses

The analyses described below are based on the definitions of objective response as determined by the investigator, according to the IMWG criteria (MM; Durie et al. Leukemia. 20(9): 1467-1473 (2006); Durie et al. Leukemia. 29: 2416-2417, 2015; Kumar et al. Lancet Oncol. 17: e328-46, 2016; and described in Table 4 and 5) and the Lugano classification (NHL; Cheson et al. J Clin Oncol. 32: 3059-3068, 2014; and described in Table 6). See the Objectives and Endpoints section above for definitions of the endpoints (e.g., ORR, DOR, PFS, OS).

Response assessment data, DOR, PFS, and OS are listed for all patients by baseline disease status (i.e., measurable, or not measurable), by tumor type and by treatment arm, when appropriate. The analysis of ORR includes patients who received any amount of the study treatment and have measurable disease at baseline. Patients with missing baseline or no response assessments are classified as non-responders. The ORR is estimated and summarized by tumor type and by treatment arm, if applicable. The analysis of DOR includes patients with an objective response. For patients who do not die or experience disease progression, DOR is censored at the day of the last tumor assessment.

The analysis of PFS includes patients who have received any amount of study treatment. For patients who do not have documented progressive disease or death before the end of the study or who are lost to follow-up, PFS is censored at the day of the last tumor assessment. For patients without a post-baseline tumor assessment, PFS is censored at the date of first study treatment plus 1 day.

The analysis of OS includes patients who have received any amount of study treatment. For patients who do not die before the end of the study or who are lost to follow-up, OS is censored at the date of last contact. Table 4: Response Categories According to IMWG Uniform Response Criteria

Table 5: Disease Progression and Relapse According to IMWG Uniform Response Criteria

Table 6: Lugano Response Criteria for Malignant Lymphoma

Pharmacokinetic Analyses

Serum tiragolumab and atezolizumab concentration data (Cmax and Cmin) are tabulated and summarized for each cycle where collected. Descriptive statistics include mean, median, standard deviation, and range, as appropriate. Other PK parameters may be determined and summarized as data warrant.

Additional PK analysis of serum concentrations of daratumumab or rituximab may be conducted as appropriate.

Data may be compared with historical data, as these results provide preliminary information on whether tiragolumab, atezolizumab, daratumumab, and/or rituximab pharmacokinetics are altered by coadministration of the other agent. Pharmacodynamic Analyses

PD analyses include assessment of PD biomarkers. Additional PD analyses are conducted as appropriate. Potential adjustment of biomarker sampling times may be applied if needed, based on observed biomarker response in earlier patients.

Immunogenicity Analyses

The immunogenicity analysis population consists of all patients with at least one tiragolumab ADA assessment. Patients are grouped according to treatment received or, if no treatment is received prior to study discontinuation, according to treatment assigned.

The numbers and proportions of tiragolumab ADA-positive patients and tiragolumab ADAnegative patients at baseline (baseline prevalence) and after drug administration (postbaseline incidence) are summarized by treatment group. The numbers and proportions of atezolizumab ADA-positive patients and atezolizumab ADA-negative patients at baseline (baseline prevalence) and after drug administration (postbaseline incidence) are summarized by treatment group. When determining postbaseline incidence, patients are considered to be ADA-positive if they are ADA-negative or have missing data at baseline but develop an ADA response following study drug exposure (treatment-induced ADA response), or if they are ADA-positive at baseline and the titer of one or more postbaseline samples is at least 0.60 titer unit greater than the titer of the baseline sample (treatment-enhanced ADA response). Patients are considered to be ADA-negative if they are ADA-negative or have missing data at baseline and all postbaseline samples are negative, or if they are ADA-positive at baseline but do not have any postbaseline samples with a titer that is at least 0.60 titer unit greater than the titer of the baseline sample (treatment unaffected).

Patients in the Phase lb portion of the study who are treated with daratumumab, or rituximab may be assessed for ADAs against daratumumab or rituximab, respectively. The relationship between ADA status and safety, activity, and PK endpoints may be analyzed and reported via descriptive statistics as appropriate.

Interim Analyses

Continuous safety monitoring is performed to guide potential early stopping of enrollment in the event of unacceptable toxicity in any given arm or a lower-than-expected response rate in the arms.

Interim Analyses for Safety

Interim analyses are conducted by the IMC for each arm in Phase la and Phase lb to guide potential early stopping of enrollment where there is evidence of an unacceptable toxicity. Safety stopping rules for all Grade 5 adverse events and for all Grade > 3 immune-mediated adverse events are implemented for each arm.

Interim Analyses for Efficacy

Interim analyses are conducted by the IMC for each arm in Phase la and Phase lb to guide potential early stopping of enrollment when there is no evidence of activity. For patients with discordant results between CT-based criteria for PR and partial metabolic response, PET-based assessments are utilized for the purposes of futility assessments (as per Cheson et al. J Clin Oncol. 32: 3059-3068, 2014), provided that the patient has an FDG-avid NHL. For patients with non-FDG-avid lymphomas, CT-based tumor assessments are utilized for futility.

Example 2: Arm C: Tiragolumab in combination with daratumumab in patients with relapsed or refractory multiple myeloma

The Phase lb study evaluates the safety, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of tiragolumab in combination with daratumumab in patients with relapsed or refractory (R/R) multiple myeloma (MM). Specific objectives and corresponding endpoints for the study are outlined below. Example 2 describes study information applicable to tiragolumab plus daratumumab (Arm C of GO41036).

A. Inclusion Criteria

In addition to the inclusion criteria disclosed in Example 1 , above, patients must also meet the following eligibility requirements.

• Patients with R/R MM who have received at least 3 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug (IMiD), and an anti-CD38 antibody.

- A line of therapy consists of > 1 complete cycle of a single agent, a regimen consisting of a combination of several drugs, or a planned sequential therapy of various drugs (e.g., induction therapy followed by stem-cell transplantation (SOT) is considered 1 line of therapy (Rajkumar et al. Blood. 126(7): 921-922, 2015)).

- Documented evidence of progressive disease (as defined by the IMWG criteria) on or after the last prior therapy, or patients who were intolerant to the last prior therapy.

- Patients who are intolerant of daratumumab or atezolizumab are not eligible.

- Total hemoglobin > 8 g/dL.

■ Patients may receive RBC transfusions or erythropoietic agents in accordance with institutional guidelines to meet this criterion.

■ Patients who do not meet criteria for hematologic function because of extensive marrow involvement of MM and/or disease-related cytopenias (e.g., immune thrombocytopenia) may be enrolled into the study.

- Serum creatinine < 2.0 mg/dL and creatinine clearance (CrCI) > 30 mL/min (either calculated or per 24-hr urine collection).

- Serum calcium (corrected for albumin) < ULN.

■ Treatment of hypercalcemia is allowed, and patients may enroll if calcium level returns to normal prior to initiation of study treatment.

• Measurable disease defined as at least one of the following:

- Serum M-protein > 1 .0 g/dL (> 10 g/L). - Urine M-protein > 200 mg/24 hr.

- Serum free light chain (SFLC) assay: involved SFLCs > 10 mg/dL (>100 mg/L) and an abnormal SFLC ratio (< 0.26 or > 1 .65).

• Agreement to provide bone marrow biopsy and aspirate samples.

• Blood type, Rh, and indirect anti-globulin test (IAT; Indirect Coombs Test) assays before the first dose of daratumumab.

• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception as defined below.

- Women must remain abstinent or use contraceptive methods with a failure rate of < 1% per year during the treatment period in all arms and for:

■ Five months after the final dose of tiragolumab or 3 months after the final dose of daratumumab, whichever is later.

• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as specified below.

- With a female partner of childbearing potential or pregnant female partner, men must remain abstinent or use a condom during the treatment period and for:

■ Three months after the final dose of tiragolumab and daratumumab, whichever is later to avoid exposing the embryo. Men must refrain from donating sperm during this same period.

B. Exclusion Criteria

In addition to the exclusion criteria disclosed in Example 1 , above, patients who meet any of the following criteria are excluded from study entry:

• Pregnant or breastfeeding, or intending to become pregnant during the study or within:

- Five months after the final dose of tiragolumab or 3 months after the final dose of daratumumab, whichever is later.

• Primary or secondary plasma cell leukemia as defined by an absolute plasma cell count exceeding 2000/pL or 20% of the peripheral blood white cells.

• Current or history of CNS involvement by MM.

• Allergy or hypersensitivity to components of the daratumumab formulation or recombinant human hyaluronidase PH20 enzyme (rHuPH20).

• Patients with severe obstructive pulmonary disease that could significantly increase risk of bronchospasm per investigator assessment.

C. Study Treatment

The dosage and administration of tiragolumab plus daratumumab is described below for the Phase lb open-label study. Tiragolumab plus daratumumab

Tiragolumab

For the tiragolumab plus daratumumab arm, tiragolumab is administered by IV infusion at a fixed dose of 600 mg on Day 1 of each 21 -day cycle. Patients start tiragolumab on Cycle 1 , Day 1 . Tiragolumab infusions are administered per the instructions outlined in Table 9 of Example 4. Tiragolumab administration continues until disease progression, loss of clinical benefit, or development of unacceptable toxicity.

The dose of daratumumab may be administered on either Day 1 or Day 2 for logistic or scheduling reasons for Cycle 1 .

When tiragolumab is given on the same day as daratumumab, tiragolumab should be administered first (unless decided otherwise in consultation with the sponsor), followed by daratumumab.

Administration of tiragolumab is performed in a monitored setting with immediate access to trained critical care personnel and adequate equipment to respond to and manage potentially serious reactions.

Daratumumab

For the tiragolumab plus daratumumab arm (Fig. 1), daratumumab is administered by SC injection at a dose of 1800 mg/30,000 U rHuPH20 weekly for a total of 6 doses, then every 3 weeks for a total of 16 doses (first dose given at Week 7), then every 4 weeks from Week 55 onward until disease progression. Daratumumab injections are administered per the instructions outlined in Table 9 of Example 4.

For Cycle 1 , the dose of daratumumab may be administered on either Day 1 or Day 2 for logistic or scheduling reasons. Based on Safety, the Sponsor might render daratumumab administration on Day 2 mandatory to alleviate any toxicities.

Antiviral prophylaxis should be initiated to prevent herpes zoster reactivation within 1 week after starting daratumumab and continued for 3 months following treatment.

For patients with a history of chronic obstructive pulmonary disease, prescribing post-injection medications should be considered, such as short- and long-acting bronchodilators, and inhaled corticosteroids. Following the first four injections, if the patient experiences no major injection reactions, these additional inhaled post-injection medications may be discontinued.

No dose modification for daratumumab is allowed.

D. Assessments

Assessments for the tiragolumab plus daratumumab arm in R/R MM patients are described in the Assessments sections of Example 1 and Example 4.

E. Analysis

See the Objectives and Endpoints and Analysis sections disclosed in Example 1 . Example 3: Arm D: Tiragolumab in combination with rituximab in patients with relapsed or refractory non-Hodgkin lymphoma

The Phase lb study evaluates the safety, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of tiragolumab in combination with rituximab in patients with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL). Specific objectives and corresponding endpoints for the study are outlined below. Example 3 describes study information applicable to tiragolumab plus rituximab (Arm D of GO41036).

A. Inclusion Criteria

In addition to the inclusion criteria disclosed in Example 1 , above, patients must also meet the following eligibility requirements:

• Patients with histologically confirmed B-cell NHL who have relapsed or failed to respond to at least two prior systemic treatment regimens and for which no suitable therapy of curative intent or higher priority exists (e.g., standard chemotherapy, ASCT).

— The Sponsor may limit the number of patients with particular NHL subtypes enrolled in the study or restrict enrolment to a particular subtype.

• A clinical indication for treatment as determined by the investigator.

— Total hemoglobin > 9 g/dL without transfusion within 21 days prior to first dose of study treatment. Patients who do not meet criteria for hematologic function because of extensive marrow involvement of NHL and/or disease-related cytopenias (e.g., immune thrombocytopenia) may be enrolled into the study.

— Serum creatinine < ULN or estimated CrCL > 50 mL/min by (either calculated or per 24-hour urine collection).

• Must have at least one bi-dimensionally measurable lesion (> 1 .5 cm in its largest dimension by computed tomography (CT) scan).

• Agreement to provide tumor samples as follows:

— For patients with more than one bi-dimensionally measurable lesion (> 1 .5 cm in the largest dimension by CT scan), agreement to undergo biopsy from a safely accessible site. Biopsies obtained at any time between the last dose of last prior anti-cancer therapy and the first dose of study treatment may be acceptable.

— Patients who are unable to undergo biopsy procedures may be eligible for study enrollment. In such cases, archival tumor tissue samples (paraffin blocks or at least 15 unstained slides) should be made available to the Sponsor.

• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception as defined below. - Women must remain abstinent or use contraceptive methods with a failure rate of < 1% per year during the treatment period in all arms and for:

■ Five months after the final dose of tiragolumab or 12 months after the final dose of rituximab, whichever is later.

■ Three months after the final dose of tiragolumab or five months after the final dose of rituximab, whichever is later to avoid exposing the embryo. Men must refrain from donating sperm during this same period.

B. Exclusion Criteria

- Five months after the final dose of tiragolumab or 12 months after the final dose of rituximab, whichever is later.

• Treatment with radiotherapy within 4 weeks prior to the first study drug administration.

— If patients have received radiotherapy within 4 weeks prior to the first study drug administration, patients must have at least one measurable lesion outside of the radiation field.

— Patients who have only one measurable lesion that was previously irradiated but subsequently progressed are eligible.

• Uncontrolled hypercalcemia (> 1 .5 mmol/L ionized calcium or Ca > 12 mg/dL or corrected serum calcium > ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab.

— Patients who are receiving bisphosphonate therapy or denosumab specifically to prevent skeletal events and who do not have a history of clinically significant hypercalcemia are eligible.

• Current or history of CNS lymphoma.

• Current eligibility for ASCT.

• Patients with allergy or hypersensitivity to components of the rituximab formulation or rHuPH20 are not permitted to use the SC rituximab formulation.

C. Study Treatment

The dosage and administration of tiragolumab plus rituximab is described below for the Phase lb open-label study.

Tiragolumab plus rituximab

Tiragolumab is administered by IV infusion at a fixed dose of 600 mg on Day 1 of each 21-day cycle. Patients will start tiragolumab on Cycle 1 , Day 1 . Tiragolumab infusions are administered per the instructions outlined in Table 7. Tiragolumab administration continues until disease progression, loss of clinical benefit, or development of unacceptable toxicity.

Patients receive a total of 8 doses of rituximab. Rituximab is administered by IV infusion for the first dose at a dose of 375 mg/m². The infusion dose is based on the patient’s body surface area at screening and remains the same for all IV infusions. After administration of at least one full infusion of IV rituximab, the subcutaneous formulation of rituximab (rituximab and rHuPH20) may be used for the remaining doses per institutional guidelines. Subcutaneous rituximab is administered subcutaneously at a dose of 1400 mg rituximab/23400 U rHuPH20 QW. Patients with hypersensitivity to rHuPH20 must not switch to SC rituximab and receive IV rituximab for all 8 doses.

For IV administration, empiric dose adjustment for obese patients (defined as a body mass index of > 30) may be implemented per institutional guidelines.

For patients enrolled in the tiragolumab plus rituximab arm (Arm D), a total of 8 doses of rituximab are administered on Cycle 1 , Days 1 , 8, and 15; Cycle 2, Days 1 , 8, and 15; and Cycle 3, Days 1 and 8. When rituximab and tiragolumab are administered on the same day, tiragolumab should be administered first.

All rituximab infusions/injections should be administered, as indicated in Table 7, to patients after premedication with oral acetaminophen (e.g., 500 mg) and an antihistamine such as diphenhydramine hydrochloride (25-50 mg) 30-60 minutes before starting each infusion (unless contraindicated). An additional glucocorticoid (e.g., 100 mg IV prednisone or prednisolone or equivalent) is allowed at the investigator’s discretion. Because transient hypotension may occur during rituximab administration, consideration should be given to withholding antihypertensive agents for 12 hours prior to rituximab administration.

During the treatment period, rituximab must be administered to patients in a setting where full emergency resuscitation facilities are immediately available. Patients should be under close supervision of the investigator at all times.

After the end of the first IV infusion, the IV line or central venous catheter should remain in place for at least 90 minutes in order to administer IV drugs if necessary. If no adverse events occur after 90 minutes, the IV line may be removed, or the central venous catheter may be de-accessed. The IV line or central venous catheter should remain in place for at least 30 minutes after the end of the infusion for subsequent IV infusions, or for at least 15 minutes after the injection for subsequent SC injections. If no adverse events occur after that time, the IV line may be removed, or the central venous catheter may be de-accessed.

No dose modifications of rituximab are allowed. At the discretion of the investigator, the IV infusion of rituximab may be split over 2 consecutive days (e.g., 125 mg/m² on Day 1 and 250 mg/m² on Day 2) if the patient is at increased risk for tumor lysis syndrome (TLS) (e.g., high tumor burden, high peripheral lymphocyte count).

Table 7. Administrations of Tiragolumab plus Rituximab

IRR = infusion-related reaction.

D. Assessments

In addition to the Assessments disclosed in Example 1 , above, patients also receive the following assessments in the tiragolumab plus rituximab arm.

Tumor and Response Evaluations for Non-Hodgkin Lymphoma Radiographic Assessments FDG PET/CT imaging is the preferred radiologic modality for assessing FDG-avid lymphomas and is recommended to assess baseline tumor burden in the study. For lymphomas that are shown to not be FDG-avid or have variable FDG uptake, or in the absence of access to PET/CT scanners, conventional CT scans are the preferred imaging modality. Following the initial PET/CT scan, PET/CT scans may be limited to areas of disease involvement if required by local health authorities.

Diagnostic CT scans and PET/CT scans should be acquired according to the guidelines in the imaging manual that will be provided to all sites. The PET/CT scanners may be used to collect diagnostic CT scans but only in accordance with the technical guidelines in the imaging manual. CT scans should be performed with contiguous cuts of < 10 mm in slice thickness and with resolution sufficient to allow accurate and consistent comparison of target lesion measurements with serial scans. CT scans with oral and IV contrast should include chest, abdomen, and pelvic scans; CT scans of the neck should be included if clinically indicated. Oral contrast may be omitted per institutional standards. CT scans for response assessment may be limited to areas of prior involvement only if required by local health authorities. At the investigator’s discretion, PET/CT or CT scans may be repeated at any time if progressive disease is suspected. MRI scans may be used instead of CT scans in patients for whom they are contraindicated.

If contrast is contraindicated (e.g., in patients with contrast allergy or impaired renal function), CT or combined PET/CT scans without contrast are permitted provided they permit consistent and precise measurement of target lesions during the study treatment period.

The same radiographic assessment modality should be used for all response evaluations, in order to ensure consistency across different timepoints (e.g., PET/CT with the same contrast protocol for CT scans). A full radiographic assessment must be performed any time disease progression or relapse is suspected.

For patients with aggressive lymphoma subtypes (e.g., DLBCL), an MRI scan of the brain should be performed at screening. The brain MRI should utilize gadolinium-based IV contrast unless contraindicated.

For patients who undergo screening/post-treatment biopsies, these lesions may not be selected as target lesions. Bone Marrow Assessments

Bone marrow examinations including both biopsy and aspirate for morphology (flow studies are optional) are required to confirm CR as needed or if clinically indicated.

For patients with DLBCL at both initial diagnosis and study entry, screening PET scan can be utilized to assess bone marrow involvement and bone marrow examinations are not required unless clinically indicated (Cheson et al. J Clin Oncol. 32: 3059-3068, 2014). Bone marrow examinations are required in the following circumstances:

• To confirm a radiologic assessment of CR.

• As evidence of relapse, e.g., if bone marrow assessment was negative at baseline and there is no radiographic evidence of progression for patients with lymphoma.

• Unsuccessful attempts at bone marrow aspiration/biopsy are not considered a protocol violation.

Tumor Assessments

For patients with more than one bi-dimensionally measurable lesion (> 1 .5 cm in the largest dimension by CT scan), tumor biopsies from safely accessible tumor sites (i.e., without unacceptable risk of major procedural complication(s) per investigator assessment) are required prior to Cycle 1 , Day 1 dosing; between Cycle 1 , Day 15 and Cycle 2, Day 1 ; and at disease progression. Patients who are rescreened after an initial screen failure do not need to undergo a repeat tumor biopsy if this assessment were completed during the initial screening period.

In some cases, imaging is clinically indicated to confirm a safely accessible tumor prior to tumor biopsy. The radiographic modality (e.g., ultrasound, MRI, CT) used for this pre-biopsy evaluation is at the discretion of the investigator. This imaging is in addition to the radiographic imaging required for tumor response assessments.

E. Analysis

See the Objectives and Endpoints and Analysis sections disclosed in Example 1 .

Example 4: Arm E: Tiragolumab in combination with daratumumab and atezolizumab in patients with relapsed or refractory multiple myeloma

The Phase lb study evaluates the safety, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of tiragolumab in combination with daratumumab and atezolizumab in patients with relapsed or refractory (R/R) multiple myeloma (MM). Specific objectives and corresponding endpoints for the study are outlined below. Example 4 describes study information applicable to tiragolumab plus daratumumab plus atezolizumab (Arm E of GO41036).

A. Inclusion Criteria

• Patients with R/R MM who have received at least 3 prior lines of therapy, including a proteasome inhibitor, an I MiD, and an anti-CD38 antibody. - A line of therapy consists of > 1 complete cycle of a single agent, a regimen consisting of a combination of several drugs, or a planned sequential therapy of various drugs (e.g., induction therapy followed by stem-cell transplantation (SCT) is considered 1 line of therapy (Rajkumar et al. Blood. 126(7): 921-922, 2015)).

- Patients who are intolerant of daratumumab or atezolizumab are not eligible.

- Prior therapy with anti-CD38 antibodies is allowed provided the patient had at least a PR to the most recent therapy with the anti-CD38 antibody, did not relapse within 60 days of weekly or biweekly anti-CD38 therapy and will have at least a 6-month anti-CD38 treatment-free interval from last dose received and first dose of study treatment on trial.

- Total hemoglobin > 8 g/dL.

Patients may receive RBC transfusions or erythropoietic agents in accordance with institutional guidelines to meet this criterion.

Patients who do not meet criteria for hematologic function because of extensive marrow involvement of MM and/or disease-related cytopenias (e.g., immune thrombocytopenia) may be enrolled into the study after consultation with the Medical Monitor.

- Serum calcium (corrected for albumin) < ULN.

Treatment of hypercalcemia is allowed, and patients may enroll if calcium level returns to normal prior to initiation of study treatment.

• Measurable disease defined as at least one of the following:

- Serum M-protein > 1 .0 g/dL (> 10 g/L).

- Urine M-protein > 200 mg/24 hr.

• Agreement to provide bone marrow biopsy and aspirate samples.

■ Ninety days after the final dose of tiragolumab, 5 months after the final dose of atezolizumab, or 3 months after the final dose of daratumumab, whichever is later.

• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as specified below. - With a female partner of childbearing potential or pregnant female partner, men must remain abstinent or use a condom during the treatment period and for:

■ Ninety days after the final dose of tiragolumab and daratumumab, whichever is later to avoid exposing the embryo. Men must refrain from donating sperm during this same period.

B. Exclusion Criteria

- Ninety days after the final dose of tiragolumab, 5 months after the final dose of atezolizumab, or 3 months after the final dose of daratumumab, whichever is later.

• Current or history of CNS involvement by MM.

• Allergy or hypersensitivity to components of the atezolizumab formulation.

C. Study Treatment

The dosage and administration of tiragolumab plus daratumumab plus atezolizumab is described below for the Phase lb open-label study.

Tiragolumab plus daratumumab plus atezolizumab

Tiragolumab

For the tiragolumab plus daratumumab plus atezolizumab arm, tiragolumab is administered by IV infusion at a fixed dose of 600 mg on Day 1 of each 21 -day cycle. Patients start tiragolumab on Cycle 1 , Day 1. Tiragolumab infusions are administered per the instructions outlined in Table 9. Tiragolumab administration continues until disease progression, loss of clinical benefit, or development of unacceptable toxicity.

When atezolizumab, daratumumab, and tiragolumab are administered on the same day, tiragolumab should be administered first, followed by atezolizumab and then daratumumab (unless decided otherwise in consulation with the Sponsor).

Administration of tiragolumab is performed in a monitored setting with immediate access to trained critical care personnel and adequate equipment to respond to and manage potentially serious reactions. Atezolizumab

For the tiragolumab plus daratumumab plus atezolizumab arm, atezolizumab is administered by IV infusion at a fixed dose of 1200 mg on Day 1 of each 21 -day cycle. Atezolizumab administration continues until disease progression, loss of clinical benefit, or development of unacceptable toxicity. Administration of atezolizumab is performed in a monitored setting with immediate access to trained critical care personnel and adequate equipment to respond to and manage potentially serious reactions (see Table 8).

There is no intrapatient dose reduction for atezolizumab in this study. Table 8. Administration of First and Subsequent Infusions of Atezolizumab

IRR = infusion-related reaction.

Daratumumab

For the tiragolumab plus daratumumab plus atezolizumab arm, daratumumab is administered by SC injection at a dose of 1800 mg/30,000 U rHuPH20 weekly for a total of 6 doses in cycles 1 and 2, then every 3 weeks on day 1 of cycles 3-19, then every 4 weeks thereafter. Alternatively, daratumumab is administered by SC injection at a dose of 1800 mg/30,000 U rHuPH20 weekly for a total of 9 doses, then every 3 weeks for a total of 5 doses (first dose given at Week 10), then every 4 weeks from Week 25 onward until disease progression. Daratumumab injections are administered per the instructions outlined in Table 9.

No dose modification for daratumumab is allowed.

Table 9. Administrations of Tiragolumab plus Atezolizumab and/or Daratumumab

IRR = infusion-related reaction. a Premedication given for daratumumab and/or atezolizumab may be given even if timing necessitates a patient receiving the medication prior to tiragolumab. D. Assessments

In addition to the Assessments disclosed in Example 1 , above, patients also receive the following assessments. Tumor and Response Evaluations for Multiple Myeloma

A bone marrow biopsy and aspirate are required prior to Cycle 1 , Day 1 dosing; at the time points indicated in the schedule of activities; and at the time of confirmation of CR or at disease progression. The bone marrow sample scheduled prior to Cycle 1 , Day 1 may be obtained after the patient’s other screening procedures have been completed and enrollment of the patient has been confirmed. Patients who are re-screened after an initial screen failure do not need to undergo a repeat bone marrow biopsy and aspirate if these assessments were completed during the initial screening period.

The following myeloma-specific tests are conducted at the beginning of every cycle and processed by the Sponsor or the Sponsor’s contracted specialty bioanalytical laboratories for analysis, starting with Cycle 1 , Day 1 (screening samples may be used for Cycle 1 , Day 1 if drawn within 28 days prior to Cycle 1 , Day 1):

• Serum protein electrophoresis (SPEP) with serum immunofixation electrophoresis (SIFE).

• Serum free light chains (SFLCs).

• Quantitative Ig levels.

If SPEP/SIFE and SFLC analyses are additionally performed locally at sites, the results of these analyses should be provided to the Sponsor.

Clinical response assessment in myeloma relies on SPEP and SIFE. As both atezolizumab and tiragolumab are monoclonal lgG1 antibodies, the SPEP and SIFE may be positive for atezolizumab or tiragolumab at the serum levels anticipated during this protocol. Therefore, samples for SPEP and SIFE should be collected predose.

The following myeloma-specific tests should be performed both locally and centrally at sites at screening and as needed (locally) to confirm a response:

• A 24-hour urine protein electrophoresis (UPEP) with urine immunofixation electrophoresis (LIIFE) for M-protein quantitation.

The following confirmatory assessments are required for all response categories (sCR, CR, VGPR, PR, and minimal response):

• If extramedullary disease was previously present, CT scan or MRI with bi-dimensional measurements to confirm reduction in size per IMWG criteria.

• If extramedullary disease was previously present, PET/CT scan, CT scan, or MRI to confirm complete resolution.

• 24-hour UPEP/UIFE (performed locally) to confirm VGPR, even if a UPEP was not performed at screening.

The following additional samples/assessments are required to confirm a sCR or CR:

• SIFE.

• SFLC.

• 24-hour UPEP/UIFE (performed locally) to confirm CR/sCR, even if a UPEP was not performed at screening.

• Bone marrow aspiration and biopsy. If extramedullary disease was previously present, PET/CT scan, CT scan, or MRI to confirm complete resolution.

To confirm progressive disease, the following are required:

• If progressive disease is suspected by rising M-protein; SPEP, UPEP, or SFLC analysis should be obtained on two consecutive assessments.

• If progressive disease is suspected on development of new bone lesions or soft tissue plasmacytomas or an increase in size of existing bone lesions or soft tissue plasmacytomas, skeletal survey/CT scan/MRI should be obtained and compared with baseline imaging.

• If progressive disease is suspected on hypercalcemia attributed solely to MM, local laboratory results levels of serum calcium should be > 11 mg/dL and confirmed on a second assessment.

Extramedullary Disease

All patients with MM who have clinically suspected extramedullary disease or known extramedullary disease at the time of screening must undergo imaging during screening to evaluate for the presence/extent of extramedullary disease. This can be performed by CT scan of the chest, abdomen, and pelvis (preferably with IV contrast if renal function is adequate), PET/CT, or whole-body MRI. Patients who are found to have extramedullary disease undergo repeat imaging (preferably the same modality as performed at screening) every 4 cycles (± 7 days). Imaging should also be performed upon clinical suspicion of progressive disease or to confirm response. Chest X-ray or ultrasound of the abdomen/liver/spleen may be substituted for CT, PET/CT, or MRI if, per the investigator’s assessment, patients are not able to safely tolerate these imaging modalities and the anatomic location of the extramedullary disease is compatible with these alternative imaging methods.

Skeletal Survey

A skeletal survey is completed at screening and as clinically indicated. The skeletal survey may be completed up to 28 days prior to Cycle 1 , Day 1 . Plain films and CT scans are both acceptable imaging modalities for assessing skeletal disease. Imaging should include the skull, long bones, chest, and pelvis. If plasmacytomas are seen on skeletal survey, bi-dimensional tumor measurements should be recorded.

The skeletal survey may be omitted if a PET/CT scan or a low-dose, whole-body CT is performed as part of screening.

E. Analysis

See the Objectives and Endpoints and Analysis sections disclosed in Example 1 .

Example 5: Biomarker analysis of a phase la/lb open-label, multicenter study of tiragolumab or tiragolumab plus rituximab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma

The phase la/lb trial evaluated the safety and pharmacokinetics of the anti-TIGIT agent, tiragolumab, alone or in combination with rituximab (Arm D of GO41036). Patients were recruited with histologically confirmed B-cell NHL whose disease had relapsed or failed to respond to >2 prior systemic treatment regimens, had ECOG PS 0-1 , adequate hematologic and end organ function, and no history of CNS lymphoma. Patients received tiragolumab at a dose of 600 mg IV Q3Wwith or without rituximab 375 mg/m² IV for the initial dose and 1400 mg SC rituximab/23400 U rHuPH20 QW for 8 doses. Here, biomarker data were collected and evaluated from patients with R/R NHL dosed with tiragolumab as a single agent or in combination with rituximab via flow cytometry and immunohistochemistry (IHC).

A. Results

At data cut-off (July 2021), biomarker data had been collected from 14 patients with NHL. Baseline CD8 T cell density within the tumor region evaluated via IHC for these patients was between 500-6000 per mmA². In the peripheral blood of the 7 patients dosed with the combination tiragolumab and rituximab, CD8 T cell expansion observed via absolute counts by flow cytometry was seen in 2 patients. Among the 7 patients, natural killer (NK)Z natural killer T (NKT) cell CD25 expression remained unchanged and a modest increase in NK cell CD69 expression was sustained above baseline in 1 patient. Overall, transient NK cell activation via increased CD69 expression was observed in 2 patients, which would be expected from the addition of rituximab. Increased PD-L1 expression was observed on multiple lymphocyte subsets in 4 of 7 patients in this cohort.

Of the 7 patients who received single agent tiragolumab, trends in increased CD69 expression on NKs in 4 patients and NK/NKT CD25 expression were observed in 3 patients. A modest CD8 T cell activation, via increased CD69 expression, was observed in 2 patients, though T cell counts remained unchanged. At baseline, TIGIT was abundantly expressed on peripheral blood CD8 T cells, while coexpression of exhaustion markers on CD8 T cells was less widely observed.

Although one subject experienced a sustained response, no other patients achieved clinical benefit. This heavily pretreated 65-year-old female patient with FL had an objective partial response (best overall response), determined via Lugano criteria, with a response duration on single-agent tiragolumab for 11 months. This patient had a two-fold upregulated CD69 expression on NKs and sixty-three-fold CD25 upregulated expression on NK/NKTs, as well as increased frequencies of PD-L1+ on immune cells over the course of treatment. In this patient, relatively higher TIGIT and lower expression of exhaustion markers on CD8 T cells was observed at baseline and over treatment compared to other patients analyzed.

B. Conclusion

In this study, tiragolumab as a single agent and in combination with rituximab was seen to result in increased PD-L1 expression on multiple lymphocyte subsets (including B, CD4/CD8 T cells, and NKs), which support the combination of tiragolumab with PD-L1/PD-1 inhibitors. Increases in NK/NKT CD25 expression could suggest a tiragolumab-mediated increase in proliferative potential, but further investigations are needed to confirm. A patient with R/R FL in this study was observed to have the first documented objective response to single-agent tiragolumab in this disease indication, suggesting the necessity of biomarker-driven combination strategies in this population. Other Embodiments

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, the descriptions and examples should not be construed as limiting the scope of the invention.

Claims

WHAT IS CLAIMED IS:

1 . A method for treating a subject having a hematologic cancer, the method comprising administering to the subject an effective amount of an anti-TIGIT antagonist antibody, an anti-CD38 antibody, and a PD- 1 axis binding antagonist.

2. The method of claim 1 , wherein the method comprises administering to the subject the anti-TIGIT antagonist antibody at a fixed dose of between about 30 mg to about 1200 mg, the anti-CD38 antibody at a dose of between about 300 mg to about 3600 mg, and the PD-1 axis binding antagonist at a dose of between about 900 mg to about 1500 mg.

3. The method of claim 1 or 2, wherein the method comprises administering to the subject the anti- TIGIT antagonist antibody, anti-CD38 antibody, and PD-1 axis binding antagonist in a dosing regimen comprising at least nine dosing cycles, wherein:

(a) the anti-TIGIT antagonist antibody is administered once every three weeks;

(b) the PD-1 axis binding antagonist is administered once every three weeks; and

(c) the anti-CD38 antibody is administered once every week during each of dosing cycles 1 -3, once every three weeks during each of dosing cycles 4-8, and once every four weeks during dosing cycle 9.

4. A method for treating a subject having a hematologic cancer, the method comprising administering to the subject an anti-TIGIT antagonist antibody at a fixed dose of between about 30 mg to about 1200 mg, an anti-CD38 antibody at a dose of between about 300 mg to about 3600 mg, and a PD-1 axis binding antagonist at a dose of between about 900 mg to about 1500 mg in a dosing regimen comprising at least nine dosing cycles, wherein:

(a) the anti-TIGIT antagonist antibody is administered once every three weeks;

(c) the anti-CD38 antibody is administered once every week during each of dosing cycles 1-3, once every three weeks during each of dosing cycles 4-8, and once every four weeks during dosing cycle 9.

5. The method of claim 1 or 2, wherein the method comprises administering to the subject the anti- TIGIT antagonist antibody, anti-CD38 antibody, and PD-1 axis binding antagonist in a dosing regimen comprising at least 19 dosing cycles, wherein:

(a) the anti-TIGIT antagonist antibody is administered once every three weeks;

(c) the anti-CD38 antibody is administered once every week during each of dosing cycles 1 and 2, once every three weeks during each of dosing cycles 3-18, and once every four weeks during dosing cycle 19.

6. A method for treating a subject having a hematologic cancer, the method comprising administering to the subject an anti-TIGIT antagonist antibody at a fixed dose of between about 30 mg to about 1200 mg, an anti-CD38 antibody at a dose of between about 300 mg to about 3600 mg, and a PD-1 axis binding antagonist at a dose of between about 900 mg to about 1500 mg in a dosing regimen comprising at least 19 dosing cycles, wherein:

(a) the anti-TIGIT antagonist antibody is administered once every three weeks;

7. The method of any one of claims 1-6, wherein the length of each dosing cycle is 21 days.

8. The method of any one of claims 1-7, wherein the anti-TIGIT antagonist antibody is administered on or about day 1 of each dosing cycle.

9. The method of any one of claims 1-4, 7, and 8, wherein the anti-CD38 antibody is administered on or about days 1 , 8, and 15 of each of dosing cycles 1 -3, on or about day 1 of each of dosing cycles 4-8, and on or about day 1 of dosing cycle 9.

10. The method of any one of claims 1 , 2, and 5-8, wherein the anti-CD38 antibody is administered on or about days 1 , 8, and 15 of each of dosing cycles 1 and 3, on or about day 1 of each of dosing cycles 3- 18, and on or about day 1 of dosing cycle 19.

11. The method of any one of claims 1-10, wherein the PD-1 axis binding antagonist is administered on or about day 1 of each dosing cycle.

12. The method of any one of claims 1-4, 7-9, and 11 , wherein the anti-TIGIT antagonist antibody, the anti-CD38 antibody, and the PD-1 axis binding antagonist are each administered on or about day 1 of each of dosing cycles 1-9.

13. The method of any one of claims 1 , 2, 5-8, 10, and 11 , wherein the anti-TIGIT antagonist antibody, the anti-CD38 antibody, and the PD-1 axis binding antagonist are each administered on or about day 1 of each of dosing cycles 1-19.

14. The method of any one of claims 1-13, wherein the anti-TIGIT antagonist antibody is administered prior to the anti-CD38 antibody and the PD-1 axis binding antagonist.

15. The method of claim 14, wherein the anti-TIGIT antagonist antibody is administered first, the PD-1 axis binding antagonist is administered second, and the anti-CD38 antibody is administered third.

16. The method of claim 14, wherein the anti-TIGIT antagonist antibody is administered first, the anti- CD38 antibody is administered second, and the PD-1 axis binding antagonist is administered third.

17. The method of claim 15, wherein the method comprises a first observation period following administration of the anti-TIGIT antagonist antibody, a second observation period following administration of the PD-1 axis binding antagonist, and a third observation period following administration of the anti- CD38 antibody.

18. The method of claim 17, wherein the first observation period and the second observation period are each between about 30 minutes to about 60 minutes in length.

19. The method of claim 17 or 18, wherein the third observation period is about 6 hours in length following the first dose of the anti-CD38 antibody and is about 60 minutes in length following subsequent doses of the anti-CD38 antibody.

20. The method of claim 16, wherein the method comprises a first observation period following administration of the anti-TIGIT antagonist antibody, a second observation period following administration of the anti-CD38 antibody, and a third observation period following administration of the PD-1 axis binding antagonist.

21 . The method of claim 20, wherein the first observation period and the third observation period are each between about 30 minutes to about 60 minutes in length.

22. The method of claim 20 or 21 , wherein the second observation period is about 6 hours in length following the first dose of the anti-CD38 antibody and is about 60 minutes in length following subsequent doses of the anti-CD38 antibody.

23. The method of any one of claims 1-13, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are administered simultaneously.

24. The method of any one of claims 1-4, 7-9, 11 , 12, and 14-23, wherein the dosing regimen comprises at least 16 dosing cycles.

25. The method of any one of claims 1 -24, further comprising administering to the subject a corticosteroid prior to the first, second, and third administrations of the anti-CD38 antibody.

26. The method of any one of claims 1 -24, further comprising administering to the subject a corticosteroid, an antipyretic, and an antihistamine prior to the first administration of the anti-CD38 antibody.

27. The method of any one of claims 1 -26, further comprising administering to the subject a leukotriene receptor antagonist prior to the first administration of the anti-CD38 antibody.

28. The method of claim any one of claims 1-27, wherein the method comprises administering to the subject a corticosteroid prior to each administration of the anti-CD38 antibody.

29. The method of any one of claims 1-28, further comprising administering to the subject an antipyretic prior to each administration of the anti-CD38 antibody.

30. The method of any one of claims 1-29, further comprising administering to the subject an antihistamine prior to each administration of the anti-CD38 antibody.

31. The method of any one of claims 1-30, wherein the method comprises administering to the subject a corticosteroid, an antipyretic, and an antihistamine prior to each administration of the anti-CD38 antibody.

32. The method of any one of claims 1-31 , wherein the method comprises administering to the subject a corticosteroid on each of the two days following the first, second, and third administrations of the anti- CD38 antibody.

33. The method of any one of claims 25-32, wherein the corticosteroid is methylprednisolone, the antipyretic is acetaminophen, the antihistamine is diphenhydramine, and/or the leukotriene receptor is montelukast.

34. The method of any one of claims 1-33, wherein the method comprises administering to the subject the anti-TIGIT antagonist antibody at a fixed dose of about 600 mg.

35. The method of any one of claims 1-34, wherein the anti-TIGIT antagonist antibody comprises the following hypervariable regions (HVRs):

(a) an HVR-H1 comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1);

(b) an HVR-H2 comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2);

(c) an HVR-H3 comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3);

(d) an HVR-L1 comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4);

(e) an HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and

(f) an HVR-L3 comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6).

36. The method of claim 35, wherein the anti-TIGIT antagonist antibody further comprises the following light chain variable region FRs:

(a) an FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7);

(b) an FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8); (c) an FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and

(d) an FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10).

37. The method of claim 35 or 36, wherein the anti-TIGIT antagonist antibody further comprises the following heavy chain variable region FRs:

(a) an FR-H1 comprising the amino acid sequence of XiVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11), wherein Xi is Q or E;

(b) an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12);

(c) an FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and

(d) an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14).

38. The method of claim 37, wherein Xi is Q.

39. The method of claim 37, wherein Xi is E.

40. The method of any one of claims 35-39, wherein the anti-TIGIT antagonist antibody comprises:

(a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of

EVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGKTYYRFKWYSDYAVSVK

GRITINPDTSKNQFSLQLNSVTPEDTAVFYCTRESTTYDLLAGPFDYWGQGTLVTVSS (SEQ ID NO: 17) or

QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGKTYYRFKWYSDYAVSVK

GRITINPDTSKNQFSLQLNSVTPEDTAVFYCTRESTTYDLLAGPFDYWGQGTLVTVSS (SEQ ID NO: 18);

(b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of

DIVMTQSPDSLAVSLGERATINCKSSQTVLYSSNNKKYLAWYQQKPGQPPNLLIYWASTRESGVPDRFSG

SGSGTDFTLTISSLQAEDVAVYYCQQYYSTPFTFGPGTKVEIK (SEQ ID NO: 19); or

(c) a VH domain as in (a) and a VL domain as in (b).

41. The method of claim 40, wherein the anti-TIGIT antagonist antibody comprises:

(a) a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18; and

(b) a VL domain comprising the amino acid sequence of SEQ ID NO: 19.

42. The method of claim 41 , wherein the anti-TIGIT antagonist antibody comprises:

(a) a VH domain comprising the amino acid sequence of SEQ ID NO: 17; and

(b) a VL domain comprising the amino acid sequence of SEQ ID NO: 19.

43. The method of any one of claims 1-42, wherein the anti-TIGIT antagonist antibody is a monoclonal antibody.

44. The method of any one of claims 1-43, wherein the anti-TIGIT antagonist antibody is a human antibody.

45. The method of any one of claims 1-44, wherein the anti-TIGIT antagonist antibody is a full-length antibody.

46. The method of any one of claims 1-45, wherein the anti-TIGIT antagonist antibody exhibits effector function.

47. The method of any one of clams 1-46, wherein the anti-TIGIT antagonist antibody is an IgG class antibody.

48. The method of claim 47, wherein the IgG class antibody is an lgG1 subclass antibody.

49. The method of any one of claims 1-37 and 39-48, wherein the anti-TIGIT antagonist antibody is tiragolumab.

50. The method of any one of claims 1-44, wherein the anti-TIGIT antagonist antibody is an antibody fragment that binds TIGIT selected from the group consisting of Fab, Fab’, Fab’-SH, Fv, single chain variable fragment (scFv), and (Fab’)2 fragments.

51. The method of any one of claims 1-34, wherein the anti-TIGIT antagonist antibody is vibostolimab, etigilimab, EOS084448, SGN-TGT, TJ-T6, BGB-A1217, AB308, domvanalimab, BMS-986207, ASP8374, or COM902.

52. The method of any one of claims 1-51 , wherein the anti-TIGIT antagonist antibody is administered intravenously.

53. The method of any one of claims 1-52, wherein the method comprises administering to the subject the anti-CD38 antibody at a dose of about 1800 mg.

54. The method of any one of claims 1-53, wherein the anti-CD38 antibody is an anti-CD38 antagonist antibody.

55. The method of any one of claims 1-54, wherein the anti-CD38 antibody comprises the following hypervariable regions (HVRs):

(a) an HVR-H1 comprising the amino acid sequence of SFAMS (SEQ ID NO: 20);

141 (b) an HVR-H2 comprising the amino acid sequence of AISGSGGGTYYADSVKG (SEQ ID NO: 21);

(c) an HVR-H3 comprising the amino acid sequence of DKILWFGEPVFDY (SEQ ID NO: 22);

(d) an HVR-L1 comprising the amino acid sequence of RASQSVSSYLA (SEQ ID NO: 23);

(e) an HVR-L2 comprising the amino acid sequence of DASNRAT (SEQ ID NO: 24); and

(f) an HVR-L3 comprising the amino acid sequence of QQRSNWPPTF (SEQ ID NO: 25).

56. The method of claim 55, wherein the anti-CD38 antibody further comprises the following light chain variable region framework regions (FRs):

(a) an FR-L1 comprising the amino acid sequence of EIVLTQSPATLSLSPGERATLSC (SEQ ID NO: 26);

(b) an FR-L2 comprising the amino acid sequence of WYQQKPGQAPRLLIY (SEQ ID NO: 27);

(c) an FR-L3 comprising the amino acid sequence of GIPARFSGSGSGTDFTLTISSLEPEDFAVYYC (SEQ ID NO: 28); and

(d) an FR-L4 comprising the amino acid sequence of GQGTKVEIK (SEQ ID NO: 29).

57. The method of claim 55 or 56, wherein the anti-CD38 antibody further comprises the following heavy chain variable region FRs:

(a) an FR-H1 comprising the amino acid sequence of EVQLLESGGGLVQPGGSLRLSCAVSGFTFN (SEQ ID NO: 30);

(b) an FR-H2 comprising the amino acid sequence of WVRQAPGKGLEWVS (SEQ ID NO: 31);

(c) an FR-H3 comprising the amino acid sequence of RFTISRDNSKNTLYLQMNSLRAEDTAVYFCAK (SEQ ID NO: 32); and

(d) an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 33).

58. The method of any one of claims 55-57, wherein the anti-CD38 antibody further comprises:

(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQAPGKGLEWVSAISGSGGGT YYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCAKDKILWFGEPVFDYWGQGTLVTVSS (SEQ ID NO: 34);

(b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIP ARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPTFGQGTKVEIK (SEQ ID NO: 35); or

(c) a VH domain as in (a) and a VL domain as in (b).

59. The method of claim 58, wherein the anti-CD38 antibody comprises:

(a) a VH domain comprising the amino acid sequence of SEQ ID NO: 34; and

(b) a VL domain comprising the amino acid sequence of SEQ ID NO: 35.

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60. The method of any one of claims 1-59, wherein the anti-CD38 antibody is a monoclonal antibody.

61. The method of any one of claims 1-60, wherein the anti-CD38 antibody is a human antibody.

62. The method of any one of claims 1-61 , wherein the anti-CD38 antibody is a full-length antibody.

63. The method of any one of claims 1-62, wherein the anti-CD38 antibody is daratumumab.

64. The method of any one of claims 1-61 , wherein the anti-CD38 antibody is an antibody fragment that binds CD38 selected from the group consisting of Fab, Fab’, Fab’-SH, Fv, single chain variable fragment (scFv), and (Fab’)2 fragments.

65. The method of any one of claims 1-63, wherein the anti-CD38 antibody is an IgG class antibody.

66. The method of claim 65, wherein the IgG class antibody is an lgG1 subclass antibody.

67. The method of any one of claims 1-66, wherein the method comprises administering to the subject the anti-CD38 antibody subcutaneously.

68. The method of claim 67, wherein the anti-CD38 antibody is formulated with recombinant human hyaluronidase PH20 (rHuPH20).

69. The method of claim 68, wherein the anti-CD38 antibody is formulated with rHuPH20 at a dose of 1800 mg of the anti-CD38 antibody per 30,000 U rHuPH20.

70. The method of any one of claims 1-66, wherein the method comprises administering to the subject the anti-CD38 antibody intravenously.

71. The method of any one of claims 1-70, wherein the method comprises administering to the subject the PD-1 axis binding antagonist at a dose of about 1200 mg.

72. The method of any one of claims 1-71 , wherein the PD-1 axis binding antagonist is selected from the group consisting of a PD-L1 binding antagonist, a PD-1 binding antagonist, and a PD-L2 binding antagonist.

73. The method of claim 72, wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist.

74. The method of claim 73, wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to one or more of its ligand binding partners.

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75. The method of claim 74, wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1 , B7-1 , or both PD-1 and B7-1.

76. The method of any one of claims 71-75, wherein the PD-L1 binding antagonist is an anti-PD-L1 antagonist antibody.

77. The method of claim 76, wherein the anti-PD-L1 antagonist antibody is atezolizumab, MDX-1105, durvalumab, avelumab, SHR-1316, CS1001 , envafolimab, TQB2450, ZKAB001 , LP-002, CX-072, IMC- 001 , KL-A167, APL-502, cosibelimab, lodapolimab, FAZ053, TG-1501 , BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311 , RC98, PDL-GEX, KD036, KY1003, YBL-007, or HS-636.

78. The method of claim 77, wherein the anti-PD-L1 antagonist antibody is atezolizumab.

79. The method of claim 76, wherein the anti-PD-L1 antagonist antibody comprises the following HVRs:

(a) an HVR-H1 sequence comprising the amino acid sequence of GFTFSDSWIH (SEQ ID NO: 60);

(b) an HVR-H2 sequence comprising the amino acid sequence of AWISPYGGSTYYADSVKG (SEQ ID NO: 61);

(c) an HVR-H3 sequence comprising the amino acid sequence of RHWPGGFDY (SEQ ID NO: 62);

(d) an HVR-L1 sequence comprising the amino acid sequence of RASQDVSTAVA (SEQ ID NO: 63);

(e) an HVR-L2 sequence comprising the amino acid sequence of SASFLYS (SEQ ID NO: 64); and

(f) an HVR-L3 sequence comprising the amino acid sequence of QQYLYHPAT (SEQ ID NO: 65).

80. The method of claim 79, wherein the anti-PD-L1 antagonist antibody comprises:

(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 66;

(b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 67; or

(c) a VH domain as in (a) and a VL domain as in (b).

81. The method of claim 80, wherein the anti-PD-L1 antagonist antibody comprises:

(a) a VH domain comprising the amino acid sequence of SEQ ID NO: 66; and

(b) a VL domain comprising the amino acid sequence of SEQ ID NO: 67.

82. The method of claim 81 , wherein the anti-PD-L1 antagonist antibody comprises:

(a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 58; and

(b) a light chain comprising the amino acid sequence of SEQ ID NO: 59.

83. The method of any one of claims 79-82, wherein the anti-PD-L1 antagonist antibody is a monoclonal antibody.

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84. The method of any one of claims 79-83, wherein the anti-PD-L1 antagonist antibody is a humanized antibody.

85. The method of claim 83 or 84, wherein the anti-PD-L1 antagonist antibody is a full-length antibody.

86. The method of any one of claims 79-84, wherein the anti-PD-L1 antagonist antibody is an antibody fragment that binds PD-L1 selected from the group consisting of Fab, Fab’, Fab’-SH, Fv, scFv, and (Fab’)2 fragments.

87. The method of any one of claims 79-85, wherein the anti-PD-L1 antagonist antibody is an IgG class antibody.

88. The method of claim 87, wherein the IgG class antibody is an lgG1 subclass antibody.

89. The method of claim 72, wherein the PD-1 axis binding antagonist is a PD-1 binding antagonist.

90. The method of claim 89, wherein the PD-1 binding antagonist inhibits the binding of PD-1 to one or more of its ligand binding partners.

91 . The method of claim 90, wherein the PD-1 binding antagonist inhibits the binding of PD-1 to PD- L1 , PD-L2, or both PD-L1 and PD-L2.

92. The method of any one of claims 89-91 , wherein the PD-1 binding antagonist is an anti-PD-1 antagonist antibody.

93. The method of claim 92, wherein the anti-PD-1 antagonist antibody is nivolumab, pembrolizumab, MEDI-0680, spartalizumab, cemiplimab, BGB-108, prolgolimab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, retifanlimab, sasanlimab, penpulimab, CS1003, HLX10, SCT-I10A, zimberelimab, balstilimab, genolimzumab, Bl 754091 , cetrelimab, YBL-006, BAT1306, HX008, budigalimab, AMG 404, CX-188, JTX-4014, 609A, Sym021 , LZM009, F520, SG001 , AM0001 , ENUM 244C8, ENUM 388D4, STI-1110, AK-103, or hAb21 .

94. The method of any one of claims 72 and 89-91 , wherein the PD-1 binding antagonist is an Fc fusion protein.

95. The method of claim 94, wherein the Fc fusion protein is AMP-224.

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96. The method of any one of claims 1-95, wherein the method comprises administering to the subject the PD-1 axis binding antagonist intravenously.

97. The method of any one of claims 1-96, wherein the hematologic cancer is a myeloma.

98. The method of claim 97, wherein the myeloma is a multiple myeloma (MM).

99. The method of claim 98, wherein the MM is a relapsed or refractory MM.

100. A method for treating a subject having a relapsed or refractory MM, the method comprising administering to the subject tiragolumab at a fixed dose of 600 mg, daratumumab at a fixed dose of 1800 mg, and atezolizumab at a fixed dose of 1200 mg in a dosing regimen comprising at least nine dosing cycles, wherein the length of each dosing cycle is 21 days, and wherein:

(a) tiragolumab is administered on or about day 1 of each dosing cycle;

(b) atezolizumab is administered on or about day 1 of each dosing cycle; and

(c) daratumumab is administered on or about days 1 , 8, and 15 of each of dosing cycles 1-3, on or about day 1 during each of dosing cycles 4-8, and once every 4 weeks beginning on or about day 1 of dosing cycle 9.

101. A method for treating a subject having a relapsed or refractory MM, the method comprising administering to the subject tiragolumab at a fixed dose of 840 mg, daratumumab at a fixed dose of 1800 mg, and atezolizumab at a fixed dose of 1680 mg in a dosing regimen comprising at least nine dosing cycles, wherein the length of each dosing cycle is 21 days, and wherein:

(a) the tiragolumab is administered once every 4 weeks;

(b) the atezolizumab is administered once every 4 weeks; and

(c) the daratumumab is administered on or about days 1 , 8, and 15 of each of dosing cycles 1 -3, on or about day 1 during each of dosing cycles 4-8, and once every 4 weeks beginning on or about day 1 of dosing cycle 9.

102. A method for treating a subject having a relapsed or refractory MM, the method comprising administering to the subject tiragolumab at a fixed dose of 420 mg, daratumumab at a fixed dose of 1800 mg, and atezolizumab at a fixed dose of 840 mg in a dosing regimen comprising at least nine dosing cycles, wherein the length of each dosing cycle is 21 days and wherein:

(a) the tiragolumab is administered once every two weeks;

(b) the atezolizumab is administered once every two weeks; and

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103. The method of any one of claims 100-102, wherein the dosing regimen comprises at least 16 dosing cycles.

104. A method for treating a subject having a relapsed or refractory MM, the method comprising administering to the subject tiragolumab at a fixed dose of 600 mg, daratumumab at a fixed dose of 1800 mg, and atezolizumab at a fixed dose of 1200 mg in a dosing regimen comprising at least 19 dosing cycles, wherein the length of each dosing cycle is 21 days, and wherein:

(a) tiragolumab is administered on or about day 1 of each dosing cycle;

(b) atezolizumab is administered on or about day 1 of each dosing cycle; and

(c) daratumumab is administered on or about days 1 , 8, and 15 of each of dosing cycles 1 and 2, on or about day 1 during each of dosing cycles 3-18, and once every 4 weeks beginning on or about day 1 of dosing cycle 19.

105. A method for treating a subject having a relapsed or refractory MM, the method comprising administering to the subject tiragolumab at a fixed dose of 840 mg, daratumumab at a fixed dose of 1800 mg, and atezolizumab at a fixed dose of 1680 mg in a dosing regimen comprising at least 19 dosing cycles, wherein the length of each dosing cycle is 21 days, and wherein:

(a) the tiragolumab is administered once every 4 weeks;

(b) the atezolizumab is administered once every 4 weeks; and

(c) the daratumumab is administered on or about days 1 , 8, and 15 of each of dosing cycles 1 and 2, on or about day 1 during each of dosing cycles 3-18, and once every 4 weeks beginning on or about day 1 of dosing cycle 19.

106. A method for treating a subject having a relapsed or refractory MM, the method comprising administering to the subject tiragolumab at a fixed dose of 420 mg, daratumumab at a fixed dose of 1800 mg, and atezolizumab at a fixed dose of 840 mg in a dosing regimen comprising at least 19 dosing cycles, wherein the length of each dosing cycle is 21 days and wherein:

(a) the tiragolumab is administered once every two weeks;

(b) the atezolizumab is administered once every two weeks; and

107. The method of any one of claims claim 100-106, wherein the method comprises administering to the subject the tiragolumab simultaneously with the atezolizumab.

108. The method of claim 100-106, wherein the method comprises administering to the subject the tiragolumab after the atezolizumab.

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109. The method of claim 100-106, wherein the method comprises administering to the subject the atezolizumab after the tiragolumab.

110. A method for treating a subject having a hematologic cancer, the method comprising administering to the subject an anti-TIGIT antagonist antibody at a fixed dose of about 840 mg, an anti- CD38 antibody at a dose of about 1800 mg, and a PD-1 axis binding antagonist at a dose of about 1680 mg in a dosing regimen comprising at least nine dosing cycles, wherein:

(a) the anti-TIGIT antagonist antibody is administered once every four weeks;

(b) the PD-1 axis binding antagonist is administered once every four weeks; and

111 . A method for treating a subject having a hematologic cancer, the method comprising administering to the subject an anti-TIGIT antagonist antibody at a fixed dose of about 420 mg, an anti- CD38 antibody at a dose of about 1800 mg, and a PD-1 axis binding antagonist at a dose of about 840 mg in a dosing regimen comprising at least nine dosing cycles, wherein:

(a) the anti-TIGIT antagonist antibody is administered once every two weeks;

(b) the PD-1 axis binding antagonist is administered once every two weeks; and

112. A method for treating a subject having a hematologic cancer, the method comprising administering to the subject an anti-TIGIT antagonist antibody at a fixed dose of about 840 mg, an anti- CD38 antibody at a dose of about 1800 mg, and a PD-1 axis binding antagonist at a dose of about 1680 mg in a dosing regimen comprising at least 19 dosing cycles, wherein:

(a) the anti-TIGIT antagonist antibody is administered once every four weeks;

(b) the PD-1 axis binding antagonist is administered once every four weeks; and

113. A method for treating a subject having a hematologic cancer, the method comprising administering to the subject an anti-TIGIT antagonist antibody at a fixed dose of about 420 mg, an anti- CD38 antibody at a dose of about 1800 mg, and a PD-1 axis binding antagonist at a dose of about 840 mg in a dosing regimen comprising at least 19 dosing cycles, wherein:

(a) the anti-TIGIT antagonist antibody is administered once every two weeks;

(b) the PD-1 axis binding antagonist is administered once every two weeks; and

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114. The method of any one of claims 110-113, wherein the length of each dosing cycle is 21 days.

115. A kit comprising an anti-TIGIT antagonist antibody, an PD-1 axis binding antagonist, and an anti- CD38 antibody, and a package insert comprising instructions to administer the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, and the anti-CD38 antibody to a subject having a hematologic cancer in accordance with the methods of any one of claimsl -99 and 110-114.

116. The kit of claim 115, wherein the anti-TIGIT antagonist antibody is tiragolumab, the PD-1 axis binding antagonist is atezolizumab, and the anti-CD38 antibody is daratumumab.