WO2018223004A1

WO2018223004A1 - Bispecific antibodies that bind cd20 and cd3

Info

Publication number: WO2018223004A1
Application number: PCT/US2018/035616
Authority: WO
Inventors: Michael Wayne SAVILLE; Paul Foster
Original assignee: Xencor, Inc.
Priority date: 2017-06-01
Filing date: 2018-06-01
Publication date: 2018-12-06

Abstract

The present invention is directed to methods of administrating bispecific anti-CD20 x anti-CD3 antibodies.

Description

BISPECIFIC ANTIBODIES THAT BIND CD20 AND CD3

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent

Application No. 62/513,922, filed June 1, 2017, which is expressly incorporated herein by reference in its entirety, with particular reference to the figures, legends and claims therein.

BACKGROUND OF THE INVENTION

[0002] Antibody-based therapeutics have been used successfully to treat a variety of diseases, including cancer and autoimmune/inflammatory disorders. Yet improvements to this class of drugs are still needed, particularly with respect to enhancing their clinical efficacy. One avenue being explored is the engineering of additional and novel antigen binding sites into antibody-based drugs such that a single immunoglobulin molecule co-engages two different antigens. Because the considerable diversity of the antibody variable region (Fv) makes it possible to produce an Fv that recognizes virtually any molecule, the typical approach to the generation of such bispecific antibodies is the introduction of new variable regions into the antibody.

[0003] A number of alternate antibody formats have been explored for bispecific targeting

(Chames & Baty, 2009, mAbs l [6]: l-9; Holliger & Hudson, 2005, Nature Biotechnology

23 [9]: 1126-1136; Kontermann, mAbs 4(2): 182 (2012), all of which are expressly incorporated herein by reference). Initially, bispecific antibodies were made by fusing two cell lines that each produced a single monoclonal antibody (Milstein et al., 1983, Nature 305:537-540). Although the resulting hybrid hybridoma or quadroma did produce bispecific antibodies, they were only a minor population, and extensive purification was required to isolate the desired antibody. An engineering solution to this was the use of antibody fragments to make bispecifics. Because such fragments lack the complex quaternary structure of a full length antibody, variable light and heavy chains can be linked in single genetic constructs. Antibody fragments of many different forms have been generated, including diabodies, single chain diabodies, tandem scFvs, and Fab₂ bispecifics (Chames & Baty, 2009, mAbs l [6]: l-9; Holliger & Hudson, 2005, Nature Biotechnology 23[9]: 1126-1136; expressly incorporated herein by reference). While these formats can be expressed at high levels in bacteria and may have favorable penetration benefits due to their small size, they clear rapidly in vivo and can present manufacturing obstacles related to their production and stability. A principal cause of these drawbacks is that antibody fragments typically lack the constant region of the antibody with its associated functional properties, including larger size, high stability, and binding to various Fc receptors and ligands that maintain long half-life in serum (i.e. the neonatal Fc receptor FcRn) or serve as binding sites for purification (i.e. protein A and protein G).

[0004] More recent work has attempted to address the shortcomings of fragment-based bispecifics by engineering dual binding into full length antibody -like formats (Wu et al., 2007, Nature Biotechnology 25[11]: 1290-1297; USSN12/477,711; Michaelson et al., 2009, mAbs 1 [2]: 128-141; PCT/US2008/074693; Zuo et al., 2000, Protein Engineering 13[5]:361-367; USSN09/865,198; Shen et al., 2006, J Biol Chem 281 [16]: 10706-10714; Lu et al., 2005, J Biol Chem 280[20]: 19665- 19672; PCT/US2005/025472; expressly incorporated herein by reference). These formats overcome some of the obstacles of the antibody fragment bispecifics, principally because they contain an Fc region. One significant drawback of these formats is that, because they build new antigen binding sites on top of the homodimeric constant chains, binding to the new antigen is always bivalent.

[0005] For many antigens that are attractive as co-targets in a therapeutic bispecific format, the desired binding is monovalent rather than bivalent. For many immune receptors, cellular activation is accomplished by cross-linking of a monovalent binding interaction. The mechanism of cross- linking is typically mediated by antibody/antigen immune complexes, or via effector cell to target cell engagement. For example, the low affinity Fc gamma receptors (FcyRs) such as FcyRIIa, FcyRIIb, and FcyRIIIa bind monovalently to the antibody Fc region. Monovalent binding does not activate cells expressing these FcyRs; however, upon immune complexation or cell-to-cell contact, receptors are cross-linked and clustered on the cell surface, leading to activation. For receptors responsible for mediating cellular killing, for example FcyRIIIa on natural killer (NK) cells, receptor cross-linking and cellular activation occurs when the effector cell engages the target cell in a highly avid format (Bowles & Weiner, 2005, J Immunol Methods 304:88-99, expressly incorporated by reference). Similarly, on B cells the inhibitory receptor FcyRIIb downregulates B cell activation only when it engages into an immune complex with the cell surface B-cell receptor (BCR), a mechanism that is mediated by immune complexation of soluble IgG's with the same antigen that is recognized by the BCR (Heyman 2003, Immunol Lett 88[2]: 157-161; Smith and Clatworthy, 2010, Nature Reviews Immunology 10:328-343; expressly incorporated by reference). As another example, CD3 activation of T-cells occurs only when its associated T-cell receptor (TCR) engages antigen-loaded MHC on antigen presenting cells in a highly avid cell-to-cell synapse (Kuhns et al., 2006, Immunity 24: 133-139). Indeed nonspecific bivalent cross-linking of CD3 using an anti-CD3 antibody elicits a cytokine storm and toxicity (Perruche et al., 2009, J Immunol 183[2]:953-61; Chatenoud & Bluestone, 2007, Nature Reviews Immunology 7:622-632; expressly incorporated by reference). Thus for practical clinical use, the preferred mode of CD3 co- engagement for redirected killing of targets cells is monovalent binding that results in activation only upon engagement with the co-engaged target.

[0006] Accordingly, there is a need for improved bispecific anti-CD20 x anti-CD3 antibodies and the use of such antibodies for use in therapy.

BRIEF SUMMARY OF THE INVENTION

[0007] In one aspect, the invention provides a method for treating a CD20-expressing cancer in a subject, comprising administering to the subject having the CD20-expressing cancer an intravenous dose of a bispecific anti-CD20 x anti-CD3 antibody, for a time period sufficient to treat the CD20- expressing cancer, in combination with at least one other therapeutic agent, wherein at least one of the other therapeutic agent is selected from the group consisting of PDl inhibitors, PDLl inhibitors, PDL2 inhibitors, TIM3 inhibitors, LAG3 inhibitors, CTLA4 inhibitors, TIGIT inhibitors, BTLA inhibitors, CD47 inhibitors, IDO inhibitors, GITR agonists, and ICOS agonists.

[0008] In an exemplary embodiment, the CD20-expressing cancer is a lymphoma.

[0009] In an exemplary embodiment, the bispecific anti-CD20 x anti-CD3 antibody comprises: a) a first monomer comprising SEQ ID NO: 1; b) a second monomer comprising SEQ ID NO: 2; and c) a light chain comprising SEQ ID NO: 3. In an exemplary embodiment, the bispecific anti-CD20 x anti-CD3 antibody comprises: a) an anti-CD20 variable heavy (VH) domain comprising SEQ ID NO: 22; b) an anti-CD20 variable light (VL) domain comprising SEQ ID NO: 23; c) an anti-CD3 variable heavy (VH) domain comprising SEQ ID NO: 24; and d) an anti-CD3 variable light (VL) domain comprising SEQ ID NO: 25. In an exemplary embodiment, the bispecific anti-CD20 x anti-CD3 antibody comprises a) an anti-CD3 VH domain comprising a VHCDR1 comprising SEQ ID NO: 26, a VHCDR2 comprising SEQ ID NO: 27 and a VHCDR3 comprising SEQ ID NO: 28; b) an anti-CD3 VL domain comprising a VLCDR1 comprising SEQ ID NO: 29, a VLCDR2 comprising SEQ ID NO: 30 and a VLCDR3 comprising SEQ ID NO: 31; c) an anti-CD20 VH domain comprising a VHCDR1 comprising SEQ ID NO: 32, a VHCDR2 comprising SEQ ID NO: 33 and a VHCDR3 comprising SEQ ID NO: 34; d) an anti-CD20 VL domain comprising a

VLCDRl comprising SEQ ID NO: 35, a VLCDR2 comprising SEQ ID NO: 36 and a VLCDR3 comprising SEQ ID NO: 37. In an exemplary embodiment, the bispecific anti-CD20 x anti-CD3 antibody is XmAbl3676.

[0010] In an exemplary embodiment, the at least one of the other therapeutic agents is a PD1 inhibitor. In an exemplary embodiment, the PD1 inhibitor is an anti-PDl antibody. In an exemplary embodiment, the anti-PDl antibody is selected from the group consisting of nivolumab (Opdivo®), pembrolizumab (Keytruda®), pidilizumab (Medivation/Pfizer), spartalizumab, JNJ- 63723283 (J&J), TSR-042 (Tesaro), cemiplimab (Sanofi), AMP-224 (Amplimmune/GSK), MEDI0680 (AstraZeneca), MGA012 (MacroGenics/Incyte), MGD013 (MacroGenics), MGD019 (MacroGenics), SHR-1210 (Shanghai Hengrui Pharma/Incyte), GLS-010 (Gloria Pharma/WuXi Biologies), JS001 (Shanghai Junshi Biosciences), tislelizumab (BeiGene/Celgene), sintilimab (Innovent), CX-188 (CytomX Therapeutics), and CS1003 (CStone Pharmaceuticals). In an exemplary embodiment, the anti-PDl antibody is selected from the group consisting of nivolumab (Opdivo®; BMS), pembrolizumab (Keytruda®; Merck), and pidilizumab (Medivation/Pfizer). In an exemplary embodiment, the anti-PDl antibody is spartalizumab. In an exemplary embodiment, the at least one of the other therapeutic agents is a PDL1 inhibitor. In an exemplary embodiment, the PDL1 inhibitor is an anti-PDLl antibody. In an exemplary embodiment, the anti-PDLl antibody is selected from the group consisting of atezolizumab (Tecentriq®; Genentech/Roche), avelumab (Bavencio®; EMD Serono), durvalumab (Imfinzi®; Medlmmune/AstraZeneca), FAZ053, LY3300054 (Lilly), ABBV-181 (Abb Vie), MSB2311 (MabSpace Biosciences), BMS- 936559, CSIOOI (CStone Pharmaceuticals), KN035 (Alphamab), CA-327 (Curis), CX-072

(CytomX Therapeutics), M7824 (EMD Serono), HTI-1316 (Hengrui Therapeutics), and JS003 (Shanghai Junshi Biosciences). In an exemplary embodiment, the at least one other therapeutic agent further comprises a chemotherapeutic. In an exemplary embodiment, the chemotherapeutic is selected from the group consisting of alkylating agents, anti-metabolites, kinase inhibitors, proteasome inhibitors, vinca alkaloids, anthracyclines, antitumor antibiotics, aromatase inhibitors, topoisomerase inhibitors, mTOR inhibitors, retinoids, and combinations thereof. In an exemplary embodiment, the at least one other therapeutic agent further comprises a side-effect ameliorating agent. In an exemplary embodiment, the side-effect ameliorating agent is selected from the group consisting of: a steroid, an antihistamine, anti-allergic agents, antinausea agents (or anti-emetics), analgesic agent, antipyretic agent, cytoprotective agents, vasopressor agents, anticonvulsant agent, TNFa inhibitor, IL6 inhibitor, and combinations thereof. In an exemplary embodiment, the side- effect ameliorating agent is selected from the group consisting of corticosteroids, TNFa inhibitors, IL-1R inhibitors, and IL-6 inhibitors wherein said side-effect ameliorating agent is a combination of a corticosteroid, Benadryl® and Tylenol®, wherein said corticosteroid, Benadryl® and

Tylenol® are administered to said human subject prior to the administration of said bispecific anti- CD20 x anti-CD3 antibody. In an exemplary embodiment, the bispecific anti-CD20 x anti-CD3 antibody and the at least one other therapeutic agent are administered concurrently. In an exemplary embodiment, the administration of the at least one other therapeutic agent begins before the administration of the bispecific anti-CD20 x anti-CD3 antibody.

[0011] In an exemplary embodiment, the subject is a mammal. In an exemplary embodiment, the subject is a human subject.

[0012] In one aspect, the intravenous dose according to the present invention is administered to a human subject between about 1 hour and about 3 hours. In some embodiments, the time period sufficient to treat a CD20-expressing cancer, e.g., a hematologic cancer, e.g., leukemia in a human subject is between about 3 weeks and 9 weeks. In some embodiments, the time period sufficient to treat a CD20-expressing cancer, e.g., a hematologic cancer, e.g., leukemia in a human subject is between about 4 weeks and 9 weeks.

[0013] In an exemplary embodiment, the CD20-expressing cancer is a lymphoma. In an exemplary embodiment, the lymphoma is Non-Hodgkin lymphoma. In an exemplary embodiment, the Non- Hodgkin lymphoma is B-cell NHL.

[0014] In one aspect, a human subject that is being treated according to the present invention has lymphoma, for example, Non-Hodgkin lymphoma is selected from the group consisting of chronic lymphocytic leukemia, small lymphocytic leukemia, B-cell prolymphoctyic leukemia, transformed leukemia, Burkitt's lymphoma, mantle cell lymphoma, hairy cell leukemia, splenic marginal zone lymphoma, Waldenstrom's macroglobulinemia, variant hairy cell leukemia, splenic B cell lymphoma/1 eukemia, lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B cell lymphoma, follicular lymphoma, in situ follicular neoplasia, duodenal follicular lymphoma, large B cell lymphoma with IFR4 rearrangement, primary cutaneous follicle center lymphoma, diffuse large B cell lymphoma (DLBCL), T-cell/histocyte-rich large B cell lymphoma, primary cutaneous DLBCL (leg type), EBV-positive DLBCL NOS, EBV-positive mucocutaneous ulcer, DLCBL associated with chronic inflammation, lymphomatoid granulomatosis, primary mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, ALK+ large B-cell lymphoma, plasmablastic lymphoma, primary effusion lymphoma, HHV8+DLBCL, Burkitt-like lymphoma with 1 lq aberration, high grade B cell lymphoma NOS, B cell lymphoma unclassifiable, and post-transplant lymphoproliferation disorder (PTLD). In an exemplary embodiment, the Non-Hodgkin lymphoma is chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).

[0015] In one aspect, the methods and antibodies of the present invention further comprise, prior to the administering, assessing the weight of the human subject. In an exemplary embodiment, the time period sufficient to treat the leukemia is between about 3 weeks and 9 weeks. In an exemplary embodiment, the time period sufficient to treat the leukemia is between about 3 weeks and 9 weeks. In an exemplary embodiment, the bispecific anti-CD20 x anti-CD3 antibody and the at least one other therapeutic agent are administered concurrently. In an exemplary embodiment, the administration of the at least one other therapeutic agent begins before the administration of the bispecific anti-CD20 x anti-CD3 antibody.

[0016] In an exemplary embodiment, the intravenous dose is between about 18 μg/kg and about 22 μg/kg; or between about 40 μg/kg and about 50 μg/kg; or between about 75 μg/kg and about 85 μg/kg; or between about 120 μg/kg and about 130 μg/kg; or between about 165 μg/kg and about 175 μ_§^_§.

BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 depicts a particularly useful bispecific format of the invention, referred to as a "bottle opener", which is also the format of XmAbl3676. It should be noted that the scFv and Fab domains can be switched (e.g. anti-CD3 as a Fab, and anti-CD20 as a scFv).

[0018] Figure 2 depicts the sequences of the three polypeptide chains that make up XmAbl3676, an anti-CD20 x anti-CD3 antibody of particular use in the present invention. The CDRs are underlined and the junction between domains is denoted by a slash ("/"). The charged scFv linker is double underlined; as will be appreciated by those in the art, the linker may be substituted with other linkers, and particularly other charged linkers that are depicted in Figure 7 of US Publication Number 2014/0288275, or other non-charged linkers (SEQ ID NO:441 of US Publication Number 2014/0288275).

[0019] Figure 3A-3E depicts additional anti-CD20 x anti-CD3 sequences of the invention, with the CDRs underlined.

[0020] Figure 4A-4D depicts additional bispecific formats of use in the present invention, as are generally described in Figure 1 and the accompanying Legend and supporting text of USSN 14/952,714 (incorporated herein by reference).

[0021] Figure 5 is a line graph showing XmAbl3676 potently kills multiple CD20-positive B cell lines.

[0022] Figure 6 is a line graph showing XmAbl3676 stimulates activation of CD8+ T cells in the presence of CD20-expressing B cell lines.

[0023] Figure 7 is a line graph showing XmAbl3676 retains RTCC activity in the presence of rituximab.

[0024] Figure 8 is a line graph showing XmAbl3676-mediated CD69 induction on CD8 T cells in CLL and normal PBMC.

[0025] Figure 9 is a bar graph showing CLL depletion in PBMC enriched with normal T cells.

[0026] Figure 10 is a dot graph showing XmAbl3676 depletes follicular lymphoma (CD19+ CD10+) cells in human subject PBMC samples.

[0027] Figure 11 is a line graph showing XmAbl3676 prevents Raji tumor growth in huPBMC-NSG mice.

DETAILED DESCRIPTION OF THE INVENTION

I. Definitions

[0028] In order that the application may be more completely understood, several definitions are set forth below. Such definitions are meant to encompass grammatical equivalents.

[0029] By "CD3" or "cluster of differentiation 3" herein is meant a T-cell co-receptor that helps in activation of both cytotoxic T-cell (e.g., CD8+ naive T cells) and T helper cells (e.g., CD4+ naive T cells) and is composed of four distinct chains: one CD3y chain (e.g., Genbank Accession Numbers NM_000073 and MP_000064 (human)), one CD35 chain (e.g., Genbank Accession Numbers M_000732, M_001040651, P_00732 and P_001035741 (human)), and two CD3s chains (e.g., Genbank Accession Numbers NM_000733 and NP_00724 (human)). The chains of CD3 are highly related cell-surface proteins of the immunoglobulin superfamily containing a single extracellular immunoglobulin domain. The CD3 molecule associates with the T-cell receptor (TCR) and ζ-chain to form the T-cell receptor (TCR) complex, which functions in generating activation signals in T lymphocytes.

[0030] By "B-lymphocyte antigen CD20" or "CD20" or "CD20 antigen" or "CD20 Receptor" or "Membrane Spanning 4-Domains Al" or "Membrane- Spanning 4-Domains, Subfamily A, Member 1" or "Leukocyte Surface Antigen Leu- 16" or "Bp35" or "B-Lymphocyte Cell-Surface Antigen 1" or "LEU-16" or "CVID5" or "MS4A1" or "Bl" or "S7" herein is meant an activated-glycosylated phosphoprotein expressed on the surface of B-cells and is encoded by the MS4A1 gene in humans (e.g., Genbank Accession Numbers NM_152866, NM_021950, NP_068769 and NP_690605 (human)). CD20 plays a role in the development and differentiation of B-cells into plasma cells.

[0031] By "bispecific" or "bispecific antibody" herein is meant any non-native or alternate antibody formats, including those described herein, that engage two different antigens (e.g., CD3 x CD20 bispecific antibodies).

[0032] By "modification" herein is meant an amino acid substitution, insertion, and/or deletion in a polypeptide sequence or an alteration to a moiety chemically linked to a protein. For example, a modification may be an altered carbohydrate or PEG structure attached to a protein. By "amino acid modification" herein is meant an amino acid substitution, insertion, and/or deletion in a polypeptide sequence. For clarity, unless otherwise noted, the amino acid modification is always to an amino acid coded for by DNA, e.g. the 20 amino acids that have codons in DNA and RNA.

[0033] By "amino acid substitution" or "substitution" herein is meant the replacement of an amino acid at a particular position in a parent polypeptide sequence with a different amino acid. In particular, in some embodiments, the substitution is to an amino acid that is not naturally occurring at the particular position, either not naturally occurring within the organism or in any organism. For example, the substitution E272Y refers to a variant polypeptide, in this case an Fc variant, in which the glutamic acid at position 272 is replaced with tyrosine. For clarity, a protein which has been engineered to change the nucleic acid coding sequence but not change the starting amino acid (for example exchanging CGG (encoding arginine) to CGA (still encoding arginine) to increase host organism expression levels) is not an "amino acid substitution"; that is, despite the creation of a new gene encoding the same protein, if the protein has the same amino acid at the particular position that it started with, it is not an amino acid substitution.

[0034] By "amino acid insertion" or "insertion" as used herein is meant the addition of an amino acid sequence at a particular position in a parent polypeptide sequence. For example, -233E or 233E designates an insertion of glutamic acid after position 233 and before position 234.

Additionally, -233ADE or A233ADE designates an insertion of AlaAspGlu after position 233 and before position 234.

[0035] By "amino acid deletion" or "deletion" as used herein is meant the removal of an amino acid sequence at a particular position in a parent polypeptide sequence. For example, E233- or E233# designates a deletion of glutamic acid at position 233. Additionally, EDA233- or EDA233# designates a deletion of the sequence GluAspAla that begins at position 233.

[0036] By "variant protein" or "protein variant", or "variant" as used herein is meant a protein that differs from that of a parent protein by virtue of at least one amino acid modification. Protein variant may refer to the protein itself, a composition comprising the protein, or the amino sequence that encodes it. Preferably, the protein variant has at least one amino acid modification compared to the parent protein, e.g. from about one to about seventy amino acid modifications, and preferably from about one to about five amino acid modifications compared to the parent. As described below, in some embodiments the parent polypeptide, for example an Fc parent polypeptide, is a human wild type sequence, such as the Fc region from IgGl, IgG2, IgG3 or IgG4, although human sequences with variants can also serve as "parent polypeptides". The protein variant sequence herein will preferably possess at least about 80% identity with a parent protein sequence, and most preferably at least about 90% identity, more preferably at least about 95-98-99%) identity. Variant protein can refer to the variant protein itself, compositions comprising the protein variant, or the

DNA sequence that encodes it. Accordingly, by "antibody variant" or "variant antibody" as used herein is meant an antibody that differs from a parent antibody by virtue of at least one amino acid modification, "IgG variant" or "variant IgG" as used herein is meant an antibody that differs from a parent IgG (again, in many cases, from a human IgG sequence) by virtue of at least one amino acid modification, and "immunoglobulin variant" or "variant immunoglobulin" as used herein is meant an immunoglobulin sequence that differs from that of a parent immunoglobulin sequence by virtue of at least one amino acid modification. "Fc variant" or "variant Fc" as used herein is meant a protein comprising an amino acid modification in an Fc domain. The Fc variants of the present invention are defined according to the amino acid modifications that compose them. Thus, for example, N434S or 434S is an Fc variant with the substitution serine at position 434 relative to the parent Fc polypeptide, wherein the numbering is according to the EU index. Likewise,

M428L/N434S defines an Fc variant with the substitutions M428L and N434S relative to the parent Fc polypeptide. The identity of the WT amino acid may be unspecified, in which case the aforementioned variant is referred to as 428L/434S. It is noted that the order in which substitutions are provided is arbitrary, that is to say that, for example, 428L/434S is the same Fc variant as M428L/N434S, and so on. For all positions discussed in the present invention that relate to antibodies, unless otherwise noted, amino acid position numbering is according to the EU index. The EU index or EU index as in Kabat or EU numbering scheme refers to the numbering of the EU antibody (Edelman et al., 1969, Proc Natl Acad Sci USA 63 :78-85, hereby entirely incorporated by reference.) The modification can be an addition, deletion, or substitution. Substitutions can include naturally occurring amino acids and, in some cases, synthetic amino acids. Examples include U.S. Pat. No. 6,586,207; WO 98/48032; WO 03/073238; US2004-0214988A1; WO 05/35727A2; WO 05/74524A2; J. W. Chin et al., (2002), Journal of the American Chemical Society 124:9026-9027; J. W. Chin, & P. G. Schultz, (2002), ChemBioChem 11 : 1135-1137; J. W. Chin, et al., (2002), PICAS United States of America 99: 11020-11024; and, L. Wang, & P. G. Schultz, (2002), Chem. 1-10, all entirely incorporated by reference.

[0037] As used herein, "protein" herein is meant at least two covalently attached amino acids, which includes proteins, polypeptides, oligopeptides and peptides. The peptidyl group may comprise naturally occurring amino acids and peptide bonds, or synthetic peptidomimetic structures, i.e. "analogs", such as peptoids (see Simon et al., PNAS USA 89(20):9367 (1992), entirely incorporated by reference). The amino acids may either be naturally occurring or synthetic (e.g. not an amino acid that is coded for by DNA); as will be appreciated by those in the art. For example, homo-phenylalanine, citrulline, ornithine and noreleucine are considered synthetic amino acids for the purposes of the invention, and both D- and L-(R or S) configured amino acids may be utilized. The variants of the present invention may comprise modifications that include the use of synthetic amino acids incorporated using, for example, the technologies developed by Schultz and colleagues, including but not limited to methods described by Cropp & Shultz, 2004, Trends Genet. 20(12):625-30, Anderson et al., 2004, Proc Natl Acad Sci USA 101 (2):7566-71, Zhang et al., 2003, 303(5656):371-3, and Chin et al., 2003, Science 301(5635):964-7, all entirely incorporated by reference. In addition, polypeptides may include synthetic derivatization of one or more side chains or termini, glycosylation, PEGylation, circular permutation, cyclization, linkers to other molecules, fusion to proteins or protein domains, and addition of peptide tags or labels.

[0038] By "residue" as used herein is meant a position in a protein and its associated amino acid identity. For example, Asparagine 297 (also referred to as Asn297 or N297) is a residue at position 297 in the human antibody IgGl .

[0039] By "Fab" or "Fab region" as used herein is meant the polypeptide that comprises the VH, CHI, VL, and CL immunoglobulin domains. Fab may refer to this region in isolation, or this region in the context of a full length antibody, antibody fragment or Fab fusion protein. By "Fv" or "Fv fragment" or "Fv region" as used herein is meant a polypeptide that comprises the VL and VH domains of a single antibody. As will be appreciated by those in the art, these generally are made up of two chains.

[0040] By "amino acid" and "amino acid identity" as used herein is meant one of the 20 naturally occurring amino acids that are coded for by DNA and RNA.

[0041] By "IgG Fc ligand" as used herein is meant a molecule, preferably a polypeptide, from any organism that binds to the Fc region of an IgG antibody to form an Fc/Fc ligand complex. Fc ligands include but are not limited to FcyRIs, FcyRIIs, FcyRIIIs, FcRn, Clq, C3, mannan binding lectin, mannose receptor, staphylococcal protein A, streptococcal protein G, and viral FcyR. Fc ligands also include Fc receptor homologs (FcRH), which are a family of Fc receptors that are homologous to the FcyRs (Davis et al., 2002, Immunological Reviews 190: 123-136, entirely incorporated by reference). Fc ligands may include undiscovered molecules that bind Fc. Particular IgG Fc ligands are FcRn and Fc gamma receptors. By "Fc ligand" as used herein is meant a molecule, preferably a polypeptide, from any organism that binds to the Fc region of an antibody to form an Fc/Fc ligand complex.

[0042] By "Fc gamma receptor", "FcyR" or "FcqammaR" as used herein is meant any member of the family of proteins that bind the IgG antibody Fc region and is encoded by an FcyR gene. In humans this family includes but is not limited to FcyRI (CD64), including isoforms FcyRIa, FcyRIb, and FcyRIc; FcyRII (CD32), including isoforms FcyRIIa (including allotypes H131 and R131), FcyRIIb (including FcyRIIb-l and FcyRIIb-2), and FcyRIIc; and FcyRIII (CD16), including isoforms FcyRIIIa (including allotypes VI 58 and F158) and FcyRIIIb (including allotypes FcyRIIb- NA1 and FcyRIIb-NA2) (Jefferis et al., 2002, Immunol Lett 82:57-65, entirely incorporated by reference), as well as any undiscovered human FcyRs or FcyR isoforms or allotypes. An FcyR may be from any organism, including but not limited to humans, mice, rats, rabbits, and monkeys.

Mouse FcyRs include but are not limited to FcyRI (CD64), FcyRII (CD32), FcyRIII (CD 16), and FCYRIII-2 (CD 16-2), as well as any undiscovered mouse FcyRs or FcyR isoforms or allotypes.

[0043] By "FcRn" or "neonatal Fc Receptor" as used herein is meant a protein that binds the IgG antibody Fc region and is encoded at least in part by an FcRn gene. The FcRn may be from any organism, including but not limited to humans, mice, rats, rabbits, and monkeys. As is known in the art, the functional FcRn protein comprises two polypeptides, often referred to as the heavy chain and light chain. The light chain is beta-2-microglobulin and the heavy chain is encoded by the FcRn gene. Unless otherwise noted herein, FcRn or an FcRn protein refers to the complex of FcRn heavy chain with beta-2-microglobulin. A variety of FcRn variants can be used to increase binding to the FcRn receptor, and in some cases, to increase serum half-life.

[0044] By "parent polypeptide" as used herein is meant a starting polypeptide that is subsequently modified to generate a variant. The parent polypeptide may be a naturally occurring polypeptide, or a variant or engineered version of a naturally occurring polypeptide. Parent polypeptide may refer to the polypeptide itself, compositions that comprise the parent polypeptide, or the amino acid sequence that encodes it. Accordingly, by "parent immunoglobulin" as used herein is meant an unmodified immunoglobulin polypeptide that is modified to generate a variant, and by "parent antibody" as used herein is meant an unmodified antibody that is modified to generate a variant antibody. It should be noted that "parent antibody" includes known commercial, recombinantly produced antibodies as outlined below.

[0045] By "Fc" or "Fc region" or "Fc domain" as used herein is meant the polypeptide comprising the constant region of an antibody excluding the first constant region immunoglobulin domain and in some cases, part of the hinge. Thus Fc refers to the last two constant region immunoglobulin domains of IgA, IgD, and IgG, the last three constant region immunoglobulin domains of IgE and

IgM, and the flexible hinge N-terminal to these domains. For IgA and IgM, Fc may include the J chain. For IgG, the Fc domain comprises immunoglobulin domains Cy2 and Cy3 (Cy2 and Cy3) and the lower hinge region between Cyl (Cyl) and Cy2 (Cy2). Although the boundaries of the Fc region may vary, the human IgG heavy chain Fc region is usually defined to include residues C226 or P230 to its carboxyl-terminus, wherein the numbering is according to the EU index as in Kabat. In some embodiments, as is more fully described below, amino acid modifications are made to the Fc region, for example to alter binding to one or more FcyR receptors or to the FcRn receptor.

[0046] By "heavy constant region" herein is meant the CHl-hinge-CH2-CH3 portion of an antibody.

[0047] By "position" as used herein is meant a location in the sequence of a protein. Positions may be numbered sequentially, or according to an established format, for example the EU index for antibody numbering.

[0048] By "target antigen" as used herein is meant the molecule that is bound specifically by the variable region of a given antibody. The two target antigens of the present invention are human CD3 and human CD20.

[0049] By "strandedness" in the context of the monomers of the heterodimeric antibodies of the invention herein is meant that, similar to the two strands of DNA that "match", heterodimerization variants are incorporated into each monomer so as to preserve the ability to "match" to form heterodimers. For example, if some pi variants are engineered into monomer A (e.g. making the pi higher) then steric variants that are "charge pairs" that can be utilized as well do not interfere with the pi variants, e.g. the charge variants that make a pi higher are put on the same "strand" or "monomer" to preserve both functionalities. Similarly, for "skew" variants that come in pairs of a set as more fully outlined below, the skilled artisan will consider pi in deciding into which strand or monomer that incorporates one set of the pair will go, such that pi separation is maximized using the pi of the skews as well.

[0050] By "target cell" as used herein is meant a cell that expresses a target antigen.

[0051] By "variable region" as used herein is meant the region of an immunoglobulin that comprises one or more Ig domains substantially encoded by any of the VK, νλ, and/or VH genes that make up the kappa, lambda, and heavy chain immunoglobulin genetic loci respectively.

[0052] By "wild type or WT" herein is meant an amino acid sequence or a nucleotide sequence that is found in nature, including allelic variations. A WT protein has an amino acid sequence or a nucleotide sequence that has not been intentionally modified. [0053] The antibodies of the present invention are generally isolated or recombinant. "Isolated," when used to describe the various polypeptides disclosed herein, means a polypeptide that has been identified and separated and/or recovered from a cell or cell culture from which it was expressed. Ordinarily, an isolated polypeptide will be prepared by at least one purification step. An "isolated antibody," refers to an antibody which is substantially free of other antibodies having different antigenic specificities. "Recombinant" means the antibodies are generated using recombinant nucleic acid techniques in exogeneous host cells.

[0054] "Specific binding" or "specifically binds to" or is "specific for" a particular antigen or an epitope means binding that is measurably different from a non-specific interaction. Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule, which generally is a molecule of similar structure that does not have binding activity. For example, specific binding can be determined by competition with a control molecule that is similar to the target.

[0055] Specific binding for a particular antigen or an epitope can be exhibited, for example, by an antibody having a KD for an antigen or epitope of at least about 10^"4 M, at least about 10^"5 M, at least about 10^"6 M, at least about 10^"7 M, at least about 10^"8 M, at least about 10^"9 M, alternatively at least about 10^"10 M, at least about 10^"11 M, at least about 10^"12 M, or greater, where KD refers to a dissociation rate of a particular antibody-antigen interaction. Typically, an antibody that specifically binds an antigen will have a KD that is 20-, 50-, 100-, 500-, 1000-, 5,000-, 10,000- or more times greater for a control molecule relative to the antigen or epitope.

[0056] Also, specific binding for a particular antigen or an epitope can be exhibited, for example, by an antibody having a KA or Ka for an antigen or epitope of at least 20-, 50-, 100-, 500-, 1000-, 5,000-, 10,000- or more times greater for the epitope relative to a control, where KA or Ka refers to an association rate of a particular antibody-antigen interaction. Binding affinity is generally measured using a Biacore assay.

[0057] As used herein, the term "target activity" refers to a biological activity capable of being modulated by a selective modulator. Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzymatic activity, tumor growth, and effects on particular biomarkers related to CD20 disorder pathology. [0058] By "refractory" in the context of a cancer is intended the particular cancer is resistant to, or non-responsive to, therapy with a particular therapeutic agent. A cancer can be refractory to therapy with a particular therapeutic agent either from the onset of treatment with the particular therapeutic agent (i.e., non-responsive to initial exposure to the therapeutic agent), or as a result of developing resistance to the therapeutic agent, either over the course of a first treatment period with the therapeutic agent or during a subsequent treatment period with the therapeutic agent.

[0059] As used herein, the ICso refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response, such as inhibition of the biological activity of CD20, in an assay that measures such response.

[0060] As used herein, ECso refers to a dosage, concentration or amount of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked or potentiated by the particular test compound.

II. Overview

[0061] In one aspect, the invention provides a method for treating a CD20-expressing cancer in a subject, comprising administering to the subject having the CD20-expressing cancer an intravenous dose of a bispecific anti-CD20 x anti-CD3 antibody, for a time period sufficient to treat the CD20- expressing cancer, in combination with at least one other therapeutic agent described herein.

[0062] In one aspect, the invention provides a method for treating a CD20-expressing cancer in a subject, comprising administering to the subject having the CD20-expressing cancer an intravenous dose of a bispecific anti-CD20 x anti-CD3 antibody, for a time period sufficient to treat the CD20- expressing cancer, in combination with at least one other chemotherapeutic agent described herein. In one aspect, the invention provides a method for treating a CD20-expressing cancer in a subject, comprising administering to the subject having the CD20-expressing cancer an intravenous dose of a bispecific anti-CD20 x anti-CD3 antibody, for a time period sufficient to treat the CD20- expressing cancer, in combination with at least one other side-effect ameliorating agent described herein.

[0063] The invention provides methods of treating a cancer that include cells expressing CD20 ("CD20-expressing cancer"), for example, a hematologic cancer, such as lymphoma or leukemia through the administration of certain bispecific anti-CD20 x anti-CD3 antibodies (e.g.,

XmAbl3676) at particular dosages. These particular dosages are reduced over those known in the art. The present invention also provides methods of combination therapies, for example, methods of treating a cancer that include cells expressing CD20 ("CD20-expressing cancer"), e.g., a hematologic cancer, such as lymphoma or leukemia, through the administration of certain bispecific anti-CD20 x anti-CD3 antibodies (e.g., XmAbl3676) in combination with one or more checkpoint inhibitors or agonists, such as an inhibitor of PD1, PDL1, TIM3, LAG3, CTLA4, TIGIT, or BTLA, or an agonist of ICOS.

III. Antibodies

[0064] The present invention is directed to the administration of bispecific anti-CD20 x anti-CD3 antibodies for the treatment of particular leukemias as outlined herein, as outlined in PCT

Application Nos. PCT/US 15/62772 (WO2016/086189), PCT/US 16/29797 (WO2016/182751), as well as USSNs 14/952,714, 15/141,350, 15/185,958, 62/085,117, 62/085,027, 62/084,908, 62/085,106, 62/159, 111, 62/251,005, and 62/250,971, all of which are expressly incorporated herein by reference, particularly for the bispecific formats of the figures, as well as all sequences, Figures and accompanying Legends therein.

[0065] In some embodiments, the bispecific anti-CD20 x anti-CD3 antibodies (e.g., XmAb 13676) have a "bottle opener" format as is generally depicted in Figure 1. In this embodiment, the anti- CD3 antigen binding domain is the scFv-Fc domain monomer and the anti-CD20 antigen binding domain is the Fab monomer (terms as used in US Publication Nos. 2014/0288275 and 2014- 0294823 as well as in USSN 15/141,350, all of which are expressly incorporated by reference in their entirety and specifically for all the definitions, sequences of anti-CD3 antigen binding domains and sequences of anti-CD20 antigen binding domains).

[0066] Alternate formats for the bispecific, heterodimeric anti-CD20 x anti-CD3 antibodies of the invention are shown in Figure 4, which also generally rely on the use of Fabs and scFv domains in different formats.

[0067] In addition, it is also possible to make non-heterodimeric anti-CD20 x anti-CD3 bispecific antibodies as are known in the art, that can be dosed at the same dosage levels as described herein for the heterodimeric bispecific anti-CD20 x anti-CD3 antibodies.

[0068] The anti-CD3 scFv antigen binding domain can have the sequence depicted in Figure 2, or can be selected from: 1) the set of 6 CDRs (vhCDRl, vhCDR2, vhCDR3, vlCDRl, vlCDR2 and vlCDR3) from any anti-CD3 antigen binding domain sequence depicted in Figures 2 and 6 of US

Publication No. 2014/0288275;

2) the variable heavy and variable light chains from any anti-CD3 antigen binding domain sequence depicted in Figures 2 and 6 of US Publication No. 2014/0288275;

3) the scFv domains from any anti-CD3 scFv sequence depicted in Figure 2 of US

Publication No. 2014/0288275;

4) any of the anti-CD3 antigen binding domains of Figure 2, 3, 4, 5, 6, and 7 of USSN 14/952,714;

5) other anti-CD3 variable heavy and variable light chains as are known in the art, that can be combined to form scFvs (or Fabs, when the format is reversed or an alternative format is used); and

6) any of the anti-CD3 antigen binding domains of Figure 2, 3, 4, 5, 6, and 7 of USSN 14/952,714.

[0069] The anti-CD20 Fab binding domain can have the sequence depicted in Figure 2 or 4, or can be selected from:

1) The set of 6 CDRs (vhCDRl, vhCDR2, vhCDR3, vlCDRl, vlCDR2 and vlCDR3) from any anti-CD20 antigen binding domain sequence depicted in USSN 62/084,908;

2) The variable heavy and variable light chains from any anti-CD20 antigen binding domain sequence depicted in USSN 62/084,908, including those depicted in Figures 2, 3 and 12; and

3) Other anti-CD20 variable heavy and variable light chains as are known in the art, that can be combined to form Fabs (or scFvs, when the format is reversed or an alternative format is used).

[0070] One bispecific antibody of particular use in the present invention, XmAbl3676, is shown in Figure 2 and Table 1 below. XmAbl3676 was alternatively known as XENP13676.

Table 1

XmAbl3676 Anti-CD20 x Anti-CD3 Sequences SEQ ID Sequence

NO

XmAbl3676 Anti-CD20 1 OVOLVOSGAEVKKPGASVKVSCKASGYTFTS x Anti-CD3 Fab-scFv- YNMHWVROAPGOGLEWMGAIYPGNGDTSYN Fc Heavy Chain 1 (Anti- QKFQGRVTITADKSISTAYMELSSLRSEDTAVY CD20 Fab-Fc YCARSTYYGGDWYFNVWGAGTLVTVSSAST (C2B8 H1)) KGP S VFPL AP S SK S T S GGT A ALGCL VKD YFPEP

VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSV

VTVPSSSLGTQTYICNVNHKPSDTKVDKKV/EP

KSCDKTHTCPPCPAPPVAGPSVFLFPPKPKDTL

MISRTPEVTCVVVDVKHEDPEVKFNWYVDGV

EVHNAKTKPREEEYNSTYRVVSVLTVLHQDW

LNGKEYKCKVS KALPAPIEKTISKAKGQPRE

PQVYTLPPSREEMTKNQVSLTCDVSGFYPSDIA

VEWESDGQPENNYKTTPPVLDSDGSFFLYSKL

TVDKSRWEQGDVFSCSVMHEALHNHYTQKSL

SLSPGK

XmAbl3676 Anti-CD20 2 EVQLVESGGGLVQPGGSLRLSCAASGFTFSTY x Anti-CD3 Fab-scFv- AMNWVROAPGKGLEWVGRIRSKYNNYATYY Fc Heavy Chain 2 (Anti- ADSVKGRFTISRDDSKNTLYLOMNSLRAEDTA CD3 scFv-Fc VYYCVRHG FGDSYVSWFAYWGOGTLVTVS (aCD3_H1.30_L1.47)) SGKPGSGKPGSGKPGSGKPGSOAVVTOEPSLT

VSPGGTVTLTCGSSTGAVTTSNYANWVOOKP

GKSPRGLIGGT KRAPGVP ARF SGSLLGGKAA

LTISGAOPEDEADYYCALWYS HWVFGGGTK

LTVL/EPKSSDKTHTCPPCPAPPVAGPSVFLFPP

KPKD TLMI SRTPE VTC V VVD VKHEDPEVKFN

WYVDGVEVHNAKTKPREEQYNSTYRVVSVLT

VLHQDWLNGKEYKCKVS KALPAPIEKTISKA

KGQPREPQVYTLPPSREQMTKNQVKLTCLVK

GF YPSDIAVEWESNGQPENNYKTTPPVLD SDG

SFFLYSKLTVDKSRWQQGNVFSCSVMHEALH HYTQKSLSLSPGK

XmAbl3676 Anti-CD20 3 OIVLTO SP S SLS AS VGDRVTITCRAS S S VS YIHW x Anti-CD3 Fab-scFv- FOOKPGKSPKPLIYATS LASGVPVRFSGSGSG Fc Light Chain (Anti- TDYTLTISSLOPEDFATYYCOOWTS PPTFGG CD20 LC (C2B8 L1)) GTKVEIK/RTVAAPSVFIFPPSDEQLKSGTASVV

CLLN FYPREAKVQWKVDNALQSGNSQESVT

EQD SKD STYSLSSTLTL SK AD YEKHK V Y ACE V

THQGL S SP VTK SF RGEC Table 1

XmAbl3676 Anti-CD20 x Anti-CD3 Sequences

SEQ ID Sequence

NO

XmAbl3676 Anti-CD20 22 OVOLVOSGAEVKKPGASVKVSCKASGYTFTS VH (C2B8 H1) YNMHWVROAPGOGLEWMGAIYPGNGDTSYN

QKFQGRVTITADKSISTAYMELSSLRSEDTAVY

YCARSTYYGGDWYFNVWGAGTLVTVSSAST

KGP S VFPL AP S SK S T S GGT A ALGCL VKD YFPEP

VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSV

VTWSSSLGTQTYICNVNHKPSDTKVDKKV

XmAbl3676 Anti-CD20 23 OIVLTO SP S SLS AS VGDRVTITCRAS S S VS YIHW VL (C2B8 L1) FOOKPGKSPKPLIYATS LASGVPVRFSGSGSG

TDYTLTISSLOPEDFATYYCOOWTS PPTFGG GTKVEIK

XmAbl3676 Anti-CD3 24 EVQLVESGGGLVQPGGSLRLSCAASGFTFSTY VH (H1.30) AMNWVROAPGKGLEWVGRIRSKYNNYATYY

ADSVKGRFTISRDDSKNTLYLOMNSLRAEDTA

VYYCVRHG FGDSYVSWFAYWGOGTLVTVS

S

XmAbl3676 Anti-CD3 25 0 AVVTOEP SLT VSPGGT VTLTCGS STGA VTT S VL (L1.47) NYANWVOOKPGKSPRGLIGGTNKRAPGVPAR

FSGSLLGGKAALTISGAOPEDEADYYCALWYS HW VF GGGTKLT VL

XmAbl3676 anti-CD3 26 TYAMN

VH CDR1

XmAbl3676 anti-CD3 27

RIRSKYNNYATYYADSVKG VH CDR2

XmAbl3676 anti-CD3 28

HG FGDSYVSWFAY VH CDR3

XmAbl3676 anti-CD3 29 GSSTGAVTTSNYAN

VL CDRl

XmAbl3676 anti-CD3 30 GTNKRAP

VL CDR2

XmAbl3676 anti-CD3 31 ALWYSNHWV

VL CDR3

XmAbl3676 anti-CD20 32 YTFTSYN

VH CDR1 Table 1

XmAbl3676 Anti-CD20 x Anti-CD3 Sequences

SEQ ID Sequence

NO

XmAbl3676 anti-CD20 33 PGNGD

VH CDR2

XmAbl3676 anti-CD20 34 STYYGGDWYFNV

VH CDR3

XmAbl3676 anti-CD20 35 SSVSY

VL CDRl

XmAbl3676 anti-CD20 36 ATSNLAS

VL CDR2

XmAbl3676 anti-CD20 37 WTSNPPT

VL CDR3

[0071] The XmAbl3676 antibody includes a first monomer comprising SEQ ID NO: 1, a second monomer comprising SEQ ID NO: 2, and a light chain comprising SEQ ID NO: 3. In some embodiments, the bispecific anti-CD20 x anti-CD3 antibody includes a first monomer comprising SEQ ID NO: 1, a second monomer comprising SEQ ID NO: 2 and a light chain comprising SEQ ID NO: 3, as depicted in Table 1. In some embodiments, the bispecific anti-CD20 x anti-CD3 antibody includes an anti-CD20 variable heavy (VH) domain comprising SEQ ID NO:22, an anti- CD20 variable light (VL) domain comprising SEQ ID NO:23, an anti-CD3 variable heavy (VH) domain comprising SEQ ID NO:24, and an anti-CD3 variable light (VL) domain comprising SEQ ID NO: 25, as depicted in Table 1. In certain embodiments, the bispecific anti-CD20 x anti-CD3 antibody includes an anti-CD3 binding domain comprising a VH CDR1 of SEQ ID NO: 26, a VH CDR2 of SEQ ID NO: 27, a VH CDR3 of SEQ ID NO: 28, a VL CDR1 of SEQ ID NO: 29, a VL CDR2 of SEQ ID NO: 30, a VL CDR3 of SEQ ID NO: 31; and an anti-CD20 binding domain comprising a VH CDR1 of SEQ ID NO: 32, a VH CDR2 of SEQ ID NO: 33, a VH CDR3 of SEQ ID NO: 34, a VL CDR1 of SEQ ID NO: 35, a VL CDR2 of SEQ ID NO: 36, and a VL CDR3 of SEQ ID NO: 37, as depicted in Table 1.

[0072] The bispecific anti-CD20 x anti-CD3 antibodies (e.g., XmAbl3676) of the invention are made as is known in the art. The invention further provides nucleic acid compositions encoding the bispecific anti-CD20 x anti-CD3 antibodies (e.g., XmAbl3676) of the invention. As will be appreciated by those in the art, the nucleic acid compositions will depend on the format and scaffold of the bispecific anti-CD20 x anti-CD3 antibodies (e.g., XmAbl3676). Thus, for example, when the format requires three amino acid sequences, such as for the triple F format (e.g. a first amino acid monomer comprising an Fc domain and a scFv, a second amino acid monomer comprising a heavy chain and a light chain), three nucleic acid sequences can be incorporated into one or more expression vectors for expression. Similarly, some formats (e.g. dual scFv formats such as disclosed in Figure 4) only two nucleic acids are needed; again, they can be put into one or two expression vectors.

[0073] As is known in the art, the nucleic acids encoding the components of the invention can be incorporated into expression vectors as is known in the art, and depending on the host cells used to produce the bispecific anti-CD20 x anti-CD3 antibodies of the invention (e.g., XmAbl3676). Generally the nucleic acids are operably linked to any number of regulatory elements (promoters, origin of replication, selectable markers, ribosomal binding sites, inducers, etc.). The expression vectors can be extra-chromosomal or integrating vectors. In some embodiments, the anti-CD20 x anti-CD3 antibody is generated from a nucleic acid composition that includes a first nucleic acid that encodes SEQ ID NO: 1, a second nucleic acid that encodes SEQ ID NO: 2, and a third nucleic acid that encodes SEQ ID NO: 3.

[0074] The nucleic acids and/or expression vectors of the invention are then transformed into any number of different types of host cells as is well known in the art, including mammalian, bacterial, yeast, insect and/or fungal cells, with mammalian cells (e.g. CHO cells), finding use in many embodiments. In some embodiments, the anti-CD20 x anti-CD3 antibody is generated from an expression vector composition that includes a first expression vector that includes a first nucleic acid that encodes SEQ ID NO: 1, a second expression vector that includes a second nucleic acid that encodes SEQ ID NO: 2, and a third expression vector that includes a third nucleic acid that encodes SEQ ID NO: 3. In some embodiments, the anti-CD20 x anti-CD3 antibody is generated from host cell that includes a first expression vector that includes a first nucleic acid that encodes SEQ ID NO: 1, a second expression vector that includes a second nucleic acid that encodes SEQ ID NO: 2, and a third nucleic acid that includes a third nucleic acid that encodes SEQ ID NO: 3.

[0075] In some embodiments, nucleic acids encoding each monomer and the optional nucleic acid encoding a light chain, as applicable depending on the format, are each contained within a single expression vector, generally under different or the same promoter controls. In embodiments of particular use in the present invention, each of these two or three nucleic acids are contained on a different expression vector. [0076] The heterodimeric bispecific anti-CD20 x anti-CD3 antibodies of the invention (e.g., XmAbl3676) are made by culturing host cells comprising the expression vector(s) as is well known in the art. Once produced, traditional antibody purification steps are done, including an ion exchange chromatography step. As discussed in USSN 14/205,248 and WO2014/145806, hereby incorporated by reference in their entirety and particularly for the discussions concerning purification, having the pis of the two monomers differ by at least 0.5 can allow separation by ion exchange chromatography or isoelectric focusing, or other methods sensitive to isoelectric point. That is, the inclusion of pi substitutions that alter the isoelectric point (pi) of each monomer so that such that each monomer has a different pi and the heterodimer also has a distinct pi, thus facilitating isoelectric purification of the "triple F" heterodimer (e.g., anionic exchange columns, cationic exchange columns). These substitutions also aid in the determination and monitoring of any contaminating dual scFv-Fc and mAb homodimers post-purification (e.g., IEF gels, cIEF, and analytical IEX columns).

[0077] Once made, the bispecific anti-CD20 x anti-CD3 antibodies (e.g., XmAbl3676) are administered to human subjects in dosages as outlined herein.

IV. Pharmaceutical Compositions and Pharmaceutical Administration

[0078] The bispecific anti-CD20 x anti-CD3 antibodies of the invention (e.g., XmAbl3676) can be incorporated into pharmaceutical compositions suitable for administration to a subject for the methods described herein, e.g., weekly, intravenous dosing. Typically, the pharmaceutical composition comprises a bispecific anti-CD20 x anti-CD3 antibody of the invention (e.g.,

XmAbl3676) and a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like that are physiologically compatible and are suitable for administration to a subject for the methods described herein. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as surfactants (such as nonionic surfactants) wetting or emulsifying agents, preservatives or buffers (such as an organic acid, which as a citrate), which enhance the shelf life or effectiveness of the bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676). An example of pharmaceutically acceptable carriers include polysorbates (polysorbate-80). In an exemplary embodiment, the pharmaceutical composition comprises an antibody described herein, and a citrate. In an exemplary embodiment, the pharmaceutical composition comprises an antibody described herein, and a polysorbate. In an exemplary embodiment, the pharmaceutical composition comprises an antibody described herein, and a citrate and a polysorbate. In an exemplary embodiment, the pharmaceutical composition comprises an antibody described herein, and sodium citrate. In an exemplary embodiment, the pharmaceutical composition comprises an antibody described herein, and polysorbate-80. In an exemplary embodiment, the pharmaceutical composition comprises an antibody described herein, and sodium citrate and polysorbate-80. In an exemplary embodiment, the pharmaceutical composition comprises an antibody described herein, and sodium chloride. In an exemplary embodiment, the pharmaceutical composition comprises an antibody described herein, and sodium chloride and polysorbate-80. In an exemplary embodiment, the pharmaceutical composition comprises an antibody described herein, and sodium citrate and sodium chloride. In an exemplary embodiment, the pharmaceutical composition comprises an antibody described herein, and sodium citrate, sodium chloride, and polysorbate-80.

[0079] The pharmaceutical compositions of this invention may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. The form depends on the intended mode of administration and therapeutic application. Exemplary compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans with other antibodies. In an exemplary embodiment, the mode of administration is intravenous. In an exemplary embodiment, the antibody is administered by intravenous infusion or injection.

[0080] Pharmaceutical compositions typically must be sterile and stable under the conditions of manufacture and storage. The pharmaceutical composition can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable to high drug

concentration. Sterile injectable solutions can be prepared by incorporating the antibody in the required amount in an appropriate solvent with one or a combination of ingredients enumerated herein, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the antibody into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated herein. In the case of sterile powders for the preparation of sterile injectable solutions, in an exemplary embodiment, the method of preparation is vacuum drying and freeze-drying that yields a powder of the antibody plus any additional desired carrier from a previously sterile-filtered solution thereof. The proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.

[0081] The bispecific anti-CD20 x anti-CD3 antibodies of the present invention (e.g.,

XmAbl3676) can be administered by a variety of methods known in the art. In an exemplary embodiment, the route/mode of administration is intravenous injection. As will be appreciated by the skilled artisan, the route and/or mode of administration will vary depending upon the desired results. In certain embodiments, the bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) may be prepared with a carrier that will protect the antibody against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyethylene glycol (PEG), polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are patented or generally known to those skilled in the art. See, e.g., Sustained and Controlled Release Drug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.

V. Methods of Treatment

[0082] In an exemplary embodiment, the invention provides methods for treating CD20+ B cell malignancies, including, but not limited to, B-cell non-Hodgkins lymphoma, chronic lymphocytic leukemia, small lymphocytic leukemia, B-cell prolymphoctyic leukemia, transformed leukemia,

Burkitt's lymphoma, mantle cell lymphoma, hairy cell leukemia, splenic marginal zone lymphoma,

Waldenstrom's macroglobulinemia, variant hairy cell leukemia, splenic B cell lymphoma/1 eukemi a, lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B cell lymphoma, follicular lymphoma, in situ follicular neoplasia, duodenal follicular lymphoma, large B cell lymphoma with IFR4 rearrangement, primary cutaneous follicle center lymphoma, diffuse large B cell lymphoma

(DLBCL), T-cell/histocyte-rich large B cell lymphoma, primary cutaneous DLBCL (leg type), EBV-positive DLBCL NOS, EBV-positive mucocutaneous ulcer, DLCBL associated with chronic inflammation, lymphomatoid granulomatosis, primary mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, ALK+ large B-cell lymphoma, plasmablastic lymphoma, primary effusion lymphoma, HHV8+DLBCL, Burkitt-like lymphoma with 1 lq aberration, high grade B cell lymphoma NOS, B cell lymphoma unclassifiable, and post-transplant

lymphoproliferation disorder (PTLD).

VI. Methods of Treating Lymphoma

[0083] In an exemplary embodiment, the invention provides a method for treating lymphoma in a human subject, comprising administering to the human subject having lymphoma an amount of a bispecific anti-CD20 x anti-CD3 antibody described herein (e.g., XmAbl3676) in a dosage regimen described herein for a time period sufficient to treat the lymphoma. In an exemplary embodiment, the lymphoma is not a Hodgkin's lymphoma. In an exemplary embodiment, the lymphoma is a non-Hodgkin's lymphoma. a) Non-Hodgkin's Lymphoma

[0084] Non-Hodgkin lymphomas (NHL) are a diverse group of malignancies that are

predominately of B-cell origin. NHL may develop in any organs associated with lymphatic system such as spleen, lymph nodes or tonsils and can occur at any age. NHL is often marked by enlarged lymph nodes, fever, and weight loss. NHL is classified as either B-cell or T-cell NHL.

Lymphomas related to lymphoproliferative disorders following bone marrow or stem cell transplantation are usually B-cell NHL. NHL has been divided into low-, intermediate-, and high- grade categories by virtue of their natural histories (see Tan et al. Blood. 2013; 122(6):981-987). The low-grade lymphomas are indolent, with a median survival of 11 to 18 years. Although chemotherapy can induce remissions in the majority of indolent lymphomas, cures are rare and most human subjects eventually relapse, requiring further therapy. The intermediate- and high- grade lymphomas are more aggressive tumors, but they have a greater chance for cure with chemotherapy. However, a significant proportion of these human subjects will relapse and require further treatment.

[0085] In an exemplary embodiment, the lymphoma is a Non-Hodgkin's lymphoma (NHL). In another exemplary embodiment, the lymphoma is a B-cell NHL. In another exemplary

embodiment, the lymphoma is selected from the group consisting of B-cell non-Hodgkins lymphoma, chronic lymphocytic leukemia, small lymphocytic leukemia, B-cell prolymphoctyic leukemia, transformed leukemia, Burkitt's lymphoma, mantle cell lymphoma, hairy cell leukemia, splenic marginal zone lymphoma, Waldenstrom's macroglobulinemia, variant hairy cell leukemia, splenic B cell lymphoma/1 eukemi a, lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B cell lymphoma, follicular lymphoma, in situ follicular neoplasia, duodenal follicular lymphoma, large B cell lymphoma with IFR4 rearrangement, primary cutaneous follicle center lymphoma, diffuse large B cell lymphoma (DLBCL), T-cell/histocyte-rich large B cell lymphoma, primary cutaneous DLBCL (leg type), EBV-positive DLBCL NOS, EBV-positive mucocutaneous ulcer, DLCBL associated with chronic inflammation, lymphomatoid granulomatosis, primary mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, ALK+ large B-cell lymphoma, plasmablastic lymphoma, primary effusion lymphoma, HHV8+DLBCL, Burkitt-like lymphoma with 1 lq aberration, high grade B cell lymphoma NOS, B cell lymphoma unclassifiable, and post- transplant lymphoproliferation disorder (PTLD).

[0086] In an exemplary embodiment, the disease is selected from the group consisting of low-grade and/or follicular NHL, diffuse large B cell lymphoma, Burkitt's or other high-grade NHL, mantle cell lymphoma, MALT lymphoma, Waldenstrom's macroglobulinemia.

[0087] Further disclosed herein, in certain embodiments, is a method for treating relapsed or refractory non-Hodgkin's lymphoma in a human subject in need thereof, comprising: administering to the human subject a therapeutically effective amount of a bispecific anti-CD20 x anti-CD3 antibody described herein (e.g., XmAbl3676). In some embodiments, the non-Hodgkin's lymphoma is relapsed or refractory diffuse large B-cell lymphoma (DLBCL), relapsed or refractory mantle cell lymphoma, or relapsed or refractory follicular lymphoma. b) CLL/SLL

[0088] Chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL) are commonly thought as the same disease with slightly different manifestations. Where the cancerous cells gather determines whether it is called CLL or SLL. When the cancer cells are primarily found in the lymph nodes, lima bean shaped structures of the lymphatic system (a system primarily of tiny vessels found in the body), it is called SLL. SLL accounts for about 5% to 10% of all lymphomas.

When most of the cancer cells are in the bloodstream and the bone marrow, it is called CLL. In an exemplary embodiment, the disease is Richter's syndrome. [0089] Both CLL and SLL are slow-growing diseases, although CLL, which is much more common, tends to grow slower. CLL and SLL are treated the same way. They are usually not considered curable with standard treatments, but depending on the stage and growth rate of the disease, most human subjects live longer than 10 years. Occasionally over time, these slow- growing lymphomas may transform into a more aggressive type of lymphoma.

[0090] Chronic lymphoid leukemia (CLL) is the most common type of leukemia. It is estimated that the prevalence of CLL is projected to increase from 120,000 in 2011 to 180,000 in 2025. From Nitin Jain, Qiushi Chen, Turgay Ayer, Susan M. O'Brien, Michael Keating, William Wierda, Hagop M. Kantarjian, Chhatwal Jagpreet. Prevalence and Economic Burden of Chronic

Lymphocytic Leukemia (CLL) in the Era of Oral Targeted Therapies. Blood Dec 2015, 126 (23) 871. Most (>75%) people newly diagnosed with CLL are over the age of 50. Currently CLL treatment focuses on controlling the disease and its symptoms rather than on an outright cure. CLL is treated by chemotherapy, targeted therapies such as ibrutinib and idelalisib, and biological therapies such as anti-CD20 antibodies. Though CLL progresses slowly in most cases, it is considered generally incurable. Certain CLLs are classified as high-risk. As used herein, "high risk CLL" means CLL characterized by at least one of the following 1) 17pl3-; 2) 1 lq22-; 3) unmutated IgVH together with ZAP-70+ and/or CD38+; or 4) trisomy 12.

[0091] CLL treatment is typically administered when the human subject's clinical symptoms or blood counts indicate that the disease has progressed to a point where it may be life-threatening or affect the human subject's quality of life.

[0092] Small lymphocytic leukemia (SLL) is very similar to CLL described supra, and is also a cancer of B-cells. In SLL the abnormal lymphocytes mainly affect the lymph nodes. However, in CLL the abnormal cells mainly affect the blood and the bone marrow. The spleen may be affected in both conditions. SLL accounts for about 1 in 25 of all cases of non-Hodgkin lymphoma. It can occur at any time from young adulthood to old age, but is rare under the age of 50. SLL is considered an indolent lymphoma. This means that the disease progresses very slowly, and human subjects tend to live many years after diagnosis. However, most human subjects are diagnosed with advanced disease, and although SLL responds well to a variety of chemotherapy drugs, it is generally considered to be incurable. Although some cancers tend to occur more often in one gender or the other, cases and deaths due to SLL are evenly split between men and women. The average age at the time of diagnosis is 60 years. [0093] Although SLL is indolent, it is persistently progressive. The usual pattern of this disease is one of high response rates to radiation therapy and/or chemotherapy, with a period of disease remission. This is followed months or years later by an inevitable relapse. Re-treatment leads to a response again, but again the disease will relapse. This means that although the short-term prognosis of SLL is quite good, over time, many human subjects develop fatal complications of recurrent disease. Considering the age of the individuals typically diagnosed with CLL and SLL, there is a need in the art for a simple and effective treatment of the disease with minimum side- effects that do not impede on the human subject's quality of life. The instant invention fulfills this long standing need in the art.

[0094] In an exemplary embodiment, the invention provides a method for treating CLL in a human subject, comprising administering to the human subject having CLL an amount of a bispecific anti- CD20 x anti-CD3 antibody described herein (e.g., XmAbl3676) in a dosage regimen described herein for a time period sufficient to treat the CLL.

[0095] In an exemplary embodiment, the invention provides a method for treating SLL in a human subject, comprising administering to the human subject having SLL an amount of a bispecific anti- CD20 x anti-CD3 antibody described herein (e.g., XmAbl3676) in a dosage regimen described herein for a time period sufficient to treat the SLL.

VII. Subject Selection

[0096] Subjects can be selected based on CD20 expression level in a sample (e.g., a tissue sample or a blood sample) obtained from the subject. CD20 expression level can be determined by an assay known in the art, e.g., flow cytometry, immunohistochemistry, Western blotting,

immunofluorescent assay, radioimmunoassay (RIA), enzyme-linked immunosorbent assay

(ELISA), homogeneous time resolved fluorescence (HTRF), positron emission tomography (PET), or any other immune detection with an antibody or antibody fragment against CD20 protein.

[0097] Blood samples can be collected from a subject using any method known in the art, e.g., by venipuncture or fingerstick. Particular types of blood cells can be isolated, expanded, frozen, and used at a later time. Tissue samples can be obtained from a subject using any method known in the art, e.g., by biopsy or surgery. CT imaging, ultrasound, or an endoscope can be used to guide this type of procedure. The sample may be flash frozen and stored at -80°C for later use. The sample may also be fixed with a fixative, such as formaldehyde, paraformaldehyde, or acetic acid/ethanol. RNA or protein may be extracted from a fresh, frozen or fixed sample for analysis.

VIII. Dosage Regimen

[0098] In some embodiments, the bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered according to a dosage regimen described herein. Dosage regimens are adjusted to provide the optimum desired response (e.g., a therapeutic response). The efficient dosages and the dosage regimens for the bispecific anti-CD20 x anti-CD3 antibodies used in the present invention (e.g., XmAbl3676) depend on the disease or condition to be treated and may be determined by the persons skilled in the art.

[0099] In an exemplary embodiment, the bispecific anti-CD20 x anti-CD3 antibody (e.g.,

XmAbl3676) is administered by infusion once every 6-8 days in an amount of from about 0.1 μg/kg and about 125 μg/kg.

[0100] In an exemplary embodiment, the bispecific anti-CD20 x anti-CD3 antibody (e.g.,

XmAbl3676) is administered intravenously by infusion monthly in an amount of from about 0.7 μg/kg to about 170 μg/kg, e.g., about 2.4 μg/kg to about 170 μg/kg, about 7.5 μg/kg to about 170 μg/kg, about 20 μg/kg to about 170 μg/kg, about 45 μg/kg to about 170 μg/kg, about 80 μg/kg to about 170 μg/kg, about 125 μg/kg to about 170 μg/kg, about 0.7 μg/kg to about 125 μg/kg, about 2.4 μg/kg to about 125 μg/kg, about 7.5 μg/kg to about 125 μg/kg, about 20 μg/kg to about 125 μg/kg, about 45 μg/kg to about 125 μg/kg, about 80 μg/kg to about 125 μg/kg, about 0.7 μg/kg to about 80 μg/kg, about 2.4 μg/kg to about 80 μg/kg, about 7.5 μg/kg to about 80 μg/kg, about 20 μg/kg to about 80 μg/kg, about 45 μg/kg to about 80 μg/kg, about 0.7 μg/kg to about 45 μg/kg, about 2.4 μg/kg to about 45 μg/kg, about 7.5 μg/kg to about 45 μg/kg, about 20 μg/kg to about 45 μg/kg, about 0.7 μg/kg to about 20 μg/kg, about 2.4 μg/kg to about 20 μg/kg, about 7.5 μg/kg to about 20 μg/kg, about 0.7 μg/kg to about 7.5 μg/kg, about 2.4 μg/kg to about 7.5 μg/kg, about 0.7 μg/kg to about 2.4 μg/kg. In an exemplary embodiment, the bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered intravenously by infusion monthly in an amount of from about 0.6 μg/kg and about 0.8 μg/kg; or about 2.3 μg/kg and about 2.5 μg/kg; or about 6.5 μg/kg and about 8.5 μg/kg; or about 18 μg/kg and about 22 μg/kg; or about 40 μg/kg and about 50 μg/kg; or about 75 μg/kg and about 85 μg/kg; or about 120 μg/kg and about 130 μg/kg; or between about 165 μg/kg and about 175 μg/kg. [0101] In an exemplary embodiment, the bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered intravenously by infusion every other week in an amount of from about 0.7 μg/kg to about 170 μg/kg, e.g., about 2.4 μg/kg to about 170 μg/kg, about 7.5 μg/kg to about 170 μg/kg, about 20 μg/kg to about 170 μg/kg, about 45 μg/kg to about 170 μg/kg, about 80 μg/kg to about 170 μg/kg, about 125 μg/kg to about 170 μg/kg, about 0.7 μg/kg to about 125 μg/kg, about 2.4 μg/kg to about 125 μg/kg, about 7.5 μg/kg to about 125 μg/kg, about 20 μg/kg to about 125 μg/kg, about 45 μg/kg to about 125 μg/kg, about 80 μg/kg to about 125 μg/kg, about 0.7 μg/kg to about 80 μg/kg, about 2.4 μg/kg to about 80 μg/kg, about 7.5 μg/kg to about 80 μg/kg, about 20 μg/kg to about 80 μg/kg, about 45 μg/kg to about 80 μg/kg, about 0.7 μg/kg to about 45 μg/kg, about 2.4 μg/kg to about 45 μg/kg, about 7.5 μg/kg to about 45 μg/kg, about 20 μg/kg to about 45 μg/kg, about 0.7 μg/kg to about 20 μg/kg, about 2.4 μg/kg to about 20 μg/kg, about 7.5 μg/kg to about 20 μg/kg, about 0.7 μg/kg to about 7.5 μg/kg, about 2.4 μg/kg to about 7.5 μg/kg, about 0.7 μg/kg to about 2.4 μg/kg. In an exemplary embodiment, the bispecific anti-CD20 x anti- CD3 antibody (e.g., XmAbl3676) is administered intravenously by infusion every other week in an amount of from about 0.6 μg/kg and about 0.8 μg/kg; or about 2.3 μg/kg and about 2.5 μg/kg; or about 6.5 μg/kg and about 8.5 μg/kg; or about 18 μg/kg and about 22 μg/kg; or about 40 μg/kg and about 50 μg/kg; or about 75 μg/kg and about 85 μg/kg; or about 120 μg/kg and about 130 μg/kg; or between about 165 μg/kg and about 175 μg/kg.

[0102] In an exemplary embodiment, the bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered intravenously by infusion weekly in an amount of from about 0.7 μg/kg to about 170 μg/kg, e.g., about 2.4 μg/kg to about 170 μg/kg, about 7.5 μg/kg to about 170 μg/kg, about 20 μg/kg to about 170 μg/kg, about 45 μg/kg to about 170 μg/kg, about 80 μg/kg to about 170 μg/kg, about 125 μg/kg to about 170 μg/kg, about 0.7 μg/kg to about 125 μg/kg, about 2.4 μg/kg to about 125 μg/kg, about 7.5 μg/kg to about 125 μg/kg, about 20 μg/kg to about 125 μg/kg, about 45 μg/kg to about 125 μg/kg, about 80 μg/kg to about 125 μg/kg, about 0.7 μg/kg to about 80 μg/kg, about 2.4 μg/kg to about 80 μg/kg, about 7.5 μg/kg to about 80 μg/kg, about 20 μg/kg to about 80 μg/kg, about 45 μg/kg to about 80 μg/kg, about 0.7 μg/kg to about 45 μg/kg, about 2.4 μg/kg to about 45 μg/kg, about 7.5 μg/kg to about 45 μg/kg, about 20 μg/kg to about 45 μg/kg, about 0.7 μg/kg to about 20 μg/kg, about 2.4 μg/kg to about 20 μg/kg, about 7.5 μg/kg to about 20 μg/kg, about 0.7 μg/kg to about 7.5 μg/kg, about 2.4 μg/kg to about 7.5 μg/kg, about 0.7 μ§/1¾ to about 2.4 μ§/1¾. In an exemplary embodiment, the bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered intravenously by infusion weekly in an amount of from about 0.6 μg/ g and about 0.8 μ§Λ¾; or about 2.3 μg/ g and about 2.5 μg/kg; or about 6.5 μg/ g and about 8.5 μg/kg; or about 18 μg/ g and about 22 μg/kg; or about 40 μg/kg and about 50 μg/kg; or about 75 μg/kg and about 85 μg/kg; or about 120 μg/kg and about 130 μg/kg; or between about 165 μg/kg and about 175 μg/kg.

[0103] In an exemplary embodiment, the bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered intravenously by infusion monthly in an amount of from about 0.45 μg/kg to about 110 μg/kg, e.g., about 1.6 μg/kg to about 110 μg/kg, about 5 μg/kg to about 110 μg/kg, about 12.5 μg/kg to about 110 μg/kg, about 28 μg/kg to about 110 μg/kg, about 5 μg/kg to about 80 μg/kg, about 12.5 μg/kg to about 80 μg/kg, about 28 μg/kg to about 80 μg/kg, about 50 μg/kg to about 80 μg/kg, about 28 μg/kg to about 50 μg/kg, about 28 μg/kg to about 100 μg/kg, about 28 μg/kg to about 90 μg/kg, about 28 μg/kg to about 70 μg/kg, about 28 μg/kg to about 60 μg/kg, about 28 μg/kg to about 50 μg/kg, about 28 μg/kg to about 40 μg/kg, about 30 μg/kg to about 80 μg/kg, about 40 μg/kg to about 80 μg/kg, about 50 μg/kg to about 80 μg/kg, about 60 μg/kg to about 80 μg/kg, about 70 μg/kg to about 80 μg/kg, about 40 μg/kg to about 70 μg/kg, about 40 μg/kg to about 60 μg/kg, about 40 μg/kg to about 50 μg/kg, about 50 μg/kg to about 70 μg/kg, about 50 μg/kg to about 60 μg/kg.

[0104] In an exemplary embodiment, the bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered intravenously by infusion every other week in an amount of from about 0.45 μg/kg to about 110 μg/kg, e.g., about 1.6 μg/kg to about 110 μg/kg, about 5 μg/kg to about 110 μg/kg, about 12.5 μg/kg to about 110 μg/kg, about 28 μg/kg to about 110 μg/kg, about 5 μg/kg to about 80 μg/kg, about 12.5 μg/kg to about 80 μg/kg, about 28 μg/kg to about 80 μg/kg, about 50 μg/kg to about 80 μg/kg, about 28 μg/kg to about 50 μg/kg, about 28 μg/kg to about 100 μg/kg, about 28 μg/kg to about 90 μg/kg, about 28 μg/kg to about 70 μg/kg, about 28 μg/kg to about 60 μg/kg, about 28 μg/kg to about 50 μg/kg, about 28 μg/kg to about 40 μg/kg, about 30 μg/kg to about 80 μg/kg, about 40 μg/kg to about 80 μg/kg, about 50 μg/kg to about 80 μg/kg, about 60 μg/kg to about 80 μg/kg, about 70 μg/kg to about 80 μg/kg, about 40 μg/kg to about 70 μg/kg, about 40 μg/kg to about 60 μg/kg, about 40 μg/kg to about 50 μg/kg, about 50 μg/kg to about 70 μg/kg, about 50 μg/kg to about 60 μg/kg.

[0105] In an exemplary embodiment, the bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered intravenously by infusion weekly in an amount of from about 0.45 μg/kg to about 110 μg/kg, e.g., about 1.6 μg/kg to about 110 μg/kg, about 5 μg/kg to about 110 μg/kg, about 12.5 μg/kg to about 110 μg/kg, about 28 μg/kg to about 110 μg/kg, about 5 μg/kg to about 80 μg/kg, about 12.5 μg/kg to about 80 μg/kg, about 28 μg/kg to about 80 μg/kg, about 50 μg/kg to about 80 μg/kg, about 28 μg/kg to about 50 μg/kg, about 28 μg/kg to about 100 μg/kg, about 28 μg/kg to about 90 μg/kg, about 28 μg/kg to about 70 μg/kg, about 28 μg/kg to about 60 μg/kg, about 28 μg/kg to about 50 μg/kg, about 28 μg/kg to about 40 μg/kg, about 30 μg/kg to about 80 μg/kg, about 40 μg/kg to about 80 μg/kg, about 50 μg/kg to about 80 μg/kg, about 60 μg/kg to about 80 μg/kg, about 70 μg/kg to about 80 μg/kg, about 40 μg/kg to about 70 μg/kg, about 40 μg/kg to about 60 μg/kg, about 40 μg/kg to about 50 μg/kg, about 50 μg/kg to about 70 μg/kg, about 50 μg/kg to about 60 μg/kg.

[0106] In an exemplary embodiment, the bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered by infusion for a period of between about one hour and about three hours. In an exemplary embodiment, the bispecific anti-CD20 x anti-CD3 antibody (e.g.,

XmAbl3676) is administered by infusion for a period of about two hours. In an exemplary embodiment, the bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered by infusion for a period of two hours.

[0107] In an exemplary embodiment, the bispecific anti-CD20 x anti-CD3 antibody (e.g.,

XmAbl3676) is administered once every 6-8 days for between about 1 and about 9 weeks. In an exemplary embodiment, the bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered once every 6-8 days for between about 2 and about 7 weeks. In an exemplary embodiment, the bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered once every 6-8 days for between about 3 and about 9 weeks. In an exemplary embodiment, the bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered once every 6-8 days for between about 1 and about 8 weeks. In an exemplary embodiment, the bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered once every 6-8 days for between about 3 and about 5 weeks. In an exemplary embodiment, the bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered once every 6-8 days for about 4 weeks. In an exemplary embodiment, the bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered once every 6-8 days for 4 weeks. In an exemplary embodiment, the bispecific anti-CD20 x anti- CD3 antibody (e.g., XmAbl3676) is administered once every 6-8 days for between about 7 and about 9 weeks. In an exemplary embodiment, the bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered once every 6-8 days for about 8 weeks. In an exemplary

embodiment, the bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered once every 6-8 days for 8 weeks.

[0108] The dosage may be determined or adjusted by measuring the amount of bispecific anti- CD20 x anti-CD3 antibody of the present invention (e.g., XmAbl3676) in the blood upon administration using techniques known in the art, for instance taking out a biological sample and using anti -idiotypic antibodies which target the antigen binding region of the bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676).

[0109] In an exemplary embodiment, the amount is between about 0.1 μg/kg and about 200 μg/kg.

[0110] In an exemplary embodiment, the amount is between about 0.1 μg/kg and about 1 μg/kg. In an exemplary embodiment, the amount is between about 0.25 μg/kg and about 0.75 μg/kg. In an exemplary embodiment, the amount is between about 0.35 μg/kg and about 0.55 μg/kg. In an exemplary embodiment, the amount is about 0.45 μg/kg. In an exemplary embodiment, the amount is 0.45 μg/kg.

[0111] In an exemplary embodiment, the amount is between about 0.2 μg/kg and about 1.2 μg/kg. In an exemplary embodiment, the amount is between about 0.3 μg/kg and about 1.1 μg/kg. In an exemplary embodiment, the amount is between about 0.4 μg/kg and about 1.0 μg/kg. In an exemplary embodiment, the amount is between about 0.5 μg/kg and about 0.9 μg/kg. In an exemplary embodiment, the amount is between about 0.6 μg/kg and about 0.8 μg/kg. In an exemplary embodiment, the amount is between about 0.65 μg/kg and about 0.75 μg/kg. In an exemplary embodiment, the amount is about 0.7 μg/kg. In an exemplary embodiment, the amount is 0.7 μg/kg.

[0112] In an exemplary embodiment, the amount is between about 1 μg/kg and about 2 μg/kg. In an exemplary embodiment, the amount is between about 1.25 μg/kg and about 1.75 μg/kg. In an exemplary embodiment, the amount is between about 1.4 μg/kg and about 1.7 μg/kg. In an exemplary embodiment, the amount is about 1.6 μg/kg. In an exemplary embodiment, the amount is 1.60 μg/ g.

[0113] In an exemplary embodiment, the amount is between about 1.9 μg/ g and about 2.9 μg/ g. In an exemplary embodiment, the amount is between about 2.0 μg/ g and about 2.8 μg/kg. In an exemplary embodiment, the amount is between about 2.1 μg/kg and about 2.7 μg/kg. In an exemplary embodiment, the amount is between about 2.2 μg/kg and about 2.6 μg/kg. In an exemplary embodiment, the amount is between about 2.3 μg/kg and about 2.5 μg/kg. In an exemplary embodiment, the amount is between about 2.35 μg/kg and about 2.45 μg/kg. In an exemplary embodiment, the amount is about 2.4 μg/kg. In an exemplary embodiment, the amount is 2.4 μg/kg.

[0114] In an exemplary embodiment, the amount is between about 1 μg/kg and about 10 μg/kg. In an exemplary embodiment, the amount is between about 2 μg/kg and about 8 μg/kg. In an exemplary embodiment, the amount is between about 3 μg/kg and about 7 μg/kg. In an exemplary embodiment, the amount is between about 4 μg/kg and about 6 μg/kg. In an exemplary

embodiment, the amount is about 5 μg/kg. In an exemplary embodiment, the amount is 5 μg/kg.

[0115] In an exemplary embodiment, the amount is between about 2.5 μg/kg and about 12.5 μg/kg. In an exemplary embodiment, the amount is between about 3.5 μg/kg and about 11.5 μg/kg. In an exemplary embodiment, the amount is between about 4.5 μg/kg and about 10.5 μg/kg. In an exemplary embodiment, the amount is between about 5.5 μg/kg and about 9.5 μg/kg. In an exemplary embodiment, the amount is between about 6.5 μg/kg and about 8.5 μg/kg. In an exemplary embodiment, the amount is between about 7.0 μg/kg and about 8.0 μg/kg. In an exemplary embodiment, the amount is about 7.5 μg/kg. In an exemplary embodiment, the amount is 7.5

[0116] In an exemplary embodiment, the amount is between about 7.5 μg/kg and about 17.50 μg/kg. In an exemplary embodiment, the amount is between about 10 μg/kg and about 15 μg/kg. In an exemplary embodiment, the amount is between about 11 μg/kg and about 14 μg/kg. In an exemplary embodiment, the amount is between about 12 μg/kg and about 13 μg/kg. In an exemplary embodiment, the amount is about 12.5 μg/kg. In an exemplary embodiment, the amount is 12.5 μg/kg. [0117] In an exemplary embodiment, the amount is between about 10 μg/kg and about 30 μg/kg. In an exemplary embodiment, the amount is between about 12 μg/ g and about 28 μg/ g. In an exemplary embodiment, the amount is between about 14 μg/ g and about 26 μg/ g. In an exemplary embodiment, the amount is between about 16 μg/kg and about 24 μg/kg. In an exemplary embodiment, the amount is between about 18 μg/kg and about 22 μg/kg. In an exemplary embodiment, the amount is between about 19 μg/kg and about 21 μg/kg. In an exemplary embodiment, the amount is about 20 μg/kg. In an exemplary embodiment, the amount is 20 μg/kg.

[0118] In an exemplary embodiment, the amount is between about 10 μg/kg and about 50 μg/kg. In an exemplary embodiment, the amount is between about 15 μg/kg and about 45 μg/kg. In an exemplary embodiment, the amount is between about 20 μg/kg and about 40 μg/kg. In an exemplary embodiment, the amount is between about 25 μg/kg and about 32 μg/kg. In an exemplary embodiment, the amount is about 28 μg/kg. In an exemplary embodiment, the amount is 28 μg/kg.

[0119] In an exemplary embodiment, the amount is between about 15 μg/kg and about 65 μg/kg. In an exemplary embodiment, the amount is between about 20 μg/kg and about 60 μg/kg. In an exemplary embodiment, the amount is between about 25 μg/kg and about 55 μg/kg. In an exemplary embodiment, the amount is between about 30 μg/kg and about 50 μg/kg. In an exemplary embodiment, the amount is between about 35 μg/kg and about 50 μg/kg. In an exemplary embodiment, the amount is between about 40 μg/kg and about 50 μg/kg. In an exemplary embodiment, the amount is between about 42 μg/kg and about 48 μg/kg. In an exemplary embodiment, the amount is about 45 μg/kg. In an exemplary embodiment, the amount is 45 μg/kg.

[0120] In an exemplary embodiment, the amount is between about 25 μg/kg and about 75 μg/kg. In an exemplary embodiment, the amount is between about 35 μg/kg and about 65 μg/kg. In an exemplary embodiment, the amount is between about 40 μg/kg and about 60 μg/kg. In an exemplary embodiment, the amount is between about 45 μg/kg and about 55 μg/kg. In an exemplary embodiment, the amount is about 50 μg/kg. In an exemplary embodiment, the amount is 50 μg/kg. [0121] In an exemplary embodiment, the amount is between about 20 μg/kg and about 140 μg/kg. In an exemplary embodiment, the amount is between about 40 μg/ g and about 120 μg/ g. In an exemplary embodiment, the amount is between about 45 μg/ g and about 115 μg/ g. In an exemplary embodiment, the amount is between about 50 μg/kg and about 110 μg/kg. In an exemplary embodiment, the amount is between about 55 μg/kg and about 105 μg/kg. In an exemplary embodiment, the amount is between about 60 μg/kg and about 100 μg/kg. In an exemplary embodiment, the amount is between about 65 μg/kg and about 95 μg/kg. In an exemplary embodiment, the amount is between about 70 μg/kg and about 90 μg/kg. In an exemplary embodiment, the amount is between about 75 μg/kg and about 85 μg/kg. In an exemplary embodiment, the amount is about 80 μg/kg. In an exemplary embodiment, the amount is 80 μg/kg. In an exemplary embodiment, the amount is between about 75 μg/kg and about 85 μg/kg. In an exemplary embodiment, the amount is about 80 μg/kg. In an exemplary embodiment, the amount is 80 μg/kg.

[0122] In an exemplary embodiment, the amount is between about 65 μg/kg and about 175 μg/kg. In an exemplary embodiment, the amount is between about 75 μg/kg and about 165 μg/kg. In an exemplary embodiment, the amount is between about 85 μg/kg and about 155 μg/kg. In an exemplary embodiment, the amount is between about 95 μg/kg and about 145 μg/kg. In an exemplary embodiment, the amount is between about 105 μg/kg and about 135 μg/kg. In an exemplary embodiment, the amount is between about 115 μg/kg and about 135 μg/kg. In an exemplary embodiment, the amount is between about 120 μg/kg and about 130 μg/kg. In an exemplary embodiment, the amount is about 125 μg/kg. In an exemplary embodiment, the amount is 125 μg/kg.

[0123] In an exemplary embodiment, the amount is between about 140 μg/kg and about 200 μg/kg. In an exemplary embodiment, the amount is between about 145 μg/kg and about 195 μg/kg. In an exemplary embodiment, the amount is between about 150 μg/kg and about 190 μg/kg. In an exemplary embodiment, the amount is between about 155 μg/kg and about 185 μg/kg. In an exemplary embodiment, the amount is between about 160 μg/kg and about 180 μg/kg. In an exemplary embodiment, the amount is between about 165 μg/kg and about 175 μg/kg. In an exemplary embodiment, the amount is about 170 μg/kg. In an exemplary embodiment, the amount is 170 μg/kg. [0124] In an exemplary embodiment, prior to the administration of the bispecific anti-CD20 x anti- CD3 antibody (e.g., XmAbl3676), the human subject is administered a steroid. In an exemplary embodiment, the human subject is administered the steroid between about 30 minutes and about 90 minutes prior to the administration of the bispecific anti-CD20 x anti-CD3 antibody (e.g.,

XmAbl3676). In an exemplary embodiment, the human subject is administered the steroid about 60 minutes prior to the administration of the bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676). In an exemplary embodiment, the steroid is dexamethasone. In an exemplary embodiment, between about 10 mg and about 30 mg of dexamethasone is administered to the human subject. In an exemplary embodiment, about 20 mg of dexamethasone is administered to the human subject.

[0125] In an exemplary embodiment, the bispecific anti-CD20 x anti-CD3 antibody (e.g.,

XmAbl3676) is administered intravenously. In an exemplary embodiment, the bispecific anti- CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered weekly until disease progression, unacceptable toxicity, or individual choice.

[0126] In some embodiments, the bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is a front line therapy, second line therapy, third line therapy, fourth line therapy, fifth line therapy, or sixth line therapy.

[0127] In some embodiments, the bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) treats a refractory lymphoma. In some embodiments, the bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is a maintenance therapy.

[0128] A medical professional having ordinary skill in the art may readily determine and prescribe the effective amount of the antibody composition required. For example, a physician could start doses of the medicament employed in the antibody composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

IX. Treatment modalities

[0129] In the methods of the invention, treatment is used to provide a positive therapeutic response with respect to a lymphoma. By "positive therapeutic response" is intended an improvement in the lymphoma, and/or an improvement in the symptoms associated with the lymphoma. For example, a positive therapeutic response would refer to one or more of the following improvements in the lymphoma: (1) a reduction in the number of CD20⁺ lymphoma-associated cells; (2) an increase in CD20⁺ lymphoma-associated cell death; (3) inhibition of CD20⁺ lymphoma-associated cell survival; (5) inhibition (i.e., slowing to some extent, preferably halting) of CD20⁺ cell proliferation; (6) an increased subject survival rate; and (7) some relief from one or more symptoms associated with the lymphoma.

[0130] Positive therapeutic responses in any given lymphoma can be determined by standardized response criteria specific to that disease or condition.

[0131] In addition to these positive therapeutic responses, the subject undergoing treatment may experience the beneficial effect of an improvement in the symptoms associated with the lymphoma. In an exemplary embodiment, a treatment of lymphoma is selected from the group consisting of feeling less tired, feeling less weak, feeling less dizzy or lightheaded, reduction in shortness of breath, reduction in fever, quicker response to infections, reduction in ease of bruising, reduction in bleeding episodes, weight gain, reduction in night sweats, gain of appetite, reduction in abdominal swelling, reduction in lymph node swelling, reduction in bone or joint pain, and reduction in thymus swelling.

[0132] An improvement in the lymphoma may be characterized as a complete response. By "complete response" is intended an absence of clinically detectable disease with normalization of any previously abnormal radiographic studies, bone marrow, and cerebrospinal fluid (CSF) or abnormal monoclonal protein in the case of myeloma.

[0133] Such a response may persist for at least 4 to 8 weeks, or sometimes 6 to 8 weeks, following treatment according to the methods of the invention. Alternatively, an improvement in the lymphoma may be categorized as being a partial response. By "partial response" is intended at least about a 50% decrease in all measurable tumor burden (i.e., the number of malignant cells present in the subject, or the measured bulk of tumor masses or the quantity of abnormal monoclonal protein) in the absence of new lesions, which may persist for 4 to 8 weeks, or 6 to 8 weeks, or months to years for CLL and indolent lymphomas.

[0134] Treatment according to the present invention includes a "therapeutically effective amount" of the medicaments used. A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result. [0135] A therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the medicaments to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the antibody are outweighed by the therapeutically beneficial effects.

[0136] A "therapeutically effective amount" for therapy may also be measured by its ability to stabilize the progression of the lymphoma. The ability of an antibody to inhibit lymphoma may be evaluated in an animal model system predictive of efficacy in a human.

[0137] Alternatively, this property of an antibody composition may be evaluated by examining the ability of the antibody to inhibit cell growth or to induce apoptosis by in vitro assays or through a PET examination known to the skilled practitioner. A therapeutically effective amount of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) may reduce the number of CD20⁺ lymphoma-associated cells, or improve other aspects related to the lymphoma (such as those described herein), and/or otherwise ameliorate symptoms in a human subject (such as those also described herein). One of ordinary skill in the art would be able to determine such amounts based on such factors as the subject's size, the severity of the subject's symptoms, and the particular antibody composition or route of administration selected.

X. Combination Therapy

[0138] In one aspect, the invention provides a method for treating a CD20-expressing cancer in a subject, comprising administering to the subject having the CD20-expressing cancer an intravenous dose of a bispecific anti-CD20 x anti-CD3 antibody, for a time period sufficient to treat the CD20- expressing cancer, in combination with at least one other therapeutic agent. In an exemplary embodiment, the at least one other therapeutic agent is an anti-cancer agent or a side-effect ameliorating agent. In an exemplary embodiment, the at least one other therapeutic agent is radiation, a chemotherapeutic agent, an antibody, or a side-effect ameliorating agent.

[0139] In certain instances, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) described herein can be used in combination with at least one other therapeutic agent.

Administered "in combination", as used herein, means that two (or more) different therapeutic agents are administered to the subject during the course of the subject's affliction with the disorder, e.g., the two or more therapeutic agents are administered after the subject has been diagnosed with the disorder and before the disorder has been cured or eliminated or treatment has ceased for other reasons. In some embodiments, the administration of one therapeutic agent is still occurring when the administration of the second begins, so that there is overlap in terms of administration. This is sometimes referred to herein as "simultaneous" or "concurrent administration". In other embodiments, the administration of one therapeutic agent ends before the administration of the other therapeutic agent begins. In some embodiments of either case, the treatment is more effective because of combined administration. For example, the second therapeutic agent is more effective, e.g., an equivalent effect is seen with less of the second agent, or the second agent reduces symptoms to a greater extent, than would be seen if the second agent were administered in the absence of the first agent, or the analogous situation is seen with the first agent. In some embodiments, administration is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one therapeutic agent administered in the absence of the other. The effect of the therapeutic agents on the subject can be partially additive, wholly additive, or greater than additive. The administration can be such that an effect of the first treatment administration is still detectable when the second is administered.

[0140] The bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) described herein and the at least one other therapeutic agent can be administered simultaneously, in the same or in separate compositions, or sequentially. For sequential administration, the bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) described herein can be administered first, and the at least one other therapeutic agent can be administered second, or the order of administration can be reversed.

[0141] The bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and/or other therapeutic agents, procedures or modalities can be administered during periods of active disorder, or during a period where there is persistent MRD, or during a period of remission or less active disease. The bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) can be administered before the other treatment, concurrently with the treatment, post-treatment, or during remission of the disorder.

[0142] When administered in combination, the bispecific anti-CD20 x anti-CD3 antibody (e.g.,

XmAbl3676) and the additional therapeutic agent (e.g., second or third therapeutic agent), or all, can be administered in an amount or dose that is higher, lower or the same than the amount or dosage of each therapeutic agent used individually, e.g., as a monotherapy. In some embodiments, the administered amount or dosage of the bispecific anti-CD20 x anti-CD3 antibody (e.g.,

XmAbl3676), the additional therapeutic agent (e.g., second or third therapeutic agent), or all, is lower (e.g., at least 20%, at least 30%, at least 40%, or at least 50%) than the amount or dosage of each therapeutic agent used individually, e.g., as a monotherapy. In other embodiments, the amount or dosage of the bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676), the additional therapeutic agent (e.g., second or third therapeutic agent), or all, that results in a desired effect (e.g., treatment of cancer) is lower (e.g., at least 20%, at least 30%, at least 40%, or at least 50% lower) than the amount or dosage of each therapeutic agent used individually, e.g., as a monotherapy, required to achieve the same therapeutic effect.

[0143] In further aspects, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) described herein may be administered with in combination with at least one therapeutic agent which is an anti-cancer agent and/or a side effect ameliorating agent.

VIII. a) Anti-cancer agent

[0144] In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g.,

XmAbl3676) described herein may be administered with in combination with at least one therapeutic agent which is an anti-cancer agent. In an exemplary embodiment, the anti-cancer agent is a chemotherapeutic, radiation, or antibody (for example antibodies directed against checkpoint inhibitors). In an exemplary embodiment, the anti-cancer agent is an immunoablative agent such as alemtuzumab, other antibody therapies, Cytoxan, fludarabine, rapamycin, mycophenolic acid, steroids, FR90165, cytokines, irradiation, or peptide vaccine, such as that described in Izumoto et al. 2008 J Neurosurg 108:963-971. In an exemplary embodiment, the anticancer agent is an immunosuppressive agent. In an exemplary embodiment, the

immunosuppressive agent is cyclosporin, azathioprine, methotrexate, mycophenolate, or FK506.

VIII. al) Radiation

[0145] In one embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) described herein can be used in combination with radiation.

VIII. a2) Chemotherapeutics

[0146] In one embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) described herein can be used in combination with an anti-cancer agent.

[0147] In an exemplary embodiment, the anti-cancer agent is a chemotherapeutic. In an exemplary embodiment, the chemotherapeutic is selected from the group consisting of alkylating agent, anti- metabolite, kinase inhibitor, proteasome inhibitor, vinca alkaloid, anthracycline, antitumor antibiotic, aromatase inhibitor, topoisomerase inhibitor, mTOR inhibitor, and retinoid.

VIII. a2A) Alkylating agents

[0148] In an exemplary embodiment, the anti-cancer agent is a chemotherapeutic, which is an alkylating agent. In an exemplary embodiment, the alkylating agent is a nitrogen mustard, nitrosourea, alkyl sulfonate, triazine, aziridine, platinum complex, or non-classical alkylating agent.

[0149] In an exemplary embodiment, the alkylating agent is a nitrogen mustard. In an exemplary embodiment, the alkylating agent is a nitrogen mustard, which is mechlorethamine

(mechlorethamine HCl), ifosfamide (IFEX®), melphalan (Alkeran®), chlorambucil,

cyclophosphamide, or a derivative thereof. In an exemplary embodiment, the alkylating agent is a nitrogen mustard, which is trofosfamide, estramustine, or a derivative thereof.

[0150] In an exemplary embodiment, the alkylating agent is a nitrosourea. In an exemplary embodiment, the alkylating agent is a nitrosourea, which is N-Nitroso-N-methylurea (MNU), streptozocin, carmustine (BCNU), lomustine (CCNU), bendamustine (such as bendamustine HCl), or a derivative thereof. In an exemplary embodiment, the alkylating agent is a nitrosourea, which is semustine, fotemustine, nimustine, ranimustine, or a derivative thereof.

[0151] In an exemplary embodiment, the alkylating agent is an alkyl sulfonate. In an exemplary embodiment, the alkylating agent is an alkyl sulfonate, which is busulfan, or a derivative thereof. In an exemplary embodiment, the alkylating agent is an alkyl sulfonate, which is treosulfan, mannosulfan, or a derivative thereof.

[0152] In an exemplary embodiment, the alkylating agent is a triazine. In an exemplary

embodiment, the alkylating agent is a triazine, which is dacarbazine, mitozolomide, temozolomide (Temodar®), or a derivative thereof.

[0153] In an exemplary embodiment, the alkylating agent is an aziridine. In an exemplary embodiment, the alkylating agent is an aziridine, which is thiotepa, altretamine, or a derivative thereof. In an exemplary embodiment, the alkylating agent is an aziridine, which is triaziquone, carboquone, mytomycin, or a derivative thereof. [0154] In an exemplary embodiment, the alkylating agent is a platinum complex. In an exemplary embodiment, the alkylating agent is a platinum complex, which is cisplatin, carboplatin, oxaliplatin, or a derivative thereof.

[0155] In an exemplary embodiment, the alkylating agent is a non-classical alkylating agent. In an exemplary embodiment, the non-classical alkylating agent is procarbazine, hexamethylmelamine, or a derivative thereof. In an exemplary embodiment, the alkylating agent is trabectedin, or a derivative thereof.

VIII. a2B) Anti-metabolites

[0156] In an exemplary embodiment, the anti-cancer agent is a chemotherapeutic, which is an antimetabolite. In an exemplary embodiment, the anti-metabolite is a pyrimidine analog, purine analog, or folate antagonist.

[0157] In an exemplary embodiment, the anti-metabolite is a pyrimidine analog. In an exemplary embodiment, the anti-metabolite is a pyrimidine analog which is a fluoropyrimidine. In an exemplary embodiment, the fluoropyrimidine is 5-fluorouracil, capecitabine, carmofur, floxuridine, doxifluridine, tegafur, or a derivative thereof. In an exemplary embodiment, the anti-metabolite is a pyrimidine analog which is cytarabine, gemcitabine, decitabine, azacitidine, or a derivative thereof. In an exemplary embodiment, the anti-metabolite is an adenosine deaminase inhibitor.

[0158] In an exemplary embodiment, the anti-metabolite is a purine analog. In an exemplary embodiment, the anti-metabolite is a purine analog, which is fludarabine (also known as 2-fluoro- ara-amp), nelarabine, clofarabine, or a derivative thereof. In an exemplary embodiment, the purine analog is an adenosine analog. In an exemplary embodiment, the adenosine analog is fludarabine (such as fludarabine phosphate), cladribine, pentostatin, or a derivative thereof. In an exemplary embodiment, the purine analog is a guanine analog. In an exemplary embodiment, the guanine analog is thioguanine, 6-mercaptopurine (6-MP), or a derivative thereof.

[0159] In an exemplary embodiment, the anti-metabolite is a folate antagonist, which is

methotrexate, pemetrexed, or a derivative thereof.

VIII. a2C) Kinase inhibitors

[0160] In an exemplary embodiment, the anti-cancer agent is a chemotherapeutic, which is a kinase inhibitor. In an exemplary embodiment, the kinase inhibitor is a tyrosine kinase inhibitor. In an exemplary embodiment, the kinase inhibitor is a Src kinase inhibitor. In an exemplary embodiment, the kinase inhibitor is a Bcr-Abl tyrosine kinase inhibitor. In an exemplary embodiment, the kinase inhibitor is asciminib, imatinib (Gleevec®), nilotinib (Tasinga®), ponatinib (Iclusig®), bosutinib (Pfizer), or dasatinib (Sprycel®). In an exemplary embodiment, the kinase inhibitor is a spleen tyrosine kinase (syk) inhibitor. In an exemplary embodiment, the kinase inhibitor is fostamatinib (Tavalisse®)(Rigel). In an exemplary embodiment, the kinase inhibitor is a Bruton's tyrosine kinase (Btk) inhibitor. In an exemplary embodiment, the kinase inhibitor is zanubrutinib also known as BGB-3111 (BeiGene), ibrutinib (e.g., Imbruvica®), evobrutinib (EMD Serono), or acalabrutinib (Acerta/AstraZeneca). In an exemplary embodiment, the kinase inhibitor is a receptor tyrosine kinase (RTK) inhibitor. In an exemplary embodiment, the kinase inhibitor inhibits the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). In an exemplary embodiment, the kinase inhibitor inhibits the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). In an exemplary embodiment, the kinase inhibitor is gefitinib (Iressa®), erlotinib (Tarceva®), pyrotinib, also known as HTI-1001 (Hengrui Therapeutics), afatinib (Gilotrif®), or lapatinib (Tykerb®). In an exemplary embodiment, the kinase inhibitor is a platelet-derived growth factor receptor (PDGF-R) inhibitor. In an exemplary embodiment, the kinase inhibitor is a vascular endothelial growth factor receptor (VEGFR) inhibitor. In an exemplary embodiment, the kinase inhibitor is sunitinib (Sutent®), lenvatinib (Lenvima®), or axitinib, formerly known as AG013736 (Inlyta®). In an exemplary embodiment, the kinase inhibitor is a vascular endothelial growth factor receptor-2 (VEGFR2) inhibitor. In an exemplary embodiment, the kinase inhibitor is apatinib, also known as YN968D1 (Jiangsu Hengrui) vatalanib, cabozantinib (Cabometyx®), golvatinib also known as E7050, or regorafenib (BAY 73-4506, Stivarga®). In an exemplary embodiment, the kinase inhibitor is a Raf kinase inhibitor. In an exemplary embodiment, the kinase inhibitor is sorafenib (Nexavar®). In an exemplary

embodiment, the kinase inhibitor is an Axl receptor tyrosine kinase. In an exemplary embodiment, the kinase inhibitor is bemcentinib, also known as BGB324 also known as R428 (Rigel), gilteritinib (Astellas). In an exemplary embodiment, the tyrosine kinase inhibitor is neratinib (HER2 Herl Her4), toceranib, or a derivative thereof. In an exemplary embodiment, the kinase inhibitor is a phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K(s)). In an exemplary embodiment, the kinase inhibitor is idelalisib (e.g., Zydelig®) (Gilead) or alpelisib. In an exemplary embodiment, the kinase inhibitor is a Chkl inhibitor. In an exemplary embodiment, the kinase inhibitor is rabusertib also known as LY2603618 (Eli Lilly).

VIII. a2D) Proteosome inhibitors

[0161] In an exemplary embodiment, the anti-cancer agent is a chemotherapeutic, which is a proteasome inhibitor. In an exemplary embodiment, the proteasome inhibitor is bortezomib (Velcade®), carfilzomib, ixazomid, or a derivative thereof.

VIII a2E) Vinca alkaloids

[0162] In an exemplary embodiment, the anti-cancer agent is a chemotherapeutic, which is a vinca alkaloid. In an exemplary embodiment, the anti-cancer agent is a chemotherapeutic, which is a monoterpenoid indole alkaloid. In an exemplary embodiment, the anti-cancer agent is a vinca alkaloid, which is vinblastine, vinorelbine, vincristine, vindesine, or a derivative thereof.

VIII a2F) Anthracyclines

[0163] In an exemplary embodiment, the anti-cancer agent is a chemotherapeutic, which is an anthracycline. In an exemplary embodiment, the anthracycline is daunorubicin, also known as daunomycin, doxorubicin (Adriamycin®) (e.g., liposomal doxorubicin), epirubicin, idarubicin

(Idamycin®), valrubicin, or a derivative thereof. IV II. a2G) Other antitumor antibiotics

[0164] In an exemplary embodiment, the anti-cancer agent is a chemotherapeutic, which is an antitumor antibiotic. In an exemplary embodiment, the antitumor antibiotic is actinomycin, bleomycin, dactinomycin, mytomycin, or a derivative thereof. In an exemplary embodiment, the antitumor antibiotic is actinomycin-D or mytomycin-C, or a derivative thereof.

[0165] In an exemplary embodiment, the anti-cancer agent is a chemotherapeutic, which is a microtubule agent. In an exemplary embodiment, the microtubule agent is docetaxel, paclitaxel, or a derivative thereof.

VIII. a2H) Aromatase inhibitors

[0166] In an exemplary embodiment, the anti-cancer agent is a chemotherapeutic, which is an aromatase inhibitor. In an exemplary embodiment, the aromatase inhibitor is a steroidal inhibitor. In an exemplary embodiment, the aromatase steroidal inhibitor is exemestane (Aromasin®), formestane, or a derivative thereof. In an exemplary embodiment, the aromatase inhibitor is a nonsteroidal inhibitor. In an exemplary embodiment, the aromatase non-steroidal inhibitor is anastrozole (Arimidex®), letrozole (Femara®), or a derivative thereof.

VIII. a2I) Topoisomerase inhibitors

[0167] In an exemplary embodiment, the anti-cancer agent is a chemotherapeutic, which is a topoisomerase inhibitor. In an exemplary embodiment, the topoisomerase inhibitor is a

topoisomerase I inhibitor. In an exemplary embodiment, the topoisomerase I inhibitor is camptothecin, or a derivative thereof. In an exemplary embodiment, the topoisomerase I inhibitor is irinotecan, topotecan, or a derivative thereof. In an exemplary embodiment, the topoisomerase inhibitor is a topoisomerase II inhibitor. In an exemplary embodiment, the topoisomerase II inhibitor is etoposide, teniposide, mitoxantrone (Novantrone®), or a derivative thereof. VIII a2J) mTOR inhibitors

[0168] In an exemplary embodiment, the anti-cancer agent is a chemotherapeutic, which is an mTOR inhibitor. In an exemplary embodiment, the mTOR inhibitor is rapamycin or a rapalog. In an exemplary embodiment, the mTOR inhibitor is temsirolimus (Torisel®), everolimus

(Afinitor®), ridaforolimus, or a derivative thereof. In an exemplary embodiment, the mTOR inhibitor is a dual PI3K/mTOR inhibitor. In an exemplary embodiment, the dual PI3K/mTOR inhibitor is dactolisib, GSK2126458, or a derivative thereof. In an exemplary embodiment, the mTOR inhibitor is ATP-competitive mTORCl/mTORC2 inhibitor. In an exemplary embodiment, the ATP-competitive mTORCl/mTORC2 inhibitor is sapanisertib, or a derivative thereof.

VIII a2K) Retinoids

[0169] In an exemplary embodiment, the anti-cancer agent is a chemotherapeutic, which is a retinoid. In an exemplary embodiment, the retinoid is all-trans retinoic acid (tretinoin), alitretinoin (9-cis RA), bexarotene (Targretin®), or a derivative thereof.

[0170] Exemplary chemotherapeutics include an anthracenedione derivative (e.g., mitoxantrone), an immune cell antibody (e.g., gemtuzumab, gemtuzumab ozogamicin, rituximab, obinutuzumab, ofatumumab, ibritumomab tiuxetan, brentuximab), an anti-CD52 Ab such as alemtuzumab

(Campath®). In an exemplary embodiment, the chemotherapeutic agent is tositumomab or aclacinomycin A or gliotoxin or pegaspargase. [0171] General chemotherapeutic agents considered for use in combination therapies include bleomycin sulfate (Blenoxane®), busulfan (Myleran®), capecitabine (Xeloda®), N4- pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine liposome injection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin (Actinomycin D, Cosmegan), daunorubicin HCl(Cerubidine®), daunorubicin citrate liposome injection (DaunoXome®), dexamethasone, docetaxel (Taxotere®), doxorubicin

HCl(Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5- fluorouracil (Adrucil®, Efudex®), gemcitabine (difluorodeoxycitidine), hydroxyurea (Hydrea®), idarubicin (Idamycin®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), leucovorin calcium, 6-mercaptopurine (Purinethol®), methotrexate (Folex®), paclitaxel (Taxol®), teniposide (Vumon®), tirapazamine (Tirazone®), topotecan HC1 for injection (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®). In an exemplary embodiment, the chemotherapeutic agent is selected from the group consisting of anastrozole (Arimidex®), bicalutamide (Casodex®), busulfan injection (Busulfex®), cytosine arabinoside (Cytosar-U®), flutamide (Eulexin®), tezacitibine, phoenix (Yttrium90/MX-DTPA), polifeprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®).

[0172] In some embodiments, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) described herein is administered to a subject in combination with one or more of the following therapeutic agents: methotrexate (e.g., Abitrexate®, Methotrexate LPF®, Mexate®, Mexate-AQ®, Folex®, Folex PFS®), nelarabine (e.g., Arranon®), doxorubicin HC1, daunorubicin in combination with cytarabine and anthracycline, or idararubicin, clofarabine (e.g., Clofarex® or Clolar®), cyclophosphamide (e.g., Cytoxan®, Neosar®, Clafen®), cytarabine (e.g., Cytosar-U®, Tarabine PFS®), dasatinib (e.g., Sprycel®), or other BCR-ABL and SRC tyrosine kinase inhibitors, Erwinaze (e.g., Asparaginase Erwinia Chrysanthemi), imatinib mesylate (e.g., Gleevec®), ponatinib HC1 (e.g., Iclusig®), mercaptopurine (e.g., Purinethol®, Purixan®), pegaspargase (e.g., Oncaspar®), ponatinib HC1, prednisone, vincristine sulfate, vincristine sulfate liposome (e.g., Marqibo®), vincasar PFS, and Hyper-CVAD. In an exemplary embodiment, the subject in the previous sentence has ALL. [0173] In some embodiments, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) described herein is administered to a subject in combination with one or more of the following therapeutic agents: daunorubicin HC1 (e.g., Cerubidine® or Rubidomycin®) (optionally in combination with cytarabine and an anthracycline, such as daunorubicin or idararubicin), idarubicin HC1 (e.g., Idamycin®), Bcl2 inhibitor (e.g., ABT-737, venetoclax (e.g., Venclexta®)),

cyclophosphamide (e.g., Cytoxan®, Clafen®, Neosar®), cytarabine (e.g., Cytosar-U®, Tarabine PFS®), doxorubicin HC1, decitabine (hypomethylating agent), fludarabine (fludara), FLT3 inhibitors (e.g., sunitinib, sorafenib, midostaurin, lestaurtinib, quizartinib, crenolanib, PLX3397), GCSF (Granulocyte-colony stimulating factor), IDH inhibitors (e.g., IDH1 inhibitors, e.g., AG120 or IDH305); IDH2 inhibitors, e.g., AG221; pan IGH1/IGH2 inhibitors, e.g., AG881), mitoxantrone HC1, thioguanine (e.g., Tabloid®), azacitidine or decitabine (e.g., hypomethylating agent), vincristine sulfate (e.g., Vincasar PFS®). In an exemplary embodiment, the subject in the previous sentence has AML.

[0174] In some embodiments, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) described herein is administered to a subject in combination with one or more of the following therapeutic agents: G100 (Immune Design), bosutinib (e.g., Bosulif®), busulfan (e.g., Busulfex®, Myleran®), cyclophosphamide (e.g., Clafen®, Cytoxan®, Neosar®), cytarabine (e.g., Cytosar-U®, Tarabine PFS®), dasatinib (e.g., Sprycel®), imatinib mesylate (e.g., Gleevec®), hydroxyurea (e.g., Hydrea®), ponatinib HC1 (e.g., Iclusig®), mechlorethamine HC1 (e.g., Mustargen®), nilotinib, omacetaxine mepesuccinate (e.g., Synribo®), and interferon-alpha. In an exemplary embodiment, the subject in the previous sentence has CML.

[0175] In some embodiments, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) described herein is administered to a subject in combination with CVP (a combination of cyclophosphamide, vincristine, and prednisone) and/or CHOP (a combination of

cyclophosphamide, hydroxydaunorubicin, Oncovin® (vincristine), and prednisone) with or without etoposide (e.g., VP- 16) and/or a combination of cyclophosphamide and pentostatin and/or a combination of chlorambucil and prednisone and/or a combination of fludarabine and

cyclophosphamide and an immunomodulator such as thalidomide or a thalidomide derivative (e.g., lenalidomide). VIII. a3) Inhibitors, such as antibodies

[0176] In one embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) described herein can be used in combination with a PDl inhibitor, a PDL1 inhibitor, a PDL2 inhibitor, a TIM3 inhibitor, a LAG3 inhibitor, a CTLA4 inhibitor, a TIGIT inhibitor, a BTLA inhibitor, a CD47 inhibitor, or a IDO inhibitor. In one embodiment, the PDl inhibitor, PDL1 inhibitor, PDL2 inhibitor, TIM3 inhibitor, LAG3 inhibitor, CTLA4 inhibitor, TIGIT inhibitor, BTLA inhibitor, CD47 inhibitor, or IDO inhibitor is a small molecule. In one embodiment, the PDl inhibitor, PDL1 inhibitor, PDL2 inhibitor, TIM3 inhibitor, LAG3 inhibitor, CTLA4 inhibitor, TIGIT inhibitor, BTLA inhibitor, CD47 inhibitor, or IDO inhibitor is an antibody.

[0177] In an exemplary embodiment, the anti-cancer agent is an antibody, such as an immuno- oncology agent.

VIII. a3A) PDl

[0178] In other embodiments, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) described herein can be used in combination with a PDl inhibitor. In other embodiments, the PDl inhibitor is a small molecule inhibitor. In other embodiments, the PDl inhibitor is CA-170 (Curis), AU P-12 (Aurigene), or a compound described in WO 2015/034820— in particular, BMS-1, BMS- 2, BMS-79, and BMS-196.

[0179] In other embodiments, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) described herein can be used in combination with an anti-PDl antibody. In other embodiments, the PDl inhibitor is nivolumab (Opdivo®), pembrolizumab (Keytruda®), pidilizumab

(Medivation/Pfizer), spartalizumab also known as PDR001, JNJ-63723283 (J&J), TSR-042 (Tesaro), cemiplimab also known as REGN2810 (Sanofi), AMP-224 (Amplimmune/GSK), MEDI0680 also known as AMP-514 (AstraZeneca), MGA012 (MacroGenics/Incyte), MGD013 (MacroGenics), MGD019 (MacroGenics), SHR-1210 (Shanghai Hengrui Pharma/Incyte), GLS-010 (Gloria Pharma/WuXi Biologies), JS001 (Shanghai Junshi Biosciences), tislelizumab also known as BGB-A317 (BeiGene/Celgene), sintilimab also known as IB 1308 (Innovent), CX-188 (CytomX Therapeutics), or CS1003 (CStone Pharmaceuticals).

[0180] Exemplary non-limiting anti-PDl antibody molecules are disclosed in US 2015/0210769, published on July 30, 2015, entitled "Antibody Molecules to PDl and Uses Thereof," incorporated by reference in its entirety. [0181] In one embodiment, the anti-PDl antibody molecule includes at least one or two heavy chain variable domain (optionally including a constant region), at least one or two light chain variable domain (optionally including a constant region), or both, comprising the amino acid sequence of BAP049-Clone-A, BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, or BAP049-Clone-E; or as described in Table 1 of US 2015/0210769, or encoded by the nucleotide sequence in Table 1; or a sequence substantially identical (e.g., at least 80%, 85%>, 90%, 92%, 95%, 97%), 98%), 99%) or higher identical) to any of the aforesaid sequences. The anti-PDl antibody molecule, optionally, comprises a leader sequence from a heavy chain, a light chain, or both, as shown in Table 4 of US 2015/0210769; or a sequence substantially identical thereto.

[0182] In yet another embodiment, the anti-PDl antibody molecule includes at least one, two, or three complementarity determining regions (CDRs) from a heavy chain variable region and/or a light chain variable region of an antibody described herein, e.g., an antibody chosen from any of BAP049-hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049- hum06, BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-humlO, BAP049-huml 1, BAP049-huml2, BAP049-huml3, BAP049-huml4, BAP049-huml5, BAP049-huml6, BAP049- Clone-A, BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, or BAP049-Clone-E; or as described in Table 1, or encoded by the nucleotide sequence in Table 1; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[0183] In yet another embodiment, the anti-PDl antibody molecule includes at least one, two, or three CDRs (or collectively all of the CDRs) from a heavy chain variable region comprising an amino acid sequence shown in Table 1 of US 2015/0210769, or encoded by a nucleotide sequence shown in Table 1. In one embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1.

[0184] In yet another embodiment, the anti-PDl antibody molecule includes at least one, two, or three CDRs (or collectively all of the CDRs) from a light chain variable region comprising an amino acid sequence shown in Table 1 of US 2015/0210769, or encoded by a nucleotide sequence shown in Table 1. In one embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1. In certain embodiments, the anti-PDl antibody molecule includes a substitution in a light chain CDR, e.g., one or more substitutions in a CDR1, CDR2 and/or CDR3 of the light chain. In one embodiment, the anti-PDl antibody molecule includes a substitution in the light chain CDR3 at position 102 of the light variable region, e.g., a substitution of a cysteine to tyrosine, or a cysteine to serine residue, at position 102 of the light variable region according to Table 1 (e.g., SEQ ID NO: 16 or 24 for murine or chimeric, unmodified; or any of SEQ ID NOs: 34, 42, 46, 54, 58, 62, 66, 70, 74, or 78 for a modified sequence).

[0185] In another embodiment, the anti-PDl antibody molecule includes at least one, two, three, four, five or six CDRs (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Table 1 of US 2015/0210769, or encoded by a nucleotide sequence shown in Table 1. In one embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1.

[0186] In one embodiment, the anti-PDl antibody molecule includes:

(a) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence of SEQ ID NO: 4, a VHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ ID NO: 14, and a VLCDR3 amino acid sequence of SEQ ID NO: 33, each disclosed in Table 1 of US 2015/0210769;

(b) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 1; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ ID NO: 11, and a VLCDR3 amino acid sequence of SEQ ID NO: 32, each disclosed in Table 1 of US 2015/0210769;

(c) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 224, a VHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDRl amino acid sequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ ID NO: 14, and a VLCDR3 amino acid sequence of SEQ ID NO: 33, each disclosed in Table 1 of US 2015/0210769; or

(d) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 224; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ ID NO: 11, and a VLCDR3 amino acid sequence of SEQ ID NO: 32, each disclosed in Table 1 of US 2015/0210769.

[0187] In another embodiment, the anti-PDl antibody molecule comprises (i) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 1, SEQ ID NO: 4, or SEQ ID NO: 224; a VHCDR2 amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 5; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and (ii) a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 10 or SEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ ID NO: 11 or SEQ ID NO: 14, and a VLCDR3 amino acid sequence of SEQ ID NO: 32 or SEQ ID NO: 33, each disclosed in Table 1 of US 2015/0210769.

[0188] In other embodiments, the PDl inhibitor is an anti-PDl antibody chosen from nivolumab, pembrolizumab, or pidilizumab. In other embodiments, the PDl inhibitor is spartalizumab (PDR001).

[0189] In some embodiments, the anti-PDl antibody is nivolumab. Alternative names for nivolumab include MDX-1106, MDX-1106-04, ONO-4538, or BMS-936558. In some

embodiments, the anti-PDl antibody is nivolumab (CAS Registry Number: 946414-94-4).

Nivolumab is a fully human IgG4 monoclonal antibody which specifically blocks PDl . Nivolumab (clone 5C4) and other human monoclonal antibodies that specifically bind to PDl are disclosed in US 8,008,449 and WO2006/121168. In one embodiment, the inhibitor of PDl is nivolumab, and having a sequence disclosed herein (or a sequence substantially identical or similar thereto, e.g., a sequence at least 85%, 90%, 95% identical or higher to the sequence specified).

[0190] The heavy and light chain amino acid sequences of nivolumab are as follows:

Heavy chain

QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKR

YYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSASTK

GPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS SWT VP S S SLGTKT YTCNVDHKP SNTKVDKRVESK YGPPCPPCPAPEFLGGP S VFLFPPKPK

DTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLT

VLHQDWLNGKEYKCKVS KGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTC

LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSV

MHEALHNHYTQKSLSLSLGK

Light chain

EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDAS RATGIPARF SGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQL K S GT A S VVCLLN F YPRE AK VQ WK VDN ALQ S GNS QE S VTEQD SKD S T YSL S S TLTL SK AD YEKHKVYACEVTHQGLS SP VTKSF RGEC

[0191] In some embodiments, the anti-PDl antibody is pembrolizumab. Pembrolizumab (also referred to as lambrolizumab, MK-3475, MK03475, SCH-900475 or KEYTRUDA®; Merck) is a humanized IgG4 monoclonal antibody that binds to PD1. Pembrolizumab and other humanized anti-PDl antibodies are disclosed in Hamid, O. et al. (2013) New England Journal of Medicine 369 (2): 134-44, US 8,354,509 and WO2009/114335. The heavy and light chain amino acid sequences of pembrolizumab are as follows:

Heavy chain

QVQLVQSGVE VKKPGASVKV SCKASGYT FT NYYMYWVRQA PGQGLEWMGG 50

INPSNGGTNF NEKFKNRVTL TTDS S TTTAY MELKSLQFDD TAVYYCARRD 100

YRFDMGFDYW GQGTTVTVS S AS TKGPSVFP LAPCSRS TSE S TAALGCLVK 150

DYFPEPVTVS WNSGALTSGV HT FPAVLQS S GLYSLS SWT VPS S SLGTKT 200

YTCNVDHKPS NTKVDKRVES KYGPPCPPCP APE FLGGPSV FLFPPKPKDT 250

LMI SRTPEVT CWVDVSQED PEVQFNWYVD GVEVHNAKTK PREEQFNS TY 300

RWSVLTVLH QDWLNGKEYK CKVSNKGLPS S IEKT I SKAK GQPREPQVYT 350

LPPSQEEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS 400

DGS FFLYSRL TVDKSRWQEG NVFSCSVMHE ALHNHYTQKS LSLSLGK 447

Light chain

E IVLTQS PAT LSLS PGERAT LSCRASKGVS TSGYSYLHWY QQKPGQAPRL 50

LI YLASYLES GVPARFSGSG SGTDFTLT I S SLEPEDFAVY YCQHSRDLPL 100

TFGGGTKVE I KRTVAAPSVF I FPPSDEQLK SGTASWCLL NNFYPREAKV 150

QWKVDNALQS GNSQESVTEQ DSKDS TYSLS S TLTLSKADY EKHKVYACEV 200

THQGLS S PVT KS FNRGEC 218'

[0192] In one embodiment, the inhibitor of PD1 is pembrolizumab disclosed in, e.g., US 8,354,509 and WO 2009/114335, and having a sequence disclosed herein (or a sequence substantially identical or similar thereto, e.g., a sequence at least 85%, 90%, 95% identical or higher to the sequence specified).

[0193] In some embodiments, the anti-PDl antibody is pidilizumab. Pidilizumab (CT-011; Cure Tech) is a humanized IgGlk monoclonal antibody that binds to PD1. Pidilizumab and other humanized anti-PDl monoclonal antibodies are disclosed in WO2009/101611.

[0194] Other anti-PDl antibodies include AMP 514 (Amplimmune), among others, e.g., anti-PDl antibodies disclosed in US 8,609,089, US 2010028330, and/or US 20120114649.

[0195] In some embodiments, the PD1 inhibitor is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD1 binding portion of PDL1 or PDL2 fused to a constant region (e.g., an Fc region of an immunoglobulin sequence). In some embodiments, the PD1 inhibitor is AMP-224 (B7-DCIg; Amplimmune; e.g., disclosed in WO2010/027827 and WO2011/066342), is a PDL2 Fc fusion soluble receptor that blocks the interaction between PD1 and B7-H1.

[0196] In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti- CD3 antibody (e.g., XmAbl3676) and PD1 inhibitor described herein, this combination further comprises another anti-cancer agent. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PD1 inhibitor described herein, this combination further comprises a chemotherapeutic. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PD1 inhibitor described herein, this combination further comprises a pyrimidine analog. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PD1 inhibitor described herein, this combination further comprises cytarabine. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PD1 inhibitor described herein, this combination further comprises anthracycline. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PD1 inhibitor described herein, this combination further comprises idarubicin. In an exemplary embodiment, for any of the

combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PD1 inhibitor described herein, this combination further comprises daunorubicin. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PD1 inhibitor described herein, this combination further comprises anthracenedione. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PDl inhibitor described herein, this combination further comprises gemtuzumab. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PDl inhibitor described herein, this combination further comprises a FLT3 inhibitor. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PDl inhibitor described herein, this combination further comprises a topoisomerase inhibitor. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PDl inhibitor described herein, this combination further comprises a topoisomerase II inhibitor. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PDl inhibitor described herein, this combination further comprises etoposide. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PDl inhibitor described herein, this combination further comprises mitoxantrone. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PDl inhibitor described herein, this combination further comprises an adenosine analog. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PDl inhibitor described herein, this combination further comprises fludarabine. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PDl inhibitor described herein, this combination further comprises cladribine. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PDl inhibitor described herein, this combination further comprises a kinase inhibitor. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PDl inhibitor described herein, this combination further comprises a Bcr-Abl inhibitor. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PDl inhibitor described herein, this combination further comprises imatinib or nilotinib or dasatinib or bosutinib or ponatinib or a combination thereof. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PDl inhibitor described herein, this combination further comprises omacetaxine. In an exemplary embodiment, for any of the combinations described in this paragraph, the PD1 inhibitor is spartalizumab.

VIII. a3B) PDLl or PDL2

[0197] In one embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) described herein can be used in combination with a PDLl inhibitor. In one embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) described herein can be used in combination with a PDL2 inhibitor.

[0198] In some embodiments, the PDLl inhibitor is an antibody molecule. In some embodiments, the anti-PDLl inhibitor is atezolizumab (Tecentriq®) formerly known as YW243.55.S70 or MPDL3280A, avelumab (Bavencio® (EMD Serono) formerly known as MSB-0010718C, durvalumab (Imfinzi®; Medlmmune/AstraZeneca) formerly known as MEDI-4736, FAZ053, LY3300054 (Lilly), ABBV-181 (Abb Vie), MSB2311 (MabSpace Biosciences), MDX-1105 also known as BMS-936559, CSlOOl formerly known as WBP3155 (CStone Pharmaceuticals), KN035 (Alphamab), CA-327 (Curis), CX-072 (CytomX Therapeutics), M7824 (EMD Serono), HTI-1316 (Hengrui Therapeutics), or JS003 (Shanghai Junshi Biosciences).

[0199] Exemplary non-limiting PDLl inhibitors are disclosed in US 2016/0108123, published on April 21, 2016, entitled "Antibody Molecules to PDLl and Uses Thereof," incorporated by reference in its entirety.

[0200] In one embodiment, the PDLl inhibitor includes at least one or two heavy chain variable domain (optionally including a constant region), at least one or two light chain variable domain (optionally including a constant region), or both, comprising the amino acid sequence of any of BAP058-hum01, BAP058-hum02, BAP058-hum03, BAP058-hum04, BAP058-hum05, BAP058- hum06, BAP058-hum07, BAP058-hum08, BAP058-hum09, BAP058-huml0, BAP058-huml 1, BAP058-huml2, BAP058-huml3, BAP058-huml4, BAP058-huml5, BAP058-huml6, BAP058- huml7, BAP058-Clone-K, BAP058-Clone-L, BAP058-Clone-M, BAP058-Clone-N, or BAP058- Clone-O; or as described in Table 1 of US 2016/0108123, or encoded by the nucleotide sequence in Table 1; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99%) or higher identical) to any of the aforesaid sequences.

[0201] In yet another embodiment, the PDLl inhibitor includes at least one, two, or three complementarity determining regions (CDRs) from a heavy chain variable region and/or a light chain variable region of an antibody described herein, e.g., an antibody chosen from any of BAP058-hum01, BAP058-hum02, BAP058-hum03, BAP058-hum04, BAP058-hum05, BAP058- hum06, BAP058-hum07, BAP058-hum08, BAP058-hum09, BAP058-huml0, BAP058-huml 1, BAP058-huml2, BAP058-huml3, BAP058-huml4, BAP058-huml5, BAP058-huml6, BAP058- huml7, BAP058-Clone-K, BAP058-Clone-L, BAP058-Clone-M, BAP058-Clone-N, or BAP058- Clone-O; or as described in Table 1 of US 2016/0108123, or encoded by the nucleotide sequence in Table 1; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[0202] In yet another embodiment, the PDLl inhibitor includes at least one, two, or three CDRs (or collectively all of the CDRs) from a heavy chain variable region comprising an amino acid sequence shown in Table 1 of US 2016/0108123, or encoded by a nucleotide sequence shown in Table 1. In one embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1.

[0203] In yet another embodiment, the PDLl inhibitor includes at least one, two, or three CDRs (or collectively all of the CDRs) from a light chain variable region comprising an amino acid sequence shown in Table 1 of US 2016/0108123, or encoded by a nucleotide sequence shown in Table 1. In one embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1. In certain embodiments, the PDLl inhibitor includes a substitution in a light chain CDR, e.g., one or more substitutions in a CDR1, CDR2 and/or CDR3 of the light chain.

[0204] In another embodiment, the PDLl inhibitor includes at least one, two, three, four, five or six CDRs (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1 of US 2016/0108123. In one embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1. [0205] In one embodiment, the PDLl inhibitor includes:

(i) a heavy chain variable region (VH) including a VHCDR1 amino acid sequence chosen from SEQ ID NO: 1, SEQ ID NO: 4 or SEQ ID NO: 195; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3, each disclosed in Table 1 of US 2016/0108123; and

(ii) a light chain variable region (VL) including a VLCDR1 amino acid sequence of SEQ ID NO: 9, a VLCDR2 amino acid sequence of SEQ ID NO: 10, and a VLCDR3 amino acid sequence of SEQ ID NO: 11, each disclosed in Table 1 of US 2016/0108123.

[0206] In another embodiment, the PDLl inhibitor includes:

(i) a heavy chain variable region (VH) including a VHCDR1 amino acid sequence chosen from SEQ ID NO: 1, SEQ ID NO: 4 or SEQ ID NO: 195; a VHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence of SEQ ID NO: 3, each disclosed in Table 1 of US 2016/0108123; and

(ii) a light chain variable region (VL) including a VLCDRl amino acid sequence of SEQ ID NO: 12, a VLCDR2 amino acid sequence of SEQ ID NO: 13, and a VLCDR3 amino acid sequence of SEQ ID NO: 14, each disclosed in Table 1 of US 2016/0108123.

[0207] In one embodiment, the PDLl inhibitor comprises the VHCDRl amino acid sequence of SEQ ID NO: 1. In another embodiment, the anti-PDLl antibody molecule comprises the VHCDRl amino acid sequence of SEQ ID NO: 4. In yet another embodiment, the PDLl inhibitor comprises the VHCDRl amino acid sequence of SEQ ID NO: 195, each disclosed in Table 1 of US

2016/0108123.

[0208] In some embodiments, the PDLl inhibitor is MSB0010718C. MSB0010718C (also referred to as A09-246-2; Merck Serono) is a monoclonal antibody that binds to PDLl . Pembrolizumab and other humanized anti-PDLl antibodies are disclosed in WO2013/079174, and having a sequence disclosed herein (or a sequence substantially identical or similar thereto, e.g., a sequence at least 85%, 90%, 95% identical or higher to the sequence specified). The heavy and light chain amino acid sequences of MSB0010718C include at least the following:

Heavy chain (SEQ ID NO: 24 as disclosed in WO2013/079174)

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYIMMWVRQAPGKGLEWVSSIYPSGGITFYA

DKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARIKLGTVTTVDYWGQGTLVTVSS Light chain (SEQ ID NO: 25 as disclosed in WO2013/079174)

QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQQHPGKAPKLMIYDVSN RPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSSSTRVFGTGTKVTVL.

[0209] In one embodiment, the PDL1 inhibitor is YW243.55.S70. The YW243.55.S70 antibody is an anti-PDLl described in WO 2010/077634 (heavy and light chain variable region sequences shown in SEQ ID Nos. 20 and 21, respectively), and having a sequence disclosed therein (or a sequence substantially identical or similar thereto, e.g., a sequence at least 85%, 90%, 95% identical or higher to the sequence specified).

[0210] In one embodiment, the PDL1 inhibitor is MDX-1105. MDX-1105, also known as BMS- 936559, is an anti-PDLl antibody described in WO2007/005874, and having a sequence disclosed therein (or a sequence substantially identical or similar thereto, e.g., a sequence at least 85%, 90%, 95% identical or higher to the sequence specified).

[0211] In one embodiment, the PDL1 inhibitor is MDPL3280A (Genentech / Roche).

MDPL3280A is a human Fc optimized IgGl monoclonal antibody that binds to PDL1.

MDPL3280A and other human monoclonal antibodies to PDL1 are disclosed in U.S. Patent No.: 7,943,743 and U.S. Publication No.: 20120039906.

[0212] In other embodiments, the PDL2 inhibitor is AMP-224. AMP-224 is a PDL2 Fc fusion soluble receptor that blocks the interaction between PDl and B7-H1 (B7-DCIg; Amplimmune; e.g., disclosed in WO2010/027827 and WO2011/066342).

[0213] In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-

CD3 antibody (e.g., XmAbl3676) and PDL1 inhibitor described herein, this combination further comprises another anti-cancer agent. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PDL1 inhibitor described herein, this combination further comprises a chemotherapeutic. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and

PDL1 inhibitor described herein, this combination further comprises a pyrimidine analog. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody

(e.g., XmAbl3676) and PDL1 inhibitor described herein, this combination further comprises cytarabine. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PDL1 inhibitor described herein, this combination further comprises anthracycline. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PDL1 inhibitor described herein, this combination further comprises idarubicin. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PDL1 inhibitor described herein, this combination further comprises daunorubicin. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PDL1 inhibitor described herein, this combination further comprises anthracenedione. In an exemplary embodiment, for any of the combinations of a bispecific anti- CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PDL1 inhibitor described herein, this combination further comprises gemtuzumab. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PDL1 inhibitor described herein, this combination further comprises a FLT3 inhibitor. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PDL1 inhibitor described herein, this combination further comprises a topoisomerase inhibitor. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PDL1 inhibitor described herein, this combination further comprises a topoisomerase II inhibitor. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PDL1 inhibitor described herein, this combination further comprises etoposide. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PDL1 inhibitor described herein, this combination further comprises mitoxantrone. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PDL1 inhibitor described herein, this combination further comprises an adenosine analog. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PDL1 inhibitor described herein, this combination further comprises fludarabine. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PDL1 inhibitor described herein, this combination further comprises cladribine. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PDL1 inhibitor described herein, this combination further comprises a kinase inhibitor. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PDL1 inhibitor described herein, this combination further comprises a Bcr-Abl inhibitor. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PDL1 inhibitor described herein, this combination further comprises imatinib or nilotinib or dasatinib or bosutinib or ponatinib or a combination thereof. In an exemplary embodiment, for any of the combinations of a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) and PDL1 inhibitor described herein, this combination further comprises omacetaxine. In an exemplary embodiment, for any of the combinations described in this paragraph, this combination further comprises a PD1 inhibitor. In an exemplary embodiment, for any of the combinations described in this paragraph, the PD1 inhibitor is spartalizumab.

VIII. a3C) TIM3

[0214] In one embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) described herein can be used in combination with a TIM3 inhibitor. In an exemplary embodiment, the TIM3 inhibitor is MGB453, INCAGN2390 (Incyte), Sym023, TSR-022 (Tesaro), and

LY3321367 (Lilly).

[0215] Exemplary non-limiting TEVI3 inhibitors are disclosed in US 2015/0218274, published on August 6, 2015, entitled "Antibody Molecules to TIM3 and Uses Thereof," incorporated by reference in its entirety.

[0216] In one embodiment, the TIM3 inhibitor includes at least one or two heavy chain variable domain (optionally including a constant region), at least one or two light chain variable domain (optionally including a constant region), or both, comprising the amino acid sequence of ABTIM3, ABTIM3-hum01, ABTIM3-hum02, ABTIM3-hum03, ABTIM3-hum04, ABTIM3-hum05, ABTIM3-hum06, ABTIM3-hum07, ABTIM3-hum08, ABTIM3-hum09, ABTIM3-huml0, ABTIM3-huml l, ABTIM3-huml2, ABTIM3-huml3, ABTIM3-huml4, ABTIM3-huml5, ABTIM3-huml6, ABTIM3-huml7, ABTIM3-huml8, ABTIM3-huml9, ABTIM3-hum20, ABTIM3-hum21, ABTEVI3-hum22, ABTIM3-hum23; or as described in Tables 1-4 of US

2015/0218274; or encoded by the nucleotide sequence in Tables 1-4; or a sequence substantially identical {e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences. The TIM3 inhibitor, optionally, comprises a leader sequence from a heavy chain, a light chain, or both, as shown in US 2015/0218274; or a sequence substantially identical thereto.

[0217] In yet another embodiment, the TIM3 inhibitor includes at least one, two, or three complementarity determining regions (CDRs) from a heavy chain variable region and/or a light chain variable region of an antibody described herein, e.g., an antibody chosen from any of ABTIM3, ABTIM3-hum01, ABTIM3-hum02, ABTIM3-hum03, ABTIM3-hum04, ABTIM3- hum05, ABTIM3-hum06, ABTIM3-hum07, ABTIM3-hum08, ABTIM3-hum09, ABTIM3-huml0, ABTIM3-huml l, ABTIM3-huml2, ABTIM3-huml3, ABTIM3-huml4, ABTIM3-huml5, ABTIM3-huml6, ABTIM3-huml7, ABTIM3-huml8, ABTIM3-huml9, ABTIM3-hum20, ABTIM3-hum21, ABTEVI3-hum22, ABTIM3-hum23; or as described in Tables 1-4 of US

2015/0218274; or encoded by the nucleotide sequence in Tables 1-4; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[0218] In yet another embodiment, the TIM3 inhibitor includes at least one, two, or three CDRs (or collectively all of the CDRs) from a heavy chain variable region comprising an amino acid sequence shown in Tables 1-4 of US 2015/0218274, or encoded by a nucleotide sequence shown in Tables 1-4. In one embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Tables 1-4, or encoded by a nucleotide sequence shown in Table 1-4.

[0219] In yet another embodiment, the TIM3 inhibitor includes at least one, two, or three CDRs (or collectively all of the CDRs) from a light chain variable region comprising an amino acid sequence shown in Tables 1-4 of US 2015/0218274, or encoded by a nucleotide sequence shown in Tables 1- 4. In one embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Tables 1-4, or encoded by a nucleotide sequence shown in Tables 1- 4. In certain embodiments, the TIM3 inhibitor includes a substitution in a light chain CDR, e.g., one or more substitutions in a CDR1, CDR2 and/or CDR3 of the light chain.

[0220] In another embodiment, the TIM3 inhibitor includes at least one, two, three, four, five or six CDRs (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Tables 1-4 of US 2015/0218274, or encoded by a nucleotide sequence shown in Tables 1-4. In one embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Tables 1-4, or encoded by a nucleotide sequence shown in Tables 1-4.

[0221] In one embodiment, the TEVI3 inhibitor includes:

(a) a heavy chain variable region (VH) comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 9; a VHCDR2 amino acid sequence of SEQ ID NO: 10; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a light chain variable region (VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 12, a VLCDR2 amino acid sequence of SEQ ID NO: 13, and a VLCDR3 amino acid sequence of SEQ ID NO: 14, each disclosed in Tables 1-4 of US

2015/0218274;

(b) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 3; a VHCDR2 amino acid sequence of SEQ ID NO: 4; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 6, a VLCDR2 amino acid sequence of SEQ ID NO: 7, and a VLCDR3 amino acid sequence of SEQ ID NO: 8, each disclosed in Tables 1-4 of US 2015/0218274;

(c) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 9; a VHCDR2 amino acid sequence of SEQ ID NO: 25; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 12, a VLCDR2 amino acid sequence of SEQ ID NO: 13, and a VLCDR3 amino acid sequence of SEQ ID NO: 14, each disclosed in Tables 1-4 of US 2015/0218274;

(d) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 3; a VHCDR2 amino acid sequence of SEQ ID NO: 24; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 6, a VLCDR2 amino acid sequence of SEQ ID NO: 7, and a VLCDR3 amino acid sequence of SEQ ID NO: 8, each disclosed in Tables 1-4 of US 2015/0218274;

(e) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 9; a VHCDR2 amino acid sequence of SEQ ID NO: 31; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 12, a VLCDR2 amino acid sequence of SEQ ID NO: 13, and a VLCDR3 amino acid sequence of SEQ ID NO: 14, each disclosed in Tables 1-4 of US 2015/0218274; or

(f) a VH comprising a VHCDRl amino acid sequence chosen from SEQ ID NO: 3; a VHCDR2 amino acid sequence of SEQ ID NO: 30; and a VHCDR3 amino acid sequence of SEQ ID NO: 5; and a VL comprising a VLCDRl amino acid sequence of SEQ ID NO: 6, a VLCDR2 amino acid sequence of SEQ ID NO: 7, and a VLCDR3 amino acid sequence of SEQ ID NO: 8, each disclosed in Tables 1-4 of US 2015/0218274.

[0222] Exemplary TIM3 inhibitor are disclosed in U.S. Patent No. : 8,552,156, WO 2011/155607, EP 2581113 and U.S. Publication No.: 2014/044728.

VIII. a3D) LAG3

[0223] In one embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) described herein can be used in combination with a LAG3 inhibitor. In one embodiment, the LAG3 Inhibitor is LAG525, TSR-033 (Tesaro), REGN3767 (Sanofi), eftilagimod alpha also known as IMP321 (Prima BioMed), MGD013 (MacroGenics), FS118 (F-star/Merck), INCAGN2385 (Incyte), or GSK2831781 (GSK).

[0224] Exemplary non-limiting LAG3 inhibitors are disclosed in US 2015/0259420 published on September 17, 2015, entitled "Antibody Molecules to LAG3 and Uses Thereof," incorporated by reference in its entirety.

[0225] In one embodiment, the LAG3 inhibitor includes at least one or two heavy chain variable domain (optionally including a constant region), at least one or two light chain variable domain

(optionally including a constant region), or both, comprising the amino acid sequence of any of

BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050- hum06, BAP050-hum07, BAP050-hum08, BAP050-hum09, BAP050-huml0, BAP050-huml 1,

BAP050-huml2, BAP050-huml3, BAP050-huml4, BAP050-huml5, BAP050-huml6, BAP050- huml7, BAP050-huml8, BAP050-huml9, BAP050-hum20, huBAP050(Ser) (e.g., BAP050- humOl-Ser, BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser,

BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser, BAP050- humlO-Ser, BAP050-huml 1-Ser, BAP050-huml2-Ser, BAP050-huml3-Ser, BAP050-huml4-Ser,

BAP050-huml5-Ser, BAP050-huml8-Ser, BAP050-huml9-Ser, or BAP050-hum20-Ser),

BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I, or BAP050-Clone-J; or as described in Table 1 of US 2015/0259420, or encoded by the nucleotide sequence in Table 1; or a sequence substantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaid sequences.

[0226] In yet another embodiment, the LAG3 inhibitor includes at least one, two, or three complementarity determining regions (CDRs) from a heavy chain variable region and/or a light chain variable region of an antibody described herein, e.g., an antibody chosen from any of BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050- hum06, BAP050-hum07, BAP050-hum08, BAP050-hum09, BAP050-huml0, BAP050-huml 1, BAP050-huml2, BAP050-huml3, BAP050-huml4, BAP050-huml5, BAP050-huml6, BAP050- huml7, BAP050-huml8, BAP050-huml9, BAP050-hum20, huBAP050(Ser) (e.g., BAP050- humOl-Ser, BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser, BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser, BAP050- humlO-Ser, BAP050-huml 1-Ser, BAP050-huml2-Ser, BAP050-huml3-Ser, BAP050-huml4-Ser, BAP050-huml5-Ser, BAP050-huml8-Ser, BAP050-huml9-Ser, or BAP050-hum20-Ser),

[0227] In yet another embodiment, the LAG3 inhibitor includes at least one, two, or three CDRs (or collectively all of the CDRs) from a heavy chain variable region comprising an amino acid sequence shown in Table 1 of US 2015/0259420, or encoded by a nucleotide sequence shown in Table 1. In one embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1.

[0228] In yet another embodiment, the LAG3 inhibitor includes at least one, two, or three CDRs (or collectively all of the CDRs) from a light chain variable region comprising an amino acid sequence shown in Table 1 of US 2015/0259420, or encoded by a nucleotide sequence shown in Table 1. In one embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1. In certain embodiments, the anti-PDLl antibody molecule includes a substitution in a light chain CDR, e.g., one or more substitutions in a CDR1, CDR2 and/or CDR3 of the light chain.

[0229] In another embodiment, the LAG3 inhibitor includes at least one, two, three, four, five or six CDRs (or collectively all of the CDRs) from a heavy and light chain variable region comprising an amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1 of US 2015/0259420. In one embodiment, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six or more changes, e.g., amino acid substitutions or deletions, relative to the amino acid sequence shown in Table 1, or encoded by a nucleotide sequence shown in Table 1.

[0230] In one embodiment, the LAG3 inhibitor includes:

(i) a heavy chain variable region (VH) including a VHCDR1 amino acid sequence chosen from SEQ ID NO: 1, SEQ ID NO: 4 or SEQ ID NO: 286; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3, each disclosed in Table 1 of US 2015/0259420; and

(ii) a light chain variable region (VL) including a VLCDR1 amino acid sequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ ID NO: 11, and a VLCDR3 amino acid sequence of SEQ ID NO: 12, each disclosed in Table 1 of US 2015/0259420.

[0231] In another embodiment, the anti-LAG3 antibody molecule includes:

(i) a heavy chain variable region (VH) including a VHCDR1 amino acid sequence chosen from SEQ ID NO: 1, SEQ ID NO: 4 or SEQ ID NO: 286; a VHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence of SEQ ID NO: 3, each disclosed in Table 1 of US 2015/0259420; and

(ii) a light chain variable region (VL) including a VLCDRl amino acid sequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ ID NO: 14, and a VLCDR3 amino acid sequence of SEQ ID NO: 15, each disclosed in Table 1 of US 2015/0259420.

[0232] In one embodiment, the anti-LAG3 antibody molecule comprises the VHCDR1 amino acid sequence of SEQ ID NO: 1. In another embodiment, the anti-LAG3 antibody molecule comprises the VHCDRl amino acid sequence of SEQ ID NO: 4. In yet another embodiment, the anti-LAG3 antibody molecule comprises the VHCDRl amino acid sequence of SEQ ID NO: 286, each disclosed in Table 1 of US 2015/0259420. [0233] In some embodiments, the anti-LAG3 antibody is relatlimab. Relatlimab (also referred to as BMS-986016 or BMS986016; Bristol-Myers Squibb) is a monoclonal antibody that binds to LAG3. Relatlimab and other humanized anti-LAG3 antibodies are disclosed in US 2011/0150892, WO2010/019570, and WO2014/008218.

VIII. a3E) CTLA4

[0234] In one embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) described herein can be used in combination with a CTLA4 inhibitor.

[0235] Exemplary anti-CTLA4 antibodies include tremelimumab (IgG2 monoclonal antibody available from Medlmmune, a subsidiary of AstraZeneca, formerly known as ticilimumab, CP- 675,206); and ipilimumab (Yervoy®) (CTLA4 antibody, also known as MDX-010, CAS No.

477202-00-9). Other exemplary anti-CTLA4 antibodies are disclosed, e.g., in U.S. Pat. No.

5,811,097. Other exemplary anti-CTLA4 antibodies include abatacept (Orencia®), IBI310

(Innovent), BMS-986249 (BMS/CytomX Therapeutics), or CS1002 (CStone Pharmaceuticals).

[0236] In one embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) described herein can be used in combination with an anti-PDl antibody molecule, e.g., as described herein, and an anti-CTLA4 antibody, e.g., ipilimumab.

VIII. a3F) TIGIT

[0237] In one embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) described herein can be used in combination with a TIGIT inhibitor. In an exemplary embodiment, the TIGIT inhibitor is OMP-313M32 (OncoMed).

VIII. a3G) BTLA

[0238] In one embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) described herein can be used in combination with a BTLA inhibitor.

VIII. a3H) CD47

[0239] In one embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) described herein can be used in combination with a CD47 inhibitor. In an exemplary embodiment, the CD47 inhibitor is TTI-621 (Trillium Therapeutics), TTI-622 (Trillium Therapeutics), Hu5F9- G4 (Forty-Seven), or CC-90002 (InhibRx/Celgene). VIII. a3I) IDO

[0240] In one embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) described herein can be used in combination with an IDO inhibitor. In an exemplary embodiment, the IDO inhibitor is navoximod also known as GDC-0919 (Genetech/NewLink Genetics), indoximod or prodrugs of indoximod such as NLG802 (NewLink Genetics), epacadostat also known as INCB024360 (Incyte), HTI-1090 also known as SHR9146 (Hengrui Therapeutics), BMS-986205 (BMS), or LY3381916 (Lilly).

VIII a3J) GITR agonist

[0241] In one embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) described herein can be used in combination with a GITR agonist.

[0242] In one embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) described herein can be used in combination with a GITR agonist. In an exemplary embodiment, the GITR inhibitor is TRX518-001, GWN323, MEDI1873 (Medlmmune), OMP-336B11

(OncoMed), or ICAGN01876 (Incyte).

[0243] Exemplary GITR agonists include, e.g., GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as, a GITR fusion protein described in U.S. Patent No. : 6, 111,090, European Patent No.: 0920505B1, U.S. Patent No. : 8,586,023, PCT Publication Nos. : WO 2010/003118 and 2011/090754, or an anti-GITR antibody described, e.g., in U.S. Patent No. : 7,025,962, European Patent No.: 1947183B1, U.S. Patent No. : 7,812,135, U.S. Patent No. :

8,388,967, U.S. Patent No.: 8,591,886, European Patent No.: EP 1866339, PCT Publication No. : WO 2011/028683, U.S. Patent No.: 8,709,424, PCT Publication No. : WO 2013/039954,

International Publication No. : WO2013/039954, U.S. Publication No.: US2014/0072566,

International Publication NO. : WO2015/026684, PCT Publication No. : WO2005/007190, PCT Publication No.: WO 2007/133822, PCT Publication No.: WO2005/055808, PCT Publication No.: WO 99/40196, PCT Publication No.: WO 2001/03720, PCT Publication No.: WO99/20758, U.S. Patent No.: 6,689,607, PCT Publication No. : WO2006/083289, PCT Publication No.: WO

2005/115451, U.S. Patent No.: 7,618,632, PCT Publication No. : WO 2011/051726, International Publication No.: WO2004060319, and International Publication No.: WO2014012479. [0244] In one embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) described herein can be used in combination with a GITR agonist and a PD1 inhibitor, e.g., as described in WO2015/026684.

[0245] In another embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) described herein can be used in combination with a GITR agonist and a TLR agonist, e.g., as described in WO2004060319, and International Publication No.: WO2014012479.

[0246] In one embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) described herein can be used in combination with a GITR agonist and a PD1 inhibitor, e.g., as described in WO2015/026684.

[0247] In another embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) described herein can be used in combination with a GITR agonist and a TLR agonist, e.g., as described in WO2004060319, and International Publication No.: WO2014012479.

VIII. a3K) ICOS agonist

[0248] In one embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) described herein can be used in combination with an ICOS agonist.

VIII. b) Side-effect ameliorating agent

[0249] In some embodiments, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) described herein is administered to a subject with a side-effect ameliorating agent. Side effects associated with the administration of a bispecific anti-CD20 x anti-CD3 antibody (e.g.,

XmAbl3676) include, but are not limited to cytokine release syndrome ("CRS"). Other possible side effects include hemophagocytic lymphohistiocytosis (HLH), also termed Macrophage Activation Syndrome (MAS). Symptoms of CRS may include high fevers, nausea, transient hypotension, hypoxia, and the like. CRS may include clinical constitutional signs and symptoms such as fever, fatigue, anorexia, myalgias, arthalgias, nausea, vomiting, and headache. CRS may include clinical skin signs and symptoms such as rash. CRS may include clinical gastrointestinal signs and symptoms such as nausea, vomiting and diarrhea. CRS may include clinical respiratory signs and symptoms such as tachypnea and hypoxemia. CRS may include clinical cardiovascular signs and symptoms such as tachycardia, widened pulse pressure, hypotension, increased cardiac output (early) and potentially diminished cardiac output. CRS may include clinical coagulation signs and symptoms such as elevated d-dimer, hypofibrinogenemia with or without bleeding. CRS may include clinical renal signs and symptoms such as azotemia. CRS may include clinical hepatic signs and symptoms such as transaminitis and hyperbilirubinemia. CRS may include clinical neurologic signs and symptoms such as headache, mental status changes, confusion, delirium, word finding difficulty or frank aphasia, hallucinations, tremor, dymetria, altered gait, and seizures.

[0250] In an exemplary embodiment, the side-effect ameliorating agent is selected from the group consisting of: steroids, antihistamines, anti-allergic agents, antinausea agents (or anti-emetics), analgesic agents, antipyretic agents, cytoprotective agents, vasopressor agents, anticonvulsant agents, antiinflammatories, and combinations thereof.

VIII. bl) Steroid

[0251] In an exemplary embodiment, the side-effect ameliorating agent is a steroid. In an exemplary embodiment, the steroid is a corticosteroid. In an exemplary embodiment, the corticosteroid is a glucorticoid. In an exemplary embodiment, the corticosteroid is selected from the group consisting of betamethasone, dexamethasone, prednisone, prednisolone,

methylprednisolone, and triamcinolone. In an exemplary embodiment, the corticosteroid is selected from the group consisting of hydrocortisone, cortisone, and ethamethasoneb. In an exemplary embodiment, the steroid is fludrocortisone.

VIII. b2) Antihistamine

[0252] In an exemplary embodiment, the side-effect ameliorating agent is an antihistamine. In an exemplary embodiment, the antihistamine is an Hi antagonist. In an exemplary embodiment, the Hi antagonist is selected from the group consisting of acrivastine, azelastine, bilastine,

bromodiphenhydramine, brompheniramine, buclizine, carbinoxamine, cetirizine (Zyrtec®), chlorodiphenhydramine, chlorphenamine, clemastine, cyclizine, cyproheptadine,

dexbrompheniramine, dexchlorpheniramine, dimenhydrinate, dimetindene, diphenhydramine, doxylamine, ebastine, embramine, fexofenadine (Allegra®), hydroxyzine (Vistaril®), loratadine (Claritin®), meclizine, mirtazapine, olopatadine, orphenadrine, phenindamine, pheniramine, phenyltoloxamine, promethazine, quetiapine (Seroquel®), rupatadine (Alergoliber®),

tripelennamine, and triprolidine. [0253] In an exemplary embodiment, the antihistamine is acrivastine. In an exemplary embodiment, the antihistamine is cetirizine. In an exemplary embodiment, the antihistamine is diphenhydramine. In an exemplary embodiment, the antihistamine is Benadryl®.

[0254] In an exemplary embodiment, the antihistamine is an Hi inverse agonist. In an exemplary embodiment, the Hi inverse agonist is selected from the group consisting of acrivastine, cetirizine, levocetirizine, desloratadine, and pyrilamine.

[0255] In an exemplary embodiment, the antihistamine is an H₂ antihistamine. In an exemplary embodiment, the H₂ antihistamine is an H₂ antagonist. In an exemplary embodiment, the H₂ antihistamine is an H₂ inverse agonist. In an exemplary embodiment, the H₂ antihistamine is selected from the group consisting of cimetidine, famotidine, lafutidine, nizatidine, ranitidine, roxatidine, and tiotidine.

VIII. b3) Anti-allergy agent

[0256] In an exemplary embodiment, the side-effect ameliorating agent is an antiallergy agent. In an exemplary embodiment, the side-effect ameliorating agent is selected from the group consisting of antihistamines, glucocorticoids, epinephrine (adrenaline), mast cell stabilizers, antileukotriene agents, anti-cholinergics, and decongestants. In an exemplary embodiment, the side-effect ameliorating agent is a decongestant. In an exemplary embodiment, the side-effect ameliorating agent is an adrenaline releasing agent. In an exemplary embodiment, the side-effect ameliorating agent is levomethamphetamine, phenylpropanolamine, propylhexedrine (Benzedrex®), or loratadine. In an exemplary embodiment, the side-effect ameliorating agent is an a-adrenergic receptor agonist. In an exemplary embodiment, the side-effect ameliorating agent is naphazoline, oxymetazoline, phenylephrine, synephrine, tetryzoline, tramazoline, or xylometazoline.

VIII. b4) Antinausea agents (or anti-emetic)

[0257] In an exemplary embodiment, the side-effect ameliorating agent is an antinausea agent. In an exemplary embodiment, the side-effect ameliorating agent is an antiemetic agent. In an exemplary embodiment, the side-effect ameliorating agent is a 5-HT₃ receptor antagonist. In an exemplary embodiment, the side-effect ameliorating agent is a dolasetron (Anzemet®), granisetron

(Kytril®, Sancuso®), ondansetron (Zofran®), tropisetron (Setrovel®, Navoban®), palonosetron

(Aloxi®), mirtazapine (Remeron®). In an exemplary embodiment, the side-effect ameliorating agent is a dopamine antagonist. In an exemplary embodiment, the side-effect ameliorating agent is a 5-HT3 receptor antagonist. In an exemplary embodiment, the side-effect ameliorating agent is domperidone (Motilium®), olanzapine (Zyprexa®), droperidol, haloperidol, chlorpromazine, prochlo erazine, alizapride, prochlorperazine (Compazine®, Stemzine®, Buccastem®, Stemetil®, Phenotil®), metoclopramide (Reglan®). In an exemplary embodiment, the side-effect ameliorating agent is a K1 receptor antagonist. In an exemplary embodiment, the side-effect ameliorating agent is aprepitant (Emend®), casopitant, rolapitant (Varubi®). In an exemplary embodiment, the side-effect ameliorating agent is an anticholinergic. In an exemplary embodiment, the side-effect ameliorating agent is scopolamine.

VIII. b5) Analgesic and/or antipyretic agent

[0258] In an exemplary embodiment, the side-effect ameliorating agent is an analgesic agent. In an exemplary embodiment, the side-effect ameliorating agent is an antipyretic agent. In an exemplary embodiment, the side-effect ameliorating agent is a salicylate, or a derivative thereof. In an exemplary embodiment, the salicylate is selected from the group consisting of aspirin, diflunisal, salsalate, and salicylic acid, or a derivative thereof. In an exemplary embodiment, the salicylate is selected from the group consisting of choline salicylate, magnesium salicylate, and sodium salicylate. In an exemplary embodiment, the side-effect ameliorating agent agent is aspirin. In an exemplary embodiment, the side-effect ameliorating agent is acetaminophen, or a derivative thereof. In an exemplary embodiment, the side-effect ameliorating agent is an NSAID, or a derivative thereof. In an exemplary embodiment, the NSAID is a propionic acid derivative. In an exemplary embodiment, the NSAID is selected from the group consisting of ibuprofen,

dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, or a derivative thereof. In an exemplary embodiment, the NSAID is ibuprofen. In an exemplary embodiment, the NSAID is naproxen. In an exemplary embodiment, the NSAID is an acetic acid derivative. In an exemplary embodiment, the NSAID is selected from the group consisting of indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, nabumetone, or a derivative thereof. In an exemplary embodiment, the NSAID is an enolic acid derivative. In an exemplary embodiment, the NSAID is selected from the group consisting of piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, phenylbutazone, or a derivative thereof. In an exemplary embodiment, the NSAID is an anthranilic acid derivative. In an exemplary embodiment, the NSAID is selected from the group consisting of mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, or a derivative thereof. In an exemplary embodiment, the side-effect ameliorating agent is selected from the group consisting of phenazone, metamizole, and nabumetone, or a derivative thereof. In an exemplary embodiment, the side-effect ameliorating agent is an opiate. In an exemplary embodiment, the side-effect ameliorating agent is codeine, morphine, thebaine, or fentanyl. In an exemplary embodiment, the side-effect ameliorating agent is dihydrocodeine, oxymorphol, oxycodone, oxymorphone, or metopon.

VIII. b6) Cytoprotective agent

[0259] In an exemplary embodiment, the side-effect ameliorating agent is a cytoprotective agent. In an exemplary embodiment, the side-effect ameliorating agent is an aminothiol compound. In an exemplary embodiment, the side-effect ameliorating agent is amifostine. In an exemplary embodiment, the side-effect ameliorating agent is bleomycin, dexrazoxane, or coenzyme M.

VIII. b7) Vasopressor agent

[0260] In an exemplary embodiment, the side-effect ameliorating agent is a vasopressor agent. In an exemplary embodiment, the vasopressor agent is selected from norepinephrine, phenylephrine, epinephrine, ephedrine, dopamine, vasopressin, or a combination thereof. In an exemplary embodiment, the vasopressor agent is selected from dobutamine, midodrine, amezinium, or a combination thereof.

VIII. b8) Anticonvulsant agent

[0261] In an exemplary embodiment, the side-effect ameliorating agent is an anticonvulsant agent.

In an exemplary embodiment, the anticonvulsant is an aldehyde. In an exemplary embodiment, the aldehyde is paraldehyde. In an exemplary embodiment, the anticonvulsant is an aromatic allylic alcohol. In an exemplary embodiment, the aromatic allylic alcohol is stiripentol. In an exemplary embodiment, the anticonvulsant is a barbiturate. In an exemplary embodiment, the barbiturate is phenobarbital, primidone, methylphenobarbital, or barbexaclone. In an exemplary embodiment, the anticonvulsant is a benzodiazepine. In an exemplary embodiment, the benzodiazepine is clobazam, clonazepam, clorazepate, diazepam, midazolam, lorazepam, nitrazepam, temazepam, and nimetazepam. In an exemplary embodiment, the anticonvulsant is a carboxamide. In an exemplary embodiment, the carboxamide is carbamazepine, oxcarbazepine, or eslicarbazepine acetate. In an exemplary embodiment, the anticonvulsant is a fatty acid. In an exemplary embodiment, the fatty acid is a valproate. In an exemplary embodiment, the valproate is valproic acid, sodium valproate, or divalproex sodium. In an exemplary embodiment, the valproate is vigabatrin, progabide, and tiagabine. In an exemplary embodiment, the anticonvulsant is a fructose derivative. In an exemplary embodiment, the fructose derivative is topiramate. In an exemplary embodiment, the anticonvulsant is a GABA analog. In an exemplary embodiment, the GABA analog is gabapentin or pregabalin. In an exemplary embodiment, the anticonvulsant is a hydantoin. In an exemplary embodiment, the hydantoin is ethotoin, phenytoin, mephenytoin, or fosphenytoin. In an exemplary embodiment, the anticonvulsant is an oxazolidinedione. In an exemplary embodiment, the oxazolidinedione is paramethadione, trimethadione, and ethadione. In an exemplary embodiment, the anticonvulsant is a propionate. In an exemplary embodiment, the anticonvulsant is a pyrimidinedione. In an exemplary embodiment, the anticonvulsant is a pyrrolidine. In an exemplary embodiment, the pyrrolidine is brivaracetam, etiracetam,

levetiracetam, or seletracetam. In an exemplary embodiment, the anticonvulsant is levetiracetam. In an exemplary embodiment, the anticonvulsant is a succinimide. In an exemplary embodiment, the succinimide is ethosuximide, phensuximide, mesuximide. In an exemplary embodiment, the anticonvulsant is a sulfonamide. In an exemplary embodiment, the succinimide is acetazolamide, sultiame, methazolamide, and zonisamide. In an exemplary embodiment, the anticonvulsant is a triazine. In an exemplary embodiment, the triazine is lamotrigine. In an exemplary embodiment, the anticonvulsant is a urea. In an exemplary embodiment, the urea is pheneturide or phenacemide. In an exemplary embodiment, the anticonvulsant is a valproylamide. In an exemplary embodiment, the anticonvulsant is a valproylamide. In an exemplary embodiment, the valproylamide is valpromide or valnoctamide. In an exemplary embodiment, the anticonvulsant is perampanel, stiripentol, or pyridoxine.

VIII. b9) TNFa inhibitor

[0262] In an exemplary embodiment, the side-effect ameliorating agent is an anti-inflammatory agent. In an exemplary embodiment, the side-effect ameliorating agent is a TNF-a inhibitor. In an exemplary embodiment, the T F-α inhibitor is an antibody. Examples of an anti-TNFa antibody molecule such as, infliximab (Remicade®), adalimumab (Humira®), certolizumab pegol

(Cimzia®), and golimumab (Simponi®). Another example of a TNFa inhibitor is a fusion protein such as entanercept (Enbrel®). In an exemplary embodiment, the TNF-a inhibitor is a small molecule. Small molecule inhibitor of TNFa include, but are not limited to, xanthine derivatives (e.g. pentoxifylline) and bupropion. VIII. blO) IL6 inhibitor

[0263] In an exemplary embodiment, the side-effect ameliorating agent is an anti-inflammatory agent. In an exemplary embodiment, the side-effect ameliorating agent is a IL-6 inhibitor. An example of an IL-6 inhibitor is an anti-IL-6 antibody molecule such as tocilizumab (toe), sarilumab, elsilimomab, CNTO 328, ALD518/BMS-945429, CNTO 136, CPSI-2364, CDP6038, VX30, ARGX-109, FE301, and FM101. In one embodiment, the anti-IL-6 antibody molecule is tocilizumab.

[0264] The methods described herein can comprise administering a bispecific anti-CD20 x anti- CD3 antibody (e.g., XmAbl3676) described herein to a subject and further administering one or more agents to manage elevated levels of a soluble factor resulting from treatment with a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676). In one embodiment, the soluble factor elevated in the subject is one or more of IFN-γ, TNFa, IL-2 and IL-6. In an embodiment, the factor elevated in the subject is one or more of IL-1, GM-CSF, IL-10, IL-8, IL-5 and fraktalkine.

Therefore, an agent administered to treat this side effect can be an agent that neutralizes one or more of these soluble factors. In one embodiment, the agent that neutralizes one or more of these soluble forms is an antibody or antigen binding fragment thereof. Examples of such agents include, but are not limited to a steroid (e.g., corticosteroid), an inhibitor of TNFa, and inhibitor of IL-1R, and an inhibitor of IL-6. An example of an IL-IR based inhibitor is anakinra.

[0265] In an exemplary embodiement, the side-effect ameliorating agent is one that reduces an immune-mediated side effect. Exemplary immune-mediated side effects include, but are not limited to pneumonitis, colitis, hepatitis, nephritis and renal disfunction, hypothyroidism, hyperthyroidism, and endocrinopathies (e.g., hypophysitis, Type 1 diabetes mellitus and thyroid disorders such as hypothyroidism and hyperthyroidism). In one embodiment, the side-effect ameliorating agent reduces embryofetal toxicity.

VIII. c) Exemplary Combinations

Combination with one other therapeutic agent

[0266] In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g.,

XmAbl3676) is administered to the subject in combination with one other therapeutic agent. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered in combination with one other anti-cancer agent. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered in combination with a side-effect ameliorating agent. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with one other anticancer agent. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with one other anti-cancer agent, which is radiation. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with one other anti-cancer agent.

[0267] In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g.,

XmAbl3676) is administered to the subject in combination with one other anti-cancer agent, which is a chemotherapeutic. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with one other chemotherapeutic, which is a pyrimidine analog. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with one other chemotherapeutic, which is cytarabine. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with one other chemotherapeutic, which is an anthracycline. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with one other chemotherapeutic, which is idarubicin. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with one other chemotherapeutic, which is daunorubicin. In an exemplary embodiment, a bispecific anti- CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with one other chemotherapeutic, which is an anthracenedione. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with one other chemotherapeutic, which is gemtuzumab. In an exemplary

embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with one other chemotherapeutic, which is an FLT3 inhibitor.

[0268] In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g.,

XmAbl3676) is administered to the subject in combination with one other chemotherapeutic, which is a topoisomerase inhibitor. In an exemplary embodiment, a bispecific anti-CD20 x anti- CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with one other chemotherapeutic, which is a topoisomerase II inhibitor. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with one other chemotherapeutic, which is etoposide. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with one other chemotherapeutic, which is mitoxantrone. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with one other chemotherapeutic, which is an adenosine analog. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with one other chemotherapeutic, which is fludarabine. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with one other chemotherapeutic, which is cladribine.

[0269] In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g.,

XmAbl3676) is administered to the subject in combination with one other anti-cancer agent, which is an antibody. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with one other anti-cancer agent, which is a PDL2 inhibitor, a TIM3 inhibitor, a LAG3 inhibitor, a CTLA4 inhibitor, a TIGIT inhibitor, a BTLA inhibitor, a CD47 inhibitor, or a IDO inhibitor. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with one other anti-cancer agent, which is a PD1 inhibitor. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with one other anti-cancer agent, which is spartalizumab. In an exemplary

embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with one other anti-cancer agent, which is a PDL1 inhibitor.

Combination with two other therapeutic agents

[0270] In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g.,

XmAbl3676) is administered in combination with two other therapeutic agents. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered in combination with two other therapeutic agents, wherein each of the two other therapeutic agents are side effect ameliorating agents. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered in combination with two other therapeutic agents, wherein each of the two other therapeutic agents are anti-cancer agents. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered in combination with two other therapeutic agents, wherein one of the other agents is an anti-cancer agent, and the other agent is a side effect ameliorating agent.

[0271] In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g.,

XmAbl3676) is administered to the subject in combination with two other anti-cancer agents, one of which is a chemotherapeutic. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with two other anticancer agents, one of which is a pyrimidine analog. In an exemplary embodiment, a bispecific anti- CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with two other anti-cancer agents, one of which is cytarabine. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with two other anti-cancer agents, one of which is an anthracycline. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with one other chemotherapeutic, one of which is idarubicin. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with two other anti-cancer agents, one of which is daunorubicin. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with two other anti-cancer agents, one of which is an anthracenedione. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with two other anti-cancer agents, one of which is gemtuzumab. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with two other anticancer agents, one of which is an FLT3 inhibitor.

[0272] In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g.,

XmAbl3676) is administered to the subject in combination with two other anti-cancer agents, one of which is a topoisomerase inhibitor. In an exemplary embodiment, a bispecific anti-CD20 x anti- CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with two other anti-cancer agents, one of which is a topoisomerase II inhibitor. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with two other anti-cancer agents, one of which is etoposide. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with two other anti-cancer agents, one of which is mitoxantrone. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with two other anti-cancer agents, one of which is an adenosine analog. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with two other anti-cancer agents, one of which is fludarabine. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with two other anti-cancer agents, one of which is cladribine. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with two other anticancer agents, one of which is cytarabine and the other is idarubicin. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with two other anti-cancer agents, one of which is cytarabine and the other is daunorubicin. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with two other anti-cancer agents, one of which is cytarabine and the other is gemtuzumab. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with two other anti-cancer agents, one of which is cytarabine and the other is midostaurin. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with two other anti-cancer agents, one of which is cytarabine and the other is etoposide. In an exemplary embodiment, a bispecific anti-CD20 x anti- CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with two other anti-cancer agents, one of which is cytarabine and the other is mitoxantrone. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with two other anti-cancer agents, one of which is cytarabine and the other is cladribine. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with two other anti-cancer agents, one of which is mitoxantrone and the other is cladribine. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with two other anti-cancer agents, one of which is mitoxantrone and the other is etoposide. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with two other anti-cancer agents, one of which is cytarabine and the other is fludarabine. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with two other anti-cancer agents, one of which is idarubicin and the other is fludarabine.

[0273] In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g.,

XmAbl3676) is administered to the subject in combination with two other therapeutic agents, wherein one of these two other therapeutic agents is radiation. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with two other therapeutic agents, wherein one of these two other therapeutic agents is a chemotherapeutic. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with two other anti-cancer agents, which are independently selected from a PDL2 inhibitor, a TIM3 inhibitor, a LAG3 inhibitor, a CTLA4 inhibitor, a TIGIT inhibitor, a BTLA inhibitor, a CD47 inhibitor, and a IDO inhibitor. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with two other therapeutic agents, wherein one of these two other therapeutic agents is an antibody. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with two other therapeutic agents, wherein one of these two other therapeutic agents is a PD1 inhibitor. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with two other therapeutic agents, wherein one of these two other therapeutic agents is spartalizumab. In an exemplary embodiment, a bispecific anti- CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with two other therapeutic agents, wherein one of these two other therapeutic agents is a PDLl inhibitor. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with two other therapeutic agents, wherein one of these two other therapeutic agents is a corticosteroid. In an exemplary embodiment, a bispecific anti- CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with two other therapeutic agents, wherein one of these two other therapeutic agents is a corticosteroid, and the other is a chemotherapeutic. In an exemplary embodiment, a bispecific anti-CD20 x anti- CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with two other therapeutic agents, wherein one of these two other therapeutic agents is a corticosteroid, and the other is an antibody. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with two other therapeutic agents, wherein one of these two other therapeutic agents is a corticosteroid, and the other is a PD1 inhibitor. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g.,

XmAbl3676) is administered to the subject in combination with two other therapeutic agents, wherein one of these two other therapeutic agents is a corticosteroid, and the other is a PDL1 inhibitor.

Combination with three other therapeutic agents

[0274] In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g.,

XmAbl3676) is administered in combination with three other therapeutic agents. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered in combination with three other therapeutic agents, wherein each of the three other therapeutic agents are side effect ameliorating agents. In an exemplary embodiment, a bispecific anti-CD20 x anti- CD3 antibody (e.g., XmAbl3676) is administered in combination with three other therapeutic agents, wherein each of the three other therapeutic agents are anti-cancer agents. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered in combination with three other therapeutic agents, wherein two of the other therapeutic agents are anti-cancer agents, and the third other therapeutic agent is a side-effect ameliorating agent. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered in combination with three other therapeutic agents, wherein one of the other therapeutic agents is an anti-cancer agent, and the other two therapeutic agents are side-effect ameliorating agents.

[0275] In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g.,

XmAbl3676) is administered to the subject in combination with three other therapeutic agents, wherein one of these three other therapeutic agents is radiation. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with three other therapeutic agents, wherein one of these three other therapeutic agents is a chemotherapeutic. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with three other anti-cancer agent, in which one of these anti-cancer agents is a PDL2 inhibitor, a TIM3 inhibitor, a LAG3 inhibitor, a CTLA4 inhibitor, a TIGIT inhibitor, a BTLA inhibitor, a CD47 inhibitor, or a IDO inhibitor. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with three other anti-cancer agent, in which two of these anti-cancer agents are independently selected from a PDL2 inhibitor, a TIM3 inhibitor, a LAG3 inhibitor, a CTLA4 inhibitor, a TIGIT inhibitor, a BTLA inhibitor, a CD47 inhibitor, or a IDO inhibitor. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with three other anti-cancer agent, in which each of these anti-cancer agents is independently selected from a PDL2 inhibitor, a TIM3 inhibitor, a LAG3 inhibitor, a CTLA4 inhibitor, a TIGIT inhibitor, a BTLA inhibitor, a CD47 inhibitor, or a IDO inhibitor. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with three other therapeutic agents, wherein one of these three other therapeutic agents is an antibody. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with three other therapeutic agents, wherein one of these three other therapeutic agents is a PD1 inhibitor. In an exemplary embodiment, a bispecific anti- CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with three other therapeutic agents, wherein one of these three other therapeutic agents is spartalizumab. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with three other therapeutic agents, wherein one of these three other therapeutic agents is a PDLl inhibitor. In an exemplary embodiment, a bispecific anti- CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with three other therapeutic agents, wherein one of these three other therapeutic agents is a

corticosteroid.

[0276] In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g.,

XmAbl3676) is administered to the subject in combination with three other therapeutic agents, wherein the agents are mitoxantrone, etoposide, and cytarabine. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with three other therapeutic agents, wherein one of the agents is cytarabine. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with three other therapeutic agents, wherein the agents are daunorubicin, etoposide, and cytarabine.

[0277] In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g.,

XmAbl3676) is administered to the subject in combination with a kinase inhibitor. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with imatinib. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with nilotinib or dasatinib or bosutinib. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with ponatinib or bosutinib. In an exemplary embodiment, for any of the combinations in this paragraph, a PDl inhibitor is also part of the combination. In an exemplary embodiment, for any of the combinations in this paragraph, a PDL1 inhibitor is also part of the combination.

[0278] In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g.,

XmAbl3676) is administered to the subject in combination with omacetaxine. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with omacetaxine and one kinase inhibitor. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with omacetaxine and two kinase inhibitors. In an exemplary embodiment, for any of the combinations in this paragraph, a PDl inhibitor is also part of the combination. In an exemplary embodiment, for any of the combinations in this paragraph, a PDL1 inhibitor is also part of the combination.

[0279] In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g.,

XmAbl3676) is administered to the subject in combination with three other therapeutic agents, wherein one is a corticosteroid and another is an PDl inhibitor. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with three other therapeutic agents, wherein one is a corticosteroid and another is an PDL1 inhibitor. In an exemplary embodiment, a bispecific anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676) is administered to the subject in combination with three other therapeutic agents, wherein one is a corticosteroid, another is Benadryl®, and the third is acetaminophen.

[0280] In an exemplary embodiment, the subject is administered one additional agent combination of a corticosteroid (e.g., dexamethasone, methylprednisolone, hydrocortisone) and Benadryl® and Tylenol®, wherein said corticosteroid, Benadryl® and Tylenol® are administered to the subject prior to the administration of the anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676). Timing of combination

[0281] In an exemplary embodiment, at least one of the other therapeutic agents is administered prior to the administration of the anti-CD20 x anti-CD3 antibody (e.g., XmAbl3676). In an exemplary embodiment, at least one of the other therapeutic agents is administered at the same time as the administration of the anti-CD20 x anti-CD3 antibody (e.g., XmAb 13676). In an exemplary embodiment, at least one of the other therapeutic agents is a corticosteroid, and this corticosteroid is administered prior to the administration of the anti-CD20 x anti-CD3 antibody (e.g.,

XmAbl3676).

[0282] All cited references are herein expressly incorporated by reference in their entirety.

[0283] Whereas particular embodiments of the invention have been described above for purposes of illustration, it will be appreciated by those skilled in the art that numerous variations of the details may be made without departing from the invention as described in the appended claims.

EXAMPLES

[0284] Examples are provided below to illustrate the present invention. These examples are not meant to constrain the present invention to any particular application or theory of operation. For all constant region positions discussed in the present invention, numbering is according to the EU index as in Kabat (Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th Ed., United States Public Health Service, National Institutes of Health, Bethesda, entirely incorporated by reference). Those skilled in the art of antibodies will appreciate that this convention consists of nonsequential numbering in specific regions of an immunoglobulin sequence, enabling a normalized reference to conserved positions in immunoglobulin families. Accordingly, the positions of any given immunoglobulin as defined by the EU index will not necessarily correspond to its sequential sequence.

[0285] General and specific scientific techniques are outlined in US Publications 2015/0307629, and 2014/0288275, as well as PCT Publication WO2014/145806, as well as US Applications 62/085,027, 14/952,714, and 15/141,350, all of which are expressly incorporated by reference in their entirety and particularly for the techniques outlined therein. EXAMPLE 1

XmAbl3676 Treatment Plan

[0286] This is a multi-dose Phase 1 dose-escalation study designed to define a maximal tolerated dose and schedule, to preliminarily describe safety, and to assess PK, immunogenicity, and potential anti-tumor activity of XmAbl3676 in human subjects with relapsed or refractory B-cell malignancies.

[0287] This study will enroll two parallel groups of human subjects: dosing cohorts that establish an MTD/RD in human subjects with non-CLL B-cell malignancies including NHL, Waldenstrom's macroglobulinemia, and hairy cell leukemia (Group NHL) and dosing cohorts that establish an MTD/RD for human subjects with CLL/SLL or Richter's transformation (Group CLL).

[0288] In both groups, escalation to higher dose cohorts will be made based on Dose Escalation Review Committee (DERC) review of the aggregate safety data through at least Day 22 on all human subjects participating in previous cohorts. The DERC will be allowed to make adaptations to the dosing schema if felt to be needed, in accordance with evolving trial data regarding the dosing regimen and in the spirit of the current study protocol (i.e., not significantly affecting the current risk profile of the study).

[0289] Once the MTD/RDs are established, the groups will be expanded with the addition of up to 6-12 human subjects to increase the safety experience and more extensively evaluate the PK and PD of XmAbl3676.

[0290] Human subjects will be assessed for tumor response every 8 weeks while on study drug. Human subjects who appear to benefit from XmAbl3676 treatment and continue to meet eligibility may continue treatment past the initial 8 weekly doses (two cycles). If human subjects tolerate their initial dose level and there have been no DLTs on the next higher dose level after all human subjects have completed the DLT period, they may be treated at the higher dose of XmAbl3676.

Number of Subjects

[0291] Up to 65 subjects will be enrolled; the total number required will depend on the number of dose cohorts required to define the MTD in both groups. Up to 10 clinical investigation sites will enroll human subjects to this study. Dose Escalation Scheme

[0292] Human subjects will be enrolled in parallel to both the NHL and CLL Groups, and dose escalation in each group will be essentially independent. Dose level increases will initially proceed according to an accelerated titration design (see Table 2 and Table 3). This design allows for more efficient dose escalation while maintaining safety standards by implementing conservative triggers for cohort expansion during the accelerated escalation phase, and may limit the number of human subjects exposed to potentially sub-therapeutic doses of XmAb l3676.

[0293] During the initial accelerated dose escalation phase (Cohorts IN, 2N, 3N, 1C, 2C, and 3C), dose escalation may occur after treatment of 1 human subject per cohort provided that there is no new >Grade 2 toxicity (i.e. no toxicity that existed prior to enrollment) during Cycle 1 and the human subject has met minimum safety assessment requirements (see Table 3). When a human subject experiences a >Grade 2 toxicity during the dose escalation safety assessment period, the accelerated escalation phase will end, the standard dose escalation phase will begin, and the cohort in which the event(s) occurred will be expanded to a total of at least 3 human subjects (2 additional human subjects will be enrolled).

Table 2: Dose Escalation Cohorts

(.roup Cohort Planned Dose Subjects

IN 0.45 μ_§/1¾ 1 (+2+3)

2N 1.6 μg/kg 1 (+2+3)

3N 5.0 μ /kg 1 (+2+3)

Non-CLL B cell

4N 12.5 μ_§/1¾ 3 (+3)

malignancies

5N 28 μ /kg 3 (+3)

(Group NHL)

6N 50 μ /kg 3 (+3)

7N 80 μ_§/1¾ 3 (+3)

8N 1 10 μ /kg 3 (+3)

Expansion-N At MTD or recommended dose : 6-12

1C 0.45 μ_§/1¾ 1 (+2+3)

2C 1.6 μg/kg 1 (+2+3)

3C 5.0 μ /kg 1 (+2+3)

CLL/SLL 4C 12.5 μ_§/1¾ 3 (+3)

(Group CLL) 5C 28 μ /kg 3 (+3)

6C 50 μ /kg 3 (+3)

7C 80 μ_§/1¾ 3 (+3)

8C 1 10 μ /kg 3 (+3) Expansion-C At MTD or recommended dose 6-12

MTD = maximum tolerated dose

Table 3: Dose Escalation Scheme

DLT= dose-limiting toxicity; MTD= maximum tolerated dose

[0294] From this cohort forward (or beginning with Cohort 4N or 4C [21 μg/kg], whichever comes first) the standard 3+3 dose escalation rules will apply:

[0295] If zero of 3 human subjects have a DLT, then dose escalation to the next level will occur.

[0296] If 1 of 3 human subjects has a DLT, then the cohort will be further expanded to a total of 6 human subjects or until a second human subject in the cohort experiences a DLT. If there are no additional human subjects with a DLT, then dose escalation to the next higher dose level will occur. [0297] The MTD is defined as the highest dose level at which no more than 1 human subject experiences DLT out of 6 human subjects assessable for toxicity at that dose level. Any cohort with 2 or more human subjects experiencing a DLT will have exceeded the MTD and there will be no further dose escalation. The dose level below the cohort at which 2 or more human subjects with DLT occurred will be expanded to at least 6 to delineate the MTD.

[0298] Before a dose-escalation decision can be reached, at least 1 human subject (in the accelerated dose escalation phase of the study) or 3 human subjects (in the standard escalation phase of the study) must meet all requirements for dose escalation safety assessment.

[0299] For the purpose of determining the incidence of DLT and defining the MTD and/or recommended dosing of XmAbl3676 for future study, only human subjects who experience DLT and those with sufficient safety data/follow-up will be evaluated. Human subjects who complete 4 doses of XmAbl3676 and undergo the planned safety evaluations through Day 22 will be considered to have sufficient safety data/follow-up. Human subjects who withdraw from study before completing Day 22 of treatment for reasons unrelated to study drug toxicity will be considered to have inadequate data to support dose escalation. In such cases, replacement human subjects will be enrolled to receive the same dose of XmAbl3676 as the human subjects who withdraw prematurely.

[0300] The decision to advance dosing to the next cohort level will be made by the DERC after review of all required dose escalation safety assessment data from human subjects in a cohort. PK and ADA data may not be routinely available during the safety assessment period as these samples may be batched for analysis so that a more uniform drug exposure analysis and ADA analysis can be performed across all study samples. However, if a human subject safety issue arises and the treating physician feels that information around drug exposure and/or ADA analysis would be useful information in determining the treatment plan for the human subjects, PK and ADA analysis may be performed on the human subject samples that have been collected to date.

[0301] Once the MTD (or RD for further study) is identified, the MTD/RD dose level may be further expanded up to an additional 12 human subjects (up to a total MTD/RD cohort of 18 human subjects) to further assess safety and PK.

[0302] The dose escalation scheme may be modified (e.g., smaller increases or decreases in dose level may be permitted, additional human subjects in a cohort may be enrolled, infusion duration and scheduling may be modified) based on the type and severity of toxicities observed in this trial, upon agreement of the DERC. Enrolling additional human subjects beyond 65 requires a protocol amendment.

EXAMPLE 2

XmAbl3676 Treatment Plan

[0303] This is a Phase 1, multiple-dose dose-escalation study designed to define a safe initial "priming dose" and a maximal tolerated dose and schedule, to describe safety and tolerability, to assess PK and immunogenicity, and to preliminarily assess potential anti-tumor activity of

XmAbl3676 in human subjects with relapsed or refractory B cell malignancies.

[0304] This study will enroll two parallel Disease Groups of human subjects: dosing cohorts that establish a priming dose and maximal tolerated dose (MTD) or recommended dose (RD) and schedule in human subjects with non-CLL B cell malignancies (Group NHL) and dosing cohorts that establish a priming dose and MTD/RD and schedule for human subjects with CLL/SLL (Group CLL).

[0305] This study is designed in two parts:

• Part A, escalating dose cohorts that establish an initial "priming dose" (the lowest initial dose with occurrence of a single DLT) as part of repeated weekly infusions at a fixed dose in a 28-day cycle; and

• Part B, escalating dose cohorts that establish a MTD/RD for a dosing schedule consisting of a "priming dose" on Cycle 1 Day 1, established in Part A, followed by cohort escalation of fixed weekly infusions for Cycle 1 Day 7 through Cycle 2 Day 22.

In both Disease Groups, escalation to higher dose cohorts will be made based on Dose Escalation Review Committee (DERC) review of the aggregate safety data through Cycle 1 Day 28 on all human subjects in Part A and through Cycle 2 Day 7 in Part B. In addition, the safety of the priming dose in Part B will be followed by continuous dose-limiting toxicity (DLT) assessment for 7 days following the priming dose in all Part B cohorts. The DERC will be allowed to make adaptations to the dosing schema if felt to be needed, in accordance with evolving trial safety and tolerability findings as long as changes do not significantly affect the risk profile of the study. [0306] Once the MTD/RD and dosing schedule are established, the Disease Groups may be expanded in Part B with up to 12 additional human subjects to increase the safety experience and more extensively evaluate the PK and PD of XmAb l3676.

Dosage and Mode of Administration

[0307] XmAb l3676 will be administered as an intravenous infusion at a constant rate over 2 hours every 7 days for 8 doses (2 cycles). Human subjects will be premedicated with dexamethasone 20 mg intravenously 1 hour prior to XmAb l3676 administration. XmAb l3676 drug product will be a liquid product supplied in single-use glass vials filled with 1 mL at a concentration of 5.0 mg/mL.

Part A Escalation

[0308] Human subjects will be enrolled in parallel to both the NHL and CLL Disease Groups, and dose escalation in each Group will be essentially independent. Dose level increases will initially proceed according to an accelerated titration design. Once a priming dose has been determined (the lowest dose with occurrence of a single DLT), Part A will end and the study will enroll all human subjects to Part B from then on.

Table 4: Dose Escalation Cohorts

(■roup! Cohort Planned Dos Subjects

1N-A 0.7 μ_§/1¾ 1 (+2+3)

2N-A 2.4 μ^ 1 (+2+3)

3N-A 7.5 μg/kg 1 (+2+3)

Non-CLL B cell

4N-A 20 μ_§/1¾ 3 (+3)

malignancies

5N-A 45 μ^ 3 (+3)

(Group NHL)

6N-A 80 μ_§/1¾ 3 (+3)

7N-A 125 μ /kg 3 (+3)

8N-A 170 μ_§/1¾ 3 (+3)

1C-A 0.7 μ /kg 1 (+2+3)

2C-A 2.4 μ^ 1 (+2+3)

3C-A 7.5 μg/kg 1 (+2+3)

CLL/SLL 4C-A 20 μ_§/1¾ 3 (+3)

(Group CLL) 5C-A 45 μ^ 3 (+3)

6C-A 80 μ_§/1¾ 3 (+3)

7C-A 125 μ /kg 3 (+3) Part B

8C-A 170 ^ig/kg 3 (+3) escalation

[0309] In Part B, the Cycle 1 Day 1 dose (the priming dose) will be fixed at the level determined in

Part A for each Disease Group. The second dose will be escalated and maintained at that level for subsequent doses. The dose to be examined in each cohort will be defined relative to the priming dose.

[0310] Dose escalation will proceed by a standard 3+3 scheme and with the same dosing levels as in Part A, however the Cycle 1 Day 1 infusion will initially be the priming dose determined in Part A for that Disease Group (denoted as "X"). Dose escalation on each Part B cohort will be based on this starting point. For example, if the priming dose determined by Group NHL Part A is 20 μg/kg, the first infusion/priming dose in Cohort 1N-B will be 20 μg/kg and the second and subsequent infusions will be at 45 μg/kg (i.e. X+1).

[0311] A minimum of 3 human subjects will be enrolled in each cohort for each Disease Group. As in Part A, no two human subjects within a cohort will start treatment with XmAb l3676 on the same day; the first human subject will be dosed and observed for a minimum of 72 hours before study drug is administered to the remainder of the cohort. [0312] The DLT observation period for the subsequent dosing escalation cohorts is Cycle 1 Day 8 through Cycle 2 Day 7. If all 3 human subjects tolerate a cohort without experiencing DLT (and the DERC agrees), enrollment will begin on the next higher cohort. If at any time during the 28-day observation period a DLT occurs, 3 additional human subjects will be added to the cohort. If there is an additional DLT among the 6 human subjects on the cohort, the previous dosing cohort will be expanded to 6 to establish a MTD and/or RD. If this occurs on cohort IB, the next 3 human subjects will be enrolled on cohort -IB (de-escalation cohort). If there are no further DLTs among the 3 additional human subjects, another 3 human subjects will be added to the cohort. If there is an additional DLT, then the MTD/RD and schedule established in Part A for that Disease Group will be recommended for further study.

[0313] Toxicity rates for the priming dose will continued to be monitored during Part B by a probability boundary function applied from Cycle 1 Day 1 through Cycle 1 Day 7. Excess toxicity rates will trigger de-escalation of the priming dose.

[0314] Duration of treatment: Human subjects will receive two 4 week cycles of therapy (8 doses); a human subject may continue on therapy past 2 cycles if, in the opinion of the investigator, he/she is deriving benefit and does not require additional non-study therapy.

EXAMPLE 3

In Vitro Antitumor Efficacy

[0315] The ability of XmAbl3676 to recruit and redirect T cells to kill CD20-expressing target cells (RTCC) was examined. T cell-dependent cytotoxicity of XmAbl3676 against CD20-positive Ramos cells was examined using purified PBMC or T cell-depleted PBMC as effector cells. In addition, T cell activation was examined by quantifying CD69 induction on both CD4+ and CD8+ T cells. XE P13245, an anti-RSV x anti-CD3 bispecific antibody, and XE P14045, an anti- CD 123 x anti-CD3 bispecific antibody, were included as negative controls.

[0316] XmAbl3676 displayed robust and potent killing of Ramos cells when supplied with human PBMC as an effector population (data not shown). The negative control antibodies failed to induce any tumor cell killing, suggesting that the cytotoxicity mediated by XmAbl3676 depends on its engagement of CD20 on the target cell population. However, when T cells were depleted from PBMC, XmAbl3676 failed to induce killing. In a second experiment, XmAbl3676-mediated killing of Ramos cells was demonstrated with purified T cells, demonstrating that T cells alone are sufficient to mediate XmAbl3676's cytotoxic activity.

[0317] Using rituximab as the detection antibody, the CD20 expression profile on various human lymphoma-derived cell lines was examined by flow cytometry. Su-DHL-6 showed the highest CD20 antigen density, with Ramos and MEC-1 showing intermediate levels, and SC-1 showing lower levels. Su-DHL-1 was used as a CD20-negative control cell line. Figure 5 shows RTCC activity against these five cell lines using purified T cells. XmAbl3676 showed robust depletion of all CD20-positive target cell lines in the presence of purified T cells. Potency of killing was higher for cell lines with high or intermediate CD20 levels (Su-DHL-6, Ramos and MEC-1), and reduced approximately 10-fold for the lower expressing SC-1, with EC₅₀ values ranging from 8 to 138 ng/ml. No significant depletion was observed for the CD20-negative cell line (Su-DHL-1).

[0318] XmAbl3676 also induced similar robust CD8⁺ (Figure 6) and CD4⁺ (not shown) T cell activation in the presence of CD20-expressing target cells, again correlating with CD20 expression levels. In contrast, XmAbl3676 failed to induce activation of CD4⁺ and CD8⁺ T cells or target cell killing in the presence of CD20-negative SuDHL-1 cells.

[0319] To assess whether XmAbl3676-induced cytotoxicity is affected by donor-to-donor T cell variability, purified T cells from six healthy human donors were tested in RTCC assays using Ramos as target cells. XmAbl3676 robustly depleted Ramos target cells in the presence of effector T cells from six different healthy donors (data not shown). The depletion potency was similar across all six donors, with EC₅₀ values between 5.3 and 14.3 ng/ml.

[0320] The anti-CD20 Fv domain of XmAbl3676 is derived from murine antibody C2B8, the same antibody used in the chimeric antibody rituximab. Therefore, it might be possible that rituximab could interfere with the activity of XmAbl3676 by competing for CD20 binding. To assess the effect of rituximab interference on XmAbl3676-induced T cell- mediated cytotoxicity, its potency was evaluated in the presence of increasing amounts of rituximab. As shown in Figure 7, XmAbl3676 stimulated Jeko-1 target cell killing with an EC₅₀ of 24 ng/ml in the absence of rituximab. As rituximab was added at increasing concentrations of 3, 10, 30 and 100 μg/ml, the potency of XmAb 13676 was correspondingly reduced (with EC₅₀ values increasing to 51, 93, 162 and 387 ng/ml). However, XmAbl3676 retains RTCC activity even in the presence of a large excess concentration of rituximab. Moreover, although XmAb 13676 became less potent in the presence of rituximab, it stimulated a similar extent of total T cell-mediated target killing efficacy. As expected, rituximab itself did not display any RTCC activity in this T cell-dependent assay.

[0321] A series of experiments was performed to assess whether XmAbl3676 could induce T cell activity in cancer human subject samples. T cell activation and killing were examined using human subject-derived PBMC from CLL or follicular NHL (FL) human subjects. T cell activation and depletion of autologous CD20-expressing target B cells derived from normal PBMC samples were also examined as a benchmark. As a non-specific antigen control, XENP 13245 (anti-RSV x anti- CD3 bsAb) was used.

[0322] Three each of CLL and normal donor PBMC samples were assessed for target cell (CD 19+ CD5+ lymphocytes for CLL cancer cells and CD 19+ for normal B cells) and effector T cell (CD4+ and CD8+ cells) number. The number of T cells in CLL samples was significantly lower than in normal PBMC, resulting in very low effector to target (E:T) ratios.

[0323] CLL and normal PBMC samples were incubated for 24 or 48 hours with 10, 1, 0.1 μg/ml of XmAbl3676 or 10 μg/ml of the control antibody XENP13245. After incubation, target cell counts were determined for CLL and normal PBMC samples. XmAbl3676 induced robust B cell depletion in the normal PBMC at either 24 or 48 hours, resulting in a drop of several orders of magnitude in detectable B cells (not shown). This depletion activity appears to saturate at concentrations of 1 μg/ml or higher. However, there was no depletion of CD19⁺ CD5⁺ cells in the CLL samples, presumably due to the low number of effector T cells in these samples. The nonspecific control antibody XENP13245 (10 μg/ml) did not decrease target cell counts in either sample set.

[0324] XmAbl3676 engagement of CD3 on the effector T cells and CD20 on the target cells is expected to activate T cells, which can be measured by detecting surface activation markers such as CD25 and CD69. As shown in Figure 8, CD8⁺ T cells were strongly activated by

XmAbl3676, as evidenced by the upregulation of CD69. Similar results were observed for CD25, and both CD69 and CD25 were also upregulated on CD4⁺ T cells (data not shown). Hence, despite the lack of CLL depletion, XmAbl3676 mediates strong activation of autologous T cells in the CLL samples. Such activation may lead to proliferation in vivo, potentially overcoming the problem with low T cell counts. [0325] As the number of effector T cells in the CLL samples was low, two CLL samples were supplemented with T cells purified from normal PBMC to assess the sensitivity of the CLL cancer cells to the XmAbl3676 bispecific antibody. The number of live PBMCs assayed from each CLL donor was 250,000 and 320,000 and purified T cells from a normal PBMC were added at equal number (1 : 1 ratio) or 5-fold access over the CLL cells (5: 1 ratio of T cells to CLL cells) and incubated for 24 hours. Figure 9 shows the number of CLL cancer cell counts in two CLL human subject PBMC incubated with either XmAbl3676 (at 0, 0.1, 1 or 10 μg/ml) or the negative control antibody XE P13245 (at 10 μg/ml). XmAbl3676 induced very effective depletion of CD19+CD5+ CLL cancer cells in both CLL human subject PBMC samples at the 5: 1 effectontarget ratio, particularly at the highest concentration of 10 μg/ml. More modest depletion was observed at lower concentrations and at the lower 1 : 1 E:T ratio. In contrast, the negative control antibody XENP 13245 (at 10 μg/ml) did not show any CLL cancer cell depletion at either 5: 1 or 1 : 1 ratios. Therefore, CLL cells are sensitive to XmAbl3676-induced T cell-mediated killing effects, in particular when sufficient T cells are present.

[0326] PBMC samples from three FL human subjects were also characterized for XmAbl3676- mediated cytotoxicity. Although CD19+CD10+ FL cells were not high in number in these FL human subject- derived PBMC samples, counts were sufficiently high to reveal XmAbl3676- mediated cytotoxicity of this target population. CD19+CD10+ FL counts in control samples not exposed to XmAbl3676 ranged from below 200 to almost 1000. In the presence of 0.1, 1.0, or 10 μg/ml concentrations of XmAbl3676, these cells were nearly completely eliminated, particularly at the two higher concentrations. The nonspecific control antibody did not have any apparent impact on the FL cells. Notably, XmAbl3676 also induced robust killing of the autologous healthy CD 19+ B cells present in the PBMC samples, with a similar extent of depletion and concentration dependence, as shown in Figure 10. Finally, in a pattern consistent with the observed depletion of B cells, XmAbl3676 strongly activated T cells in the FL samples, as evidenced by CD69 and CD25 upregulation on both CD4 and CD 8 T cells.

EXAMPLE 4

Antitumor Activity in a Mouse Lymphoma Mode

[0327] XmAbl3676 does not cross-react with either mouse CD3 or CD20. Therefore, XmAbl3676 was evaluated for its anti-tumor efficacy in NSG mice engrafted systemically with luciferase- transgenic human Raji cells (RajiTrS) as well as human PBMC. As shown in Figure 11, In Vivo Imaging System (IVIS) analysis revealed that XmAbl3676 prevented tumor growth at all doses tested, including 0.03 mg/kg, 0.1 mg/kg, 0.3 mg/kg, 1.0 mg/kg, 3.0 mg/kg. The data suggest that even lower doses would also be likely to have significant tumor prevention activity.

Claims

WHAT IS CLAIMED IS:

1. A method for treating a CD20-expressing cancer in a human subject, comprising: administering to the human subject having the CD20-expressing cancer an intravenous dose of a bispecific anti-CD20 x anti-CD3 antibody in combination with at least one other therapeutic agent, for a time period sufficient to treat the CD20-expressing cancer, wherein at least one of the other therapeutic agents is selected from the group consisting of PDl inhibitors, PDLl inhibitors, PDL2 inhibitors, TIM3 inhibitors, LAG3 inhibitors, CTLA4 inhibitors, TIGIT inhibitors, BTLA inhibitors, CD47 inhibitors, IDO inhibitors, GITR agonists, and ICOS agonists,

thereby treating said CD20-expressing cancer.

2. The method of claim 1, wherein the bispecific anti-CD20 x anti-CD3 antibody comprises:

a) a first monomer comprising SEQ ID NO: 1;

b) a second monomer comprising SEQ ID NO: 2; and

c) a light chain comprising SEQ ID NO: 3.

3. The method of claim 1, wherein the bispecific anti-CD20 x anti-CD3 antibody comprises:

a) an anti-CD20 variable heavy (VH) domain comprising SEQ ID NO: 22;

b) an anti-CD20 variable light (VL) domain comprising SEQ ID NO: 23;

c) an anti-CD3 variable heavy (VH) domain comprising SEQ ID NO: 24; and d) an anti-CD3 variable light (VL) domain comprising SEQ ID NO: 25.

4. The method of claim 1, wherein the bispecific anti-CD20 x anti-CD3 antibody comprises:

a) an anti-CD3 VH domain comprising a VHCDR1 comprising SEQ ID NO:

26, a VHCDR2 comprising SEQ ID NO: 27 and a VHCDR3 comprising SEQ ID NO: 28;

b) an anti-CD3 VL domain comprising a VLCDRl comprising SEQ ID NO:

29, a VLCDR2 comprising SEQ ID NO: 30 and a VLCDR3 comprising SEQ ID NO: 31; c) an anti-CD20 VH domain comprising a VHCDRl comprising SEQ ID NO:

32, a VHCDR2 comprising SEQ ID NO: 33 and a VHCDR3 comprising SEQ ID NO: 34;

d) an anti-CD20 VL domain comprising a VLCDR1 comprising SEQ ID NO:

35, a VLCDR2 comprising SEQ ID NO: 36 and a VLCDR3 comprising

SEQ ID NO: 37.

5. The method of claim 1, wherein the bispecific anti-CD20 x anti-CD3 antibody is XmAbl3676.

6. The method of claim 1, wherein the at least one of the other therapeutic agents is a PD 1 inhibitor.

7. The method of claim 6, wherein the PD1 inhibitor is an anti-PDl antibody.

8. The method of claim 7, wherein the anti-PDl antibody is selected from the group consisting of nivolumab, pembrolizumab, pidilizumab, spartalizumab, JNJ-63723283, TSR-042, cemiplimab, AMP-224, MEDI0680, MGA012, MGD013, MGD019, SHR-1210, GLS-010, JS001, tislelizumab, sintilimab, CX-188, and CS1003.

9. The method of claim 7, wherein the anti-PDl antibody is selected from the group consisting of nivolumab, pembrolizumab, and pidilizumab.

10. The method of claim 7, wherein the anti-PDl antibody is spartalizumab.

11. The method of claim 1, wherein the at least one of the other therapeutic agents is a PDL1 inhibitor.

12. The method of claim 11, wherein the PDL1 inhibitor is an anti-PDLl antibody.

13. The method of claim 12, wherein the anti-PDLl antibody is selected from the group consisting of atezolizumab, avelumab, durvalumab, FAZ053, LY3300054, ABBV-181, MSB2311, BMS-936559, CSlOOl, KN035, CA-327, CX-072, M7824, HTI-1316, and JS003.

14. The method of claim 1, wherein the at least one other therapeutic agent further comprises a chemotherapeutic.

15. The method of claim 14, wherein said chemotherapeutic is selected from the group consisting of alkylating agents, anti-metabolites, kinase inhibitors, proteasome inhibitors, vinca alkaloids, anthracyclines, antitumor antibiotics, aromatase inhibitors, topoisomerase inhibitors, mTOR inhibitors, retinoids, and combinations thereof.

16. The method of claim 1, wherein the at least one other therapeutic agent further comprises a side-effect ameliorating agent.

17. The method of claim 16, wherein said side-effect ameliorating agent is selected from the group consisting of: a steroid, an antihistamine, anti-allergic agents, antinausea agents (or anti-emetics), analgesic agent, antipyretic agent, cytoprotective agents, vasopressor agents, anticonvulsant agent, TNFa inhibitor, IL6 inhibitor, and combinations thereof.

18. The method of claim 16, wherein said side-effect ameliorating agent is selected from the group consisting of corticosteroids, TNFa inhibitors, IL-1R inhibitors, and IL-6 inhibitors.

19. The method of claim 16, wherein said side-effect ameliorating agent is a combination of a corticosteroid, Benadryl® and Tylenol®, wherein said corticosteroid, Benadryl® and Tylenol® are administered to said human subject prior to the administration of said bispecific anti-CD20 x anti-CD3 antibody.

20. The method of claim 1, wherein the CD20-expressing cancer is a lymphoma.

21. The method of claim 20, wherein the lymphoma is Non-Hodgkin lymphoma.

The method of claim 21, wherein the Non-Hodgkin lymphoma is B-cell NHL.

23. The method of claim 21, wherein the Non-Hodgkin lymphoma is selected from the group consisting of chronic lymphocytic leukemia, small lymphocytic leukemia, B-cell prolymphoctyic leukemia, transformed leukemia, Burkitt's lymphoma, mantle cell lymphoma, hairy cell leukemia, splenic marginal zone lymphoma, Waldenstrom's macroglobulinemia, variant hairy cell leukemia, splenic B cell lymphoma/1 eukemi a, lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B cell lymphoma, follicular lymphoma, in situ follicular neoplasia, duodenal follicular lymphoma, large B cell lymphoma with IFR4 rearrangement, primary cutaneous follicle center lymphoma, diffuse large B cell lymphoma (DLBCL), T-cell/histocyte- rich large B cell lymphoma, primary cutaneous DLBCL (leg type), EBV-positive DLBCL NOS, EBV-positive mucocutaneous ulcer, DLCBL associated with chronic inflammation,

lymphomatoid granulomatosis, primary mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, ALK+ large B-cell lymphoma, plasmablastic lymphoma, primary effusion lymphoma, HHV8+DLBCL, Burkitt-like lymphoma with 1 lq aberration, high grade B cell lymphoma NOS, B cell lymphoma unclassifiable, and post-transplant

lymphoproliferation disorder (PTLD).

24. The method of claim 21, wherein the Non-Hodgkin lymphoma is chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).

25. The method of any preceding claims, wherein the intravenous dose is:

between about 18 μg/kg and about 22 μg/kg; or

between about 40 μg/kg and about 50 μg/kg; or

between about 75 μg/kg and about 85 μg/kg; or

between about 120 μg/kg and about 130 μg/kg; or

between about 165 μg/kg and about 175 μg/kg.

26. The method of any preceding claims, wherein the intravenous dose is

administered to the human subject between about 1 hour and about 3 hours.

27. The method of any preceding claims, wherein the time period sufficient to treat the leukemia is between about 3 weeks and 9 weeks.

28. The method of any preceding claims, wherein the bispecific anti-CD20 x anti- CD3 antibody and the at least one other therapeutic agent are administered concurrently.

29. The method of any preceding claims, wherein the administration of the at least one other therapeutic agent begins before the administration of the bispecific anti-CD20 x anti- CD3 antibody.

30. The method of any preceding claims, further comprising, prior to the administering, assessing the weight of the human subject.