WO2015116729A2

WO2015116729A2 - Anti-cd37 antibody and anti-cd20 antibody combination therapy for treatment of b-cell malignancies and disorders

Info

Publication number: WO2015116729A2
Application number: PCT/US2015/013367
Authority: WO
Inventors: Scott STROMATT; Brian Gordon
Original assignee: Emergent Product Development Seattle, Llc
Priority date: 2014-01-28
Filing date: 2015-01-28
Publication date: 2015-08-06
Also published as: WO2015116729A3

Abstract

The present invention provides methods of treating a patient with a B-cell malignancy or disorder comprising administering an anti-CD37 antibody or antibody fragment in combination with an anti-CD20 antibody or antibody fragment. In one embodiment, the invention provides methods for B-cell reduction comprising contacting B-cells with an anti-CD37 antibody or antibody fragment and an anti-CD20 antibody or antibody fragment. The invention includes compositions and kits comprising anti-CD37 antibody and antibody fragments for use in combination with an anti-CD20 antibody or antibody fragment. The methods and compositions of the invention may further include a BCR antagonist such as a SYK inhibitor, a BTK inhibitor, a PI3K inhibitor, or a CXCR4 antagonist.

Description

ANTI-CD37 ANTIBODY AND ANTI-CD20 ANTIBODY COMBINATION THERAPY FOR

TREATMENT OF B-CELL MALIGNANCIES AND DISORDERS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No.

61/932,518, filed January 28, 2014, and U.S. Provisional Application No. 62/088,179, filed December 5, 2014, both of which are incorporated herein by reference in their entireties for all purposes.

FIELD OF THE INVENTION

[0002] The present invention provides methods for the treatment of patients with B cell malignancies and disorders comprising administering an anti-CD37 antibody with an anti- CD20 antibody. The provided methods further comprise administering a B-cell receptor (BCR) pathway antagonist, for instance a Spleen Tyrosine Kinase (SYK) inhibitor, a Bruton's Tyrosine Kinase (BTK) inhibitor, a Phosphotidylinositol-3-Kinase (PI3K) inhibitor, or a CXCR4 antagonist. The invention provides methods for B-cell reduction comprising contacting B cells with a combination of an anti-CD37 antibody and an anti-CD20 antibody. The invention further provides compositions for the treatment of B cell malignancies comprising an anti-CD37 for use in combination with an anti-CD20 antibody. The provided compositions may further comprise a BCR pathway antagonist.

DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY

[0003] The contents of the text file submitted electronically herewith are incorporated herein by reference in their entirety: A computer readable format copy of the Sequence Listing (filename: EMER-023_01_WO_SeqList_ST25.txt, date recorded: January 28, 2015, file size 121 kilobytes).

BACKGROUND OF THE INVENTION

[0004] In its usual role, the human immune system protects the body from damage from foreign substances and pathogens. One way in which the immune system protects the body is by production of specialized cells called B lymphocytes or B-cells. B-cells produce antibodies that bind to, and in some cases mediate destruction of, a foreign substance or pathogen. [0005] In some instances though, the human immune system and specifically the B lymphocytes of the human immune system go awry and disease results. There are numerous malignancies that involve uncontrolled proliferation of B-cells. B cell malignancies include Chronic Lymphocytic Leukemia (CLL) and Non-Hodgkin's lymphoma (NHL). Rituximab (marketed by Biogen) targets the B-cell antigen CD20 and is approved as first-line therapy in CLL and NHL (as well as in the immune disorders rheumatoid arthritis, Wegener's

granulomatosis and microscopic polyangiitis). In NHLs of B-cell origin, chemotherapy with or without rituximab is often administered. For example, rituximab in combination with CHOP (cyclophosphamide plus doxorubicin plus vincristine plus prednisone) is the standard therapy for patients newly diagnosed with diffuse large B-cell lymphoma, one of the most common forms of NHL. Even so, around one-third of patients will develop relapsed or refractory disease, which has a poor prognosis.

[0006] CLL is a heterogeneous disease, primarily afflicting the elderly. For many years treatment for this disease has focused on palliative chemotherapy based approaches as monotherapy or in combination. The introduction of the chimeric monoclonal antibody rituximab that targets CD20 demonstrated the potential efficacy of antibody mediated treatment approaches with clinical activity in CLL prompting exploration in conjunction with chemotherapy. Non-randomized and randomized trials have shown that chemoimmunotherapy combining rituximab with fludarabine and cyclophosphamide offers a survival advantage. See, for instance, Hallek et al., 2008, Blood. 1 1 1 :5446-56; Hallek et al., 2010, Lancet. 376:1 164-74; Keating et al., 2005, J. Clin. Oncol. 23:4079-88; Robak et al., 2010, J. Clin. Oncol. 28:1756-65; Tarn et al., 2008, Blood. 1 12:975-80; and Wierda et al., 2005, J. Clin. Oncol. 23:4070-8.

Although the therapy is often successful, around half of patients are either unresponsive or experience early relapse as is common with fludarabine-based chemotherapy. Moreover, many elderly patients are not candidates for chemoimmunotherapy due to the toxicity and lack of benefit of single agent fludarabine in individuals over age 65. Accordingly, there is a need for the identification of new treatments for B-cell malignancies such as CLL.

[0007] CD37 is one such potential alternative target for antibody directed therapy.

CD37 is a member of the tetraspanin superfamily of molecules which as a class of proteins are generally implicated in diverse processes, including cellular activation and proliferation, cell motility, and cell-cell adhesion. CD37 is a heavily glycosylated cell surface protein expressed constitutively at high levels on mature human B cells and transformed mature human B-cell leukemia and lymphoma cells. CD37 is not expressed on pro-B cells or terminally differentiated plasma cells. CD37 is either absent or expressed weakly on normal T cells, monocytes, and neutrophils, and is absent from natural killer (NK) cells, platelets, and erythrocytes. CD37 is considered to be a lineage-specific marker of mature human B cells restricted to the surface of B lymphocytes and therefore represents a unique therapeutic target. Because normal mature B-cells also express CD37, normal B-cells are depleted by an anti-CD37 antibody (Press et al., 1989, J. Clin. Oncol. 7(3): 1027-1038). After anti-CD37 treatment is completed, however, normal B-cells can be regenerated from CD37-negative B-cell precursors; therefore, patients treated with anti-CD37 therapy do not experience significant immunosuppression.

[0008] Until recently, only minimal effort has been directed toward CD37 immune therapy. Early therapeutics designed to target CD37 included MB-1 , a murine lgG1 monoclonal antibody labeled with ¹³¹1 and tested in clinical trials for therapy of NHL. See Press et al., J. Clin. Oncol., 7(3): 1027-1038 (1989); Bernstein et al., Cancer Res. (Suppl.), 50: 1017-1021 (1990); Press et al., Front. Radiat. Ther. Oncol., 24: 204-213 (1990); Press et al., Adv. Exp. Med. Biol., 303: 91 -96 (1991 ) and Brown et al., Nucl. Med. Biol., 24: 657-663 (1997). MB-1 lacked Fc effector functions such as antibody-dependent cellular cytotoxicity (ADCC), and it did not inhibit tumor growth in an in vivo xenograft model unless labeled with an isotope

(Buchsbaum et al. , Cancer Res., 52(83): 6476-6481 (1992). Favorable biodistribution of ¹³¹ l- MB-1 was seen in lymphoma patients who had lower tumor burdens (<1 kg) and therapy of these patients resulted in complete tumor remissions lasting from 4 to 1 1 months (Press et al., 1989 and Bernstein et al. 1990).

[0009] An antibody conjugate composed of the drug adriamycin linked to G28-1 , another anti-CD37 murine antibody, was evaluated in mice and showed effects through internalization and intracellular release of the drug. See Braslawsky et al., Cancer Immunol. Immunother., 33(6): 367-374 (1991 ).

[0010] TRU-016 (also known as otlertuzumab) is a CD37-specific antibody-like therapeutic protein comprising, from amino to carboxyl terminus, a binding domain derived from G28-1 (i.e., scFv), an immunoglobulin hinge and a modified lgG1 Fc domain lacking a CH1 . See, for instance, US 8,333,966 which is incorporated by reference in its entirety. Pre-clinical studies with SMIP-016, a murine version of TRU-016, demonstrated its ability to mediate NK- cell antibody dependent cellular toxicity (ADCC) against human CLL cells superior to that observed with rituximab. In vivo studies with several lymphoma xenograft models supported both the in vivo activity of murine TRU-016 as monotherapy and in combination with therapies such as bendamustine and rituximab. SMIP-016 has been shown to induce apoptosis of CLL cells in vitro in a tyrosine phosphorylation-dependent manner that suggests an alternative signaling mechanism of action compared to rituximab. A recent publication demonstrated that CD37 has both ITIM and ITAM-like signaling activity, and ligation of this antigen by SMIP-016 prompts recruitment of the phosphatase SHP1 , inhibition of the PI3-kinase pathway, and up- regulation of BIM, which is responsible for apoptosis mediated by this agent. Given the unique mechanism of killing through CD37 distinct from CD20, selective binding of TRU-016 to mature B-cells and promising in vivo activity, the fully humanized TRU-016 was moved into the clinic for testing.

[001 1] TRU-016 is the furthest along in the clinic of anti-CD37 therapeutics currently in development. In one trial, fifty-seven patients were treated in the dose-escalation phase and 26 in the expansion phase. A maximum tolerated dose (MTD) was not identified.

Pharmacokinetics of TRU-016 was dose-proportional with a median terminal half-life of 8 days. Clinical activity was observed with partial responses in untreated and relapsed patients including individuals with del(17p13.1 ). Specifically, lymphocyte reduction≥50% was observed in 55% (46/83) of all patients treated and 19 (23%) attained a response by NCI-96 criteria. All responses were partial responses and occurred more commonly in patients with symptomatic untreated CLL (6/7) or 1-2 prior therapies (12/29) compared to those with 3 or more therapies (1/47). TRU-016 has demonstrated a favorable safety profile.

[0012] In addition to TRU-016, chimeric and humanized anti-CD37 antibodies derived from murine antibody G28-1 have been developed with engineered CH2 domains for improved binding to human Fey receptors. One such chimeric antibody, mAb 37.1 has been reported to show high intrinsic proapoptotic activity on malignant B cells accompanied by homotypic aggregation. It has also been reported to exhibit Ab-mediated high Ab-dependent cell-mediated cytotoxicity (ADCC) on lymphoma and primary CLL cells. It has been reported that mAb 37.1 strongly depleted normal B cells as well as spiked B-lymphoma cells in blood samples from healthy donors as well as malignant B cells in blood from CLL patients. A single dose of mAb CD37.1 administered to human CD37-transgenic mice resulted in a reversible, dose-dependent reduction of peripheral B cells. In a Ramos mouse model of human B-cell lymphoma, administration of mAb 37.1 strongly suppressed tumor growth. See, for instance, Heider ef a/., 201 1 , Blood. 1 18(15):4159-69.

[0013] Another anti-CD37 antibody-like polypeptide in development is IMGN529, an antibody-drug conjugate targeting hCD37 that consists of the CD37-targeting K7153A antibody linked to the maytansinoid DM1 via the thioether SMCC linker. In preclinical studies, IMGN529 has been reported to exhibit anti-leukemic effects in a murine model of aggressive B-cell malignancy. Based on data from an engraftment model, it is believed that IMGN529 is capable of eliminating widespread and highly proliferative mouse leukemia by a mechanism that is both CD37 antigen and conjugate dependent. See, for instance, Beckwith et al., ASH 2012 poster abstract 188.

[0014] Another B-cell lineage-specific cell surface molecule is CD20. CD20 was the first human B-cell lineage-specific surface molecule identified by a monoclonal antibody. It is a non-glycosylated, hydrophobic 35 kDa B-cell transmembrane phosphoprotein that has both its amino and carboxy ends situated inside the cell. See, Einfeld et al., EMBO J., 7:71 1-17 (1998). CD20 is expressed by all normal mature B-cells, but is not expressed by precursor B-cells or plasma cells. Natural ligands for CD20 have not been identified, and the function of CD20 in B- cell biology is still incompletely understood.

[0015] Various groups have investigated the use of anti-CD20 antibodies to treat B- cell related diseases. One treatment consists of anti-CD20 antibodies prepared in the form of radionuclides for treating B-cell lymphoma (e.g., ³ l-labeled anti-CD20 antibody), as well as a ⁸⁹Sr-labeled form for the palliation of bone pain caused by prostate and breast cancer metastases [Endo, Gan To Kagaku Ryo o, 26: 744-748 (1999)].

[0016] Another group developed a chimeric monoclonal antibody specific for CD20, consisting of heavy and light chain variable regions of mouse origin fused to human lgG1 heavy chain and human kappa light chain constant regions. The chimeric antibody reportedly retained the ability to bind to CD20 and the ability to mediate ADCC and to fix complement. See, Liu et al., J. Immunol. 139:3521-26 (1987). Yet another chimeric anti-CD20 antibody was made from IDEC hybridoma C2B8 and was named rituximab. The mechanism of anti-tumor activity of rituximab is thought to be a combination of several activities, including ADCC, complement fixation, and triggering of signals that promote apoptosis in malignant B-cells, although the large size of the chimeric antibody prevents optimal diffusion of the molecule into lymphoid tissues that contain malignant B-cells, thereby limiting its anti-tumor activities. ADCC is a cell-mediated reaction in which nonspecific cytotoxic cells that express Fc receptors (FcRs) (e.g. Natural Killer (NK) cells, neutrophils, and macrophages) recognize bound antibody on a target cell and subsequently cause lysis of the target cell. Complement fixation or complement-dependent cytotoxicity (CDC) is the ability of a molecule to lyse a target in the presence of complement. The complement activation pathway is initiated by the binding of the first component of the complement system (C1 q) to a molecule (e.g. an antibody) complexed with a cognate antigen. The large size of rituximab prevents optimal diffusion of the molecule into lymphoid tissues that contain malignant B-cells, thereby limiting these anti-tumor activities.

[0017] Rituximab, typically administered in 4 weekly infusions, is currently used to treat low-grade or follicular B-cell non-Hodgkin's lymphoma [McLaughlin at al., Oncology, 12: 1763-1777 (1998); Leget et al., Curr. Opin, Oncol . ,10: 548-551 (1998)] and in relapsed stage lll/IV follicular lymphoma [White et al., Pharm. Sci. Technol. Today, 2: 95-101 (1999)]. Other disorders treatable with rituximab include follicular centre cell lymphoma (FCC), mantle cell lymphoma (MCL), diffuse large cell lymphoma (DLCL), and small lymphocytic lymphoma (SLL) [Nguyen et al., Eur J Haematol., 62:76-82 (1999)]. Rituximab administered in weekly infusions is also used to treat CLL [Lin et al., Sem Oncol., 30:483-92 (2003)].

[0018] In addition to rituximab, other anti-CD20 antibodies have been developed that exhibit augmented antitumor activity compared with rituximab by increasing CDC or ADCC. See, for instance, Robak T, 2009, Curr Opin Investig Drugs, 10(6), 588-596, which is hereby incorporated by reference herein in its entirety for all purposes. These newer anti-CD20 antibodies are humanized to reduce the likelihood of immunogenicity and infusion reactions compared to chimeric antibodies such as rituximab, enabling safer and shorter intravenous infusions. For instance, ofatumumab is a second-generation, fully human lgG1 monoclonal antibody that is approved for the treatment of CLL. Ofatumumab recognizes a different CD20 epitope than rituximab, and has demonstrated a higher cytotoxic potential than rituximab (Robak T, 2009). Veltuzumab is another second-generation, humanized lgG1 mAb that is in phase II clinical trials for the treatment of NHLs and CLL (Robak T, 2009). Veltuzumab differs from rituximab by one amino acid in the complementarity-determining region 3 of the variable heavy chain, and has demonstrated enhanced binding avidities and a stronger effect on CDC than rituximab (Robak T, 2009). Ocrelizumab is a humanized lgG1 mAb that is in phase III trials for the treatment of autoimmune diseases, such as rheumatoid arthritis, and in phase II trials for hematological neoplasm (Robak T, 2009). Compared with rituximab, ocrelizumab has demonstrated the potential for enhanced efficacy in the treatment of NHLs as a result of increased binding affinity for FcYRIIIa (Robak T, 2009).

[0019] Another humanized anti-CD20 antibody is a third-generation, glyco- engineered, type II lgG1 monoclonal antibody GA-101 or obinutuzumab, which is being developed for the potential treatment of B-cell malignancies. GA-101 is engineered for enhanced ADCC, superior direct cell killing properties and lower CDC activity compared with currently available type I CD20 antibodies. GA-101 is in clinical trials for the treatment of NHL and hematological neoplasms in patients with CD20-positive B-cell malignancies (Robak T, 2009).

[0020] Another B-cell surface molecule is B-cell receptor (BCR). BCR signaling is thought to promote cell proliferation, adhesion, and survival in many types of B-cell

malignancies (cancers). B-cell malignancies including non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) can be driven by aberrant activity of cellular signaling pathways and by extrinsic factors from the micro-environment which interacts with the BCR (Caligaris-Cappio and Chiorazzi, 2010).

[0021] BCR activation initiates signal transduction in B-cells via the Src family kinase Lyn mediated phosphorylation of immune-receptor tyrosine-based activation motifs (ITAMs). This leads to the recruitment, autophosphorylation, and sustained activity of spleen tyrosine kinase (Syk), a 72kDa cytoplasmic tyrosine kinase, and the activation of a number of downstream effectors (Mocsai et al. 2010). Increased Syk expression and/or activity has been implicated in a number of NHL histologies (Rinaldi et al., 2006; Tavolaro et al., 2006; Chen et al., 2008; Davis et al., 2010). In CLL, constitutive Syk activity, as well as activation after BCR cross-linking, have been described (Baudot et al., 2009; Gobessi et al., 2009). Increased expression of BCR associated kinases including Syk is associated with a shorter treatment-free interval (Rodriguez et al., 2007), and Syk inhibition results in apoptosis (Baudot et al., 2009; Hoellenriegel et al., 201 1 ) and disruption of chemokine activity (Rodriguez et al., 2007;

Hoellenriegel et al., 201 1 ).

[0022] The Bruton tyrosine kinase (Btk) is specifically required for BCR signaling as demonstrated by human and mouse mutations that disrupt Btk function and prevent B-cell maturation at steps that require a functional BCR pathway. See for instance, Honigberg et al., 2010, Proc. Natl. Acad. Sci. USA. 107(29): 13075-80. Subsequent BTK autophosphorylation and activation leads to phosphorylation of PLC-gamma, inducing calcium flux and eventually leading to activation of transcription factors including NF-kB and N-FAT. BTK is also known to play a role in migration of lymphoma cells by acting downstream of chemokine receptors via pathways still under investigation.

[0023] Another important kinase that may be targeted in B cell disorders is phosphatidylinositol-3-kinase (PI3K). PI3K plays a key role in signal transduction, cell metabolism and survival and is commonly deregulated in cancer (Brana and Liu, BMC Med. 2012, 10:161 ). For example, the overexpression of the δ isoform of the p1 10 subunit of PI3k has been observed in a wide range of lymphoproliferative disorders including chronic lymphocytic leukemia (Herman et al., Blood 2010, 1 16:2078-2088). Given its prominent role in cancer, several inhibitors are being developed to target different members of the PI3K signaling pathway. For instance, idelalisib, also known as GS-1 101 or CAL-101 , is an inhibitor of the PI3K5 isoform that is currently being developed as a treatment for B cell malignancies including CLL (Brana and Liu, BMC Med. 2012, 10:161 ).

[0024] Inhibiting the BCR signaling pathway has been shown to be effective in inducing apoptosis in malignant cells and in preventing chemokine-mediated migration of malignant cells into the protective environment of stromal tissue. See, for instance,

Hoellenriegel et al., 2012, Leukemia. 26(7): 1576-83, which is hereby incorporated by reference herein its entirety for all purposes.

[0025] Although there has been extensive research carried out on antibody-based therapies, there remains a need in the art for improved methods to treat diseases associated with aberrant B cell activity. For instance, in B cell malignancies such as CLL, there are no therapeutics available that cure the disease (with the exception of a bone marrow transplant which is unavailable to most CLL patients) and patients relapse.

SUMMARY OF THE INVENTION

[0026] The present invention includes methods and compositions based on the combination of an anti-CD37 antibody and an anti-CD20 antibody for treatment of a B cell malignancy or disorder. The present invention also includes methods and compositions based on the combination of an anti-CD37 antibody, an anti-CD20 antibody, and a BCR pathway antagonist for treatment of a B cell malignancy or disorder.

[0027] The present invention provides methods of treating a patient with a B-cell malignancy or disorder comprising administering to the patient a therapeutically effective amount of an anti-CD37 antibody or antibody fragment and an anti-CD20 antibody or antibody fragment. In one embodiment, the anti-CD20 antibody is obinutuzumab. In another embodiment, the anti-CD20 antibody is not rituximab. In yet another embodiment, the provided methods of treating a patient with a B-cell malignancy or disorder further comprise

administering to the patient a therapeutically effective amount of a molecule that actively mobilizes an egress of B-cells from lymph nodes into peripheral blood, such as a BCR antagonist. The BCR antagonist can inhibit signaling downstream of the B-cell receptor. For instance, the methods and compositions of the invention include BCR antagonists such as a Bruton's tyrosine kinase (BTK) inhibitor, a spleen tyrosine kinase (SYK) inhibitor, a PI3K inhibitor, or a CXCR4 antagonist. In one embodiment of the invention, the molecule that actively mobilizes an egress of B-cells from lymph nodes into peripheral cells is not an anti- CD20 molecule or anti-CD37 molecule.

[0028] In another embodiment, the present invention provides methods of treating a patient with a B-cell malignancy or disorder comprising administering to the patient a therapeutically effective amount of an anti-CD37 antibody or antibody fragment and an anti- CD20 antibody or antibody fragment in combination with a kinase inhibitor. In one embodiment, the kinase inhibitor is a BTK inhibitor, a SYK inhibitor or PI3K inhibitor.

[0029] In another embodiment, the invention provides methods of reducing B-cells using anti-CD37 antibodies or antibody fragments in combination with anti-CD20 antibodies or antibody fragments. In a further embodiment, the methods of reducing B-cells comprise using a BCR antagonist such as a SYK inhibitor, BTK inhibitor, PI3K inhibitor, or CXCR4 antagonist. In yet another embodiment, the invention provides methods of depleting B-cells using anti- CD37 antibodies or antibody fragments in combination with anti-CD20 antibodies or antibody fragments. In yet another embodiment, the invention provides methods of depleting B-cells using a combination of anti-CD37 antibodies or antibody fragments, anti-CD20 antibodies or antibody fragments, and a BCR antagonist such as a SYK inhibitor, BTK inhibitor, PI3K inhibitor, or CXCR4 antagonist. In yet another embodiment, the invention provides methods of depleting B-cells using a combination of anti-CD37 antibodies or antibody fragments, anti-CD20 antibodies or antibody fragments, and a kinase inhibitor such as a PI3K inhibitor, SYK inhibitor or BTK inhibitor. The invention includes reducing B-cells or depleting B-cells in a patient with a B-cell malignancy or disorder comprising administering to the patient a therapeutically effective amount of an anti-CD37 antibody or antibody fragment and an anti-CD20 antibody or antibody fragment, optionally with a SYK inhibitor, BTK inhibitor, PI3K inhibitor or CXCR4 antagonist. For instance, in one embodiment, a patient with a B-cell malignancy is administered an anti- CD37 antibody or antibody fragment in combination with an anti-CD20 antibody or antibody fragment and a BTK inhibitor to reduce or deplete B cells. In another embodiment, a patient with a B-cell malignancy is administered an anti-CD37 antibody or antibody fragment in combination with an anti-CD20 antibody or antibody fragment and a PI3K inhibitor to reduce or deplete B cells. In one embodiment of the invention, the BCR antagonist administered in combination with an anti-CD37 antibody or antibody fragment is not an anti-CD20 molecule or anti-CD37 molecule.

[0030] In one embodiment, the anti-CD20 antibody of the methods, compositions and kits of the invention is obinutuzumab (recommended INN, WHO Drug Information, Vol. 26, No. 4, 2012, p. 453). In another embodiment, the anti-CD20 antibody is ofatumumab, veltuzumab, or ocrelizumab. In yet another embodiment, the anti-CD20 antibody of the invention is not rituximab. In one embodiment, the anti-CD20 antibody is an antibody or antibody fragment that binds to the same epitope as rituximab, ofatumumab, veltuzumab, ocrelizumab or obinutuzumab. In another embodiment, the anti-CD20 antibody is an antibody or antibody fragment that binds to a different epitope from the epitope bound by rituximab, ofatumumab, veltuzumab, ocrelizumab, or obinutuzumab. In another embodiment, the anti- CD20 antibody is an antibody or antibody fragment that is derived from rituximab, ofatumumab, veltuzumab, ocrelizumab or obinutuzumab. In an embodiment, the anti-CD20 antibody or antibody fragment is administered prior to, concurrently with or after administration of an anti- CD37 antibody or antibody fragment.

[0031] In one embodiment, the methods of the invention include administering an anti-CD37 antibody or antibody fragment and an anti-CD20 antibody or antibody fragment to a patient with a B-cell malignancy or B cell disorder. In another embodiment, the methods of the invention include treating a patient with a B cell disorder by reducing or depleting B cells using a combination of an anti-CD37 antibody or antibody fragment and an anti-CD20 antibody or antibody fragment. For instance, the invention includes treating a patient with a B-cell malignancy or B cell disorder with TRU-016 and obinutuzumab.

[0032] In one embodiment, the methods of the invention include treating a patient with a B-cell malignancy or B cell disorder by administering an anti-CD37 antibody or antibody fragment and an anti-CD20 antibody or antibody fragment along with a BCR antagonist. In an embodiment, the BCR antagonist of the methods, compositions and kits of the invention is a SYK inhibitor. As used herein, a "SYK inhibitor" is a compound or molecule that selectively inhibits or suppresses one or more activities regulated by Syk. In one embodiment, a Syk inhibitor selectively inhibits or suppresses Syk tyrosine kinase activity (e.g., phosphorylation). Many SYK inhibitors have been described in the art such as fostamatinib, PRT062607 and PRT-318.

[0033] In one embodiment, the BCR antagonist is a reversible SYK inhibitor. In one embodiment, the BCR antagonist of the methods, compositions and kits of the invention comprises fostamatinib. In another embodiment, the BCR antagonist of the methods, compositions and kits of the invention comprises [(4-(3-(2H-1 ,2,3-triazol-2-yl)phenylamino)-2- ((1 R,2S)-2-aminocyclohexylamino)pyrimidine-5-carboxamide acetate], also known as

PRT062607 or P505-15. In another embodiment, the BCR antagonist of the methods, compositions and kits of the invention comprises a derivative of pyrimidine-5-carboxamide such as PRT-318, also referred to as P142-76. For instance, the invention includes methods of administering a therapeutically effective amount of an anti-CD37 antibody or antibody fragment, a therapeutically effective amount of an anti-CD20 antibody or antibody fragment, and fostamatinib, PRT-318 or PRT062607. In one embodiment, the SYK inhibitor is administered prior to, concurrently with or after administration of an anti-CD37 antibody or antibody fragment. In one embodiment, a patient with a B-cell malignancy or disorder is administered an anti-CD37 antibody or antibody fragment with the same epitope as G28-1 , MB371 , BL14, NMN46, IP024, HH1 , WR17, HD28 or K7153A, and an anti-CD20 antibody or antibody fragment with a SYK inhibitor such as fostamatinib, PRT-318 or PRT062607. In another embodiment, a patient with a B-cell malignancy or disorder is administered an anti-CD37 antibody or antibody fragment derived from G28-1 , MB371 , BL14, NMN46, IP024, HH1 , WR17, HD28 or K7153A, and an anti-CD20 antibody or antibody fragment with a SYK inhibitor such as fostamatinib, PRT-318 or PRT062607. In another embodiment of the invention, a patient with a B-cell malignancy or disorder is administered a humanized or chimeric anti-CD37 antibody or antibody fragment derived from G28-1 , MB371 , BL14, NMN46, IP024, HH1 , WR17, HD28 or K7153A, and an anti-CD20 antibody or antibody fragment with a SYK inhibitor such as fostamatinib or

PRT062607. For instance, the invention includes treating a patient with a B cell malignancy or a B cell disorder by administering TRU-016, obinutuzumab, and a SYK inhibitor such as fostamatinib or PRT062607.

[0034] In one embodiment, the BCR antagonist of the methods, compositions and kits of the invention is a BTK inhibitor. As used herein, a "BTK inhibitor" is a compound or molecule that selectively inhibits or suppresses one or more activities regulated by Btk. In one embodiment, a Btk inhibitor selectively inhibits or suppresses Btk tyrosine kinase activity (e.g., phosphorylation).

[0035] In one embodiment, the BCR antagonist is an irreversible BTK inhibitor. In one embodiment, the BTK inhibitor is capable of covalently binding BTK. For instance, the invention includes a BTK inhibitor that binds a cysteine residue on BTK such as cysteine residue 481. In another embodiment of the invention, a Michael acceptor moiety on the BTK inhibitor binds a cysteine residue of a BTK, for instance, cysteine residue 481. The Michael acceptor moiety can be acrylamide, vinyl sulfonamide or propargylamide.

[0036] In another embodiment of the methods, compositions and kits of the invention, the BTK inhibitor is capable of forming a non-covalent bond with a BTK.

[0037] The methods of the invention include administering an anti-CD37 antibody or antibody fragment, an anti-CD20 antibody or antibody fragment, and a BTK inhibitor to a patient with a B-cell malignancy or B cell disorder. For instance, the invention includes administering to a patient an anti-CD37 antibody or antibody fragment, an anti-CD20 antibody or antibody fragment, and ibrutinib. The invention also includes administering to a patient an anti-CD37 antibody or antibody fragment, an anti-CD20 antibody or antibody fragment, and AVL-292. In one embodiment, the BTK inhibitor, such as ibrutinib, is administered prior to, concurrently with or after administration of an anti-CD37 antibody or antibody fragment. In one embodiment, a patient with a B-cell malignancy or disorder is administered an anti-CD37 antibody or antibody fragment with the same epitope as G28-1 , MB371 , BL14, NMN46, IP024, HH1 , WR17, HD28 or K7153A, and an anti-CD20 antibody or antibody fragment with a BTK inhibitor such as ibrutinib or AVL-292. In another embodiment, a patient with a B-cell malignancy or disorder is administered an anti-CD37 antibody or antibody fragment derived from G28-1 , MB371 , BL14, NMN46, IP024, HH1 , WR17, HD28 or K7153A and an anti-CD20 antibody or antibody fragment with a BTK inhibitor such as ibrutinib or AVL-292. In another embodiment of the invention, a patient with a B-cell malignancy or disorder is administered a humanized or chimeric anti-CD37 antibody or antibody fragment derived from G28-1 , MB371 , BL14, NMN46, IP024, HH1 , WR17, HD28 or K7153A and an anti-CD20 antibody or antibody fragment with a BTK inhibitor such as ibrutinib or AVL-292. For instance, the invention includes treating a patient with TRU-016, obinutuzumab, and a BTK inhibitor such as ibrutinib or AVL-292. [0038] The present invention provides methods for treating a patient with a B-cell malignancy or disorder comprising administering to the patient a therapeutically effective amount of an anti-CD37 antibody or antibody fragment, an anti-CD20 antibody or antibody fragment and a BCR pathway antagonist such that the combination therapy prevents the down- regulation of CXCR4 expression. In one embodiment, CXCR4 expression is greater in a patient with a B-cell malignancy or disorder after administration of an anti-CD37 antibody or fragment, an anti-CD20 antibody or fragment and a BCR pathway antagonist as compared to a similar patient that is administered a placebo or a monotherapy therapeutic selected from the group consisting of anti-CD37 antibody, anti-CD20 antibody, PI3K inhibitor, MTOR inhibitor, or purine nucleoside analog. In another embodiment, CXCR4 expression is greater in a patient with a B-cell malignancy or disorder after administration of an anti-CD37 antibody or fragment, an anti-CD20 antibody or fragment and a BCR pathway antagonist compared to the expression levels in the same patient prior to starting treatment. For instance, the invention includes methods of treating a patient with an anti-CD37 antibody or fragment, an anti-CD20 antibody or fragment and a BCR pathway antagonist that results in about a 1.5 fold, 2 fold, 3 fold or 4 fold or more difference in expression in CXCR4 as compared to a patient without treatment with the combination of an anti-CD37 antibody or fragment, an anti-CD20 antibody or fragment and a BCR pathway antagonist.

[0039] In another embodiment of the invention, the BCR pathway antagonist is a CXCR4 antagonist. As used herein, a "CXCR4 antagonist" is any compound or molecule that antagonizes an activity of CXCR4. For instance, in one embodiment, a CXCR4 antagonist prevents CXCR4 expression levels from dropping as a result of a B-cell malignancy. In one embodiment, CXCR4 antagonists selectively interact with CXCR4. In one embodiment, a CXCR4 antagonist disrupts one or more activities associated with CXCR4 during the course of a B-cell malignancy or disorder such as those described in Vlad et al., Cancer Res. 69:6387- 6395 which is herein incorporated by reference in its entirety for all purposes.

[0040] The methods of the invention include administering an anti-CD37 antibody or antibody fragment, an anti-CD20 antibody or antibody fragment and a CXCR4 antagonist to a patient with a B-cell malignancy or B cell disorder, including for instance, a patient with one or more poor prognostic factors (e.g., 17p deletion, TP53 mutations, 1 1q deletion, trisomy 12,

ZAP70+). For instance, the invention includes administering to a patient an anti-CD37 antibody or antibody fragment, an anti-CD20 antibody or antibody fragment and plerixafor. The invention also includes administering to a patient an anti-CD37 antibody or antibody fragment, an anti-

CD20 antibody or antibody fragment and a T140 analog. In one embodiment, the CXCR4 antagonist, such as plerixafor, is administered prior to, concurrently with or after administration of an anti-CD37 antibody or antibody fragment. In one embodiment, a patient with a B-cell malignancy or disorder is administered an anti-CD37 antibody or antibody fragment with the same epitope as G28-1 , MB371 , BL14, NMN46, IP024, HH1 , WR17, HD28 or K7153A and an anti-CD20 antibody or antibody fragment and a CXCR4 antagonist such as plerixafor or a T140 analog. In another embodiment, a patient with a B-cell malignancy or disorder is administered an anti-CD37 antibody or antibody fragment derived from G28-1 , MB371 , BL14, NMN46, IP024, HH1 , WR17, HD28 or K7153A and an anti-CD20 antibody or antibody fragment and a CXCR4 antagonist such as plerixafor or a T140 analog. In another embodiment of the invention, a patient with a B-cell malignancy or disorder is administered a humanized or chimeric anti-CD37 antibody or antibody fragment derived from G28-1 , MB371 , BL14, NMN46, IP024, HH1 , WR17, HD28 or K7153A and an anti-CD20 antibody or antibody fragment and a CXCR4 antagonist such as plerixafor or a T140 analog. For instance, the invention includes treating a patient with TRU-016, obinutuzumab and a CXCR4 antagonist such as plerixafor or T140 analog.

[0041] In one embodiment, the methods of the invention include treating a patient with a B-cell malignancy or B cell disorder by administering an anti-CD37 antibody or antibody fragment and an anti-CD20 antibody or antibody fragment along with a kinase inhibitor, such as, a PI3K inhibitor. In an embodiment, the PI3K inhibitor of the methods, compositions and kits of the invention is idelalisib. For instance, the invention includes methods of administering a therapeutically effective amount of an anti-CD37 antibody or antibody fragment, a

therapeutically effective amount of an anti-CD20 antibody or antibody fragment, and idelalisib. In one embodiment, the PI3K inhibitor is administered prior to, concurrently with or after administration of an anti-CD37 antibody or antibody fragment. In one embodiment, a patient with a B-cell malignancy or disorder is administered an anti-CD37 antibody or antibody fragment with the same epitope as G28-1 , MB371 , BL14, NMN46, IP024, HH1 , WR17, HD28 or K7153A, and an anti-CD20 antibody or antibody fragment with a PI3K inhibitor such as idelalisib. In another embodiment, a patient with a B-cell malignancy or disorder is

administered an anti-CD37 antibody or antibody fragment derived from G28-1 , MB371 , BL14, NMN46, IP024, HH1 , WR17, HD28 or K7153A, and an anti-CD20 antibody or antibody fragment with a PI3K inhibitor such as idelalisib. In another embodiment of the invention, a patient with a B-cell malignancy or disorder is administered a humanized or chimeric anti-CD37 antibody or antibody fragment derived from G28-1 , MB371 , BL14, NMN46, IP024, HH1 , WR17, HD28 or K7153A, and an anti-CD20 antibody or antibody fragment with a PI3K inhibitor such as idelalisib. For instance, the invention includes treating a patient with a B cell malignancy or a B cell disorder by administering TRU-016, obinutuzumab, and a PI3K inhibitor such as idelalisib.

[0042] The invention includes a medicament for treatment of a B-cell malignancy or disorder comprising an anti-CD37 antibody or antibody fragment and an anti-CD20 antibody or antibody fragment. For instance, the invention includes a medicament comprising TRU-016 and obinutuzumab. In one embodiment, the anti-CD20 antibody is not rituximab. In a further embodiment, the medicament further comprises a BCR antagonist such as a SYK inhibitor, BTK inhibitor, PI3K inhibitor, or CXCR4 antagonist. For instance, in one embodiment, the invention includes a medicament comprising TRU-016, obinutuzumab, and a SYK inhibitor such as fostamatinib or PRT062607. In another embodiment, the invention includes a medicament comprising TRU-016, obinutuzumab, and a BTK inhibitor such as ibrutinib or AVL-292. In yet another embodiment, the invention includes a medicament comprising TRU-016,

obinutuzumab, and a CXCR4 antagonist such as plerixafor or a T140 analog. In yet another embodiment, the invention includes a medicament comprising an anti-CD37 antibody or fragment, an anti-CD20 antibody or fragment and a kinase inhibitor. For instance, in one embodiment, the invention includes a medicament comprising TRU-016, obinutuzumab, and PI3K inhibitor, such as idelalisib.

[0043] Compositions comprising an anti-CD37 antibody or antibody fragment and an anti-CD20 antibody or antibody fragments are within the scope of the invention. For instance, in one embodiment, the composition comprises an anti-CD37 antibody or antibody fragment for use with an anti-CD20 antibody or antibody fragment for treatment of a B-cell malignancy or disorder. In a further embodiment, the compositions of the invention comprise a BCR antagonist such as a SYK inhibitor, BTK inhibitor or CXCR4 antagonist. For instance, in one embodiment, the composition for treatment of a B-cell malignancy or disorder comprises an anti-CD37 antibody or antibody fragment for use in combination with an anti-CD20 antibody or antibody fragment and a BCR antagonist such as a SYK inhibitor, BTK inhibitor or CXCR4 antagonist. In another embodiment, the compositions of the invention comprise a CD37 antibody or fragment, a CD20 antibody or fragment and a PI3K inhibitor. For instance, in one embodiment, the compositions of the invention comprise TRU-016, obinutuzumab and idelalisib.

[0044] The anti-CD37 antibody or antibody fragment of the invention comprises an antibody or antibody fragment that binds human CD37. In some embodiments, an anti-CD37 antibody or antibody fragment comprises or consists essentially of an amino acid sequence with at least about 90%, 95% or with 100% identity to the amino acid of SEQ ID NO:3, or with at least about 90%, 95%, or with 100% identity to amino acids 21 to 503 of SEQ ID NO:1. The anti-CD37 antibody or antibody fragment can be a fully human, humanized or chimeric antibody or fragment thereof capable of binding CD37. In one embodiment, the anti-CD37 antibody comprises an anti-CD37 antibody or fragment thereof selected from the group consisting of

G28-1 , MB371 , BL14, NMN46, IP024, HH1 , WR17, HD28 and K7153A. In another embodiment, the anti-CD37 antibody is a humanized or chimeric antibody or fragment thereof derived from G28-1 , MB371 , BL14, NMN46, IP024, HH1 , WR17, HD28 or K7153A. In another embodiment, the anti-CD37 antibody is a humanized or chimeric antibody or fragment thereof that comprises the same epitope or an overlapping epitope as G28-1 , MB371 , BL14, NMN46, IP024, HH1 , WR17, HD28 or K7153A. In yet another embodiment, the anti-CD37 antibody or antibody fragment of the invention competes for binding with G28-1 , MB371 , BL14, NMN46, IP024, HH1 , WR17, HD28 or K7153A to CD37.

[0045] In one embodiment of the invention, the anti-CD37 antibody is derived from murine monoclonal antibody G28-1. For instance, the invention includes a humanized or chimeric anti-CD37 antibody derived from G28-1. An antibody derived from G28-1 may have CDRs with modifications that differ from that of G28-1 provided the antibody competes with G28-1 for binding to CD37. The anti-CD37 antibody of the invention may also comprises modifications in the Fc region that alter ADCC or CDC function.

[0046] In one embodiment, an anti-CD37 antibody or antibody fragment of the methods, compositions and kits of the invention comprises a variable heavy chain with a HCDR1 , HCDR2 and an HCRD3 and comprises a variable light chain with a LCDR1 , LCDR2, and LCDR3, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:8, HCDR2 comprises the amino acid sequence of SEQ ID NO:1 1 , and HCDR3 comprises the amino acid sequence of SEQ ID NO: 14. In another embodiment, the anti-CD37 antibody or antibody fragment of the invention comprises a variable heavy chain with a HCDR1 , HCDR2 and an HCRD3 and comprises a variable light chain with a LCDR1 , LCDR2, and LCDR3, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:9 or SEQ ID NO:10, HCDR2 comprises the amino acid sequence of SEQ ID NO:12 or SEQ ID NO:13, and HCDR3 comprises the amino acid sequence of SEQ ID NO:15, SEQ ID NO:16 or SEQ ID NO:17. In one embodiment, an anti-CD37 antibody or antibody fragment of the invention comprises a variable heavy chain with a HCDR1 , HCDR2 and an HCRD3 and comprises a variable light chain with a LCDR1 , LCDR2, and LCDR3, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:30, HCDR2 comprises the amino acid sequence of SEQ ID NO:31 , and HCDR3 comprises the amino acid sequence of SEQ ID NO:32.

[0047] The methods, compositions and kits of the invention include an anti-CD37 antibody or antibody fragment that comprises a variable heavy chain with a HCDR1 , HCDR2 and an HCRD3 and comprises a variable light chain with a LCDR1 , LCDR2, and

LCDR3,wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:8, HCDR2 comprises the amino acid sequence of SEQ ID NO:1 1 , HCDR3 comprises the amino acid sequence of SEQ ID NO:14, LCDR1 comprises the amino acid sequence of SEQ ID NO:18, LCDR2 comprises the amino acid sequence of SEQ ID NO:22, and LCDR3 comprises the amino acid sequence of SEQ ID NO:24. In another embodiment, an anti-CD37 antibody or antibody fragment of the invention comprises the amino acid sequence of SEQ ID NO:9 or SEQ ID NO:10, HCDR2 comprises the amino acid sequence of SEQ ID NO:12 or SEQ ID NO:13, HCDR3 comprises the amino acid sequence of SEQ ID NO:15, SEQ ID NO:16 or SEQ ID NO:17, LCDR1 comprises the amino acid sequence of SEQ ID NO:19 or SEQ ID NO:20, LCDR2 comprises the amino acid sequence of SEQ ID NO:23, and LCDR3 comprises the amino acid sequence of SEQ ID NO:25. In another embodiment, an anti-CD37 antibody or antibody fragment of the invention comprises the amino acid sequence of SEQ ID NO:30, HCDR2 comprises the amino acid sequence of SEQ ID NO:31 , HCDR3 comprises the amino acid sequence of SEQ ID NO:32, LCDR1 comprises the amino acid sequence of SEQ ID NO:33, LCDR2 comprises the amino acid sequence of SEQ ID NO:34, and LCDR3 comprises the amino acid sequence of SEQ ID NO:35.

[0048] The methods, compositions and kits of the invention include an antibody or antibody fragment that binds CD37 and includes a variable heavy chain comprising an amino acid sequence with at least about 90% identity or at least about 95% identity to the amino acid of SEQ ID NO:5 or SEQ ID NO:27. In another embodiment, the variable heavy chain comprises the amino acid sequence of SEQ ID NO:5 or SEQ ID NO:27. In yet another embodiment, the invention includes an antibody or antibody fragment that binds CD37 and includes a variable heavy chain comprising an amino acid sequence with 95% identity to the amino acid of SEQ ID NO:5 or SEQ ID NO:27 and includes a variable light chain comprising an amino acid sequence with 95% identity to the amino acid sequence of SEQ ID NO:7 or SEQ ID NO:29. The invention includes, for instance, methods, compositions and kits comprising an antibody or antibody fragment that binds CD37 with specific and comprising the amino acids of SEQ ID NO:7 or SEQ ID N029.

[0049] In one embodiment of the methods, compositions and kits of the invention, the anti-CD37 antibody or antibody fragment comprises a polypeptide comprising, from amino to carboxyl terminus, a binding domain capable of binding CD37, an immunoglobulin hinge domain, an immunoglobulin CH2 region and an immunoglobulin CH3 region. For instance, the binding domain may comprise a variable heavy chain and a variable light chain joined by a linker. The binding domain may be in the orientation V_H-linker-V_L or V_L-linker-V_H. In one embodiment, the linker comprises 3-25 amino acids. In another embodiment, the linker comprises 10-25 amino acids. In yet another embodiment, the linker comprises more than about 15 amino acids. In one embodiment, the polypeptide forms a dimer.

[0050] In another embodiment of the methods, compositions and kits of the invention, the anti-CD37 antibody or antibody fragment comprises an anti-CD37 antibody or antibody fragment conjugated or fused to a toxin or small molecule. In yet another embodiment of the methods, compositions and kits of the invention, the anti-CD37 antibody or antibody fragment comprises a bivalent or multivalent polypeptide capable of binding CD37.

[0051] The methods, compositions and kits of the invention can be used to treat a patient or subject with a B-cell malignancy or condition. A B-cell malignancy or condition is one associated with (e.g., causing or resulting from) aberrant B-cell activity. In one embodiment, the B-cell malignancy is a B-cell cancer that includes B-cell lymphomas, such as various forms of Hodgkin's disease, non-Hodgkin's lymphoma (NHL) or central nervous system lymphomas, small lymphocytic lymphoma, leukemias such as prolymphocytic leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), hairy cell leukemia and chronic myoblastic leukemia and myelomas (such as multiple myeloma).

Additional B-cell cancers include small lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma (including Waldenstrom's macroglobulinemia), marginal zone lymphomas (including splenic marginal zone lymphoma and nodal marginal zone B-cell lymphoma), plasma cell myeloma/plasmacytoma, solitary plasmacytoma of bone, extraosseous plasmacytoma, nodal marginal zone lymphoma, extra-nodal marginal zone B-cell lymphoma of mucosa-associated (MALT) lymphoid tissue), follicular lymphoma, mantle cell lymphoma (MCL), diffuse large B-cell lymphoma, transforming large B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma/leukemia, B-cell proliferations of uncertain malignant potential,

lymphomatoid granulomatosis, and post-transplant lymphoproliferative disorder.

[0052] The invention includes compositions, kits and methods for treating a patient with a relapsed or refractory B-cell malignancy. For instance, the compositions, kits and methods of the invention include treating a patient with relapsed or refractory CLL. The compositions and methods also include treating a patient with relapsed or refractory NHL. In one embodiment of the invention, a patient with a relapsed or refractory B-cell malignancy is refractory to fludarabine treatment. In another embodiment of the invention, a patient with a relapsed or refractory B-cell malignancy is non-responsive to rituximab treatment. The invention includes patients with a relapsed or refractory B-cell malignancy with one or more genetic markers indicative of a poor prognosis such a TP53 mutation or 17p deletion.

[0053] In another embodiment of the compositions, methods and kits of the invention, the B-cell malignancy or condition is a disorder characterized by autoantibody production (e.g., autoimmune diseases). For instance, in one embodiment, the B-cell malignancy or condition is an autoimmune disease such as arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, polychondritis, psoriatic arthritis, psoriasis, dermatitis, polymyositis/dermatomyositis, inclusion body myostitis, inflammatory myositis, toxic epidermal necrolysis, systemic scleroderma and sclerosis, CREST syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, respiratory distress syndrome, meningitis, encephalitis, uveitis, colitis, glomerulonephritis, allergic conditions, eczema, asthma, conditions involving infiltration of T cells and chronic inflammatory responses, atherosclerosis,

autoimmune myocarditis, leukocyte adhesion deficiency, systemic lupus erythematosus (SLE), subacute cutaneous lupus erythematosus, lupus, juvenile onset diabetes, multiple sclerosis, allergic encephalomyelitis, neuromyelitis, rheumatic fever, Sydenham's chorea, immune responses associated with acute and delayed hypersensitivity mediated by cytokines and T- lymphocytes, tuberculosis, sarcoidosis, granulomatosis including Wegener's granulomatosis and Churg-Strauss disease, agranulocytosis, vasculitis, (including hypersensitivity

vasculitis/angiitis, ANCA and rheumatoid vasculitis), aplastic anemia, Diamond Blackfan anemia, immune hemolytic anemia including autoimmune hemolytic anemia (AIHA), pernicious anemia, pure red cell aplasia (PRCA), Factor VIII deficiency, hemophilia A, autoimmune neutropenia, pancytopenia, leukopenia, diseases involving leukocyte diapedesis, central nervous system (CNS) inflammatory disorders, multiple organ injury syndrome, myasthenia gravis, antigen-antibody complex mediated diseases, anti-glomerular basement membrane disease, anti-phospholipid antibody syndrome, allergic neuritis, Behcet disease, Castleman's syndrome, Goodpasture's syndrome, Lambert-Eaton Myasthenic Syndrome, Reynaud's syndrome, Sjorgen's syndrome, Stevens-Johnson syndrome, solid organ transplant rejection, graft versus host disease (GVHD), pemphigoid bullous, pemphigus, autoimmune

polyendocrinopathies, seronegative spondyloarthropathies, Reiter's disease, stiff-man syndrome, giant cell arteritis, immune complex nephritis, IgA nephropathy, IgM

polyneuropathies or IgM mediated neuropathy, idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), Henoch-Schonlein purpura, autoimmune thrombocytopenia, autoimmune disease of the testis and ovary including autoimmune orchitis and oophoritis, primary hypothyroidism; autoimmune endocrine diseases including autoimmune thyroiditis, chronic thyroiditis (Hashimoto's Thyroiditis), subacute thyroiditis, idiopathic hypothyroidism, Addison's disease, Grave's disease, autoimmune polyglandular syndromes (or polyglandular endocrinopathy syndromes), Type I diabetes also referred to as insulin- dependent diabetes mellitus (IDDM) and Sheehan's syndrome; autoimmune hepatitis, lymphoid interstitial pneumonitis (HIV), bronchiolitis obliterans (non-transplant) vs NSIP, Guillain-Barre' Syndrome, large vessel vasculitis (including polymyalgia rheumatica and giant cell (Takayasu's) arteritis), medium vessel vasculitis (including Kawasaki's disease and polyarteritis nodosa), polyarteritis nodosa (PAN) ankylosing spondylitis, Berger's disease (IgA nephropathy), rapidly progressive glomerulonephritis, primary biliary cirrhosis, Celiac sprue (gluten enteropathy), cryoglobulinemia, cryoglobulinemia associated with hepatitis, chronic obstructive pulmonary disease (COPD), amyotrophic lateral sclerosis (ALS), coronary artery disease, familial Mediterranean fever, microscopic polyangiitis, Cogan's syndrome, Whiskott-Aldrich syndrome and thromboangiitis obliterans, autoimmune thyroid disease (such as Graves' disease and Hashimoto's thyroiditis), Sjogren's syndrome, and idiopathic inflammatory myopathy (MM), including dermatomyositis (DM) and polymyositis (PM).

BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 shows the chemical structure of fostamatinib (FigurelA) and fostamatinib disodium (Figure 1 B).

[0055] Figure 2 shows the chemical structure of ibrutinib.

[0056] Figure 3 shows the chemical structure of plerixafor.

[0057] Figure 4 shows the chemical structure of GDC-0834.

[0058] Figure 5 shows the randomization of groups of mice in the in vivo combination study of otiertuzumab and obinutuzumab by tumor volume (Figure 5A) and body weight (Figure 5B).

[0059] Figure 6 shows Day 15 tumor volumes in various treatment groups of mice in the in vivo combination study of otiertuzumab and obinutuzumab. Day 15 was the last time point in which all mice in all groups were alive.

[0060] Figure 7 shows Day 21 tumor volumes in various treatment groups of mice in the in vivo combination study of otiertuzumab and obinutuzumab. Day 21 was the last time point in which all mice treated with TRU-016 and/or obinutuzumab were alive.

[0061] Figure 8 shows mean tumor volumes over time for all groups of study mice in the in vivo combination study of otiertuzumab and obinutuzumab.

[0062] Figure 9 shows mean tumor volumes over time for a subset of mice groups with otiertuzumab and obinutuzumab treatment at 30 μg doses in the in vivo combination study of otiertuzumab and obinutuzumab.

[0063] Figure 10 shows mean tumor volumes over time for a subset of mice group with otiertuzumab and obinutuzumab treatment at 10 μg dose in the in vivo combination study of otiertuzumab and obinutuzumab. [0064] Figure 1 1 shows mean tumor volumes over time for a subset of mice group with otiertuzumab treatment at 30 μg and obinutuzumab treatment at 10 μg dose in the in vivo combination study of otiertuzumab and obinutuzumab.

[0065] Figure 12 shows percentage survival of mice over time in various treatment groups in the in vivo combination study of otiertuzumab and obinutuzumab.

[0066] Figure 13 shows the randomization of groups of mice in the in vivo triple combination study of otiertuzumab, obinutuzumab, and a PI3K inhibitor, by tumor volume (Figure 13A) and body weight (Figure 13B).

[0067] Figure 14 shows Day 13 tumor volumes in various treatment groups of mice in the in vivo triple combination study of otiertuzumab, obinutuzumab, and a PI3K inhibitor. Day 13 was the last time point in which all mice in all groups were alive.

[0068] Figure 15 shows Day 17 tumor volumes in various treatment groups of mice in the in vivo triple combination study of otiertuzumab, obinutuzumab, and a PI3K

inhibitor.Day 17 was the last time point in which all mice treated with LY2940002, TRU-016 and/or obinutuzumab were alive.

[0069] Figure 16 shows mean tumor volumes over time for all groups of study mice in the in vivo triple combination study of otiertuzumab, obinutuzumab, and a PI3K inhibitor.

[0070] Figure 17 shows percentage survival of mice over time in various treatment groups in the in vivo triple combination study of otiertuzumab, obinutuzumab, and a PI3K inhibitor.

[0071] Figure 18 shows the randomization of groups of mice by tumor volume (Figure 18A) and body weight (Figure 18B) in the in vivo triple combination study of otiertuzumab, obinutuzumab and a btk inhibitor.

[0072] Figure 19 shows Day 22 tumor volumes in various treatment groups of mice. Day 22 was the last time point when all study mice were alive, including human IgG control group in the in vivo triple combination study of otiertuzumab, obinutuzumab and a btk inhibitor.

[0073] Figure 20 shows Day 27 tumor volumes in various treatment groups of mice. Day 27 was the last time point when all mice treated with otiertuzumab, obinutuzumab or/and ibrutinib were alive in the in vivo triple combination study of otiertuzumab, obinutuzumab and a btk inhibitor.

[0074] Figure 21 shows mean tumor volumes over time for all groups of study mice in the in vivo triple combination study of otiertuzumab, obinutuzumab and a btk inhibitor. [0075] Figure 22 shows mean tumor volumes over time for a subset of groups with otiertuzumab and obinutuzumab at 1 C^g dose treatments.

[0076] Figure 23 shows mean tumor volumes over time for a subset of groups with otiertuzumab and ibrutinib treatments.

[0077] Figure 24 shows mean tumor volumes over time for a subset of groups with obinutuzumab and ibrutinib treatments.

[0078] Figure 25 shows mean tumor volumes over time for a subset of groups with the triple combination treatment of otiertuzumab, obinutuzumab and a btk inhibitor vs. each of the agents.

[0079] Figure 26 shows mean tumor volumes over time for a subset of groups with the triple combination treatment of otiertuzumab, obinutuzumab and a btk inhibitor vs. the dual combination treatments.

[0080] Figure 27 shows percentage survival of mice over time in various treatment groups in the in vivo triple combination study of otiertuzumab, obinutuzumab and a btk inhibitor.

DETAILED DESCRIPTION OF THE INVENTION

[0081] In one embodiment, the methods and compositions of the invention are based on the activity of an anti-CD37 antibody in combination with an anti-CD20 antibody. In another embodiment, the methods and compositions of the invention are based on the activity of an anti-CD37 antibody in combination with an anti-CD20 antibody and a BCR antagonist. In some embodiments, the methods and compositions of the invention are based on synergistic activity of an anti-CD37 antibody in combination with an anti-CD20 antibody or synergistic activity of an anti-CD37 antibody in combination with an anti-CD20 antibody and a BCR antagonist. In comparison to traditional combination therapies for treatment of B-cell malignancies such as CLL and NHL, the combination therapies disclosed in the instant specification may provide for improved response rates, longer remission periods and extended survival for patients, including patients with relapsed or refractory disease and patients with poor prognostic factors (e.g., 17p deletion, TP53 mutations, 1 1q deletion, trisomy 12, ZAP-70+).

[0082] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited herein, including but not limited to patents, patent applications, articles, books, and treatises, are hereby expressly incorporated by reference in their entirety for any purpose. In the event that one or more of the incorporated documents or portions of documents defines a term that contradicts that term's definition in the application, the definition that appears in this application controls.

[0083] The use of the singular includes the plural unless specifically stated otherwise. The word "a" or "an" means "at least one" unless specifically stated otherwise. The use of "or" means "and/or" unless stated otherwise. The meaning of the phrase "at least one" is equivalent to the meaning of the phrase "one or more." Furthermore, the use of the term "including," as well as other forms, such as "includes" and "included," is not limiting. Also, terms such as "element" or "component" encompass both elements or components comprising one unit and elements or components comprising more than one unit unless specifically stated otherwise.

[0084] The term "kinase inhibitor" as used herein refers to molecules (e.g., small molecules, nucleic acids, polypeptides, antibodies and the like) that inhibit the activity of kinase enzymes that play a role in B cell malignancies and B cell disorders. As discussed above, protein kinases such as BTK and SYK and lipid kinases such as PI3K have been implicated in B cell malignancies and B cell disorders. In one embodiment, the kinase inhibitor is a BTK inhibitor such as ibrutinib or AVL-292. In another embodiment, the kinase inhibitor is a SYK inhibitor such as fostamatinib or PRT062607. In yet another embodiment, the kinase inhibitor is a PI3K inhibitor.

[0085] The terms "BCR antagonist" and "kinase inhibitor" may be used

interchangeably in this disclosure.

[0086] The term "BCR antagonist" refers to molecules (e.g., small molecules, nucleic acids, polypeptides, antibodies and the like) that inhibit the activity of one or more protein kinases in the B-cell receptor signaling pathway. In one embodiment, the BCR antagonist is an inhibitor of a tyrosine kinase of the BCR signaling pathway. In another embodiment, the BCR antagonist blocks, prevents or reduces phosphorylation of the tyrosine kinase of the BCR pathway. In one embodiment, administration of the inhibitor of a tyrosine kinase in the BCR pathway in combination with an anti-CD37 antibody or antibody fragment and an anti-CD20 antibody or antibody fragment reduces the signaling of BCR through the BCR pathway and /or blocks, prevents or reduces phosphorylation of the tyrosine kinase.

[0087] In addition to ligand-induced BCR signaling, there are critical "tonic" (nonligand dependent) BCR maintenance or survival signals that occur in the absence of receptor engagement. In one embodiment of the invention, a BCR antagonist is a molecule that selectively targets a kinase involved in tonic BCR signaling. In one embodiment, administration of a BCR antagonist in combination with an anti-CD37 antibody or antibody fragment and an anti-CD20 antibody or antibody fragment blocks or reduces tonic BCR signaling.

[0088] A BCR antagonist of the methods and compositions of the invention includes a Btk inhibitor, Syk inhibitor, PI3K inhibitor, and a CXCR4 antagonist.

[0089] In one embodiment, the Syk inhibitor comprises or consists essentially of fostamatinib or a salt of fostamatinib (e.g., fostamatinib disodium) or a Syk inhibitor that is an ATP-competitive Syk inhibitor. In one embodiment, the Syk inhibitor comprises or consists essentially of 2/-/-Pyrido[3,2-0]-1 ,4-oxazin-3(4/-/)-one, 6-[[5-fluoro-2-[(3,4,5- trimethoxyphenyl)amino]- 4-pyrimidinyl]amino]-2,2-dimethyl-4-[(phosphonooxy)methyl]-, disodium salt, hexahydrate. In another embodiment, the Syk inhibitor comprises [6-({5-fluoro-2- [(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}amino)-2,2-dimethyl-3- oxo-2,3-dihydro-4/-/- pyrido[3,2-0]-1 ,4-oxazin-4-yl]methyl disodium phosphate hexahydrate.

[0090] In some embodiments, a Syk inhibitor (e.g., fostamatinib disodium) is capable of selectively targeting tonic BCR signaling and lymphoma cell survival. In one embodiment, the Syk inhibitor is a reversible Syk inhibitor.

[0091] Fostamatinib disodium (R788; R935788 sodium) is an experimental drug candidate for the treatment of a variety of diseases, including, for instance, non-Hodgkin lymphoma, CLL, immune thromboctopenic purpura (ITP), rheumatoid arthritis, and advanced colorectal, non-small cell lung, head and neck cancers. Fostamatinib disodium has been found to be well tolerated at a dosage of 200 mg - 250 mg BID.

[0092] In some embodiments, a Syk inhibitor comprises or consists essentially of [(4-(3-(2H-1 ,2,3-triazol-2-yl)phenylamino)-2-((1 R,2S)-2-aminocyclohexylamino)pyrimidine-5- carboxamide acetate]. In another embodiment, a Syk inhibitor comprises or consists essentially of PRT062607 or P505-15. In some embodiments, a Syk inhibitor actively engages a catalytic domain of Syk. PRT062607 is a highly selective and orally bioavailable small- molecule SYK inhibitor (SYK IC50 = 1 nM) with anti-SYK activity.

[0093] In one embodiment, a BCR antagonist comprises or consists essentially of a BTK inhibitor. In one embodiment, the BTK inhibitor covalently binds BTK. For instance, the invention includes an irreversible BTK inhibitor that covalently binds a cysteine residue on BTK such as cysteine residue 481. In one embodiment, the BTK inhibitor contains a Michael acceptor moiety that binds to a cysteine residue on BTK. Examples of a Michael acceptor moiety include, for instance, acrylamide, vinyl sulfonamide or propargylamide. [0094] BTK inhibitors include, but are not limited to, ibrutinib (PCI-32765) and AVL- 292. In one embodiment, a BTK inhibitor comprises or consists essentially of 1-{(3R)-3-[4- Amino-3-(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl}-2-propen-1-one.

[0095] In another embodiment, the BTK inhibitor is GDC-0834. In one embodiment, the BTK inhibitor comprises or consists essentially of [R-/V-(3-(6-(4-(1 ,4-dimethyl-3- oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)- 4,5,6,7-tetrahydrobenzo[0]thiophene-2-carboxamide]. See, for instance, Liu et al., 201 1 , J. Pharm. and Exp. Ther. 338(1 ):154-163, which is incorporated by reference in its entirety.

[0096] Multiple clinical trials are ongoing or recruiting to assess the efficacy and safety of ibrutinib alone and in combination with rifampin, cyclophosphamide, rituximab, bendamustine, doxorubicin, vincristine and prednisone for the treatment of patients with B-cell malignancies, including relapsed and refractory disease. See www.clinicaltrials.gov. In early clinical studies, treatment with ibrutinib was found to result in a rapid reduction in

lymphadenopathy accompanied by a transient lymphocytosis. See, for instance, Gordon et al., 201 1 , Blood. 117:6287-6297. Ibrutinib has also been reported to reduce CLL cell chemotaxis towards the chemokines CXCL12 and CXCL13, and inhibit cellular adhesion following stimulation at the B cell receptor. See, for instance, Ponader et al., 2012, Blood. 1 19:1 182- 1 189 and deRooij et al., 2012, Blood. 1 19:2590-2594.

[0097] In one embodiment, a BCR antagonist is a BTK inhibitor disclosed in

US7,982,036; US7,989,456; US8.329.901 ; US8.088.781 ; US8.158.786; and US8.232.280, each of which is hereby incorporated by reference in its entirety.

[0098] A BCR antagonist of the methods and compositions of the invention includes a molecule that inhibits Syk or Btk tyrosine phosphorylation and abrogates downstream survival pathways of Syk and Btk including ERK1/2, PI3K, and NF-KB.

[0099] In another embodiment, a BCR antagonist comprises or consists essentially of an antagonist of a BCR signaling pathway chemokine receptor such as a CXCR4. For instance, in one embodiment, a CXCR4 antagonist comprises or consists essentially of plerixafor. The invention includes a CXCR4 antagonist comprising 1 ,1 '-[1 ,4- Phenylenebis(methylene)]bis [1 ,4,8,1 1-tetraazacyclotetradecane].

[00100] In another embodiment, a CXCR4 antagonist comprises or consists essentially of a T140 analog capable of disrupting CLL-cell adhesion to a bone marrow stromal cell and/or mobilizing CLL cells from protective tissue microenvironments to the blood.

[00101] The methods and compositions of the invention include a BCR antagonist comprising an inhibitor of a tyrosine kinase of the B-cell receptor signaling pathway (e.g., Syk and Btk). In this embodiment, the tyrosine kinase, in the absence of the inhibitor, may function to promote B-cell survival, B-cell migration, B-cell proliferation, BCR signaling, chemokine receptor signaling and chemokine secretion. Also, a tyrosine kinase of the BCR signaling pathway may function in the absence of a BCR antagonist to promote malignant B-cell survival, promote malignant B-cell migration to lymphoid tissues and promote malignant B-cell proliferation including clonal expansion of malignant B cells (e.g., clonal expansion of CLL cells). In one embodiment of the invention, a BCR antagonist comprises a molecule, which when administered to a subject with a B-cell malignancy or disorder, blocks or inhibits one or more of the activities associated with a tyrosine kinase of the BCR signaling pathway. For instance, administration of a BCR antagonist can block or reduce the migration of malignant B- cells to lymphoid tissues.

[00102] A BCR antagonist of the invention is a molecule or antibody that binds a component of the BCR pathway with specificity. A BCR antagonist that is "specific" for a target binds to that target with a greater affinity than any other target. For example, a BTK inhibitor binds to BTK with a greater affinity than to any other target, a SYK inhibitor binds to Syk with a greater affinity than to any other target. BCR antagonists of the invention may have affinities for their targets of a Ka of greater than or equal to about 10⁴ M^"1, preferably of greater than or equal to about 10⁵ M^~1 , more preferably of greater than or equal to about 10⁶ M^"1 and still more preferably of greater than or equal to about 10⁷ M^"1. Affinities of even greater than about 10⁷ M^" ¹ are still more preferred, such as affinities equal to or greater than about 10⁷ M^"1 , about 10⁸ M^"1 and about 10⁹ M^~1 , and about 10¹⁰ M^"1. Affinities of BCR antagonists according to the present invention can be readily determined using conventional techniques, for example those described by Scatchard et al., Ann. N.Y. Acad. Sci. 51 :660 (1949).

[00103] Certain BCR antagonists contemplated by the invention have affinities for a BCR pathway target (e.g., Syk or BTK) of about 0.5 to about 10nM.

[00104] In another embodiment, a BCR antagonist inhibits the BCR pathway and selectively inhibits activated B cells.

[00105] A BCR antagonist of the methods and compositions of the invention includes a molecule that increases CXCR4 and / or CD62L membrane expression in a patient with a B-cell malignancy or disorder. In one embodiment, CXCR4 and / or CD62L are increased in a subject with a B-cell malignancy or disorder such that CXCR4 and / or CD62L membrane expression levels are comparable to a subject without a B-cell malignancy or disorder. The invention includes, for instance, a BCR antagonist that increases expression levels of CXCR4 and / or CD62L such that expression levels are no more than about 2%, no more than about 5% or no more than about 10% lower than CXCR4 and / or CD62L levels of a subject without a B-cell malignancy. For instance, a BCR pathway receptor antagonist of the disclosed methods and compositions may prevent or reduce the down-regulation of CXCR4 and / or CD62L by BCR associate with B-cell malignancies. In one embodiment, a BCR antagonist of the methods and compositions of the invention is a molecule that increases CXCR4 and / or CD62L membrane expression in a patient with a B-cell malignancy or disorder.

[00106] The term "PI3K inhibitor" refers to molecules (e.g., small molecules, nucleic acids, polypeptides, antibodies and the like) that inhibit the activity of various isoforms of PI3K. For instance, in one embodiment, the PI3K inhibitor is an inhibitor of the p1 105 subunit of PI3K. In another embodiment, the PI3K inhibitor is an inhibitor of the p1 10a subunit of PI3K. In certain embodiments, the methods and compositions of the invention comprise idelalisib as a PI3K inhibitor.

[00107] A PI3K inhibitor of the invention is a molecule or antibody that binds a subunit of PI3K with specificity. A PI3K inhibitor that is "specific" for a particular subunit binds to that subunit with a greater affinity than any other subunit or target. For example, a PI3K inhibitor that inhibits the p1 105 subunit binds to the δ subunit with a greater affinity than to any other subunit or target. PI3K inhibitors of the invention may have affinities for their targets of a Ka of greater than or equal to about 10⁴ M^~1 , preferably of greater than or equal to about 10⁵ M^" more preferably of greater than or equal to about 10⁶ M^~1 and still more preferably of greater than or equal to about 10⁷ M^"1. Affinities of even greater than about 10⁷ M^"1 are still more preferred, such as affinities equal to or greater than about 10⁷ M^"1 , about 10⁸ M^"1 , and about 10⁹ M^"1 , and about 10¹⁰ M^"1. Affinities of PI3K inhibitors according to the present invention can be readily determined using conventional techniques, for example those described by Scatchard et al., Ann. N.Y. Acad. Sci. 51 :660 (1949).

[00108] Certain PI3K inhibitors contemplated by the invention have affinities for a PI3K subunit of about 0.5 to about 10nM.

[00109] "A molecule that actively mobilizes an egress of B cells from the lymphoid tissues into peripheral blood" refers to a molecule that, when administered to a patient with a B- cell malignancy or disorder in combination with an anti-CD37 antibody or antibody fragment and an anti-CD20 antibody or antibody fragment, reduces the ability of malignant B lymphocytes to home or hide in the sanctuary of lymph nodes and other lymphoid tissues. For instance, in some B-cell malignancies such as aggressive forms of chronic lymphocytic leukemia, patients suffer from enlarged lymph nodes and splenomegaly as a result of the accumulation of malignant B lymphocytes within secondary lymphoid organs. Patients with relapsed or refractory B-cell malignancies are at particular risk of having malignant B-cells seek sanctuary from convention therapeutics in lymphoid tissue. The methods and compositions of the invention can be used to treat patients with CLL and other B-cells malignancies by forcing malignant cells out of the sanctuary of lymphoid tissues and into peripheral blood where anti- CD37 antibodies and antibody fragments may be more efficacious at killing. In one embodiment of the invention, a molecule that actively mobilizes an egress of B cells from the lymphoid tissues into peripheral blood refers to a BCR antagonist, for instance, an inhibitor or antagonist that modulates the BCR pathway signal.

[001 10] "Aberrant B-cell activity" refers to B-cell activity that deviates from the normal, proper, or expected course. For example, aberrant B-cell activity may include inappropriate proliferation of cells whose DNA or other cellular components have become damaged or defective. Aberrant B-cell activity may include cell proliferation whose

characteristics are associated with a disease caused by, mediated by, or resulting in inappropriately high levels of cell division, inappropriately low levels of apoptosis, or both. Such diseases may be characterized, for example, by single or multiple local abnormal proliferations of cells, groups of cells or tissue(s), whether cancerous or non-cancerous, benign or malignant. Aberrant B-cell activity may also include aberrant antibody production, such as production of autoantibodies, or overproduction of antibodies typically desirable when produced at normal levels. It is contemplated that aberrant B-cell activity may occur in certain subpopulations of B- cells and not in other subpopulations. Aberrant B-cell activity may also include inappropriate stimulation of T-cells, such as by inappropriate B-cell antigen presentation to T-cells or by other pathways involving B-cells.

[001 11] "Treatment" or "treating" refers to either a therapeutic treatment or prophylactic/preventative treatment. A therapeutic treatment may improve at least one symptom of disease in an individual receiving treatment or may delay worsening of a progressive disease in an individual, or prevent onset of additional associated diseases.

[001 12] A "therapeutically effective amount," "therapeutically effective dose" or "effective dose" refers to that amount of the antibody or compound sufficient to result in amelioration of one or more symptoms of the disease being treated. When applied to an individual active ingredient, administered alone, a therapeutically effective dose refers to that ingredient alone. When applied to a combination, a therapeutically effective dose refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered serially or simultaneously. The invention specifically contemplates that one or more specific therapeutic molecules may be administered according to methods of the invention, each in an effective dose. The effective dose can be determined empirically through dose studies. [001 13] In one embodiment of the invention, administration of a therapeutically effective amount of an anti-CD37 antibody or antibody fragment and an anti-CD20 antibody or antibody fragment can, at the end of a treatment regimen, results in B-cell reduction, reduction in the size of a patient's lymph nodes, reduction in size and or number of tumors, and / or reduction of spleen size when administered to a patient at a dose and period of time sufficient for B-cell reduction, reduction in lymph node size, reduction in size and or number of tumors and / or reduction of spleen size. Similarly, in another embodiment, administration of a therapeutically effective amount of an anti-CD37 antibody or antibody fragment, an anti-CD20 antibody and a BCR antagonist or a kinase inibitor can, at the end of a treatment regimen, result in B-cell reduction, reduction in the size of a patient's lymph nodes, reduction in size and or number of tumors, and / or reduction of spleen size when administered to a patient at a dose and period of time sufficient for B-cell reduction, reduction in lymph node size, reduction in size and or number of tumors and / or reduction of spleen size. In yet another embodiment of the invention, a therapeutically effective dose is a dose that is a maximum tolerated dose or less than a maximum tolerated dose.

[001 14] "A patient with a B-cell malignancy or disorder" is a subject with a disease, symptom or condition that may be caused by aberrant B-cell activity, may be exacerbated by aberrant B-cell activity, or may be relieved by regulation of B-cell activity. Examples of such diseases are a B-cell cancer (for example, B-cell lymphoma, a B-cell leukemia or a B-cell myeloma), a disease characterized by autoantibody production or a disease characterized by inappropriate T-cell stimulation caused by inappropriate B-cell antigen presentation to T-cells or caused by other pathways involving B-cells.

[001 15] An "anti-CD37 antibody or antibody fragment" refers to a monoclonal or recombinant antibody or antibody fragment that binds to human CD37 with specificity.

Similarly, an "anti-CD20 antibody or antibody fragment" refers to a monoclonal or recombinant antibody or antibody fragment that binds to human CD20 with specificity. The antibodies of the invention can be human, humanized or chimeric. As antibodies can be modified in a number of ways, the term "antibody" should be construed as covering any antibody or substance having a binding domain with the required specificity. Thus, this term covers antibody fragments, derivatives, functional equivalents and homologues of antibodies, humanized antibodies, including any polypeptide comprising an immunoglobulin binding domain, whether natural or wholly or partially synthetic. Chimeric molecules comprising an immunoglobulin binding domain, or equivalent, fused to another polypeptide are therefore included. Cloning and expression of chimeric antibodies are described, for instance, in EP-A-0120694 and EP-A-0125023. A humanized antibody may be a modified antibody having the variable regions of a non-human, e.g., murine, antibody and the constant region of a human antibody. Methods for making humanized antibodies are described for instance, in U.S. Pat. No. 5,225,539.

[001 16] The term "anti-CD37 antibody" as used herein includes recombinant polypeptides, fusion proteins and immunoconjugates that bind CD37 and comprise an antibody fragment or are derived in part from a monoclonal or polyclonal anti-CD37 antibody. Similarly, the term "anti-CD20 antibody" as used herein includes recombinant polypeptides, fusion proteins and immunoconjugates that bind CD20 and comprise an antibody fragment or are derived in part from a monoclonal or polyclonal anti-CD20 antibody. As used herein, the term "derived" when used to refer to a recombinant anti-CD37 antibody, polypeptide, fusion protein or immunoconjugate or a recombinant anti-CD20 antibody, polypeptide, fusion protein or immunoconjugate means a molecule or polypeptide that is capable of binding with specificity to the same epitope as the reference anti-CD37 antibody or the reference anti-CD20 antibody. A recombinant anti-CD37 antibody "derived" from an anti-CD37 antibody includes a molecule or polypeptide comprising at least about 10 contiguous amino acids, at least about 20 contiguous amino acids or at least about 50 or more contiguous amino acids as the reference anti-CD37 antibody. In one embodiment of the invention, a recombinant anti-CD37 antibody "derived" from an anti-CD37 antibody comprises the same CDRs as the reference anti-CD37 molecule or contains CDRs with at least about 90% or at least about 95% identity as compared to the reference anti-CD37 molecules. Similarly, a recombinant anti-CD20 antibody "derived" from an anti-CD20 antibody includes a molecule or polypeptide comprising at least about 10 contiguous amino acids, at least about 20 contiguous amino acids or at least about 50 or more contiguous amino acids as the reference anti-CD20 antibody. In another embodiment of the invention, a recombinant anti-CD20 antibody "derived" from an anti-CD20 antibody comprises the same CDRs as the reference anti-CD20 molecule or contains CDRs with at least about 90% or at least about 95% identity as compared to the reference anti-CD20 molecules.

[001 17] Anti-CD37 antibodies and antibody fragments used in the methods and compositions of the invention are capable of binding to human CD37 with specificity. An anti- CD37 antibody or antibody fragment that is "specific" for CD37 binds to CD37 with a greater affinity than any other target. For example, an anti-CD37 antibody binds to CD37 with a greater affinity than to any other target. Similarly, anti-CD20 antibodies and antibody fragments used in the methods and compositions of the invention are capable of binding to human CD20 with specificity. An anti-CD20 antibody or antibody fragment that is "specific" for CD20 binds to CD20 with a greater affinity than any other target. For example, an anti-CD20 antibody binds to CD20 with a greater affinity than to any other target. Anti-CD37 antibodies and anti-CD20 antibodies of the invention may have affinities for their targets of a Ka of greater than or equal to about 10⁴ M^"1 , preferably of greater than or equal to about 10⁵ M^"1 , more preferably of greater than or equal to about 10⁶ M^"1 and still more preferably of greater than or equal to about 10⁷ M^" Affinities of even greater than about 10⁷ M^"1 are still more preferred, such as affinities equal to or greater than about 10⁷ M^"1 , about 10⁸ M^"1 , and about 10⁹ M^"1 , and about 10¹⁰ M^"1. Affinities of antibodies according to the present invention can be readily determined using conventional techniques, for example those described by Scatchard et al., Ann. N.Y. Acad. Sci. 51 :660 (1949).

[001 18] The methods and compositions of the invention include a human anti-CD37 antibody and a human anti-CD20 antibody. A human antibody can be an antibody derived from a human or an antibody obtained from a transgenic organism that has been "engineered" to produce specific human antibodies in response to antigenic challenge and can be produced by any method known in the art. In certain techniques, elements of the human heavy and light chain loci are introduced into strains of the organism derived from embryonic stem cell lines that contain targeted disruptions of the endogenous heavy chain and light chain loci. The transgenic organism can synthesize human antibodies specific for human antigens, and the organism can be used to produce human antibody-secreting hybridomas. A human antibody can also be an antibody wherein the heavy and light chains are encoded by a nucleotide sequence derived from one or more sources of human DNA. A fully human antibody also can be constructed by genetic or chromosomal transfection methods, as well as phage display technology, or in vitro activated B cells, all of which are known in the art.

[001 19] In one embodiment, anti-CD37 antibodies and anti-CD20 antibodies are recombinant antibodies or polypeptides. Recombinant antibodies and polypeptides include, for instance, Fc fusions, toxin fusions, fusions to enzymatic activities, minibodies, diabodies, linear antibodies, single chain antibodies, bispecific antibody fragments, scFv and Fab fragments. A recombinant anti-CD37 antibody includes a molecule or polypeptide that incorporates an amino acid sequence derived from an anti-CD37 antibody and which is capable of binding human CD37 with specificity. Recombinant anti-CD37 antibodies include molecules that are optimized, for instance, for stability, solubility, in vitro and in vivo binding. Similarly, a recombinant anti- CD20 antibody includes a molecule or polypeptide that incorporates an amino acid sequence derived from an anti-CD20 antibody and which is capable of binding human CD20 with specificity. Recombinant anti-CD20 antibodies include molecules that are optimized, for instance, for stability, solubility, in vitro and in vivo binding.

[00120] In one embodiment, an anti-CD37 antibody is optimized by altering the Fc region. For instance, modifications may be made to the amino acid sequence of the Fc region to modify effector function. In one embodiment, modifications are made to the Fc region to increase ADCC or CDC activity. The methods and compositions of the invention include, for instance, the modified anti-CD37 antibodies disclosed in published patent applications US 201 10165153 and US20100189722. In some embodiments, an anti-CD20 antibody is similarly optimized by altering the Fc region.

[00121] In another embodiment, an anti-CD37 antibody or antibody fragment of the methods and compositions of the invention comprises an antibody or antigen-binding fragment linked via a linker to a cytotoxic agent to form an immunoconjugate. In some other

embodiments, an anti-CD20 antibody or antibody fragment of the methods and compositions of the invention comprises an antibody or antigen-binding fragment linked via a linker to a cytotoxic agent to form an immunoconjugate. In these embodiments, the linker may comprise a synthetic linker selected from N-succinimidyl 4-(2-pyridyldithio)pentanoate (SPP); N- succinimidyl 4-(2-pyridyldithio)butanoate (SPDB) or N-succinimidyl 4-(2-pyridyldithio)-2- sulfobutanoate (sulfo-SPDB); N-succinimidyl 4-(maleimidomethyl)cyclohexanecarboxylate (SMCC); N-sulfosuccinimidyl 4-(maleimidomethyl)cyclohexanecarboxylate (sulfoSMCC); N- succinimidyl-4-(iodoacetyl)-aminobenzoate (SIAB); and N-succinimidyl-[(N- maleimidopropionamido)-tetraethyleneglycol]ester (NHS-PEG4-maleimide). In these embodiments, the cytotoxic agent may comprise, for instance, maytansinoid, maytansinoid analog, doxorubicin, a modified doxorubicin, benzodiazepine, taxoid, CC-1065, CC-1065 analog, duocarmycin, duocarmycin analog, calicheamicin, dolastatin, dolastatin analog, auristatin, tomaymycin derivative, and leptomycin derivative or a prodrug of any of the above. For instance, an anti-CD37 antibody of the methods and compositions of the invention includes the immunoconjugates disclosed in published patent application US201202761 19 which is incorporated by reference in its entirety.

[00122] The terms "antibody" and "antibody fragment" are used interchangeably herein. Examples of anti-CD37 antibody fragments and anti-CD20 antibody fragments of the invention include, but are not limited to, (i) the Fab fragment consisting of VL, VH, CL and CHI domains; (ii) the Fd fragment consisting of the VH and CHI domains; (iii) the Fv fragment consisting of the VL and VH domains of a single antibody; (iv) the dAb fragment (Ward, E. S. et al., Nature 341 : 544-546 (1989)) which consists of a VH domain; (v) isolated CDR regions; (vi) F(ab')₂ a bivalent fragment comprising two linked Fab fragments; (vii) single chain Fv molecules (scFv), wherein a VH domain and a VL domain are linked by a peptide linker which allows the two domains to associate to form an antigen binding site (Bird et al., Science 242: 423-426 (1988); Huston et al., PNAS USA 85: 5879-5883 (1988)); (viii) bispecific single chain Fv dimers (PCT/US92/09965) and (ix) "diabodies", multivalent or multispecific fragments constructed by gene fusion (WO94/13804; P. Hollinger et al., Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993)). [00123] In one embodiment, an anti-CD37 antibody is a diabody. In another embodiment, an anti-CD20 antibody is a diabody. Diabodies are multimers of polypeptides, each polypeptide comprising a first domain comprising a binding region of an immunoglobulin light chain and a second domain comprising a binding region of an immunoglobulin heavy chain, the two domains being linked (e.g., by a peptide linker) but unable to associated with each other to form an antigen binding site: antigen binding sites are formed by the association of the first domain of one polypeptide within the multimer with the second domain of another polypeptide within the multimer. See WO94/13804 which is incorporated by reference in its entirety.

[00124] In one embodiment, an "anti-CD37 antibody" is a scFv. In another embodiment, an anti-CD20 antibody is a scFv. A scFv is constructed by joining a variable heavy chain and a variable light chain with a linker using recombinant methods. The linker that enables the V_H and V_L regions to be made as a single chain protein. See, for instance, Bird et al., 1988, Science 242:423-426 and Huston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879- 5883. In one embodiment, the scFv comprises V_H and V_L regions that are identical or derived from a reference anti-CD37 antibody.

[00125] In one embodiment, an anti-CD37 antibody fragment of the invention is an Fv. In another embodiment, an anti-CD20 antibody fragment is an Fv. An Fv is an antibody fragment which contains a complete antigen-recognition and binding site. This region consists of a dimer of one heavy and one light chain variable domain in tight, non-covalent or covalent association. It is in this configuration that the three CDRs of each variable domain interact to define an antigen-binding site on the surface of the V_H-V_L dimer. Collectively, the six CDRs confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site. In one embodiment, the Fv comprises V_H and V_L regions that are identical or derived from a reference anti-CD37 antibody. In another embodiment, the Fv comprises V_H and V_L regions that are identical or derived from a reference anti-CD20 antibody.

[00126] In one embodiment of the invention, an anti-CD37 antibody is a single chain polypeptide comprising, from amino to carboxyl terminus, a binding domain (e.g., scFv), an immunoglobulin hinge region and an immunoglobulin constant region. In another embodiment of the invention, an anti-CD20 antibody is a single chain polypeptide comprising, from amino to carboxyl terminus, a binding domain (e.g., scFv), an immunoglobulin hinge region and an immunoglobulin constant region. In these embodiments, the single chain polypeptide forms a dimer in solution. [00127] Anti-CD37 and anti-CD20 antibodies of the invention may comprise, for instance, an lgG1 , lgG2, lgG2, lgG4, IgA, IgM or IgE hinge region. Single chain polypeptide antibodies described above as well other recombinant anti-CD37 and anti-CD20 antibodies of the invention containing a hinge region may comprise one or more modifications to the hinge. For instance, the anti-CD37 and anti-CD20 antibodies may contain mutations at one, two or three cysteine residues. Anti-CD37 and anti-CD20 antibodies of the invention may comprise a modified hinge region polypeptide having zero, one or two cysteine residues. In one embodiment, the anti-CD37 antibody has one or two cysteine (Cys) residues in the hinge region. For instance, in one embodiment, the first cysteine residue of the hinge is mutated.

[00128] Single chain polypeptide antibodies described above as well as other recombinant anti-CD37 and anti-CD20 antibodies of the invention may also have a modified constant region. For instance, in one embodiment, the anti-CD37 antibody does not contain a CH1 region or domain. In another embodiment, the anti-CD37 antibody contains a truncated CH3 region or domain. Similarly, the anti-CD20 antibody may not contain a CH1 region or may contain a truncated CH3 region.

[00129] An anti-CD37 antibody in the single chain polypeptide recombinant antibody format may contain a binding domain that is identical or derived from a reference anti- CD37 antibody. For instance, an anti-CD37 antibody in the single chain polypeptide format may contain a binding domain derived from murine monoclonal antibody G28-1. The anti-CD37 antibody may comprise amino acid modifications in one or more CDRs to improve binding to human CD37. Similarly, an anti-CD20 antibody in the single chain polypeptide recombinant antibody format may contain a binding domain that is identical or derived from a reference anti- CD20 antibody. For instance, an anti-CD20 antibody in the single chain polypeptide format may contain a binding domain derived from murine monoclonal antibody B-ly1. The anti-CD20 antibody may comprise amino acid modifications in one or more CDRs to improve binding to human CD20. Moreover, the single chain polypeptide antibodies of the invention may be humanized or chimeric. In the chimeric format, the single chain polypeptide antibodies comprises a human immunoglobulin hinge and constant region. In the humanized format, the single chain polypeptide antibodies also contain modifications in the framework region of the binding domain consistent with a human amino acid sequence (e.g., modifications can be made by comparing the sequence to one or more human germline sequences and selectively modifying amino acid sequences to those of the human germline sequence).

[00130] The anti-CD37 antibodies, anti-CD20 antibodies and the respective fragments used in the compositions and methods of the invention may optionally comprise sufficient amino acid sequence derived from a constant region of an immunoglobulin to provide an effector function, for instance, ADCC and/or CDC. Thus, the anti-CD37 antibodies, anti- CD20 antibodies and the respective fragments may comprise an amino acid sequence derived from a CH2 domain of an immunoglobulin or CH2 and CH3 domains derived from one or more immunoglobulins. In one embodiment of the invention, the Fc region is derived from a human lgG1 immunoglobulin. In another embodiment, the Fc region is derived from a human lgG3, lgG4, IgA or IgE immunoglobulin.

[00131 ] The anti-CD37 antibodies of the compositions and methods of the invention may be multispecific antibodies having specificity for at least two different antigens or epitopes, at least one of which is CD37 epitope. Similarly, the anti-CD20 antibodies of the compositions and methods of the invention may be multispecific antibodies having specificity for at least two different antigens or epitopes, at least one of which is CD20 epitope. The term "multispecific antibody" in the present invention encompasses an anti-CD37 antibody and an anti-CD20 antibody having specificity for two or more (such as three) antigens. An anti-CD37 antibody of the invention that is a multispecific antibody binds at least one epitope of CD37 and an anti- CD20 antibody of the invention that is a multispecific antibody binds at least one epitope of CD20.

[00132] In one embodiment of the invention, the anti-CD37 antibody comprises a CD37 binding domain and a CD3 binding domain. In one embodiment, the anti-CD37 antibody comprising an anti-CD37 domain and an anti-CD3 domain is capable of redirected T-cell cytotoxicity. In another embodiment, the anti-CD37 antibody comprising an anti-CD37 domain and an anti-CD3 domain may comprise a modified hinge region, a modified Fc region, and / or a C-terminus linker. In one embodiment, for multispecific anti-CD37 antibodies capable of redirected T-cell cytotoxicity, it may be preferable for the antibody to not contain an Fc domain or to contain a modified Fc domain that lacks effector function. In another embodiment, a multispecific anti-CD37 antibody or fragment of the methods, compositions and kits of the invention comprise a sequence selected from the group consisting of SEQ ID NOs: 46, 48, 50, 52, 54, 56, 58, 60, and 63.

[00133] A multispecific or multivalent antibody may comprise a full length antibody or a fragment of such an antibody. In some embodiments of the invention, the anti-CD37 and anti-CD20 antibodies are scFv dimers or diabodies rather than whole antibodies. Diabodies and scFv can be constructed without an Fc region, using only variable domains. Diabodies are bivalent, bispecific antibodies in which V_H and V_L domains are expressed on a single polypeptide chain, but using a linker that is too short to allow for pairing between the two domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain and creating two antigen binding sites (see e.g., Holliger, P., et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak, R. J., et al. (1994) Structure 2:1 121-1 123). Such antibody binding portions are known in the art (Kontermann and Dubel eds., Antibody

Engineering (2001 ) Springer-Verlag. New York. 790 pp. (ISBN 3-540-41354-5).

[00134] In one embodiment of the invention, the multivalent or multispecific anti- CD37 and anti-CD20 antibodies comprise two dimerized single chain polypeptides. For instance, in one embodiment, each single chain polypeptide comprises, from amino to carboxyl terminus, a first binding domain (e.g., scFv), an immunoglobulin hinge region, an

immunoglobulin constant region (with or without a CH1 region), a C-terminus linker, and a second binding domain. The C-terminus linker may comprise, for instance, an amino acid linker derived from an amino acid sequence of an immunoglobulin hinge region (e.g., an immunoglobulin "core" hinge region), an amino acid sequence derived from a stalk region of a type II C lectin (e.g., NKG2A, NKG2D). In one embodiment, the C-terminus linker comprises an amino acid sequence such as (A₄S)³ or (G₄S)³. The single chain polypeptide may also comprise a heterodimerization domain so that each single chain polypeptide dimerizes with a different single chain polypeptide such that a heterodimer is formed with up to four different binding domains. The invention includes, but is not limited to, compositions and methods comprising anti-CD37 multi-specific antibodies and multi-valent antibodies in a format as disclosed in US 2009/0175867, US 2012/0034245 and WO 201 1/090762, each of which is herein incorporated by reference in its entirety.

[00135] In one embodiment, the present invention provides a method of treating a B cell disorder or malignancy in a patient comprising administering a multispecific CD37 antibody in combination with a CD20 antibody. In yet another embodiment, the present invention provides a method of treating a B cell disorder or malignancy in a patient comprising administering a multispecific CD37 antibody, a CD20 antibody and a kinase inhibitor such as a BTK inhibitor, SYK inhibitor or PI3K inhibitor. The present invention also encompasses compositions, medicaments and kits comprising a multispecific CD37 antibody in combination with a CD20 antibody and optionally, a kinase inhibitor. For instance, in one embodiment, the methods, compositions and kits of the invention include a combination of a multispecific CD37 antibody, obinutuzumab, and optionally, a kinase inhibitor such as ibrutinib, fostamatinib or idelalisib. In one embodiment, the multispecific CD37 antibody of the methods, compositions and kits of the invention is an anti-CD37 antibody comprising a CD37 binding domain and a CD3 binding domain.

[00136] An "anti-CD37 antibody" of the methods and compositions of the invention includes a molecule or polypeptide comprising one or more CDRs derived from an anti-CD37 antibody. In another embodiment of the invention, an "anti-CD37 antibody" is a molecule or polypeptide comprising 6 CDRs derived from an anti-CD37 antibody. Similarly, an "anti-CD20 antibody" of the methods and compositions of the invention includes a molecule or polypeptide comprising one or more CDRs derived from an anti-CD20 antibody. In another embodiment of the invention, an "anti-CD20 antibody" is a molecule or polypeptide comprising 6 CDRs derived from an anti-CD20 antibody.

[00137] In one embodiment, the compositions and methods of the invention comprise a humanized or chimeric anti-CD37 antibody or antibody fragment with a HCDR1 , HCDR2 and an HCRD3 and a variable light chain with a LCDR1 , LCDR2, and LCDR3; wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:8, HCDR2 comprises the amino acid sequence of SEQ ID NO:1 1 , and HCDR3 comprises the amino acid sequence of SEQ ID NO: 14; or wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:9 or SEQ ID NO:10, HCDR2 comprises the amino acid sequence of SEQ ID NO:12 or SEQ ID NO:13, and HCDR3 comprises the amino acid sequence of SEQ ID NO: 15, SEQ ID NO:16 and SEQ ID NO:17; or wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:30, HCDR2 comprises the amino acid sequence of SEQ ID NO:31 , and HCDR3 comprises the amino acid sequence of SEQ ID NO:32.

[00138] In another embodiment, the compositions and methods of the invention include a humanized or chimeric anti-CD37 antibody or antibody fragment with a variable heavy chain with a HCDR1 , HCDR2 and an HCDR3 and comprises a variable light chain with a LCDR1 , LCDR2, and LCDR3; wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:8, HCDR2 comprises the amino acid sequence of SEQ ID NO:1 1 , HCDR3 comprises the amino acid sequence of SEQ ID NO: 14, LCDR1 comprises the amino acid sequence of SEQ ID NO: 18, LCDR2 comprises the amino acid sequence of SEQ ID NO:22, and LCDR3 comprises the amino acid sequence of SEQ ID NO:24; or wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:9 or SEQ ID NO:10, HCDR2 comprises the amino acid sequence of SEQ ID NO:12 or SEQ ID NO:13, and HCDR3 comprises the amino acid sequence of SEQ ID NO:15, SEQ ID NO:16 or SEQ ID NO:17, LCDR1 comprises the amino acid sequence of SEQ ID NO: 19 or SEQ ID NO:20, LCDR2 comprises the amino acid sequence of SEQ ID NO:23, and LCDR3 comprises the amino acid sequence of SEQ ID NO:25; or wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:30, HCDR2 comprises the amino acid sequence of SEQ ID NO:31 , and HCDR3 comprises the amino acid sequence of SEQ ID NO:32, LCDR1 comprises the amino acid sequence of SEQ ID NO:33, LCDR2 comprises the amino acid sequence of SEQ ID NO:34, and LCDR3 comprises the amino acid sequence of SEQ ID NO:35. [00139] An "anti-CD37 antibody" of the invention includes a molecule or polypeptide comprising a variable heavy chain and / or a variable light chain derived from an anti-CD37 antibody. For instance, in one embodiment, the anti-CD37 antibody or antibody fragment comprises a variable heavy chain comprising an amino acid with at least about 90% identity, about 95% identity or about 99% identity to the amino acid of SEQ ID NO: 5 or SEQ ID NO:27. In one embodiment, an anti-CD37 antibody or antibody fragment comprises a variable heavy chain of SEQ ID NO: 5 or SEQ ID NO:27. The methods and compositions of the invention also include an anti-CD37 antibody or antibody fragment with a variable light chain comprising an amino acid with at least about 90% identity, 95% identity or about 99% identity to the amino acid of SEQ ID NO:7 or SEQ ID NO:29. In one embodiment, the anti-CD37 antibody or antibody fragment comprises a variable light chain of SEQ ID NO:7 or SEQ ID NO:29. The invention includes an anti-CD37 antibody or antibody fragment with a variable heavy chain comprising an amino acid with at least about 90% identity, 95% identity or about 99% identity or more to the amino acid sequence of SEQ ID NO:5 or SEQ ID NO:27 and a variable light chain comprising an amino acid sequence with at least about 90% identity, 95% identity or about 99% identity or more to the amino acid sequence of SEQ ID NO:7 or SEQ ID NO:29.

[00140] The methods and compositions of the invention also include, for instance, an anti-CD37 antibody or antibody fragment with a variable heavy chain comprising an amino acid sequence with at least about 90% identity, 95% identity or 99% identity or more to SEQ ID NO:38 or SEQ ID NO:39. For instance, the invention includes an anti-CD37 antibody or antibody fragment comprising SEQ ID NO:38 or SEQ ID NO:39. The method of claim 23, wherein the anti-CD37 antibody or antibody fragment comprises a variable heavy chain comprising an amino acid with 90% identity to the amino acid of SEQ ID NO:38 or SEQ ID NO:39. The invention also includes, for instance, an anti-CD37 antibody or antibody fragment with a variable light chain comprising at least about 90% identity, 95% identity or 99% identity or more to the amino acid sequence of SEQ ID NO:43. The invention includes, for instance, an anti-CD37 antibody or antibody fragment with a variable heavy chain comprising at least about 90% identity, 95% identity or 99% identity or more to the amino acid sequence of SEQ ID NO:38 or SEQ ID NO:39 and a variable light chain comprising at least about 90% identity, 95% identity or 99% identity or more to the amino acid sequence of SEQ ID NO:43.

[00141] Anti-CD37 and anti-CD20 antibodies may be modified according to methods standard in the art to improve its binding affinity, diminish its immunogenicity, alter its effector functions and/or improve its availability in the body of an individual. Such modifications may include, for example, amino acid sequence modifications or expression as a fusion protein. [00142] The anti-CD37 antibodies and antibody fragments of the invention include anti-CD37 antibodies and antibody fragments derived from anti-CD37 antibodies such as G28- 1 , MB371 , BL14, NMN46, IP024, HH1 , WR17, HD28 and K7153A. The methods and compositions of the invention also include, for instance, the CD37-specific antibodies used to characterize the CD37 antigen in the Third HLDA Workshop such as HD28, G28-1 , HH1 , BI14, WR17 and F93G6. See, Ling and MacLennan, pp. 302-335 in Leucocyte Typing III. White Cell Differentiation Antigens, Oxford University Press (1987). Other CD37-specific antibodies that have been described and are compatible with the methods and compositions of the invention include RFB-7, Y29/55, MB-1 , M-B371 , M-B372 and IPO-24. See, for instance, Moldenhaurer, J. Biol., Regul. Homeost. Agents, 14: 281-283 (2000) and Schwartz-Albiez et al., 14: 905-914 (1988). Another CD37-specific antibody envisioned for the methods and compositions of the invention is S-B3 (Biosys).

[00143] The anti-CD20 antibodies and antibody fragments of the invention include ofatumumab, veltuzumab, ocrelizumab and obinutuzumab. In a particular embodiment, the anti-CD20 antibody is obinutuzumab. In another embodiment, the anti-CD20 antibody is not rituximab. In one embodiment, the anti-CD20 antibody is an antibody or antibody fragment that is derived from anti-CD20 antibodies such as rituximab, ofatumumab, veltuzumab, ocrelizumab and obinutuzumab. In another embodiment, the anti-CD20 antibody is an antibody or antibody fragment that contains the same epitope or an epitope that overlaps with the epitope of rituximab, ofatumumab, veltuzumab, ocrelizumab and obinutuzumab. In yet another embodiment, the anti-CD20 antibody is an antibody or antibody fragment that competes for binding to CD20+ B cells with rituximab, ofatumumab, veltuzumab, ocrelizumab and obinutuzumab.

[00144] In one embodiment, the anti-CD37 antibodies and antibody fragments of the methods and compositions of the invention bind the same epitope or an epitope that overlaps with the epitope of G28-1 , MB371 , BL14, NMN46, IP024, HH1 , WR17, HD28, BI14, F93G6, RFB-7, Y29/55, MB-1 , M-B371 , IPO-24, S-B3 or K7153A. The compositions and methods of the invention include anti-CD37 antibodies that compete for binding to CD37+ B cells with G28- 1 , MB371 , BL14, NMN46, IP024, HH1 , WR17, HD28, BI14, F93G6, RFB-7, Y29/55, MB-1 , M- B371 , IPO-24, S-B3 or K7153A.

[00145] Monoclonal antibody technology and genetic engineering methods have led to development of immunoglobulin molecules for diagnosis and treatment of human diseases. Protein engineering has been applied to improve the affinity of an antibody for its cognate antigen, to diminish problems related to immunogenicity, and to alter an antibody's effector functions. The domain structure of immunoglobulins is amenable to engineering, in that the antigen binding domains and the domains conferring effector functions may be exchanged between immunoglobulin classes and subclasses. Immunoglobulin structure and function are reviewed, for example, in Harlow et al., Eds., Antibodies: A Laboratory Manual, Chapter 14, Cold Spring Harbor Laboratory, Cold Spring Harbor (1988). An extensive introduction as well as detailed information about all aspects of recombinant antibody technology can be found in the textbook "Recombinant Antibodies" (John Wiley & Sons, NY, 1999). A comprehensive collection of detailed antibody engineering lab Protocols can be found in R. Kontermann and S. Dubel (eds.), "The Antibody Engineering Lab Manual" (Springer Verlag, Heidelberg/New York, 2000). The invention includes anti-CD37 antibodies created using recombinant methods. For instance, the compositions and methods of the invention include an anti-CD37 antibody with at least about 90% identity, at least about 95% identity or at least about 99% identity to an amino acid sequence of SEQ ID NOS: 1 , 46, 48, 50, 52, 54, 56, 58, 60 and 63. In one embodiment, the compositions and methods of the invention comprise an anti-CD37 antibody or antibody fragment comprising or consisting essentially of an amino acid of SEQ ID NO:46, SEQ ID NO:48, SEQ ID NO:50, SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:56, SEQ ID NO:58, SEQ ID NO:60, SEQ ID NO:63 or amino acids 21-503 of SEQ ID NO:1.

[00146] As used herein, "reference antibody" refers to an anti-CD37 antibody and an CD20 antibody that are known in the art and which serve as the basis for a humanized, chimeric or recombinant anti-CD37 and anti-CD20 antibodies of the invention. Reference antibodies for generating anti-CD37 antibodies include, but are not limited to, G28-1 , MB371 , BL14, NMN46, IP024, HH1 , WR17, HD28, BI14, F93G6, RFB-7, Y29/55, MB-1 , M-B371 , IPO- 24, S-B3 and K7153A. Reference antibodies for generating anti-CD20 antibodies include, but are not limited to, rituximab, ofatumumab, veltuzumab, ocrelizumab, obinutuzumab and murine antibody B-ly1. The reference antibody may be a non-human, (e.g., murine), human, humanized, chimeric and / or recombinant antibody or antibody-like polypeptide.

[00147] In one embodiment, the anti-CD37 antibodies and antibody fragments of the invention are capable of binding CD37 and are capable of depleting CD37+ B-cells. In one embodiment, an anti-CD37 antibody is a B-cell depleting agent. Similarly, the anti-CD20 antibodies and antibody fragments of the invention are capable of binding CD20 and are capable of depleting CD20+ B-cells. In one embodiment, an anti-CD20 antibody is a B-cell depleting agent.

[00148] An "antigen binding domain" or "binding domain" is the part of an antibody which comprises the area which specifically binds to and is complementary to part or all of an antigen. Where an antigen is large, an antibody may only bind to a particular part of the antigen, which part is termed an epitope. An antigen binding domain may be provided by one or more antibody variable domains. An antigen binding domain may comprise an antibody light chain variable region (V_L) and an antibody heavy chain variable region (V_H). The invention includes binding domains in the V_H-V_L orientation and binding domains in the V_L-V_H orientation.

[00149] In one embodiment, anti-CD37 and anti-CD20 antibodies of the invention may comprise one or more binding domains or binding regions, such as variable light chain and variable heavy chain binding regions derived from one or more immunoglobulin superfamily members, such as an immunoglobulin. In one embodiment, a binding domain may comprise a V_H and V|_ region separated with a linker (e.g., an scFv). The linker may be any linker peptide known in the art to be compatible with domain or region joinder in a polypeptide (e.g., an scFv or a single chain polypeptide antibody molecule). Exemplary linkers are linkers based on the Gly₄Ser linker motif, such as (Gly₄Ser)_n, where n=1-5.

[00150] A binding domain "specifically binds" a target if it binds the target with an affinity or K_a (i.e., an equilibrium association constant of a particular binding interaction with units of 1/M) equal to or greater than 10⁵ M^"1 , while not significantly binding other components present in a test sample. Binding domains can be classified as "high affinity" binding domains and "low affinity" binding domains. "High affinity" binding domains refer to those binding domains with a K_a of at least 10⁷ M^"1 , at least 10⁸ M^"1 , at least 10⁹ M^"1 , at least 10¹⁰ M^"1 , at least 10¹¹ M^"1, at least 10¹² M^"1 , or at least 10¹³ M^"1. "Low affinity" binding domains refer to those binding domains with a K_a of up to 10⁷ M^"1 , up to 10⁶ M^"1 , up to 10⁵ M^"1. Alternatively, affinity can be defined as an equilibrium dissociation constant (K_d) of a particular binding interaction with units of M (e.g., 10^"5 M to 10^"13 M). Affinities of binding domain polypeptides and single chain polypeptides according to the present disclosure can be readily determined using conventional techniques (see, e.g., Scatchard et al. (1949) Ann. N.Y. Acad. Sci. 51 :660; and U.S. Patent Nos. 5,283,173, 5,468,614, or the equivalent).

[00151] In one embodiment, the anti-CD37 antibodies and anti-CD20 antibodies of the methods and compositions of the invention exhibit affinities for CD37 and CD20, respectively, of about 0.5 to about 10nM. Another characteristic of certain anti-CD37 and anti- CD20 antibodies contemplated by the invention is they exhibit a half life in circulation of about 7 to about 30 days.

[00152] In yet another aspect, the invention includes compositions comprising the anti-CD37 antibodies and antibody fragments, anti-CD20 antibodies and antibody fragments, and a pharmaceutically acceptable carrier. In yet another aspect, the compositions of the invention may comprise one or more BCR antagonist.

[00153] In yet another aspect, the invention includes kits for reducing B-cells comprising the compositions of the invention and protocols for using the kits to reduce B cells. Such kits may comprise one or more anti-CD37 antibodies and / or antibody fragments, anti- CD20 antibodies and / or antibody fragments, and one or more BCR antagonists (e.g., a BTK inhibitor, a SYK inhibitor and / or a CXCR4 antagonist).

[00154] A "synergistic combination" of an anti-CD37 antibody or antibody fragment and an anti-CD20 antibody or antibody fragment is a combination that has an effect that is greater than the sum of the effects of the molecules when administered alone. In some embodiments, the synergistic combination further comprises a BCR antagonist or a kinase inhibitor. The invention includes methods of administering an anti-CD37 antibody or antibody fragment and an anti-CD20 antibody or antibody fragments to a patient to achieve synergistic killing of B-cells (e.g., malignant B-cells). In some embodiments, the methods further comprise administering a BCR antagonist or a kinase inhibitor to the patient to achieve synergistic killing of B-cells. In one embodiment of the invention, a synergistic combination of an anti-CD37 antibody, an anti-CD20 antibody and a BCR antagonist (e.g., BTK inhibitor, SYK inhibitor, PI3K inhibitor, or CXCR4 antagonist) is administered to a patient with a B-cell malignancy or disorder. The invention includes, for instance, methods of treating a patient with a B-cell malignancy or disorder comprising administering an anti-CD37 antibody and an anti-CD20 antibody to achieve synergistic killing of B-cells, synergistic reduction in size and / or number of tumors, synergistic reduction in size of lymphoid tissue (e.g., lymph nodes and spleen), and / or other indication of disease regression that is greater than the sum of the two agents combined. In another embodiment, the invention includes methods of treating a patient with a B-cell malignancy or disorder comprising administering an anti-CD37 antibody, an anti-CD20 antibody, and a BTK inhibitor to achieve synergistic killing of B-cells, synergistic reduction in size and / or number of tumors, synergistic reduction in size of lymphoid tissue (e.g., lymph nodes and spleen), and / or other indication of disease regression that is greater than the sum of the three agents combined. In yet another embodiment, the invention includes methods of treating a patient with a B-cell malignancy or disorder comprising administering an anti-CD37 antibody, an anti-CD20 antibody, and a SYK inhibitor to achieve synergistic killing of B-cells, synergistic reduction in size and / or number of tumors, synergistic reduction in size of lymphoid tissue (e.g., lymph nodes and spleen), and / or other indication of disease regression that is greater than the sum of the three agents combined. In yet another embodiment, the invention includes, for instance, methods of treating a patient with a B-cell malignancy or disorder comprising administering an anti-CD37 antibody, an anti-CD20 antibody, and a CXCR4 antagonist to achieve synergistic killing of B-cells, synergistic reduction in size and / or number of tumors, synergistic reduction in size of lymphoid tissue (e.g., lymph nodes and spleen), and / or other indication of disease regression that is greater than the sum of the three agents combined. In yet another embodiment, the invention includes methods of treating a patient with a B-cell malignancy or disorder comprising administering an anti-CD37 antibody, an anti-CD20 antibody, and a PI3K inhibitor to achieve synergistic killing of B-cells, synergistic reduction in size and / or number of tumors, synergistic reduction in size of lymphoid tissue (e.g., lymph nodes and spleen), and / or other indication of disease regression that is greater than the sum of the three agents combined.

[00155] The invention also includes synergistic compositions comprising at least one anti-CD20 antibody or antibody fragment and at least one anti-CD37 antibody or antibody fragment. For instance, the invention includes a composition comprising TRU-016 and obinutuzumab and a pharmaceutically acceptable carrier. The synergistic composition comprising an anti-CD37 antibody and an anti-CD20 antibody, when administered to a patient with a B-cell malignancy or disorder, results in synergistic killing of B-cells, synergistic reduction in size and / or numbers of tumors, synergistic reduction in size of lymphoid tissue (e.g., lymph nodes and spleen), and / or other indication of disease regression that is greater than the sum of the two agents combined. The invention also includes synergistic compositions comprising at least one BCR antagonist (e.g., a BTK inhibitor, a SYK inhibitor, PI3K inhibitor, or a CXCR4 inhibitor), an anti-CD37 antibody or antibody fragment, and an anti-CD20 antibody or antibody fragment. In one embodiment of the invention, the composition comprises a BTK inhibitor, an anti-CD37 antibody or antibody fragment, and an anti-CD20 antibody or antibody fragment that when administered to a patient with a B-cell malignancy or disorder result in synergistic killing of B-cells, synergistic reduction in size and / or numbers of tumors, synergistic reduction in size of lymphoid tissue (e.g., lymph nodes and spleen), and / or other indication of disease regression that is greater than the sum of the three agents combined. In another embodiment of the invention, the composition comprises a SYK inhibitor, an anti-CD37 antibody or antibody fragment, and an anti-CD20 antibody or antibody fragment that when administered to a patient with a B-cell malignancy or disorder result in synergistic killing of B-cells, synergistic reduction in size and / or numbers of tumors, synergistic reduction in size of lymphoid tissue (e.g., lymph nodes and spleen), and / or other indication of disease regression that is greater than the sum of the three agents combined. In yet another embodiment of the invention, the composition comprises a CXCR4 antagonist, an anti-CD37 antibody or antibody fragment, and an anti-CD20 antibody or antibody fragment that when administered to a patient with a B-cell malignancy or disorder result in synergistic killing of B-cells, synergistic reduction in size and / or numbers of tumors, synergistic reduction in size of lymphoid tissue (e.g., lymph nodes and spleen), and / or other indication of disease regression that is greater than the sum of the three agents combined. The invention also includes synergistic compositions comprising at least one PI3K inhibitor (e.g., idelalisib), an anti-CD37 antibody or antibody fragment, and an anti-CD20 antibody or antibody fragment. In one embodiment of the invention, the composition comprises a PI3K inhibitor, an anti-CD37 antibody or antibody fragment, and an anti-CD20 antibody or antibody fragment that when administered to a patient with a B-cell malignancy or disorder result in synergistic killing of B-cells, synergistic reduction in size and / or numbers of tumors, synergistic reduction in size of lymphoid tissue (e.g., lymph nodes and spleen), and / or other indication of disease regression that is greater than the sum of the three agents combined.

[00156] Without wishing to be held to a hypothesis, it is believed that the synergy achieved from administering an anti-CD37 antibody, an anti-CD20 antibody, and a BCR antagonist is related to the ability of the BCR antagonist to reduce the ability of malignant B- cells to home to the protective sanctuary of the lymphoid tissue and the ability of anti-CD37 and anti-CD20 antibodies to deplete B-cells.

[00157] It should be understood that the anti-CD37 antibody or antibody fragment and an anti-CD20 antibody or antibody fragment of the invention are formulated as

pharmaceutical compositions when administered to a human patient. In one aspect of the invention, the pharmaceutical composition further comprises a BCR antagonist or a kinase inhibitor. In one aspect of the invention, the anti-CD37 antibody or antibody fragment, anti- CD20 antibody or antibody fragment, and BCR antagonist or kinase inhibitor are administered in one or more pharmaceutical compositions to a patient with a B-cell malignancy or disorder. In one embodiment, to administer the anti-CD37 antibody or antibody fragment, anti-CD20 antibody or antibody fragment, and BCR antagonist or kinase inhibitor to human or test animals, the anti-CD37 antibody or antibody fragment, anti-CD20 antibody or antibody fragment, and BCR antagonist or kinase inhibitor are formulated in compositions comprising one or more pharmaceutically acceptable carriers. The phrase "pharmaceutically or pharmacologically acceptable" refer to molecular entities and compositions that do not produce allergic, or other adverse reactions when administered using routes well-known in the art, as described below. "Pharmaceutically acceptable carriers" include any and all clinically useful solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.

[00158] In addition, compounds may form solvates with water or common organic solvents. Such solvates are contemplated as well.

[00159] The anti-CD37 antibody or antibody fragment, anti-CD20 antibody or antibody fragment, BCR antagonist, and kinase inhibitor may be administered orally, topically, transdermal^, parenterally, by inhalation spray, vaginally, rectally, and / or by intracranial injection. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intracisternal injection, or infusion techniques. Administration by intravenous, intradermal, intramusclar, intramammary, intraperitoneal, intrathecal, retrobulbar, intrapulmonary injection and or surgical implantation at a particular site is contemplated as well. Generally, compositions are essentially free of pyrogens, as well as other impurities that could be harmful to the recipient. In one embodiment the BCR antagonist (e.g., BTK inhibitor, SYK inhibitor, PI3K inhibitor, or CXCR4 antagonist) is administered orally and the anti-CD37 antibody or antibody fragment and the anti-CD20 antibody or antibody fragment are

administered parenterally (e.g., infusion).

[00160] The anti-CD37 antibodies and antibody fragments, anti-CD20 antibodies and antibody fragments and BCR antagonists of the methods and compositions of the invention may contain pharmaceutically acceptable carriers, diluents, excipients, and other additives depending on the route of administration. Examples of such carriers or additives include water, a pharmaceutical acceptable organic solvent, collagen, polyvinyl alcohol, polyvinylpyrrolidone, a carboxyvinyl polymer, carboxymethylcellulose sodium, polyacrylic sodium, sodium alginate, water-soluble dextran, carboxymethyl starch sodium, pectin, methyl cellulose, ethyl cellulose, xanthan gum, gum Arabic, casein, gelatin, agar, diglycerin, glycerin, propylene glycol, polyethylene glycol, Vaseline, paraffin, stearyl alcohol, stearic acid, human serum albumin (HSA), mannitol, sorbitol, lactose, a pharmaceutically acceptable surfactant and the like.

Additives used are chosen from, but not limited to, the above or combinations thereof, as appropriate, depending on the dosage form of the present invention.

[00161 ] Formulation of the anti-CD37 antibody or antibody fragment, anti-CD20 antibody or antibody fragment and BCR antagonist or kinase inhibitor will vary according to the route of administration selected (e.g., solution, emulsion). An appropriate composition comprising the active agent to be administered can be prepared in a physiologically acceptable vehicle or carrier. For solutions or emulsions, suitable carriers include, for example, aqueous or alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles can include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils. Intravenous vehicles can include various additives, preservatives, or fluid, nutrient or electrolyte replenishers

[00162] The pharmaceutical compositions may be in the form of a sterile injectable aqueous, oleaginous suspension, dispersions or sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. The suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1 ,3-butane diol. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, vegetable oils, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[00163] In all cases the form must be sterile and must be fluid to the extent that easy syringability exists. The proper fluidity 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. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The prevention of the action of microorganisms can be brought about by various antibacterial an antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be desirable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[00164] Compositions useful for administration may be formulated with uptake or absorption enhancers to increase their efficacy. Such enhancers include for example, salicylate, glycocholate/linoleate, glycholate, aprotinin, bacitracin, SDS, caprate and the like. See, e.g., Fix (J. Pharm. Sci., 85: 1282-1285, 1996) and Oliyai and Stella {Ann. Rev.

Pharmacol. Toxicol., 32:521 -544, 1993).

[00165] In one aspect, methods of the invention include a step of administering an an anti-CD37 antibody or antibody fragment and a step of administering an anti-CD20 antibody or antibody fragment. In another aspect, methods of the invention include a step of administering an anti-CD37 antibody or antibody fragment, a step of administering an anti- CD20 antibody or antibody fragment and a step of administering a BCR antagonist (e.g., a BTK inhibitor, a SYK inhibitor or a CXCR4 antagonist) or a kinase inhibitor.

[00166] Methods of the invention are performed using any medically-accepted means for introducing a therapeutic directly or indirectly into a mammalian individual, including but not limited to injections, oral ingestion, intranasal, topical, transdermal, parenteral, inhalation spray, vaginal, or rectal administration. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, and intracisternal injections, as well as catheter or infusion techniques. Administration by, intradermal, intramammary, intraperitoneal, intrathecal, retrobulbar, intrapulmonary injection and or surgical implantation at a particular site is contemplated as well. [00167] In one embodiment, administration is performed at the site of a cancer or affected tissue needing treatment by direct injection into the site or via a sustained delivery or sustained release mechanism, which can deliver the formulation internally. For example, biodegradable microspheres or capsules or other biodegradable polymer configurations capable of sustained delivery of a composition (e.g., a soluble polypeptide, antibody, or small molecule) can be included in the formulations of the invention implanted near the cancer.

[00168] Therapeutic compositions may also be delivered to the patient at multiple sites. The multiple administrations may be rendered simultaneously or may be administered over a period of time. In certain cases it is beneficial to provide a continuous flow of the therapeutic composition. Additional therapy may be administered on a period basis, for example, hourly, daily, weekly or monthly.

[00169] In one embodiment of the invention, the anti-CD37 antibody or antibody fragment is administered prior to, concurrent with, or after administration of the anti-CD20 antibody or antibody fragment. For instance, the anti-CD37 antibody or antibody fragment may be administered by IV weekly for up to 8 weeks followed by 4 monthly doses ranging from 0.03 to 20 mg/kg in the dose escalation phase and 10 to 30 mg/kg in the expansion phase and the treatment with anti-CD20 antibody or antibody fragment may be initiated before, concurrently with or after treatment with the anti-CD37 antibody or antibody fragment.

[00170] In one embodiment of the invention, the BCR antagonist (e.g., a BTK inhibitor, a SYK inhibitor, PI3K inhibitor, or a CXCR4 antagonist) is administered orally and is administered once or twice daily. In this embodiment, the anti-CD37 antibody or antibody fragment and anti-CD20 antibody or antibody fragment are administered prior to, concurrent with, or after administration of the BCR antagonist. For instance, the anti-CD37 antibody or antibody fragment may be administered by IV weekly for up to 8 weeks followed by 4 monthly doses ranging from 0.03 to 20 mg/kg in the dose escalation phase and 10 to 30 mg/kg in the expansion phase and the treatment with anti-CD20 antibody or antibody fragment and a BCR antagonist may be initiated before, concurrently with or after treatment with the CD37 antibody or antibody fragment.

[00171] In one embodiment, the methods of the invention comprise administering an anti-CD37 antibody or antibody fragment and an anti-CD20 antibody or antibody fragments on separate days. In another embodiment, the methods comprise administering an anti-CD37 antibody or antibody fragment and an anti-CD20 antibody or antibody fragments on the same day. In some embodiments, the period of administration of an anti-CD37 antibody or antibody fragment and the period of administration of an anti-CD20 antibody or antibody fragment may or may not overlap. [00172] In one embodiment, a BCR antagonist or kinase inhibitor is administered orally on a daily basis and an anti-CD37 antibody or antibody fragment and an anti-CD20 antibody are administered by infusion once a week. In this embodiment, the treatment regimen will include days when all three agents are administered to a patient, days when only two agents are administered and / or days when only a single agent is administered.

[00173] The invention includes administration of an additional therapeutic agent in combination with an anti-CD37 antibody or antibody fragment and an anti-CD20 antibody or antibody fragment. Similarly, the invention includes administration of an additional therapeutic agent in combination with an anti-CD37 antibody or antibody fragment, an anti-CD20 antibody or antibody fragment and a BCR antagonist (e.g., SYK inhibitor, BTK inhibitor, PI3K inhibitor, and CXCR4 antagonist). In one embodiment, the additional therapeutic agent comprises a B- cell-associated molecule. Other B-cell-associated molecules contemplated by the invention include binding molecules which bind to B-cell surface molecules that are not CD37, CD20 or B-cell receptor. B-cell-associated molecules, include but are not limited to, CD19 (B- lymphocyte antigen CD19, also referred to as B-lymphocyte surface antigen B4, or Leu-12), CD21 , CD22 (B-cell receptor CD22, also referred to as Leu-14, B-lymphocyte cell adhesion molecule, or BL-CAM), CD23, CD40 (B-cell surface antigen CD40, also referred to as Tumor Necrosis Factor receptor superfamily member 5, CD40L receptor, or Bp50), CD80 (T lymphocyte activation antigen CD80, also referred to as Activation B7-1 antigen, B7, B7-1 , or BB1 ), CD86 (T lymphocyte activation antigen CD86, also referred to as Activation B7-2 antigen, B70, FUN-1 , or BU63), CD137 (also referred to as Tumor Necrosis Factor receptor superfamily member 9), CD152 (also referred to as cytotoxic T-lymphocyte protein 4 or CTLA-4), L6 (Tumor-associated antigen L6, also referred to as Transmembrane 4 superfamily member 1 , Membrane component surface marker 1 , or M3S1 ), CD30 (lymphocyte activation antigen CD30, also referred to as Tumor Necrosis Factor receptor superfamily member 8, CD30L receptor, or Ki-1 ), CD50 (also referred to as Intercellular adhesion molecule-3 (ICAM3), or ICAM-R), CD54 (also referred to as Intercellular adhesion molecule-1 (ICAM1 ), or Major group rhinovirus receptor), B7-H1 (ligand for an immunoinhibitory receptor expressed by activated T cells, B-cells, and myeloid cells, also referred to as PD-L1 ; see Dong, et al., "B7-H1 , a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion," Nat. Med., 5:1365-1369 (1999), CD134 (also referred to as Tumor Necrosis Factor receptor superfamily member 4, OX40, OX40L receptor, ACT35 antigen, or TAX-transcriptionally activated glycoprotein 1 receptor), 41 BB (4-1 BB ligand receptor, T-cell antigen 4-1 BB, or T-cell antigen ILA), CD153 (also referred to as Tumor Necrosis Factor ligand superfamily member 8, CD30 ligand, or CD30-L), CD154 (also referred to as Tumor Necrosis Factor ligand superfamily member 5, TNF-related activation protein, TRAP, or T cell antigen Gp39) and Toll receptors. The above list of construct targets and/or target antigens is exemplary only and is not exhaustive.

[00174] In another embodiment, cytokines and growth factors are the additional therapeutic agents that may be administered in conjunction with an anti-CD37 antibody or antibody fragment and an anti-CD20 antibody or antibody fragment and optionally, a BCR antagonist (such as BTK inhibitor, SYK inhibitor, PI3K inhibitor or CXCR4 antagonists).

Cytokines and growth factors include, without limitation, one or more of TNF, IL-1 , IL-2, IL-3, IL- 4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-1 1 , IL-12, IL-13, IL-14, IL-15, IL-16, IL- 7, IL-18, IFN, G- CSF, Meg-CSF, GM-CSF, thrombopoietin, stem cell factor, and erythropoietin. The additional agent therapeutics may also include other known angiopoietins, for example Ang-1 , Ang-2, Ang-4, Ang-Y, and/or the human angiopoietin-like polypeptide, and/or vascular endothelial growth factor (VEGF). Growth factors for use as additional agent therapeutics in the methods and compositions of the invention include, for instance, angiogenin, bone morphogenic protein- 1 , bone morphogenic protein-2, bone morphogenic protein-3, bone morphogenic protein-4, bone morphogenic protein-5, bone morphogenic protein-6, bone morphogenic protein-7, bone morphogenic protein-8, bone morphogenic protein-9, bone morphogenic protein-10, bone morphogenic protein-1 1 , bone morphogenic protein-12, bone morphogenic protein-13, bone morphogenic protein-14, bone morphogenic protein-15, bone morphogenic protein receptor IA, bone morphogenic protein receptor IB, brain derived neurotrophic factor, ciliary neutrophic factor, ciliary neutrophic factor receptor a, cytokine-induced neutrophil chemotactic factor 1 , cytokine-induced neutrophil chemotactic factor 2a, cytokine-induced neutrophil chemotactic factor 2β, β endothelial cell growth factor, endothelin 1 , epidermal growth factor, epithelial- derived neutrophil attractant, fibroblast growth factor 4, fibroblast growth factor 5, fibroblast growth factor 6, fibroblast growth factor 7, fibroblast growth factor 8, fibroblast growth factor 8b, fibroblast growth factor 8c, fibroblast growth factor 9, fibroblast growth factor 10, fibroblast growth factor acidic, fibroblast growth factor basic, glial cell line-derived neutrophic factor receptor α1 , glial cell line-derived neutrophic factor receptor a2, growth related protein, growth related protein a, growth related protein β, growth related protein γ, heparin binding epidermal growth factor, hepatocyte growth factor, hepatocyte growth factor receptor, insulin-like growth factor I, insulin-like growth factor receptor, insulin-like growth factor II, insulin-like growth factor binding protein, keratinocyte growth factor, leukemia inhibitory factor, leukemia inhibitory factor receptor a, nerve growth factor, nerve growth factor receptor, neurotrophin-3, neurotrophin-4, placenta growth factor, placenta growth factor 2, platelet derived endothelial cell growth factor, platelet derived growth factor, platelet derived growth factor A chain, platelet derived growth factor AA, platelet derived growth factor AB, platelet derived growth factor B chain, platelet derived growth factor BB, platelet derived growth factor receptor a, platelet derived growth factor receptor β, pre-B cell growth stimulating factor, stem cell factor, stem cell factor receptor, transforming growth factor a, transforming growth factor β, transforming growth factor β1 , transforming growth factor β1.2, transforming growth factor β2, transforming growth factor β3, transforming growth factor β5, latent transforming growth factor β1 , transforming growth factor β binding protein I, transforming growth factor β binding protein II, transforming growth factor β binding protein III, tumor necrosis factor receptor type I, tumor necrosis factor receptor type II, urokinase-type plasminogen activator receptor, vascular endothelial growth factor, and chimeric proteins and biologically or immunologically active fragments thereof.

[00175] In another embodiment, an anti-CD37 antibody and an anti-CD20 antibody are administered to a patient in conjunction with a chemotherapeutic agent or

chemotherapeutic cocktail (e.g., CHOP). In yet another embodiment, an anti-CD37 antibody, an anti-CD20 antibody and a BCR antagonist or kinase inhibitor are administered to a patient in conjunction with a chemotherapeutic agent or chemotherapeutic cocktail. Examples of chemotherapeutic agents contemplated include, but are not limited to, alkylating agents, such as nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, ifosfamide, melphalan, and chlorambucil); nitrosoureas (e.g., carmustine (BCNU), lomustine (CCNU), and semustine (methyl-CCNU)); ethyleneimines and methyl-melamines (e.g., triethylenemelamine (TEM), triethylene thiophosphoramide (thiotepa), and hexamethylmelamine (HMM, altretamine)); alkyl sulfonates (e.g., buslfan); and triazines (e.g., dacabazine (DTIC)); antimetabolites, such as folic acid analogs (e.g., methotrexate, trimetrexate, and pemetrexed (multi-targeted antifolate)); pyrimidine analogs (such as 5-fluorouracil (5-FU), fluorodeoxyuridine, gemcitabine, cytosine arabinoside (AraC, cytarabine), 5-azacytidine, and 2,2'-difluorodeoxycytidine); and purine analogs (e.g., 6-mercaptopurine, 6-thioguanine, azathioprine, 2'-deoxycoformycin (pentostatin), erythrohydroxynonyladenine (EHNA), fludarabine phosphate, 2-chlorodeoxyadenosine

(cladribine, 2-CdA)); Type I topoisomerase inhibitors such as camptothecin (CPT), topotecan, and irinotecan; natural products, such as epipodophylotoxins (e.g., etoposide and teniposide); and vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine); anti-tumor antibiotics such as actinomycin D, doxorubicin, and bleomycin; radiosensitizers such as 5-bromodeozyuridine, 5- iododeoxyuridine, and bromodeoxycytidine; platinum coordination complexes such as cisplatin, carboplatin, and oxaliplatin; substituted ureas, such as hydroxyurea; and methylhydrazine derivatives such as N-methylhydrazine (MIH) and procarbazine.

[00176] Non-limiting examples of chemotherapeutic agents, radiotherapeutic agents and other active and ancillary agents that can be used in the methods of the invention are also shown in Table 1. TABLE 1

Alkylating agents Natural products

Nitrogen mustards Antimitotic drugs

mechlorethamine

cyclophosphamide

ifosfamide Taxanes

melphalan paclitaxel

chlorambucil Vinca alkaloids

vinblastine (VLB)

Nitrosoureas vincristine

carmustine (BCNU) vinorelbine

lomustine (CCNU) Taxotere® (docetaxel) semustine (methyl-CCNU) estramustine

estramustine phosphate

Ethylenemine/Methyl-melamine

thriethylenemelamine (TEM) Epipodophylotoxins triethylene thiophosphoramide etoposide

(thiotepa) teniposide

hexamethylmelamine

(HMM, altretamine) Antibiotics

actimomycin D

Alkyl sulfonates daunomycin (rubido-mycin) busulfan doxorubicin (adria-mycin) mitoxantroneidarubicin

Triazines bleomycin

dacarbazine (DTIC) splicamycin (mithramycin) mitomycinC

Antimetabolites dactinomycin

Folic Acid analogs aphidicolin

methotrexate

Trimetrexate Enzymes

Pemetrexed L-asparaginase

(Multi-targeted antifolate) L-arginase

Pyrimidine analogs Radiosensitizers

5-fluorouracil metronidazole

fluorodeoxyuridine misonidazole

gemcitabine desmethylmisonidazole cytosine arabinoside pimonidazole

(AraC, cytarabine) etanidazole

5- azacytidine nimorazole

2,2^'- difluorodeoxy-cytidine RSU 1069

E09

Purine analogs RB 6145

6- mercaptopurine SR4233

6-thioguanine nicotinamide

azathioprine 5-bromodeozyuridine 2'-deoxycoformycin 5-iododeoxyuridine

(pentostatin) bromodeoxycytidine erythrohydroxynonyl-adenine (EHNA)

fludarabine phosphate

2-chlorodeoxyadenosine Miscellaneous agents (cladribine, 2-CdA) Platinium coordination complexes

cisplatin

Carboplatin

Type I Topoisomerase Inhibitors oxaliplatin

camptothecin Anthracenedione

topotecan mitoxantrone

irinotecan

Substituted urea

Biological response modifiers hydroxyurea

G-CSF

GM-CSF Methylhvdrazine derivatives

N-methylhydrazine (MIH)

Differentiation Agents procarbazine

retinoic acid derivatives

Adrenocortical suppressant

Hormones and antagonists mitotane (ο,ρ^'- DDD)

Adrenocorticosteroids/ antagonists ainoglutethimide

prednisone and equivalents

dexamethasone Cytokines

ainoglutethimide interferon (α, β, γ)

interleukin-2

Progestins

hydroxyprogesterone caproate Photosensitizers

medroxyprogesterone acetate hematoporphyrin derivatives

megestrol acetate Photofrin®

benzoporphyrin derivatives

Estrogens Npe6

diethylstilbestrol tin etioporphyrin (SnET2)

ethynyl estradiol/ equivalents pheoboride-a

bacteriochlorophyll-a

Antiestrogen naphthalocyanines

tamoxifen phthalocyanines

zinc phthalocyanines

Androgens

testosterone propionate Radiation

fluoxymesterone/equivalents X-ray

ultraviolet light

Antiandrogens gamma radiation

flutamide visible light

gonadotropin-releasing infrared radiation

hormone analogs microwave radiation

leuprolide

Nonsteroidal antiandrogens

flutamide

[00177] Additional therapeutic agents that can be used in the methods of the invention for treatment of autoimmune diseases include immunosuppressive agents, which act to suppress or mask the immune system of the individual being treated. Immunosuppressive agents include, for example, non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, glucocorticoids, disease-modifying antirheumatic drugs (DMARDs) for the treatment of arthritis, or biologic response modifiers. Compositions in the DMARD description are also useful in the treatment of many other autoimmune diseases aside from RA.

[00178] The invention includes methods of administering an anti-CD37 antibody and an anti-CD20 antibody to a patient for treatment of a B-cell malignancy or disorder. The invention also includes methods of administering an anti-CD37 antibody, an anti-CD20 antibody and a BCR antagonist or kinase inhibitor to a patient for treatment of a B-cell malignancy or disorder. As should be apparent to one of skill in the art, the methods described herein can be used with any anti-CD37 antibody and any anti-CD20 antibody, including, but not limited to the anti-CD37 and anti-CD20 antibodies disclosed herein. Moreover, it should be understood that the methods can be performed with any BCR antagonists (e.g., BTK inhibitors, CXCR4 antagonists, PI3K inhibitors, and SYK inhibitors) including, but not limited to those compounds specifically disclosed herein.

[00179] In one embodiment of the invention, an individual treated by methods of the invention demonstrates a response to treatment that is better than, or improved relative to, the response to treatment with an anti-CD37 antibody or antibody fragment as a monotherapy, an anti-CD20 antibody or antibody fragment as a monotherapy, a BTK inhibitor as a monotherapy, a SYK inhibitor as a monotherapy, a PI3K inhibitor as a monotherapy, a CXCR4 antagonist as a monotherapy or another kinase inhibitor as a monotherapy. A response which is improved over treatment with a monotherapy refers to a clinical response wherein treatment by a method of the invention results in a clinical response in a patient that is better than a clinical response in a patient receiving the single drug therapy, such as an anti-CD37 antibody (e.g., a humanized antibody derived from G28-1 ), an anti-CD20 antibody (e.g., obinutuzumab), BTK inhibitor (e.g., ibrutinib or AVL-292), SYK inhibitor (e.g., fostamatinib, PRT062607 and PRT-318), a CXCR4 antagonist (e.g., plerixafor, T140 analog and KRH-3955) or a PI3K inhibitor (e.g. idelalisib). An improved response is assessed by comparison of clinical criteria well-known in the art and described herein. Exemplary criteria include, but are not limited to, duration of B cell depletion, reduction in B cell numbers overall, reduction in B cell numbers in a biological sample, reduction in tumor size, reduction in the number of tumors existing and/or appearing after treatment, and improved overall response as assessed by patients themselves and physicians, e.g., using an International Prognostic Index. The improvement may be in one or more than one of the clinical criteria. An improved response with the method of the invention may be due to an inadequate response to previous or current treatment, for example, because of toxicity and/or inadequate efficacy of the monotherapy treatment. In one embodiment of the methods of the invention, treatment with an anti-CD37 antibody or antibody fragment and an anti-CD20 antibody or antibody fragment result in one or more improved patient responses. In another embodiment of the methods of the invention, treatment with an anti-CD37 antibody or antibody fragment, an anti-CD20 antibody or antibody fragment and BCR antagonist result in one or more improved patient responses. In yet another embodiment of the methods of the invention, treatment with an anti-CD37 antibody or antibody fragment, an anti-CD20 antibody or antibody fragment and PI3K inhibitor result in one or more improved patient responses. In one embodiment, the patient is a patient with one or more poor prognostic factors such as 17p deletion, TP53 mutation, 11 q deletion, trisomy 12, ZAP70+.

[00180] In one embodiment of the invention, the anti-CD37 antibody or antibody fragment and anti-CD20 antibody or antibody fragment act synergistically when administered to a patient or subject in need. In another embodiment, the anti-CD37 antibody or antibody fragment, anti-CD20 antibody or antibody fragment and BCR antagonist act synergistically when administered to a patient or subject in need. In yet another embodiment, the anti-CD37 antibody or antibody fragment, anti-CD20 antibody or antibody fragment and kinase inhibitor act synergistically when administered to a patient or subject in need. As used herein, "synergy" or a "synergistic" response (e.g., "synergistic reduction in tumor size or number" or "synergistic increase in survival time") refers to an activity or improvement that is greater than the sum of the effect of each therapy as a monotherapy. As can be appreciated by a skilled artisan, synergy can be shown in vitro, ex vivo and in vivo. For example, synergy can be determined using the isobologram method, e.g., as discussed in Example 12.

[00181 ] Moreover, for the determination of synergy, dosing may be different for the combination treatment as compared to monotherapies due to toxicities and must therefore be taken into account. In one embodiment, an activity associated with efficacy may not appear synergistic (for instance, perhaps there is no synergistic reduction in B-cells or tumor size) but the combination treatment may nonetheless be beneficial if the same level of activity can be accomplished with the administration of less drug substance (and fewer side effects).

[00182] In one embodiment, administration of an anti-CD37 antibody or antibody fragment and an anti-CD20 antibody or antibody fragment results in synergistic B cell reduction or B cell depletion. In another embodiment, administration of an anti-CD37 antibody or antibody fragment, an anti-CD20 antibody or antibody fragment and a BCR antagonist or kinase inhibitor results in synergistic B cell reduction or B cell depletion. For instance, a synergistic reduction in B cells may be about a 5%, 10%, 15%, 20%, 25% or 30% or more greater reduction in B cells as compared to the sum of B cell depletion following treatment with anti-CD37 as a monotherapy, anti-CD20 as a monotherapy, a BCR antagonist as a

monotherapy or kinase inhibitor as a monotherapy. As should be appreciated, synergy can be implied by comparing average B cell depletion rates for monotherapy treatment as compared to the combination treatment. [00183] The invention includes reducing or depleting B cells comprising exposing B cells to a synergistic combination of at least one anti-CD37 antibody and at least one anti-CD20 antibody or a synergistic combination of at least one anti-CD37 antibody, at least one anti- CD20 antibody and at least one BCR antagonist. Alternatively, the invention includes reducing or depleting B cells comprising exposing B cells to a synergistic combination of at least one anti-CD37 antibody, at least one anti-CD20 antibody and at least one kinase inhibitor, such as, a PI3K inhibitor. Exposure of B cells for determination of synergy in response to combination therapy can be in vitro, ex vivo or in vivo.

[00184] In another embodiment, the combination therapy of an anti-CD37 antibody and an anti-CD20 antibody results in a synergistic reduction of tumor size or number of tumors. In yet another embodiment, the combination therapy of an anti-CD37 antibody, an anti-CD20 antibody and a BCR antagonist or kinase inhibitor results in a synergistic reduction of tumor size or number of tumors. For instance, a synergistic reduction in tumor size may be about a 5%, 10%, 15%, 20%, 25% or 30% or more greater reduction in tumor size as compared to the sum of the decrease in tumor size resulting from anti-CD37 monotherapy, anti-CD20 monotherapy and BCR antagonist or kinase inhibitor monotherapy. In another embodiment, a synergistic reduction in number of tumors is evidenced when the average number of tumors after the combination therapies of the invention is less than the sum of the average number of tumors after treatment with the same anti-CD37 antibody as a monotherapy, the same anti- CD20 antibody as a monotherapy and the same BCR antagonist or kinase inhibitor as a monotherapy. In one embodiment of the invention, the patient administered the synergistic combinations of the invention is a patient with one or more poor prognostic factors, for instance, 17p deletion, TP53 mutations, 1 q deletion, trisomy 12, and/or ZAP70+.

[00185] In another embodiment of the invention, administration of the anti-CD37 antibody or antibody fragment and anti-CD20 antibody or antibody fragment results in a synergistic survival time. In yet another embodiment of the invention, administration of the anti- CD37 antibody or antibody fragment , anti-CD20 antibody or antibody fragment and BCR antagonist or kinase inhibitor results in a synergistic survival time. By "synergistic survival time" it is meant that the average survival time following treatment with the combination therapy (i.e., an anti-CD37 antibody and an anti-CD20 antibody or an anti-CD37 antibody, an anti-CD20 antibody and a BCR antagonist such as a BTK inhibitor like ibrutinib or an anti-CD37 antibody, an anti-CD20 antibody and a BCR antagonist such as a PI3K inhibitor such as idelalisib) is greater than the average survival times following monotherapy with an anti-CD37 antibody, an anti-CD20 antibody, a BCR antagonist. [00186] In another embodiment of the invention, administration of an anti-CD37 antibody or fragment, an anti-CD20 antibody or fragment and a BCR antagonist prevents or reduces the down-regulation of CXCR4 expression which is common in B-cell malignancies. A reduction in CXCR4 expression may be associated with an increase of B cells (including malignant B cells) homing to lymphoid tissues where they are more difficult to treat with therapeutics. By preventing or reducing the down-regulation of CXCR4 expression, administration of the combination therapy of the invention results in a greater number of malignant B cells in peripheral blood where the cells are more susceptible to therapy.

[00187] The invention includes methods, compositions and kits for the treatment of patients with B-cell malignancies and disorders. B-cell malignancies and disorders include B- cell lymphomas [such as various forms of Hodgkin's disease, non-Hodgkin's lymphoma (NHL) or central nervous system lymphomas], leukemias [such as acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hairy cell leukemia and chronic myoblastic leukemia] and myelomas (such as multiple myeloma). Additional B cell cancers include small lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, solitary plasmacytoma of bone, extraosseous plasmacytoma, extra-nodal marginal zone B-cell lymphoma of mucosa-associated (MALT) lymphoid tissue, nodal marginal zone B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, B-cell proliferations of uncertain malignant potential, lymphomatoid granulomatosis, and post- transplant lymphoproliferative disorder. In one embodiment of the methods, compositions and kits of the invention, a patient with a B-cell malignancy has a poor prognostic factor such as 17p deletion, TP53 mutation, 1 q deletion, trisomy 12 or ZAP-70+.

[00188] The invention also includes compositions and kits for treating B cell malignancies and disorders. For instance, in one embodiment, the composition comprises an anti-CD37 antibody or antibody fragment for use with an anti-CD20 antibody or antibody fragment for treatment of a B cell malignancy. In a further embodiment, the composition comprises an anti-CD37 antibody or antibody fragment for use with obinubuzumab for treatment of B cell malignancy. In another embodiment, the compositions of the invention comprise a BCR antagonist such as a SYK inhibitor, BTK inhibitor, PI3K inhibitor, or CXCR4 antagonist. For instance, in one embodiment, the composition for treatment of a B cell malignancy comprises an anti-CD37 antibody or antibody fragment for use in combination with an anti-CD20 antibody or antibody fragment and a BCR antagonist such as a SYK inhibitor,

BTK inhibitor, PI3K inihbitor, or CXCR4 antagonist. In another embodiment, the compositions of the invention comprise a CD37 antibody or fragment, a CD20 antibody or fragment and a kinase inhibitor for treatment of a B cell malignancy. In one embodiment, the compositions of the invention comprise an anti-CD37 antibody or antibody fragment, obinutuzumab and idelalisib for treatment of a B cell malignancy. In another embodiment, the compositions of the invention comprise an anti-CD37 antibody or antibody fragment, obinutuzumab, and ibrutinib for treatment of a B cell malignancy.

[00189] The invention includes methods and compositions for treatment of B-cell disorders characterized by autoantibody production and autoimmune diseases. In one embodiment, the invention encompasses methods for treating a patient with an autoimmune disease comprising administering to the patient a therapeutically effective amount of an anti- CD37 antibody or fragment and an anti-CD20 antibody or fragment. For instance, the methods of the invention include administering an anti-CD37 antibody such as TRU-016 and an anti- CD20 antibody such as obinutuzumab to a patient with an autoimmune disease. The invention also encompasses methods for treating a patient with an autoimmune disease comprising administering to the patient a therapeutically effective amount of an anti-CD37 antibody or fragment, an anti-CD20 antibody or fragment, and a BCR antagonist or kinase inhibitor. For instance, in one embodiment, the invention includes administering to a patient with an autoimmune disease an anti-CD37 antibody or fragment, an anti-CD20 antibody or fragment, and a BTK inhibitor, such as ibrutinib or AVL-292. In another embodiment, the invention includes administering to a patient with an autoimmune disease an anti-CD37 antibody or fragment, an anti-CD20 antibody or fragment, and a SYK inhibitor, such as fostamatinib or PRT062607. In yet another embodiment, the invention includes administering to a patient with an autoimmune disease an anti-CD37 antibody or fragment, an anti-CD20 antibody or fragment, and a CXCR4 antagonist, such as plerixafor or T140 analog. In yet another embodiment, the invention includes administering to a patient with an autoimmune disease an anti-CD37 antibody or fragment, an anti-CD20 antibody or fragment, and a PI3K inhibitor, such as idelalisib.

[00190] In one embodiment, a patient with an autoimmune disease is administered an anti-CD37 antibody or antibody fragment with the same epitope as G28-1 , MB371 , BL14, NMN46, IP024, HH1 , WR17, HD28 or K7153A, and an anti-CD20 antibody or antibody fragment and optionally, a BCR antagonist or kinase inhibitor. In another embodiment, a patient with an autoimmune disease is administered an anti-CD37 antibody or antibody fragment derived from G28-1 , MB371 , BL14, NMN46, IP024, HH1 , WR17, HD28 or K7153A and an anti-CD20 antibody or antibody fragment and optionally, a BCR antagonist or a kinase inhibitor. In yet another embodiment of the invention, a patient with an autoimmune disease is administered a humanized or chimeric anti-CD37 antibody or antibody fragment derived from G28-1 , MB371 , BL14, NMN46, IP024, HH1 , WR17, HD28 or K7153A and an anti-CD20 antibody or antibody fragment and optionally, a BCR antagonist or kinase inhibitor.

[00191] The invention also includes compositions and kits for treating autoimmune diseases. For instance, in one embodiment, the composition comprises an anti-CD37 antibody or antibody fragment for use with an anti-CD20 antibody or antibody fragment for treatment of an autoimmune disease. In a further embodiment, the composition comprises an anti-CD37 antibody or antibody fragment for use with obinubuzumab for treatment of autoimmune disease. In another embodiment, the compositions of the invention comprise a BCR antagonist such as a SYK inhibitor, BTK inhibitor, PI3K inhibitor, or CXCR4 antagonist. For instance, in one embodiment, the composition for treatment of an autoimmune disease comprises an anti-CD37 antibody or antibody fragment for use in combination with an anti-CD20 antibody or antibody fragment and a BCR antagonist such as a SYK inhibitor, BTK inhibitor, PI3K inihbitor, or CXCR4 antagonist. In another embodiment, the compositions of the invention comprise a CD37 antibody or fragment, a CD20 antibody or fragment and a kinase inhibitor for treatment of an autoimmune disease. In one embodiment, the compositions of the invention comprise an anti-CD37 antibody or antibody fragment, obinutuzumab and idelalisib for treatment of an autoimmune disease. In another embodiment, the compositions of the invention comprise an anti-CD37 antibody or antibody fragment, obinutuzumab, and ibrutinib for treatment of an autoimmune disease.

[00192] Autoimmune diseases that can be treated with the methods and

compositions of the invention include, but are not limited to: arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, polychondritis, psoriatic arthritis, psoriasis, dermatitis, polymyositis/dermatomyositis, inclusion body myositis, inflammatory myositis, toxic epidermal necrolysis, systemic scleroderma and sclerosis, CREST syndrome, responses associated with inflammatory bowel disease, Crohn's disease, ulcerative colitis, respiratory distress syndrome, adult respiratory distress syndrome (ARDS), meningitis, encephalitis, uveitis, colitis, glomerulonephritis, allergic conditions, eczema, asthma, conditions involving infiltration of T cells and chronic inflammatory responses, atherosclerosis, autoimmune myocarditis, leukocyte adhesion deficiency, systemic lupus erythematosus (SLE), subacute cutaneous lupus erythematosus, discoid lupus, lupus myelitis, lupus cerebritis, juvenile onset diabetes, multiple sclerosis, allergic encephalomyelitis, neuromyelitis optica, rheumatic fever,

Sydenham's chorea, immune responses associated with acute and delayed hypersensitivity mediated by cytokines and T-lymphocytes, tuberculosis, sarcoidosis, granulomatosis including

Wegener's granulomatosis and Churg-Strauss disease, agranulocytosis, vasculitis (including hypersensitivity vasculitis/angiitis, ANCA and rheumatoid vasculitis), aplastic anemia, Diamond

Blackfan anemia, immune hemolytic anemia including autoimmune hemolytic anemia (AIHA), pernicious anemia, pure red cell aplasia (PRCA), Factor VIII deficiency, hemophilia A, autoimmune neutropenia, pancytopenia, leukopenia, diseases involving leukocyte diapedesis, central nervous system (CNS) inflammatory disorders, multiple organ injury syndrome, myasthenia gravis, antigen-antibody complex mediated diseases, anti-glomerular basement membrane disease, anti-phospholipid antibody syndrome, allergic neuritis, Behcet disease, Castleman's syndrome, Goodpasture's syndrome, Lambert-Eaton Myasthenic Syndrome, Reynaud's syndrome, Sjorgen's syndrome, Stevens-Johnson syndrome, solid organ transplant rejection, graft versus host disease (GVHD), pemphigoid bullous, pemphigus, autoimmune polyendocrinopathies, seronegative spondyloarthropathies, Reiter's disease, stiff-man syndrome, giant cell arteritis, immune complex nephritis, IgA nephropathy, IgM

polyneuropathies or IgM mediated neuropathy, idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), Henoch-Schonlein purpura, autoimmune thrombocytopenia, autoimmune disease of the testis and ovary including autoimmune orchitis and oophoritis, primary hypothyroidism; autoimmune endocrine diseases including autoimmune thyroiditis, chronic thyroiditis (Hashimoto's Thyroiditis), subacute thyroiditis, idiopathic hypothyroidism, Addison's disease, Grave's disease, autoimmune polyglandular syndromes (or polyglandular endocrinopathy syndromes), Type I diabetes also referred to as insulin- dependent diabetes mellitus (IDDM) and Sheehan's syndrome; autoimmune hepatitis, lymphoid interstitial pneumonitis (HIV), bronchiolitis obliterans (non-transplant) vs NSIP, Guillain-Barre' Syndrome, large vessel vasculitis (including polymyalgia rheumatica and giant cell (Takayasu's) arteritis), medium vessel vasculitis (including Kawasaki's disease and polyarteritis nodosa), polyarteritis nodosa (PAN) ankylosing spondylitis, Berger's disease (IgA nephropathy), rapidly progressive glomerulonephritis, primary biliary cirrhosis, Celiac sprue (gluten enteropathy), cryoglobulinemia, cryoglobulinemia associated with hepatitis, amyotrophic lateral sclerosis (ALS), coronary artery disease, familial Mediterranean fever, microscopic polyangiitis, Cogan's syndrome, Whiskott-Aldrich syndrome and thromboangiitis obliterans.

[00193] Rheumatoid arthritis (RA) is a chronic disease characterized by

inflammation of the joints, leading to swelling, pain, and loss of function. Patients having RA for an extended period usually exhibit progressive joint destruction, deformity, disability and even premature death.

[00194] Crohn's disease and a related disease, ulcerative colitis, are the two main disease categories that belong to a group of illnesses called inflammatory bowel disease (IBD). Crohn's disease is a chronic disorder that causes inflammation of the digestive or

gastrointestinal (Gl) tract. Although it can involve any area of the Gl tract from the mouth to the anus, it most commonly affects the small intestine and/or colon. In ulcerative colitis, the Gl involvement is limited to the colon. [00195] Crohn's disease may be characterized by antibodies against neutrophil antigens, i.e., the "perinuclear anti-neutrophil antibody" (pANCA), and Saccharomyces cervisiae, i.e. the "anti-Saccharomyces cervisiae antibody" (ASCA). Many patients with ulcerative colitis have the pANCA antibody in their blood, but not the ASCA antibody, while many Crohn's patients exhibit ASCA antibodies, and not pANCA antibodies. One method of evaluating Crohn's disease is using the Crohn's disease Activity Index (CDAI), based on 18 predictor variables scores collected by physicians. CDAI values of 150 and below are associated with quiescent disease; values above that indicate active disease, and values above 450 are seen with extremely severe disease [Best et al., "Development of a Crohn's disease activity index." Gastroenterology 70:439-444 (1976)]. However, since the original study, some researchers use a 'subjective value' of 200 to 250 as an healthy score.

[00196] Systemic Lupus Erythematosus (SLE) is an autoimmune disease caused by recurrent injuries to blood vessels in multiple organs, including the kidney, skin, and joints. In patients with SLE, a faulty interaction between T cells and B-cells results in the production of autoantibodies that attack the cell nucleus. There is general agreement that autoantibodies are responsible for SLE, so new therapies that deplete the B-cell lineage, allowing the immune system to reset as new B-cells are generated from precursors, would offer hope for long lasting benefit in SLE patients.

[00197] Multiple sclerosis (MS) is also an autoimmune disease. It is characterized by inflammation of the central nervous system and destruction of myelin, which insulates nerve cell fibers in the brain, spinal cord, and body. Although the cause of MS is unknown, it is widely believed that autoimmune T cells are primary contributors to the pathogenesis of the disease. However, high levels of antibodies are present in the cerebral spinal fluid of patients with MS, and some theories predict that the B-cell response leading to antibody production is important for mediating the disease.

[00198] Autoimmune thyroid disease results from the production of autoantibodies that either stimulate the thyroid to cause hyperthyroidism (Graves' disease) or destroy the thyroid to cause hypothyroidism (Hashimoto's thyroiditis). Stimulation of the thyroid is caused by autoantibodies that bind and activate the thyroid stimulating hormone (TSH) receptor.

Destruction of the thyroid is caused by autoantibodies that react with other thyroid antigens.

[00199] Sjogren's syndrome is an autoimmune disease characterized by destruction of the body's moisture-producing glands.

[00200] Immune thrombocytopenic purpura (ITP) is caused by autoantibodies that bind to blood platelets and cause their destruction. [00201] Myasthenia Gravis (MG) is a chronic autoimmune neuromuscular disorder characterized by autoantibodies that bind to acetylcholine receptors expressed at

neuromuscular junctions leading to weakness of the voluntary muscle groups.

[00202] Psoriasis, is characterized by autoimmune inflammation in the skin and also associated with arthritis in 30% of cases, scleroderma, inflammatory bowel disease, including Crohn's disease and ulcerative colitis,

[00203] Also contemplated is the treatment of idiopathic inflammatory myopathy (MM), including dermatomyositis (DM) and polymyositis (PM). Inflammatory myopathies have been categorized using a number of classification schemes. Miller's classification schema (Miller, Rheum Dis Clin North Am. 20:81 1-826, 1994) identifies 2 idiopathic inflammatory myopathies (MM), polymyositis (PM) and dermatomyositis (DM).

[00204] Polymyositis and dermatomyositis are chronic, debilitating inflammatory diseases that involve muscle and, in the case of DM, skin. These disorders are rare, with a reported annual incidence of approximately 5 to 10 cases per million adults and 0.6 to

3.2 cases per million children per year in the United States (Targoff, Curr Probl Dermatol. 1991 , 3:131-180). Idiopathic inflammatory myopathy is associated with significant morbidity and mortality, with up to half of affected adults noted to have suffered significant impairment (Gottdiener et al., Am J Cardiol. 1978, 41 :1 141-49). Miller {Rheum Dis Clin North Am. 1994, 20:81 1-826 and Arthritis and Allied Conditions, Ch. 75, Eds. Koopman and Moreland, Lippincott Williams and Wilkins, 2005) sets out five groups of criteria used to diagnose MM, i.e., Idiopathic Inflammatory Myopathy Criteria (IIMC) assessment, including muscle weakness, muscle biopsy evidence of degeneration, elevation of serum levels of muscle-associated enzymes, electromagnetic triad of myopathy, evidence of rashes in dermatomyositis, and also includes evidence of autoantibodies as a secondary criteria.

[00205] MM associated factors, including muscle-associated enzymes and autoantibodies include, but are not limited to, creatine kinase (CK), lactate dehydrogenase, aldolase, C-reactive protein, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and antinuclear autoantibody (ANA), myositis-specific antibodies (MSA), and antibody to extractable nuclear antigens.

[00206] The invention includes compositions comprising an anti-CD20 antibody or fragment and an anti-CD37 antibody or fragment. The invention includes a composition comprising an anti-CD20 antibody or fragment for administration to a patient in combination with an antibody that binds CD37 or a fragment thereof capable of binding CD37 for treatment of a B-cell malignancy or disorder. For instance, the invention includes a pharmaceutical composition comprising an anti-CD20 antibody or fragment and a pharmaceutically acceptable carrier for the express use in combination with an anti-CD37 antibody for the treatment of a B- cell malignancy or disorder. In one embodiment, the invention includes a pharmaceutical composition comprising obinutuzumab and a pharmaceutically acceptable carrier for the express use in combination with an anti-CD37 antibody or fragment for the treatment of a B-cell malignancy or disorder. In a particular embodiment, the invention includes a pharmaceutical composition comprising obinutuzumab and a pharmaceutically acceptable carrier for the express use in combination with TRU-016 for the treatment of a B-cell malignancy or disorder.

[00207] The invention includes a composition comprising an anti-CD37 antibody or antibody fragment for administration to a patient in combination with an anti-CD20 antibody or fragment for treatment of a B-cell malignancy or disorder. For instance, the invention includes a pharmaceutical composition comprising an anti-CD37 antibody and a pharmaceutically acceptable carrier for the express use in combination with an anti-CD20 antibody or fragment for the treatment of a B-cell malignancy or disorder. In this embodiment of the invention, the anti-CD37 antibody includes, for instance, the anti-CD37 antibodies disclosed herein (e.g., antibodies that are derived from or compete for binding to CD37 with G28-1 , MB371 , BL14, NMN46, IP024, HH1 , WR17, HD28, BI14, F93G6, RFB-7, Y29/55, MB-1 , M-B371 , IPO-24, S- B3 and K7153A) and the anti-CD20 antibody includes, for instance, the anti-CD20 antibodies disclosed herein (e.g. ofatumumab, veltuzumab, ocrelizumab and obinutuzumab as well as antibodies that are derived from or compete for binding to CD20 with rituximab, ofatumumab, veltuzumab, ocrelizumab and obinutuzumab).

[00208] In another embodiment, the invention includes methods of treating a patient suffering from a B-cell malignancy or disorder by administering to the patient obinutuzumab and a CD37 antibody or antibody fragment.

[00209] The invention includes compositions comprising fostamatinib disodium, an anti-CD37 antibody or fragment, and an anti-CD20 antibody or fragment. The invention includes a composition comprising fostamatinib disodium for administration to a patient in combination with an antibody that binds CD37 or a fragment thereof capable of binding CD37 and an antibody that binds CD20 or a fragment thereof capable of binding CD20 for treatment of a B-cell malignancy or disorder. For instance, the invention includes a pharmaceutical composition comprising fostamatinib and a pharmaceutically acceptable carrier for the express use in combination with an anti-CD37 antibody and an anti-CD20 antibody for the treatment of a B-cell malignancy or disorder.

[00210] The invention includes a composition comprising an anti-CD37 antibody or antibody fragment and an anti-CD20 antibody or antibody fragment for administration to a patient in combination with fostamatinib disodium for treatment of a B-cell malignancy or disorder. For instance, the invention includes a pharmaceutical composition comprising an anti-CD37 antibody, an anti-CD20 antibody and a pharmaceutically acceptable carrier for the express use in combination with fostamatinib for the treatment of a B-cell malignancy or disorder. In this embodiment of the invention, the anti-CD37 antibody includes, for instance, the anti-CD37 antibodies disclosed herein (e.g., antibodies that are derived from or compete for binding to CD37 with G28-1 , MB371 , BL14, NMN46, IP024, HH1 , WR17, HD28, BI14, F93G6, RFB-7, Y29/55, MB-1 , M-B371 , IPO-24, S-B3 and K7153A) and the anti-CD20 antibody includes, for instance, the anti-CD20 antibodies disclosed herein (e.g. ofatumumab, veltuzumab, ocrelizumab and obinutuzumab as well as antibodies that are derived from or compete for binding to CD20 with rituximab, ofatumumab, veltuzumab, ocrelizumab and obinutuzumab).

[00211] In another embodiment, the invention includes methods of treating a patient suffering from a B-cell malignancy or disorder by administering to the patient fostamatinib disodium, a CD37 antibody or antibody fragment, and a CD20 antibody or antibody fragment.

[00212] The invention includes compositions comprising PRT-062607 or PRT-318, an anti-CD37 antibody or fragment, and an CD20 antibody or fragment. The invention includes a composition comprising PRT-062607 or PRT-318 for administration to a patient in combination with an antibody that binds CD37 or a fragment thereof capable of binding CD37 and an antibody that binds CD20 or a fragment thereof capable of binding CD20 for treatment of a B-cell malignancy or disorder. For instance, the invention includes a pharmaceutical composition comprising PRT-062607 or PRT-318 and a pharmaceutically acceptable carrier for use in combination with an anti-CD37 antibody and an anti-CD20 antibody for the treatment of a B-cell malignancy or disorder.

[00213] The invention includes a composition comprising an anti-CD37 antibody or antibody fragment and an anti-CD20 antibody or antibody fragment for administration to a patient in combination with a SYK inhibitor such as PRT-062607 or PRT318 for treatment of a B-cell malignancy or disorder. For instance, the invention includes a pharmaceutical composition comprising an anti-CD37 antibody, an anti-CD20 antibody, and a pharmaceutically acceptable carrier for the express use in combination with PRT-62607 or PRT318 for the treatment of a B-cell malignancy or disorder. In this embodiment of the invention, the anti- CD37 antibody includes, for instance, the anti-CD37 antibodies disclosed herein (e.g., antibodies that are derived from or compete for binding to CD37 with G28-1 , MB371 , BL14, NMN46, IP024, HH1 , WR17, HD28, BI14, F93G6, RFB-7, Y29/55, MB-1 , M-B371 , IPO-24, S- B3 and K7153A) and the anti-CD20 antibody includes, for instance, the anti-CD20 antibodies disclosed herein (e.g. ofatumumab, veltuzumab, ocrelizumab and obinutuzumab as well as antibodies that are derived from or compete for binding to CD20 with rituximab, ofatumumab, veltuzumab, ocrelizumab and obinutuzumab).

[00214] In another embodiment, the invention includes methods of treating a patient suffering from a B-cell malignancy or disorder by administering to the patient a SYK inhibitor such as PRT-062607 or PRT-318, a CD37 antibody or antibody fragment and a CD20 antibody or antibody fragment.

[00215] The invention includes compositions comprising a BTK inhibitor that irreversibly binds BTK, an anti-CD37 antibody or fragment, and an anti-CD20 antibody or fragment. For instance, in one embodiment, the compositions and methods of treatment include a BTK inhibitor that covalently binds a cysteine residue on BTK. In this embodiment, a Michael moiety on the BTK inhibitor (e.g., acrylamide, vinyl sulfonamide, proparygylamide) binds cysteine residue 481 on BTK. BTK inhibitors that act through this mechanism of action include, for instance, ibrutinib and AVL-292. The invention includes a composition comprising ibrutinib or AVL-292 for administration to a patient in combination with an antibody that binds CD37 or a fragment thereof capable of binding CD37 and an antibody that binds CD20 or a fragment thereof capable of binding CD20 for treatment of a B-cell malignancy or disorder. For instance, the invention includes a pharmaceutical composition comprising a BTK inhibitor with the functional properties of ibrutinib or AVL-292 and a pharmaceutically acceptable carrier for express use in combination with an anti-CD37 antibody and an anti-CD20 antibody for the treatment of a B-cell malignancy or disorder.

[00216] The invention includes a composition comprising an anti-CD37 antibody or antibody fragment and an anti-CD20 antibody or antibody fragment for administration to a patient in combination with a BTK inhibitor such as ibrutinib or AVL-292 for treatment of a B-cell malignancy or disorder. For instance, the invention includes a pharmaceutical composition comprising an anti-CD37 antibody, an anti-CD20 antibody and a pharmaceutically acceptable carrier for the express use in combination with a BTK inhibitor such as ibrutinib or AVL-292 for the treatment of a B-cell malignancy or disorder. In this embodiment of the invention, the anti- CD37 antibody includes, for instance, the anti-CD37 antibodies disclosed herein (e.g., antibodies that are derived from or compete for binding to CD37 with G28-1 , MB371 , BL14, NMN46, IP024, HH1 , WR17, HD28, BI14, F93G6, RFB-7, Y29/55, MB-1 , M-B371 , IPO-24, S- B3 and K7153A) and the anti-CD20 antibody includes, for instance, the anti-CD20 antibodies disclosed herein (e.g. ofatumumab, veltuzumab, ocrelizumab and obinutuzumab as well as antibodies that are derived from or compete for binding to CD20 with rituximab, ofatumumab, veltuzumab, ocrelizumab and obinutuzumab). [00217] In another embodiment, the invention includes methods of treating a patient suffering from a B-cell malignancy or disorder by administering to the patient a BTK inhibitor such as ibrutinib or AVL-292, a CD37 antibody or antibody fragment, and a CD20 antibody or antibody fragment.

[00218] The invention includes administering other BTK inhibitors to a patient in combination with a CD37 antibody or antibody fragment and a CD20 antibody or antibody fragment. For instance, in one embodiment, the invention includes a composition comprising a BTK inhibitor that non-covalently binds BTK, an anti-CD37 antibody or antibody fragment and an anti-CD20 antibody or antibody fragment. For instance, in one embodiment, the invention includes compositions and methods comprising a BTK inhibitor that is reversible and stabilizes an inactive conformation of BTK.

[00219] In another embodiment, the invention includes compositions and methods of treating a patient suffering from a B-cell malignancy or disorder comprising administering BTK inhibitor such as ONO-WG-307 or GDC-0834 to a patient in combination with a CD37 antibody or antibody fragment and a CD20 antibody or antibody fragment.

[00220] In another embodiment, the compositions and methods of the invention do not include a BTK inhibitor that forms a non-covalent bond with BTK and / or stabilizes an inactive conformation of the Btk enzyme. For instance, in one embodiment, the compositions and methods of the invention do not include BTK inhibitor CG11746.

[00221] The invention includes compositions comprising a CXCR4 antagonist (e.g., plerixafor, a T140 analog or KRH-3955), an anti-CD37 antibody or fragment and a CD20 antibody or antibody fragment. The invention includes a composition comprising plerixafor, a T140 analog or KRH-3955 for administration to a patient expressly in combination with an antibody that binds CD37 or a fragment thereof capable of binding CD37 and an antibody that binds CD20 or a fragment thereof capable of binding CD20 for treatment of a B-cell malignancy or disorder. For instance, the invention includes a pharmaceutical composition comprising plerixafor, a T140 analog or KRH-3955 and a pharmaceutically acceptable carrier for use in combination with an anti-CD37 antibody and an anti-CD20 antibody for the treatment of a B-cell malignancy or disorder.

[00222] The invention includes a composition comprising an anti-CD37 antibody or antibody fragment and an anti-CD20 antibody or antibody fragment for administration to a patient in combination with a CXCR4 antagonist such as plerixafor, T140 analog, or KRH-3955 for treatment of a B-cell malignancy or disorder. For instance, the invention includes a pharmaceutical composition comprising an anti-CD37 antibody, an anti-CD20 antibody and a pharmaceutically acceptable carrier for the express use in combination with a CXCR4 antagonist such as plerixafor, T140 analog, or KRH-3955 for the treatment of a B-cell malignancy or disorder. In this embodiment of the invention, the anti-CD37 antibody includes, for instance, the anti-CD37 antibodies disclosed herein (e.g., antibodies that are derived from or compete for binding to CD37 with G28-1 , MB371 , BL14, NMN46, IP024, HH1 , WR17, HD28, BI14, F93G6, RFB-7, Y29/55, MB-1 , M-B371 , IPO-24, S-B3 and K7153A) and the anti-CD20 antibody includes, for instance, the anti-CD20 antibodies disclosed herein (e.g. ofatumumab, veltuzumab, ocrelizumab and obinutuzumab as well as antibodies that are derived from or compete for binding to CD20 with rituximab, ofatumumab, veltuzumab, ocrelizumab and obinutuzumab).

[00223] In another embodiment, the invention includes methods of treating a patient suffering from a B-cell malignancy or disorder by administering to the patient a CXCR4 antagonist such as plerixafor, T140 analog or KRH-3955, a CD37 antibody or antibody fragment and a CD20 antibody or antibody fragment.

[00224] The invention includes compositions comprising idelalisib, an anti-CD37 antibody or fragment, and an CD20 antibody or fragment. For example, the invention includes compositions comprising idelalisib, an anti-CD37 antibody or fragment, and obinutuzumab. The invention includes a composition comprising idelalisib for administration to a patient in combination with an antibody that binds CD37 or a fragment thereof capable of binding CD37 and an antibody that binds CD20 or a fragment thereof capable of binding CD20 for treatment of a B-cell malignancy or disorder. For instance, the invention includes a pharmaceutical composition comprising idelalisib and a pharmaceutically acceptable carrier for use in combination with an anti-CD37 antibody and an anti-CD20 antibody for the treatment of a B-cell malignancy or disorder.

[00225] The invention includes a composition comprising an anti-CD37 antibody or antibody fragment and an anti-CD20 antibody or antibody fragment for administration to a patient in combination with a PI3K inhibitor such as idelalisib for treatment of a B-cell malignancy or disorder. For instance, the invention includes a pharmaceutical composition comprising an anti-CD37 antibody, an anti-CD20 antibody, and a pharmaceutically acceptable carrier for the express use in combination with idelalisib for the treatment of a B-cell malignancy or disorder. In this embodiment of the invention, the anti-CD37 antibody includes, for instance, the anti-CD37 antibodies disclosed herein (e.g., antibodies that are derived from or compete for binding to CD37 with G28-1 , MB371 , BL14, NMN46, IP024, HH1 , WR17, HD28, BI14, F93G6, RFB-7, Y29/55, MB-1 , M-B371 , IPO-24, S-B3 and K7153A) and the anti-CD20 antibody includes, for instance, the anti-CD20 antibodies disclosed herein (e.g. ofatumumab, veltuzumab, ocrelizumab and obinutuzumab as well as antibodies that are derived from or compete for binding to CD20 with rituximab, ofatumumab, veltuzumab, ocrelizumab and obinutuzumab).

[00226] In another embodiment, the invention includes methods of treating a patient suffering from a B-cell malignancy or disorder by administering to the patient a PI3K inhibitor such as idelalisib, a CD37 antibody or antibody fragment and a CD20 antibody or antibody fragment such as obinutuzumab.

[00227] In one embodiment of the invention, administration of a BCR antagonist, an anti-CD37 antibody or antibody fragment and an anti-CD20 antibody or antibody fragment depletes B cells in a patient with a B-cell malignancy or disorder. Administered alone, certain BCR antagonists such as ibrutinib are not believed to deplete B-cells.

[00228] In one embodiment, administration of a CD37 antibody or fragment and a CD20 antibody or fragment prevents or reduces the likelihood of clonal expansion of malignant B-cells such as CLL cells. In another embodiment, administration of a CD37 antibody or fragment, a CD20 antibody or fragment and a BCR antagonist (e.g., a BTK inhibitor such as ibrutinib or a PI3K inhibitor (e.g., idelalisib) prevents or reduces the likelihood of clonal expansion of malignant B-cells such as CLL cells. In yet another embodiment of the invention, administration of a CD37 antibody and a CD20 antibody or alternatively, administration of a CD37 antibody, a CD20 antibody and a BCR antagonist (e.g., a BTK inhibitor such as ibrutinib or a PI3K inhibitor (e.g., idelalisib) promotes or increases B-cell apoptosis (e.g., apoptosis of activated B cells or malignant B-cells), blocks or inhibits B-cell proliferation and/or prevents or reduces the ability of malignant cells to respond to survival stimuli of the microenvironment as compared to the administration of an anti-CD37 antibody alone, an anti-CD20 antibody alone, a BCR antagonist alone, or a kinase inhibitor alone.

[00229] In one embodiment, the combination of the anti-CD37 antibody or antibody fragment and anti-CD20 antibody or antibody fragment synergistically prevents or reduces B cell expansion; synergistically promotes or increases apoptosis of B cells; and/or synergistically blocks or inhibits B cell proliferation or survival at particular dose levels. In another

embodiment, the combination of the anti-CD37 antibody or fragment, anti-CD20 antibody or fragment and BCR antagonist (e.g., BTK inhibitor such as ibrutinib) synergistically prevents or reduces B cell expansion; synergistically promotes or increases apoptosis of B cells; and/or synergistically blocks or inhibits B cell proliferation or survival at particular dose levels. In yet another embodiment, the combination of the anti-CD37 antibody or fragment, anti-CD20 antibody or fragment and kinase inhibitor (e.g., BTK inhibitor such as ibrutinib, SYK inhibitor such as fostamatinib, PI3K inhibitor such as idelalisib) synergistically prevents or reduces B cell expansion; synergistically promotes or increases apoptosis of B cells; and/or synergistically blocks or inhibits B cell proliferation or survival at particular dose levels. For example, in one embodiment, the combinations of the invention exhibit a synergistic effect in the 25% to 95% effective dose range. In a further embodiment, the combinations exhibit synergistic effect in the 45% to 90% effective dose range.

[00230] It is contemplated the anti-CD37 antibody or fragment and anti-CD20 antibody or fragment may be given simultaneously in the same formulation. Alternatively, the anti-CD37 antibody or fragment and anti-CD20 antibody or fragment are administered in a separate formulation but concurrently, with concurrently referring to agents given within about 30 minutes of each other. The BCR antagonist or kinase inhibitor may be given simultaneously in the same formulation along with the anti-CD37 and anti-CD20 antibodies or fragments. Alternatively, the anti-CD37 antibody or fragment, anti-CD20 antibody or fragment and BCR antagonist or kinase inhibitor are administered in a separate formulation but concurrently, with concurrently referring to agents given within about 30 minutes of each other.

[00231] In another aspect, the CD20 antibody or antibody fragment is administered prior to administration of the anti-CD37 antibody or antibody fragment. Prior administration includes, for instance, administration of the CD20 antibody or antibody fragment within the range of about one week prior to treatment with the CD37 antibody or fragment to up to 30 minutes before administration of the CD37 antibody or fragment. Prior administration may also include, for instance, administration of the CD20 antibody or antibody fragment within the range of about 2 weeks prior to treatment with the CD37 antibody or fragment to up to 30 minutes before administration of the CD37 antibody or fragment so long as the CD20 antibody or antibody fragment is still asserting at least one activity in the body. In yet another embodiment, prior administration may include administration of a CD20 antibody or antibody fragment within the range of about 4 weeks or about three weeks prior to treatment of CD37 antibody or fragment to up to 30 minutes before administration of the CD37 antibody or fragment so long as the CD20 antibody or antibody fragment is still asserting at least one activity on the body. In another embodiment, the CD20 antibody or antibody fragment is administered prior to administration of the anti-CD37 antibody or antibody fragment, and administration of an anti- CD37 antibody or antibody fragment occurs during a period of time when one or more effects of the CD20 antibody or fragment are being asserted on the body.

[00232] In another embodiment of the invention, the CD20 antibody or antibody fragment is administered subsequent to administration of the anti-CD37 antibody or antibody fragment. Subsequent administration includes, for instance, administration from 30 minutes after CD37 antibody treatment up to about one week after CD37 antibody administration. In another embodiment, subsequent administration includes administration from 30 minutes after CD37 antibody treatment up to about two weeks after CD37 antibody treatment so long as at least one effect of the anti-CD37 antibody is still exerted on the body. In yet another embodiment, subsequent administration includes administration from about 30 minutes after CD37 antibody treatment up to about three weeks or up to about four weeks after CD37 antibody treatment so long as at least one effect of the anti-CD37 antibody is still exerted in the body.

[00233] In one embodiment of the invention, the CD20 antibody or antibody fragment is administered subsequent to administration of a course of treatment comprising an anti-CD37 antibody or antibody fragment. In this embodiment, the CD20 antibody or antibody fragment is administered during a period of time that overlaps with one or more effects of the anti-CD37 antibody or antibody fragment, including, but not limited to, B-cell depletion or reduced B-cell levels. In one embodiment of the invention, the CD20 antibody or antibody fragment is administered within about 6 months from treatment with an anti-CD37 antibody or antibody fragment. In another embodiment, the CD20 antibody or antibody fragment is administered within at least about 4, within at least about 3, within at least about 3 or within at least about 1 month from the last date of anti-CD37 antibody or antibody fragment treatment.

[00234] In one embodiment of the invention, the CD20 antibody or antibody fragment and anti-CD37 antibody or antibody fragment are administered such that both agents exert action on the body at the same time. In another embodiment of the invention, the CD20 antibody or antibody fragment is administered at about the time of the end of the half-life of the anti-CD37 antibody or antibody fragment. In another embodiment of the invention, the anti- CD37 antibody or antibody fragment is administered at about the time of the end of the half-life of the CD20 antibody or antibody fragment.

[00235] In the embodiment, where the methods comprise administration of a CD37 antibody, a CD20 antibody and a BCR antagonist or kinase inhibitor, the sequence of administration of the three agents can vary. For instance, in one embodiment, all three agents may be administered simultaneously in the same formulation. Alternatively, the three agents may be administered in separate formulations but concurrently, with concurrently referring to agents given within about 30 minutes of each other.

[00236] In another embodiment, the BCR antagonist or kinase inhibitor may be administered prior to administration of the CD37 antibody or fragment and CD20 antibody or fragment. In this embodiment, the CD20 antibody or fragment may be administered concurrently with, prior to or subsequent to administration of the CD37 antibody or fragment. In yet another embodiment, the BCR antagonist or kinase inhibitor may be administered subsequent to administration of the CD37 antibody or fragment and CD20 antibody or fragment. In this embodiment, the CD20 antibody or fragment may be administered concurrently with, prior to or subsequent to administration of the CD37 antibody or fragment.

[00237] In another embodiment, the BCR antagonist or kinase inhibitor may be administered subsequent to administration of the CD37 antibody or fragment but prior to administration of the CD20 antibody or fragment. In yet another embodiment, the BCR antagonist or kinase inhibitor may be administered prior to administration of the CD37 antibody or fragment but subsequent to administration of the CD20 antibody or fragment.

[00238] Prior administration includes, for instance, administration of the first agent within the range of about one week to up to 30 minutes prior to administration of the second agent. Prior administration may also include, for instance, administration of the first agent within the range of about 2 weeks to up to 30 minutes prior to administration of the second agent so long as the first agent is still asserting at least one activity in the body. In yet another embodiment, prior administration may include administration of the first agent within the range of about 4 weeks or about three weeks to up to 30 minutes prior to administration of the second agent so long as the first agent is still asserting at least one activity on the body. In another embodiment, the first agent is administered prior to administration of the second agent, and administration of the second agent occurs during a period of time when one or more effects of the first agent are being asserted on the body. For instance, it is contemplated that one or more antibodies or fragments of the invention can be administered prior to the time when Syk , Btk.and / or PI3K levels increase to pre-treatment levels. In another embodiment, it is contemplated that one or more antibodies or fragments of the invention are administered when CXCR4 expression levels are about the same as or within 10% of normal levels (i.e., levels of a person not suffering from a B-cell malignancy). In another embodiment, one or more antibodies or fragments of the invention are administered at a time when malignant B-cells are still at high levels in peripheral blood (and prior to increased homing to lymphoid tissues as is associated with decreased CXCR4 levels).

[00239] Subsequent administration includes, for instance, administration of the second agent from 30 minutes to about one week after administration of the first agent. In another embodiment, subsequent administration includes administration from 30 minutes to about two weeks after administration of the first agent so long as at least one effect of the first agent is still exerted on the body. In yet another embodiment, subsequent administration includes administration from about 30 minutes to about three weeks or up to about four weeks after administration of the first agent so long as at least one effect of the first agent is still exerted in the body. [00240] In one embodiment of the invention, the BCR pathway antagonist or kinase inhibitor is administered subsequent to administration of a course of treatment comprising one or more antibodies or fragments of the invention. In this embodiment, the BCR pathway antagonist or kinase inhibitor is administered during a period of time that overlaps with one or more effects of the antibodies or fragments of the invention, including, but not limited to, B-cell depletion or reduced B-cell levels. In one embodiment of the invention, the BCR pathway antagonist or kinase inhibitor is administered within about 6 months from treatment with one or more antibodies or fragments of the invention. In another embodiment, the BCR pathway antagonist or kinase inhibitor is administered within at least about 4, within at least about 3, or within at least about 1 month from the last date of antibody treatment.

[00241] In one embodiment of the invention, the BCR pathway antagonist or kinase inhibitor, a CD37 antibody or fragment and a CD20 antibody or fragment are administered such that all three agents exert action on the body at the same time. In another embodiment of the invention, the BCR pathway antagonist or kinase inhibitor is administered at about the time of the end of the half-life of one or more antibodies or fragments of the invention. In another embodiment of the invention, one or more antibodies or fragments of the invention are administered at about the time of the end of the half-life of the BCR pathway antagonist or kinase inhibitor.

[00242] It is further contemplated that administration of a CD20 antibody or fragment and a CD37 antibody or fragment may be performed in conjunction with the administration of a chemotherapeutic agent, a radiotherapeutic agent or radiation therapy. Alternatively, administration of a CD20 antibody or fragment, a CD37 antibody or fragment and a BCR antagonist or administration of a CD20 antibody or fragment, a CD37 antibody or fragment and a kinase inhibitor may be performed in conjunction with the administration of a

chemotherapeutic agent, a radiotherapeutic agent or radiation therapy. The chemotherapeutic agent, radiotherapeutic agent or radiation therapy administered in combination with the therapeutic agents of the invention is administered as determined by the treating physician, and at doses typically given to patients being treated for cancer.

[00243] The amounts of a BCR pathway inhibitor or kinase inhibitor, an anti-CD37 antibody or antibody fragment or an anti-CD20 antibody or antibody fragment in a given dose will vary according to the size of the individual to whom the therapy is being administered as well as the characteristics of the disorder being treated. In exemplary treatments, it may be necessary to administer about 1 mg/day, about 5 mg/day, about 10 mg/day, about 20 mg/day, about 50 mg/day, about 75 mg/day, about 100 mg/day, about 150 mg/day, about 200 mg/day, about 250 mg/day, about 500 mg/day or about 1000 mg/day. The doses may also be administered based on weight of the patient, at a dose of about 0.01 to about 50 mg/kg. In a related embodiment, the CD37 antibody, CD20 antibody, BCR antagonist or kinase inhibitor may be administered in a dose range of about 0.015 to about 30 mg/kg. In an additional embodiment, the CD37 antibody, CD20 antibody, BCR antagonist or kinase inhibitor is administered in a dose of about 0.015, about 0.05, about 0.15, about 0.5, about 1.5, about 5, about 15 or about 30 mg/kg.

[00244] In one embodiment, an anti-CD37 antibody or antibody fragment is administered in a dose range of about 0.01 to about 50 mg/kg. In another embodiment, an anti- CD37 antibody is administered in a dose range of about 0.015 to about 30 mg/kg. In yet another embodiment, an anti-CD37 antibody or antibody fragment is administered at a dose range of about 6, 10, or 20 mg/kg. In one embodiment, about 1000 mg of an anti-CD20 antibody, such as obinutuzumab, is administered to the patient in combination with 6, 10, or 20 mg/kg of anti-CD37 antibody. In one embodiment, about 500 mg of an anti-CD20 antibody, such as obinutuzumab, is administered to the patient in combination with 6, 10, or 20 mg/kg of anti-CD37 antibody.

[00245] These compositions may be administered in a single dose or in multiple doses. Standard dose-response studies, first in animal models and then in clinical testing, reveal optimal dosages for particular disease states and patient populations.

[00246] In one embodiment of the invention, the administration of a CD37 antibody and a CD20 antibody decreases the B-cell population by at least 20% after the first dose of combined therapeutics. In another embodiment, the administration of a CD37 antibody, a CD20 antibody and a BCR antagonist or the administration of a CD37 antibody, a CD20 antibody and a kinase inhibitor decreases the B-cell population by at least 20% after the first dose of combined therapeutics. In one embodiment, the B-cell population is decreased by at least about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90 or about 100%. B-cell reduction is defined as a decrease in absolute B-cell count below the lower limit of the normal range. B-cell recovery is defined as a return of absolute B-cell count to either of the following: 70% of subject's baseline value or normal range.

[00247] The administration of one or more BCR antagonists or kinase inhibitors and one or more anti-CD37 and anti-CD20 antibodies or antibody fragments may also result in enhanced apoptosis in particular B-cell subsets. Apoptosis refers to the induction of programmed cell death of a cell, manifested and assessed by DNA fragmentation, cell shrinkage, cell fragmentation, formation of membrane vesicles, or alteration of membrane lipid composition as assessed by annexin V staining. [00248] Further, the administration of a CD37 antibody and CD20 antibody results in desired clinical effects in the disease or disorder being treated. In another embodiment, the administration of a CD37 antibody, CD20 antibody and BCR antagonist or the administration of a CD37 antibody, CD20 antibody and kinase inhibitor results in desired clinical effects in the disease or disorder being treated. For example, in patients affected by rheumatoid arthritis, in one aspect the administration improves the patient's condition by a clinically significant amount [e.g., achieves the American College of Rheumatology Preliminary Detection of Improvement (ACR20)], and/or an improvement of 20% in tender and swollen joint and 20% improvement in 3/5 remaining ACR measures (Felson et al., Arthritis Rheum. 1995, 38:727-35). Biological measures for improvement in an RA patient after administration of the combinations of the invention include measurement of changes in cytokine levels, measured via protein or RNA levels. Cytokines of interest include, but are not limited to, TNF-a, IL-1 , interferons, Blys, and APRIL. Cytokine changes may be due to reduced B cell numbers or decreased activated T cells. In RA patients, markers relevant to bone turnover (bone resorption or erosion) are measured before and after administration of the combinations of the invention. Relevant markers include, but are not limited to, alkaline phosphatase, osteocalcin, collagen breakdown fragments, hydroxyproline, tartrate-resistant acid phosphatase, and RANK ligand (RANKL). Other readouts relevant to the improvement of RA include measurement of C reactive protein (CRP) levels, erythrocyte sedimentation rate (ESR), rheumatoid factor, CCP (cyclic citrullinated peptide) antibodies and assessment of systemic B cell levels and lymphocyte count via flow cytometry. Specific factors can also be measured from the synovium of RA patients, including assessment of B-cell levels in synovium from synovium biopsy, levels of RANKL and other bone factors and cytokines set out above.

[00249] In a related aspect, the effects of combination administration on other diseases is measured according to standards known in the art. For example, it is contemplated that Crohn's disease patients treated according to the invention achieve an improvement in Crohn's Disease Activity Index (CDAI) in the range of about 50 to about 70 units, wherein remission is at 150 units (Simonis et al, Scand. J Gastroent. 1998, 33:283-8). A score of 150 or 200 is considered normal, while a score of 450 is considered a severe disease score. It is further desired that administration of the combinations of the invention results in a reduction in perinuclear anti-neutrophil antibody (pANCA) and anti-Saccharomyces cervisiae antibody (ASCA) in individuals affected by inflammatory bowel disease.

[00250] It is further contemplated that adult and juvenile myositis patients treated according to the invention achieve an improvement in core set of evaluations, such as 3 out of 6 of the core set measured improved by approximately 20%, with not more than 2 of the core measurements worse by approximately 25% (see Rider et al., Arthritis Rheum. 2004, 50:2281- 90).

[00251] It is further contemplated that SLE patients treated according to the invention achieve an improvement in Systemic Lupus Activity Measure (SLAM) or SLE Disease Activity Index (SLEDAI) score of at least 1 point (Gladman et al, J Rheumatol 1994, 21 :1468- 71 ) (Tan et al., Arthritis Rheum. 1982, 25:1271-7). A SLAM score of >5, or SLEDAI score >2, is considered clinically active disease. A response to treatment may be defined as improvement or stabilization over the in 2 disease activity measures (the SLE Disease Activity Index

[SLEDAI] and the Systemic Lupus Activity Measure) and 2 quality of life measures (patient's global assessment and the Krupp Fatigue Severity Scale) (Petri et al., Arthritis Rheum. 2004, 50:2858-68.) It is further contemplated that administration of the combinations of the invention to SLE patients results in a reduction in anti-double-stranded DNA antibodies. Alternatively, improvement may be gauged using the British Isles Lupus Assessment Group Criteria (BILAG).

[00252] It is further contemplated that multiple sclerosis patients treated according to the invention achieve an improvement in clinical score on the Kurtzke Expanded Disability status scale (EDSS) (Kurtzke, F., Neurology 1983, 33:1444-52) of at least 0.5, or a delay in worsening of clinical disease of at least 1.0 on the Kurtzke scale (Rudick et al., Neurology 1997, 49:358-63).

[00253] It is further contemplated that patients suffering from MM receiving a CD37 antibody and CD20 antibody or a CD37 antibody, CD20 antibody and BCR antagonist achieve a reduction in at least one of five criteria set out in the Idiopathic Inflammatory Myopathy Criteria (IIMC) assessment (Miller, F., supra). It is further contemplated that administration to MM patients results in a reduction in MM associated factors selected from the group consisting of creatine kinase (CK), lactate dehydrogenase, aldolase, C-reactive protein, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and antinuclear autoantibody (ANA), myositis-specific antibodies (MSA), and antibody to extractable nuclear antigens. Alternatively, patients meet 3 out of 6 of the criteria set out in Rider et al., Arthritis Rheum., 50(7):2281-2290 (2004), with worsening in no more than 2 criteria.

[00254] In some embodiments, patients suffering from a B cell malignancy receive treatment according to the invention and demonstrate an overall beneficial response to the treatment, based on clinical criteria well-known and commonly used in the art, and as described below, such as a decrease in tumor size, decrease in tumor number and/or an improvement in disease symptoms.

[00255] Exemplary clinical criteria are provided by the U.S. National Cancer Institute

(NCI), which has divided some of the classes of cancers into the clinical categories of "indolent" and "aggressive" lymphomas. Indolent lymphomas include follicular cell lymphomas, separated into cytology "grades," diffuse small lymphocytic lymphoma/chronic lymphocytic leukemia (CLL), lymphoplasmacytoid/Waldenstrom's Macroglobulinemia, Marginal zone lymphoma and Hairy cell leukemia. Aggressive lymphomas include diffuse mixed and large cell lymphoma, Burkitt's lymphoma/diffuse small non-cleaved cell lymphoma, Lymphoblastic lymphoma, Mantle cell lymphoma and AIDS-related lymphoma. In some cases, the International Prognostic Index (IPI) is used in cases of aggressive and follicular lymphoma. Factors to consider in the IPI include Age (<60 years of age versus >60 years of age), serum lactate dehydrogenase (levels normal versus elevated), performance status (0 or 1 versus 2-4) (see definition below), disease stage (I or II versus III or IV), and extranodal site involvement (0 or 1 versus 2-4). Patients with 2 or more risk factors have less than a 50% chance of relapse-free and overall survival at 5 years.

[00256] Performance status in the aggressive IPI is defined as follows: Grade Description: 0 Fully active, able to carry on all pre-disease performance without restriction; 1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; 2 Ambulatory and capable of all selfcare but unable to carry out any work activities, up to and about more than 50% of waking hours; 3 Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours; 4 Completely disabled, unable to carry on any selfcare, totally confined to bed or chair; and, 5 Dead. (See., The International Non-Hodgkin's Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin's lymphoma. N Engl J Med. 329:987-94, 1993)

[00257] Typically, the grade of lymphoma is clinically assessed using the criterion that low-grade lymphoma usually presents as a nodal disease and is often indolent or slow- growing. Intermediate- and high-grade disease usually presents as a much more aggressive disease with large extranodal bulky tumors.

[00258] The Ann Arbor classification system is also used to measure progression of tumors, especially non-Hodgkin's lymphomas. In this system, stages I, II, III, and IV of adult NHL can be classified into A and B categories depending on whether the patient has well- defined generalized symptoms (B) or not (A). The B designation is given to patients with the following symptoms: unexplained loss of more than 10% body weight in the 6 months prior to diagnosis, unexplained fever with temperatures above 38° C. and drenching night sweats. Definitions of the stages are as follows: Stage l-involvement of a single lymph node region or localized involvement of a single extralymphatic organ or site. Stage I l-involvement of two or more lymph node regions on the same side of the diaphragm or localized involvement of a single associated extralymphatic organ or site and its regional lymph nodes with or without other lymph node regions on the same side of the diaphragm. Stage Ill-involvement of lymph node regions on both sides of the diaphragm, possibly accompanying localized involvement of an extralymphatic organ or site, involvement of the spleen, or both. Stage IV-disseminated (multifocal) involvement of one or more extralymphatic sites with or without associated lymph node involvement or isolated extralymphatic organ involvement with distant (non-regional) nodal involvement. For further details, see The International Non-Hodgkin's Lymphoma Prognostic Factors Project: A predictive model for aggressive non-Hodgkin's lymphoma, New England J. Med. (1993) 329:987-994.

[00259] In one aspect, a therapeutic effect of the methods according to the invention is determined by the level of response, for example a partial response is defined as tumor reduction to less than one-half of its original size. A complete response is defined as total elimination of disease confirmed by clinical or radiological evaluation. In one embodiment, the individual receiving treatment according to the invention demonstrates at least a partial response to treatment.

[00260] According to the Cheson criteria for assessing NHL developed in collaboration with the National Cancer Institute (Cheson et al., J Clin Oncol. 1999, 17:1244; Grillo-Lopez et al., Ann Oncol. 2000, 1 1 :399-408), a complete response is obtained when there is a complete disappearance of all detectable clinical and radiographic evidence of disease and disease-related symptoms, all lymph nodes have returned to normal size, the spleen has regressed in size, and the bone marrow is cleared of lymphoma. In one embodiment of the invention, administration of a therapeutically effective dose of a CD37 antibody and CD20 antibody or a therapeutically effective dose of a CD37 antibody, CD20 antibody and BCR antagonist to a patient suffering with NHL results in a complete response. In another embodiment of the invention, administration of a therapeutically effective dose of a CD37 antibody and CD20 antibody or a therapeutically effective dose of a CD37 antibody,CD20 antibody and BCR antagonist (e.g., a BTK inhibitor such as ibrutinib or AVL-292) to patients with NHL results in a complete response rate in at least about 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% or more patients.

[00261] An unconfirmed complete response is obtained when a patient shows complete disappearance of the disease and the spleen regresses in size, but lymph nodes have regressed by more than 75% and the bone marrow is indeterminate. An unconfirmed complete response meets and exceeds the criteria for partial response. An overall response is defined as a reduction of at least 50 percent in overall tumor burden.

[00262] Similar criteria have been developed for various other forms of cancers or hyperproliferative diseases and are readily available to a person of skill in the art. See, e.g., Cheson et al., Clin Adv Hematol Oncol. 2006, 4:4-5, which describes criteria for assessing CLL; Cheson et al., J Clin Oncol. 2003, 21 :4642-9, which describes criteria for AML; Cheson et al., Blood 2000, 96:3671-4, which describes criteria for myelodysplastic syndromes.

[00263] In another aspect, a therapeutic response in patients having a B cell malignancy is demonstrated as a slowing of disease progression compared to patients not receiving therapy. Measurement of slowed disease progression or any of the above factors may be carried out using techniques well-known in the art, including bone scan, CT scan, gallium scan, lymphangiogram, MRI, PET scans, ultrasound, and the like. In one embodiment of the invention, administration of the combinations of the invention to a patient in need slows disease progression as compared to a patient receiving anti-CD37 antibody monotherapy, anti- CD20 monotherapy, BCR antagonist monotherapy or kinase inhibitor monotherapy.

[00264] It will also be apparent that dosing may be modified if traditional therapeutics are administered in combination with the anti-CD37 antibodies or fragments, anti- CD20 antibodies or fragments and BCR antagonists or kinase inhibitors of the invention.

[00265] As an additional aspect, the invention includes kits which comprise one or more compounds or compositions useful in the methods of the invention packaged in a manner which facilitates their use to practice methods of the invention. In a simplest embodiment, such a kit includes a compound or composition described herein as useful for practice of a method of the invention packaged in a container such as a sealed bottle or vessel, with a label affixed to the container or included in the package that describes use of the compound or composition to practice the method of the invention. For instance, the invention includes a kit comprising an anti-CD37 antibody or antibody fragment with a label for use for treatment of a B-cell malignancy or disorder in combination with an anti-CD20 antibody or antibody fragment (e.g. obinutuzumab) and further in combination with a BCR antagonist (e.g., BTK inhibitor, SYK inhibitor, PI3K inhibitor, or CXCR4 antagonist). In one embodiment, the kit comprises an anti- CD37 antibody packaged with a pharmaceutically acceptable carrier, diluent or excipient and packaged with written directions for use in combination with an anti-CD20 antibody or antibody fragment (e.g. obinutuzumab) and further in combination with a BCR antagonist or kinase inhibitor for treatment of a B cell malignancy. In this embodiment, the written directions may include dosage regimens for anti-CD37 and anti-CD20 antibody combination therapy or anti- CD37 antibody, anti-CD20 antibody and BTK inhibitor (e.g., ibrutinib, AVL-292, or ONO-WG- 307) combination therapy. In another embodiment, a kit contains a pharmaceutical composition comprising a BCR antagonist or kinase inhibitor and a pharmaceutically acceptable carrier, diluent or excipient and packaged with written directions for use in combination with an anti-CD37 antibody or antibody fragment and an anti-CD20 antibody or antibody fragment for treatment of a B cell malignancy.

[00266] As used herein, "written insert," "written directions" and "label" are used interchangeably and include packaging language required by regulatory authorities as well as voluntary package inserts. Written inserts may include detailed information about drug indications, contraindications, dosing and modes of approved use.

[00267] In one embodiment, the CD37 antibody or fragment and / or CD20 antibody or fragment are packaged in a unit dosage form. Alternatively, the CD37 antibody or fragment, CD20 antibody or fragment and / or BCR pathway inhibitor are packaged in a unit dosage form. In yet another embodiment, the CD37 antibody or fragment, CD20 antibody or fragment and / or kinase inhibitor are packaged in a unit dosage form. The kit may further include a device suitable for administering the composition according to a preferred route of administration (for instance, by infusion in the case of CD37 and CD20 antibodies or fragments) or for practicing a screening assay. The kit may include a label that describes use of the therapeutic in a method of the invention.

[00268] The present invention also comprises articles of manufacture. Such articles comprise one or more anti-CD37 antibodies or fragments and / or one or more anti-CD20 antibodies or fragments, optionally together with one or more BCR antagonists or kinase inhibitors, a pharmaceutical carrier or diluent, and at least one label describing a method of use according to the invention.

[00269] The present invention also includes use of a composition comprising an anti-CD37 antibody or fragment and an anti-CD20 antibody or fragment in the manufacture of a medicament for the treatment or prophylaxis of a disease involving aberrant B-cell activity. The present invention also includes use of a composition comprising an anti-CD37 antibody or fragment, an anti-CD20 antibody or fragment and a BCR antagonist (e.g., a BTK inhibitor, a SYK inhibitor, PI3K inhibitor or a CXCR4 antagonist) in the manufacture of a medicament for the treatment or prophylaxis of a disease involving aberrant B-cell activity. In yet another embodiment, the present invention includes use of a composition comprising an anti-CD37 antibody or fragment, an anti-CD20 antibody or fragment and a kinase inhibitor (e.g., a PI3K inhibitor, a SYK inhibitor or a BTK inhibitor) in the manufacture of a medicament for the treatment or prophylaxis of a disease involving aberrant B-cell activity

[00270] In another embodiment, the invention includes use of an anti-CD37 antibody or antibody fragment in the manufacture of a medicament for treatment of a B-cell malignancy or disorder, for use in combination with a CD20 antibody or fragment or in combination with a

CD20 antibody or fragment and a BCR antagonist (for instance, a BTK inhibitor, a SYK inhibitor, PI3K inhibitor, or a CXCR4 antagonist). In yet another embodiment, the invention includes use of a CD20 antibody or fragment (e.g. obinutuzumab) in the manufacture of a medicament for treatment of a B-cell malignancy or disorder, for use in combination with a CD37 antibody or fragment or in combination with a CD37 antibody or fragment and a BCR antagonist or kinase inhibitor. In yet another embodiment, the invention includes use of a BCR antagonist in the manufacture of a medicament for treatment of a B-cell malignancy or disorder, for use in combination with a CD37 antibody or fragment or in combination with a CD37 antibody or fragment and a CD20 antibody or a fragment. In yet another embodiment, the invention includes use of a kinase inhibitor in the manufacture of a medicament for treatment of a B-cell malignancy or disorder, for use in combination with a CD37 antibody or fragment or in combination with a CD37 antibody or fragment and a CD20 antibody or a fragment. The invention also includes use a CD37 antibody or fragment, a CD20 antibody or fragment, BCR antagonist and kinase inhibitor in the manufacture of a medicament for treatment of a B-cell malignancy or disorder.

EXAMPLES

[00271] The invention will be further clarified by the following examples, which are intended to be purely exemplary of the invention and in no way limiting.

Example 1 : Production of a recombinant, monospecific anti-CD37 antibody

[00272] Various recombinant anti-CD37 antibodies can be made with exemplary components provided herein, for instance, the components disclosed in the sequence listing. For example, the anti-CD37 antibodies can be chimeric, humanized, or human. Recombinant, anti-CD37 antibodies comprising a CD37 binding domain, hinge domain and constant region are described, for instance, in co-owned patent application 2009/0214539 and US 8,333,966, each of which is incorporated by reference in its entirety and for all purposes. An exemplary recombinant, monospecific anti-CD37 antibody comprising dimerized single chain polypeptides, each polypeptide comprising a CD37 binding domain, a hinge domain and a constant region can be produced as described below.

[00273] TRU-016 (also known as otlertuzumab, used interchangeably throughout) is a humanized recombinant, single chain polypeptide that forms a homodimer and binds specifically to human CD37. The binding domain comprises a humanized scFv based on the G28-1 antibody variable region CDRs, including mutations in the heavy chain CDR3 and in the light chain CDR1. The variable domains are linked by a (G₄S)₅ (25 amino acid) sequence, which is connected via an amino acid junction region to the amino terminus of a modified upper and core lgG1 hinge region (wherein the first two of three cysteines found in these hinge regions are each substituted with a serine). The carboxyl-terminus of the hinge is fused to an effector domain comprising CH2 and CH3 domains of IgGi . The amino acid of TRU-016 comprises amino acids 21-503 of SEQ ID NO:1 (amino acids 1-20 are a leader sequence that is typically cleaved from the protein post-transcription).

[00274] A recombinant anti-CD37 antibody such as TRU-016 may be produced by isolating total RNA from the G28-1 hybridoma or other anti-CD37 hybridoma of interest using Trizol RNA (Gibco) reagent according to the manufacturer's instructions. cDNA can be prepared using the RNA, random primers and Superscript II Reverse Transcriptase (GIBCO BRL). The variable domains can be cloned using pools of degenerate primers for the different murine VK or VH gene families. For instance, the variable domains from the G28-1 hybridoma can be cloned into PCR 2.1 TOPO cloning vectors (Invitrogen) and DNA from transformants with correct size inserts sequenced. Heavy and light chain variable regions from correct clones can then be used as templates for PCR amplification of a G28-1 -derived scFv joined together, for instance, in the VH-VL orientation with a linker. The anti-CD37 scFv can then be attached to a modified human lgG1 hinge, CH2, and CH3 domains. In order to ensure adequate expression by mammalian cells (e.g., Chinese hamster ovary or CHO cells), modifications of the variable regions can be selected that provide increases in expression by mammalian cells. For instance, a leucine was changed to a serine at position 1 1 of the scFV. Essentially anytime during this process, the variable domains could be humanized and the humanized variable domains can be inserted into the recombinant anti-CD37 antibody.

[00275] Recombinant anti-CD37 antibodies in the dimerized single chain format of TRU-016 may be purified from CHO culture supernatants by Protein A affinity chromatography. For instance, using dPBS, a 50 mL rProtein A FF sepharose column (GE Healthcare rProtein A Sepharose FF, Catalog # 17-0974-04) can be equilibrated at 5.0 mls/min (150 cm/hr) for 1.5 column volumes (CV). The culture supernatant can be loaded to the rProtein A Sepharose FF column at a flow rate of 1.7mls/min using the AKTA Explorer 100 Air (GE healthcare AKTA Explorer 100 Air, Catalog # 18-1403-00), to capturing the recombinant antibody. The column can be washed with dPBS for 5 Column Volumes (CV), then 1.0 M NaCI, 20mM Sodium Phosphate, pH 6.0, and then with 25 mM NaCI, 25mM NaOAc, pH 5.0. These washing steps can be used to remove nonspecifically bound CHO host cell proteins from the rProtein A column that contribute to product precipitation after elution.

[00276] The recombinant antibody can then be eluted from the column, for instance, with l OOmM Glycine, pH 3.5. 10ml_ fractions of the eluted product were recovered and the eluted product was then brought to pH 5.0 with 20% of the eluted volume of 0.5 M 2-(N- Morpholino)ethanesulfonic acid (MES) pH6.0. The eluted product can be prepared for GPC purification by concentration of the sample to approximately 25 mg/mL and then filter sterilized in preparation for GPC purification.

EXAMPLE 2: Construction of anti-CD37 x anti-CD3 multispecific homodimer antibody molecules

[00277] The compositions and methods of the invention include multispecific anti- CD37 antibodies, for instance, anti-CD37 x anti-CD3 antibodies that are capable of redirected T cell cytotoxicity.

[00278] Two starting constructs were designed in silico using SEQ ID NO: 1 as a starting sequence (from amino to carboxyl terminus, a signal sequence, a humanized scFv derived from anti-CD37 antibody G28-1 , a modified immunoglobulin lgG1 hinge and wild-type lgG1 CH2 and CH3 regions). The modified lgG1 hinge of SEQ ID NO: 1 (with cysteine to serine mutations at first two cysteines) was changed to a modified lgG1 hinge with a cysteine to serine mutation at the first cysteine residue only (i.e., SCC). The wild-type lgG1 Fc sequence was modified to remove or reduce effector function and a C-terminus linker was added at the C- terminus of each Fc. These two starting sequences are named anti-CD37lgG1 null2 H75 and anti-CD37lgG4 N297A ADCC- H75, respectively. These two molecules also contained the signal peptide with Hind 111 restriction site at the N-terminus and EcoRI restriction site at the C- terminus of the H75 linker. Two silent mutations were introduced into the constructs to remove undesirable restriction sites, namely the EcoRI site in the scFv sequence and the BsiWI site in the Fc region. In addition, a Xhol restriction site was introduced at the junction of the scFv and the lgG1 hinge. These constructs were then digested with Hind 111 and EcoRI restriction enzymes to release the fragment from the vector. Each construct was then ligated into the PD28 expression vector along with an anti-CD3 scFv fragment that had been cut with EcoRI and Notl restriction enzymes. The resultant ligation gave two constructs: anti-CD37-anti-CD3 lgG1 null2 H75 (CAS105; SEQ ID NO:45 and SEQ ID NO:46) and anti-CD37-anti-CD3lgG4 N297A ADCC- H75 (CAS106; SEQ ID NO:47 and SEQ ID NO:48). These sequences of these two constructs were subsequently verified by DNA sequencing. These two constructs were used as template to generate additional molecules as described below.

[00279] Construction of additional anti-CD37 x anti-CD3 molecules containing variations in the linker sequence: Briefly, using the two constructs (CAS105 and CAS106) as template, PCR reactions were set up to generate anti-CD37 lgG1 null2 and anti-CD37 lgG4

N297A ADCC- fragments containing variations in the C-terminus linkers. PCR generated fragments were then digested with Hind 111 and EcoRI restriction enzymes and ligated into the PD28 vector along with a humanized anti-CD3 scFv that had been previously digested with EcoRI and NotI in the 3 way ligation reactions. The sequences of the constructs were verified by DNA sequencing. A table below includes exemplary constructs.

Table 2: Description of Exemplary Multispecific Anti-CD37 Antibody Constructs

Example 3: anti-CD20 antibodies

[00280] The compositions and methods of the invention include the use of anti- CD20 antibodies that are known in the art. For instance, the invention includes the use of ofatumumab, veltuzumab, ocrelizumab and obinutuzumab.

[00281] Synthesis and pre-clinical and clinical development of obinutuzumab, also known as GA-101 , is described in detail in Robak T, 2009, Curr Opin Investig Drugs, 10(6), 588-596, which is hereby incorporated by reference herein in its entirity for all purposes.

[00282] The invention also includes the use of anti-CD20 antibodies or fragments derived from CD20 antibodies such as rituximab, ofatumumab, veltuzumab, ocrelizumab and obinutuzumab. The invention also includes the use of anti-CD20 antibodies or fragments that contain the same epitope or an epitope that overlaps with the epitope of CD20 antibodies such as rituximab, ofatumumab, veltuzumab, ocrelizumab and obinutuzumab. The invention further includes the use of anti-CD20 antibodies or fragments that compete for binding to CD20+ B cells with CD20 antibodies such as rituximab, ofatumumab, veltuzumab, ocrelizumab and obinutuzumab.

Example 4: SYK Inhibitors

[00283] The compositions and methods of the invention include the use of SYK inhibitors that have published, for instance, fostamatinib disodium. Figure 1 provides the chemical structure of fostamatinib (Figure 1A) and fostamatinib sodium (Figure 1 B). [00284] Another SYK inhibitor that can be used in the compositions and methods of the invention is PRT062607. Synthesis and characterization of P505-15 [(4-(3-(2H-1 ,2,3- triazol-2-yl)phenylamino)-2-((1 R,2S)-2-aminocyclohexylamino)pyrimidine-5-carboxamide acetate] (PRT062607) as well as its potency and selectivity for SYK have been reported. See, for instance, Spurgeon et al., J. Pharma. Exp. Ther. 344(2):378-87 and Hoellenriegel et al., 2012, Leukemia. 26(7): 1576-83, each of which is herein incorporated by reference in its entirety for all purposes.

[00285] PRT-318 is another SYK inhibitor. PRT318, also referred to as P142-76, is a derivative of pyrimidine-5-carboxamide. See, for instance, U.S. 6,432,963, which is herein incorporated by reference in its entirety. See also, for instance, Reilly et al., 201 1 , Blood. 1 17(1 ):2241-2246 and Hoellenriegel et al., 2012, Leukemia. 26(7): 1576-83, each of which is incorporated by reference in its entirety for all purposes.

[00286] SYK inhibitors may be manufactured using chemical synthesis methods known in the art. Research grade material (for use, for instance in in vitro, ex vivo and animal studies) may also be purchased from chemical supply companies.

Example 5: BTK Inhibitors

[00287] The compositions and methods of the invention include BTK inhibitors, for instance, ibrutinib and AVL-292 which inhibit BTK by covalently binding to cysteine residue 481 on BTK. The chemical structure of ibrutinib is provided in Figure 2. See, also, BTK inhibitors, including ibrutinib and AVL-292 disclosed in US 7,982,036; US 7,989,456; US 8,329,901 ; US 8,088,781 ; US 8,158,786 and US8,232,280 for disclosure of methods of making BTK inhibitors.

[00288] Another BTK inhibitor is GDC0834, (R)-N-(3-(6-(4-(1 ,4-dimethyl-3- oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)- 4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide, is also a selective and potent inhibitor of BTK. The structure of GDC0834 is provided in Figure 4.

[00289] BTK inhibitors can be manufactured by chemical synthesis methods known in the art, and research grade BTK inhibitors are available for purchase from chemical supply companies.

Example 6: CXCR4 Antagonists

[00290] CXCR4 antagonists that are available for use with the methods and compositions of the invention include plerixafor (see Figure 3), a T140 analog and KRH-3955. KRH-3955 is disclosed, for instance, in Murakami et al., 2009, Antimicrob. Agents. Chemother. 53(7):2940-2948. CXCR4 antagonists can be manufactured by chemical synthesis methods known in the art, and research grade material is available for purchase from chemical supply companies.

Example 7: Effect of Combination of Anti-CD37 Antibody and Anti-CD20 Antibody and

Combination of Anti-CD37 Antibody, Anti-CD20 Antibody and BCR antagonist on Apoptosis in B cells

[00291] Annexin/PI Analysis can be performed as follows: Ramos (ATCC# CRL- 1596) or Daudi cells can be incubated for about 24 or 48 hours at 37°C in 5% C02 in Iscoves (Gibco) complete media with 10% FBS at 3 X 105 cells/mL and anti-CD37 antibody alone, anti- CD20 antibody alone, a BCR antagonist alone, a combination of anti-CD37 antibody and anti- CD20 antibody or a combination of an anti-CD37 antibody, anti-CD20 antibody and BCR antagonist. The anti-CD37 antibody and anti-CD20 antibody may be cross-linked prior to addition to cells by co-incubation with goat anti-human IgG F(ab)'₂ for about 15 minutes at room temperature. Alternatively, if necessary, goat anti-human IgG can be added directly to reaction wells in order to cross link reagents on the cell surface. Cells are then stained with Annexin V- FITC and propidium iodide using, for instance, the BD Pharmigen Apoptosis Detection Kit I (#556547), and processed according to kit instructions. Briefly, cells can be washed twice with cold PBS and resuspended in "binding buffer" at 1X10⁶ cells/ml_. One hundred microliters of the cells in binding buffer can then be stained with 5 μΙ_ of Annexin V-FITC and 5 μΙ_ of propidium iodide. The cells are gently vortexed and incubated in the dark at room temperature for about 15 minutes. Four hundred microliters of binding buffer can then be added to each sample. Samples can be read and analyzed on a FACsCalibur (Becton Dickinson) instrument using Cell Quest software (Becton Dickinson).

[00292] The effect of anti-CD37 antibody, anti-CD20 antibody, BCR antagonist and their combinations on in vitro cell killing is expressed as the percentage of cells positive for annexin V staining relative to control using the formula: 100x(1-(( 100-Percent Annexin V positive of test drug)/(100-Percent Annexin V positive of control))). Combination index analysis comparing effects of an individual agent to effects of dual and triple combinations is performed, for instance, using Calcusyn software (Biosoft, Cambridge, UK). Combination index values are averaged over the 20% to 90% effect range and interaction types are determined from their means and 95% confidence intervals. Example 8: Measuring CDC activity of TRU-016 and/or obinutuzumab

[00293] Experiments can be performed to study if TRU-016 mediates significant levels of complement dependent killing of B cell targets. To investigate the complement dependent killing of B cell targets by TRU-016 dimers, experiments can be performed to determine if TRU-016 activates the classical complement activation pathway. Specifically, the binding of TRU-016 to C1q is studied. C1q, is a subunit of the C1 enzyme complex that activates the serum complement system, and is the recognition component of the classical complement activation pathway.

[00294] C1q binding studies are performed as described in Cragg et al., Blood 2004, 103:2738-2743, which is hereby incorporated by reference herein in its entirity for all purposes. Briefly, Ramos B-cells in Iscoves media (#12440-053, Gibco/lnvitrogen, Grand Island, NY) with no serum are plated in 96-well V bottom plates at 5 X 10⁵ cells/well in 100 μΙ. Cells are incubated with reagents for 15 minutes at 37°C, and normal human serum (NHS, #A1 13, Quidel Corp., San Diego, CA) diluted in Iscoves is then added at a volume of 50 μΙ to each well for a final concentration of 10, 5, 2.5, or 1.25 % human serum. Fifty μΙ of media is added to the control well. For cobra venom factor (CVF) experiments, CVF is added to human serum complement samples at 20 Units of CVF per ml of serum for 90 minutes at 37°C prior to addition of serum to complement assays, and the dilution of serum by CVF is accounted for when making sample dilutions.

[00295] The cells and complement source are incubated for an additional 5 minutes at 37°C, and washed twice with cold PBS (#14040-133, Gibco/lnvitrogen, Grand Island, NY) via centrifugation and resuspended in 100 μΙ of PBS. Fifty μΙ sample from each well was transferred to a second plate for second step control staining. Both plates are stained for 15 minutes in the dark on ice with either FITC sheep anti-HU C1q (#C7850-06A, US Biological, Swampscott, Mass) or FITC Sheep IgG (#1 1904-56P, US Biological, Swampscott, Mass). Samples are washed, resuspended in cold PBS, and read immediately on a FACsCalibur flow cytometer and analyzed with Cell Quest software (Becton Dickinson, San Jose, CA).

[00296] CDC assays can be performed to compare the ability of the purified forms of TRU-016 and obinutuzumab to mediate cell killing in the presence or absence of CVF and human serum complement. Propidium iodide staining can be used to perform CDC assays in order to distinguish between live and dead cells after incubation of target cells with antibody, fusion proteins, ascites fluid, TRU-016 molecular forms, or media, and a source of complement such as human serum. Briefly, 3 x 10⁵ Ramos cells are pre-incubated with test reagents for 30- 45 minutes at 37°C prior to addition of complement. The prebound samples are centrifuged, washed, and resuspended in Iscoves with human serum (# A1 13, Quidel, San Diego, CA) at desired concentrations and incubated for 90 minutes at 37°C. Samples are washed and propidium iodide (# P-16063, Molecular Probes, Eugene, OR) is added to a final concentration of 0.5 g/ml in PBS. The cells are incubated with propidium iodide for 15 minutes at room temperature in the dark and then analyzed by flow cytometry on a FACsCalibur instrument with CellQuest software (Becton Dickinson).

[00297] Human and rabbit complements are then compared for their CDC activity in the presence of TRU-016 and/or obinutuzumab. The CDC activity of TRU-016 molecular forms incubated with Ramos B cells and human or rabbit complement is measured. Ramos B cells are added to wells in serum free media. Obinutuzumab or the dimer, HMW A2, or pA fractions of TRU-016 are added to cells to give a final concentration of 10 μg/ml, and incubated for 15 minutes at 37°C, prior to washing 1.5X in serum free media and addition of normal human serum (NHS) or rabbit complement (Pelfreez) at 10, 5, or 2.5 %. Cells and complement source are incubated for 90 minutes at 37°C. Cells are washed once with cold PBS and propidium iodide (Molecular Probes #P3566) is added to a final concentration of 0.5 μg/ml in cold PBS. Cells with propidium iodide are incubated in the dark at room temperature for 15 minutes and analyzed by flow cytometry.

Example 9: Determining CDC Activity from a Combination of Anti-CD37 Antibody and Anti- CD20 Antibody and Combination of Anti-CD37 Antibody, Anti-CD20 Antibody and a BCR antagonist

[00298] Experiments are performed to determine the CDC activity of combinations of anti-CD37 antibody with anti-CD20 antibody and combinations of anti-CD37 antibody, anti- CD20 antibody and BCR antagonists against B cells. The amount of each agent can vary but, in one instance, 0.5 μg/ml of anti-CD37 antibody or antibody fragment, 0.5 μg/ml of anti-CD20 antibody or antibody fragment and 0.5 μg/ml BCR antagonist can be used. In some

experiments, the concentration of one agent can be held constant at a suboptimal

concentration, while the concentration of other agent or agents is varied to explore the minimal levels of the agent required to observe augmentation effects on CDC. In some experiments, the concentrations of the agents are varied to study a dose response. In some experiments, agents are mixed at several ratios to prepare various combinations.

[00299] Cells are suspended in Iscoves (#12440-053, Gibco/lnvitrogen, Grand Island, NY) at 5x10E5 cells/well in 75 μΙ. An anti-CD37 antibody, an anti-CD20 antibody (e.g., obinutuzumab) and a BCR inhibitor, or combinations of these therapeutic agents are added to the cells at desired concentrations and / or ratios. Binding reactions are allowed to proceed for about 45 minutes prior to centrifugation and washing in serum free Iscoves. Cells are resuspended in Iscoves with human serum (#A1 13, Quidel, San Diego, CA) at desired concentrations. The cells are incubated for 60 minutes at 37°C. Cells are then washed by centrifugation and resuspended in 125 μΙ PBS with 2% FBS (#16140-071 , Gibco, Invitrogen, Grand Island, NY), staining media. The cells can then be transferred to FACS cluster tubes (#4410, CoStar, Corning, NY) and 125 μΙ staining media with 5 μΙ propidium iodide (PI, #P- 16063, Molecular Probes, Eugene OR) is added. Samples are incubated about 15 minutes at room temperature in the dark prior to analysis by flow cytometry using a FACsCalibur and CellQuest software (Becton Dickinson).

Example 10: Determining ADCC Activity from Combination of Anti-CD37 Antibody and Anti- CD20 Antibody and Combination of Anti-CD37 Antibody, Anti-CD20 Antibody and a BCR antagonist

[00300] BJAB, Ramos, and Daudi lymphoblastoid B cells (10E7) cells are labeled with 500 μθί/ηιί ⁵¹Cr sodium chromate for about 2 hours at 37°C in IMDM/10%FBS. The labeled cells are washed three times in RPMI/10% FBS and resuspended at 4x10E5 cells/mL in RPMI. Heparinized, human whole blood is obtained from anonymous, in-house donors and PBMC isolated by fractionation over Lymphocyte Separation Media (LSM, ICN Biomedical) gradients. Buffy coats are harvested and washed twice in RPMI/10% FBS prior to

resuspension in RPMI/10% FBS at a final concentration of 3x10E6 cells/ml. Cells are counted by trypan blue exclusion using a hemacytometer prior to use in subsequent assays. Reagent samples (e.g., anti-CD37 antibody, anti-CD20 antibody such as obinutuzumab, and a BCR antagonist, each alone or in double or triple combinations) are added to RPMI media with 10% FBS at, for instance, 4 times the final concentration and five serial dilutions for each reagent are prepared. For combinations, the reagents can be premixed at several ratios and diluted prior to addition to the wells. These reagents are then added to 96 well U bottom plates at the indicated final concentrations. The ⁵¹Cr labeled cells are added to the plates at 50 μΙ/well (2x10E4 cells/well). The PBMCs are added to the plates at 100 μ l/well (3x10E5 cells/well) for a final ratio of 15:1 effectors (PBMC):target (BJAB/Ramos/Daudi).

[00301] Effectors and targets are added to media alone to measure background killing. The ⁵¹Cr labeled cells are added to media alone to measure spontaneous release of ⁵¹Cr and to media with 5% NP40 (e.g.,#28324, Pierce, Rockford, IL) to measure maximal release of ⁵¹Cr. Reactions are set up in quadruplicate wells of a 96-well plate. Anti-CD37 antibodies, anti-CD20 antibodies, and / or BCR antagonists are added to wells at a final concentration ranging from, for instance, 12 ng/mL to ^g/mL. For wells containing combinations of therapeutic agents, it is preferable that the agents be mixed prior to addition to the wells. Each data series plots a different single therapeutic or combination at the titration ranges described. Reactions are allowed to proceed, for instance, for 6 hours at 37°C in 5% C0₂ prior to harvesting and counting. Fifty μΙ of the supernatant from each well is then transferred to a Luma Plate 96 (e.g., #6006633, Perkin Elmer, Boston, Mass) and dried overnight at room temperature. CPM released is measured, for instance, on a Packard TopCounNXT. Percent specific killing can be calculated by subtracting (cpm {mean of quadruplicate samples} of sample - cpm spontaneous release)/(cpm maximal release-cpm spontaneous release) x100.

[00302] Data can be plotted as % specific killing versus therapeutic concentration.

Example 1 1 : Effect of Combination of Anti-CD37 Antibody and Anti-CD20 Antibody and Combination of Anti-CD37 Antibody, Anti-CD20 Antibody and a BCR antagonist on Tumor Volume in a Murine Tumor Xenograft Model

[00303] Mouse tumor xenograft studies exploring combination therapies comprising an anti-CD37 antibody and an anti-CD20 antibody such as obinutuzumab can be performed using nude mice (Harlan) and Ramos or Daudi human tumor lines. Briefly, Ramos or Daudi tumor cells are grown in IMDM/10% FBS until they reach about 80% confluency. Five million (5x10⁶) cells are used as a tumor inoculum per mouse. Cells are injected subcutaneously in the right flank using PBS in a total volume of 0.1 mL or 5.0x10⁷/mL. Nude mice are allowed to develop tumors and sorted into groups based on tumor size/volume. For each treatment group, mice with similar average tumor volumes are used. Animals are injected intravenously (IV) at days 0, 2, 4, 6, and 8 with one of the following reagents: an anti-CD37 antibody, an anti-CD20 antibody, a BCR antagonist, or human IgG (control) as single reagents and in combinations (e.g., anti-CD37 antibody + anti-CD20 antibody; anti-CD37 antibody + anti-CD20 antibody + SYK inhibitor; anti-CD37 antibody + anti-CD20 antibody + BTK inhibitor; anti-CD37 antibody + anti-CD20 antibody + CXCR4 antagonist). Tumor volume can be measured daily with calipers until completion of the experiment (sacrifice or regression). Tumor volume as a function of treatment time can be plotted for each animal and results averaged within each group.

Example 12: Effect of Combination of Anti-CD37 Antibody and Anti-CD20 Antibody on Survival in a Murine Tumor Xenograft Model

[00304] Mouse tumor xenograft studies are performed to examine the efficacy of an anti-CD37 antibody alone, anti-CD20 antibody (e.g., obinutuzumab) alone, and their combination in increasing long-term survival using nude mice and either Ramos or Daudi human tumor cell lines.

[00305] Ramos and Daudi tumor cells are separately grown and cells (e.g., about 5x10⁶) injected subcutaneously in the mice to initiate the formation of mouse tumor xenografts. After tumor development, mice are sorted into groups based on tumor size/volume (day 0). Animals are administered (e.g., intravenously) an anti-CD37 antibody or fragment (e.g., TRU- 016 recombinant antibody, a monoclonal antibody derived from G28-1 , and / or a recombinant anti-CD37 x anti-CD3 bispecific antibody), an anti-CD20 antibody or fragment (e.g., rituximab, ofatumumab, veltuzumab, ocrelizumab and obinutuzumab), a combination of the anti-CD37 antibody and anti-CD20 antibody, or a control over a period of time (for instance, at days 0, 2, 4, 6, and 8). Tumor volume is measured at set time points (e.g., three times a week) until completion of the experiment (sacrifice or regression).

[00306] Results can be analyzed using standard statistical methodologies. For instance, tumor volume as a function of treatment time can be plotted for each animal and results averaged within each group. A synergistic effect can be determined, for instance, by use of the isobologram method. To identify synergy, the effect of a drug combination is compared to the effect of each drug alone. This is based on the equation: Ca/Ca,b + Cb/Cb,a = CI, where Ca and Cb are the concentration of drug A and drug B alone, respectively, to produce a desired effect (e.g., 50% cell death). Ca,b and Cb,a are the concentrations of drug A and drug B in a combination, respectively, to produce the same effect. CI is the combination index. The concentrations of an anti-CD37 antibody and an anti-CD20 antibody which elicit 50% death (IC50) can be determined and graphed. The straight line between these two points on the axes is the line of additive effect. Subsequently, different combinations of the anti-CD37 and anti-CD20 antibodies that achieve 50% cell death can also be determined from the viability study and plotted to the same graph. When points fall below the additivity line, synergy is indicated. When points rise above the line, antagonism is indicated. When points are on the line, additivity is indicated.

Example 13: Effect of Combination of Anti-CD37 Antibody, Anti-CD20 Antibody and a BTK inhibitor on Survival in a Murine Tumor Xenograft Model

[00307] Mouse tumor xenograft studies are performed to examine the efficacy of an anti-CD37 antibody alone, anti-CD20 antibody (e.g., obinutuzumab) alone, a BTK inhibitor (e.g., ibrutinib) alone and the combination of anti-CD37 antibody, anti-CD20 antibody and BTK inhibitor in increasing long-term survival using nude mice and either Ramos or Daudi human tumor cell lines. [00308] Ramos and Daudi tumor cells are separately grown and cells (e.g., about 5x10⁶) injected subcutaneously in the mice to initiate the formation of mouse tumor xenografts. After tumor development, mice are sorted into groups based on tumor size/volume (day 0). Animals are administered (e.g., intravenously) an anti-CD37 antibody or fragment (e.g., TRU- 016 recombinant antibody, a monoclonal antibody derived from G28-1 , and / or a recombinant anti-CD37 x anti-CD3 bispecific antibody), an anti-CD20 antibody or fragment (e.g., obinutuzumab), a BTK inhibitor (e.g., ibrutinib), a combination of the anti-CD37 antibody, anti- CD20 antibody and BTK inhibitor, or a control over a period of time (for instance, at days 0, 2, 4, 6, and 8). Tumor volume is measured at set time points (e.g., three times a week) until completion of the experiment (sacrifice or regression).

[00309] Results can be analyzed using standard statistical methodologies. For instance, tumor volume as a function of treatment time can be plotted for each animal and results averaged within each group. A synergistic effect can be determined, for instance, by use of the isobologram method. To identify synergy, the effect of a drug combination is compared to the effect of each drug alone. This is based on the equation: Ca/Ca,b + Cb/Cb,a = CI, where Ca and Cb are the concentration of drug A and drug B alone, respectively, to produce a desired effect (e.g., 50% cell death). Ca,b and Cb,a are the concentrations of drug A and drug B in a combination, respectively, to produce the same effect. CI is the combination index. The concentrations of an anti-CD37 antibody, an anti-CD20 antibody and a BTK pathway inhibitor which elicit 50% death (IC50) can be determined and graphed. The straight line between these two points on the axes is the line of additive effect. Subsequently, different combinations of the therapeutic agents that achieve 50% cell death can also be determined from the viability study and plotted to the same graph. When points fall below the additivity line, synergy is indicated. When points rise above the line, antagonism is indicated. When points are on the line, additivity is indicated.

Example 14: Effect of Combination of Anti-CD37 Antibody, Anti-CD20 Antibody and a SYK inhibitor on Survival in a Murine Tumor Xenograft Model

[00310] Mouse tumor xenograft studies are performed to examine the efficacy of an anti-CD37 antibody alone, an anti-CD20 antibody (e.g., obinutuzumab) alone, a SYK inhibitor (e.g., fostamatinib and / or PRT062607) alone and a combination of anti-CD37 antibody, anti- CD20 antibody and a SYK inhibitor in increasing long-term survival using nude mice and either Ramos or Daudi human tumor cell lines.

[00311] Ramos and Daudi tumor cells are separately grown and cells (e.g., about

5x10⁶) injected subcutaneously in the mice to initiate the formation of mouse tumor xenografts. After tumor development, mice are sorted into groups based on tumor size/volume (day 0). Animals are administered (e.g., intravenously) over a period of time (for instance, at days 0, 2, 4, 6, and 8) an anti-CD37 antibody or antibody fragment (e.g., TRU-016 recombinant antibody, a monoclonal antibody derived from G28-1 , and / or a recombinant anti-CD37 x anti-CD3 bispecific antibody), an anti-CD20 antibody or fragment (e.g., obinutuzumab), a SYK inhibitor (e.g., fostamatinib and / or PRT062607), a combination of an anti-CD37 antibody, anti-CD20 antibody and a SYK inhibitor or a control. Tumor volume is measured at set time points (e.g., three times a week) until completion of the experiment (sacrifice or regression).

[00312] Results can be analyzed using standard statistical methodologies. For instance, tumor volume as a function of treatment time can be plotted for each animal and results averaged within each group. A synergistic effect can be determined, for instance, by use of the isobologram method (see Example 13).

Example 15: Effect of Combination of Anti-CD37 Antibody, Anti-CD20 Antibody and CXCR4 Antagonist on Survival in a Murine Tumor Xenograft Model

[00313] Mouse tumor xenograft studies are performed to examine the efficacy of an anti-CD37 antibody alone, an anti-CD20 antibody (e.g., obinutuzumab) alone, a CXCR4 antagonist (e.g., plerixafor and / or a T140 analog) alone and a combination of anti-CD37 antibody, anti-CD20 antibody and a CXCR4 antagonist in increasing long-term survival using nude mice and either Ramos or Daudi human tumor cell lines

[00314] Ramos and Daudi tumor cells are separately grown and cells (e.g., about 5x10⁶) injected subcutaneously in the mice to initiate the formation of mouse tumor xenografts. After tumor development, mice are sorted into groups based on tumor size/volume (day 0). Animals are administered (e.g., intravenously) over a period of time (for instance, at days 0, 2, 4, 6, and 8) an anti-CD37 antibody or antibody fragment (e.g., TRU-016 recombinant antibody, a monoclonal antibody derived from G28-1 , and / or a recombinant anti-CD37 x anti-CD3 bispecific antibody), an anti-CD20 antibody or fragment (e.g., obinutuzumab), a CXCR4 antagonist (e.g., plerixafor and / or a T140 analog), a combination of an anti-CD37 antibody, anti-CD20 antibody and a CXCR4 antagonist, or a control. Tumor volume is measured at set time points (e.g., three times a week) until completion of the experiment.

[00315] Results can be analyzed using standard statistical methodologies. For instance, tumor volume as a function of treatment time can be plotted for each animal and results averaged within each group. A synergistic effect can be determined, for instance, by use of the isobologram method. See Example 13. Example 16: Effect of Combination of Anti-CD37 Antibody, Anti-CD20 Antibody and a PI3K inhibitor Antagonist on Survival in a Murine Tumor Xenograft Model

[00316] Mouse tumor xenograft studies are performed to examine the efficacy of an anti-CD37 antibody alone, an anti-CD20 antibody (e.g., obinutuzumab) alone, a PI3K inhibitor (e.g., idelalisib) alone and a combination of anti-CD37 antibody, anti-CD20 antibody and a PI3K inhibitor in increasing long-term survival using nude mice and either Ramos or Daudi human tumor cell lines

[00317] Ramos and Daudi tumor cells are separately grown and cells (e.g., about 5x10⁶) injected subcutaneously in the mice to initiate the formation of mouse tumor xenografts. After tumor development, mice are sorted into groups based on tumor size/volume (day 0). Animals are administered (e.g., intravenously) over a period of time (for instance, at days 0, 2, 4, 6, and 8) an anti-CD37 antibody or antibody fragment (e.g., TRU-016 recombinant antibody, a monoclonal antibody derived from G28-1 , and / or a recombinant anti-CD37 x anti-CD3 bispecific antibody), an anti-CD20 antibody or fragment (e.g., obinutuzumab), a PI3K inhibitor (e.g., idelalisib), a combination of an anti-CD37 antibody, anti-CD20 antibody and a PI3K inhibitor (e.g., idelalisib), or a control. Tumor volume is measured at set time points (e.g., three times a week) until completion of the experiment.

[00318] Results can be analyzed using standard statistical methodologies. For instance, tumor volume as a function of treatment time can be plotted for each animal and results averaged within each group. A synergistic effect can be determined, for instance, by use of the isobologram method. See Example 13.

Example 17. A Phase 1 b study of an anti-CD37 antibody in combination with an anti-CD20 antibody

[00319] A study can be conducted to evaluate the efficacy and safety of an anti- CD37 antibody such as TRU-016 in combination with an anti-CD20 antibody such as obinutuzumab.

[00320] For example a study is conducted to evaluate efficacy and safety of TRU- 016 and obinutuzumab in elderly, treatment naive patients with CLL. The study is a multicenter, open label study with two stages. Stage II will be conducted if the response rate per IWCLL of the 50 patients in Stage I is >70% and the combination is tolerable. Treatment naive CLL patients will receive six 28 day cycles of treatment. [00321] Stage I: 6 patients will receive TRU-016 (20mg/kg) in combination with obinutuzumab (1 ,000 mg). If < 1 dose limiting toxicity (DLT) is observed, then 44 additional patients will be enrolled.

[00322] If > 1 DLT occurs in the first 6 patients, then the dose of TRU-016 will be reduced to 10 mg/kg. If > 1 DLT occurs at this dose of TRU-016, then the dose of TRU-016 will be reduced to 6 mg/kg, for all patients going forward. If > 1 DLT occurs at this dose of TRU- 016, then the dose of obinutuzumab will be reduced to 500 mg, for all patients going forward. A total of 50 patients will be enrolled in Stage 1.

[00323] Stage II: An additional 100 will be randomized (stratified by del17p) equally to 1 of 2 treatment arms provided Stage I supports such dosing as follows:

1. TRU-016 (10 mg/kg) + Obinutuzumab (1 ,000 mg)

2. TRU-016 (6 mg/kg) + Obinutuzumab (500 mg)

[00324] Dosing will be as follows:

• TRU-016 20 mg/kg will be dosed weekly for 3 weeks followed by 5 monthly

intravenous (IV) infusions. The first dose will be 6 mg/kg and all subsequent doses will be 20, 10, or 6 mg/kg.

• Obinutuzumab 100 mg will be infused on Day 2 and 900 mg IV will be infused on Day 3. Then 1 ,000 mg obinutuzumab will be dosed after TRU-016 (15 minutes to 80 hours) on Day 1 of Cycles 2-6.

[00325] All patients will receive pre-medication with acetaminophen 650-1 ,000 mg oral, diphenhydramine 25-50 mg IV or oral, and hydrocortisone 100 mg IV or equivalent. The hydrocortisone may be discontinued after the first cycle if the patient had no clinically significant infusion reactions. Dosing decisions will be made based on hematology values before each dose. Serum samples will be collected for serial pharmacokinetic assessment for TRU-016 drug levels, and TRU-016 antibody formation.

[00326] Patients will have response assessment monthly (clinical signs and symptoms and CBC), at the EOT visit, 8 weeks after EOT and then every 3 months until evidence of disease progression occurs, initiation of new therapy, or completion of 24 months of follow-up evaluations. CT scan will be performed at baseline and repeated 2 months after the EOT visit if the patient has stable disease (SD), a partial response (PR) or complete response (CR) by clinical evaluation and CBC. A bone marrow biopsy and aspirate will be performed at screening and repeated 2 months after the EOT visit (which is 3 months after last dose of study drugs), if a CT scan confirms stable disease (SD), PR, or CR. The bone marrow aspirate will be tested by sensitive flow cytometry (5 color) to detect minimal residual disease (MRD). If bone marrow aspirate is not available for flow cytometry then MRD status will be determined from peripheral blood.

[00327] The primary endpoint is the percentage of patients with minimal residual disease. Secondary endpoints will be:

• ORR by the 2008 International Workshop on CLL (IWCLL) Criteria

• CR rate by the 2008 IWCLL Criteria

• Progression-free survival (PFS)

• Overall survival (OS)

• Duration of response (DOR)

• Resolution of disease-related symptoms

[00328] Safety assessments will include incidence and severity of adverse events; and changes from baseline in laboratory parameters, vital signs, and physical examinations.

[00329] Pharmacokinetic (PK) parameters will include C_max, C_min, AUC₀-_t and AUC₀-«, CL, V_d, and t_1/2; and development of antibodies to TRU-016.

[00330] Exploratory assessments will include:

• Baseline prognostic assessment: interphase cytogenetics, stimulated karyotype, IgVH

mutational status, β2Μ and ZAP-70 methylation

• Serial Pharmacodynamic monitoring:

- B-cell signaling (pAKT, SHP1-1 phosphorylation, pGSK-β, pERK, pFOX03A, BIM, Ki67), miR expression (nanostring), RNA seq, and lgM/CD40/CpG activation potential. T-cell number and signaling (activation of different subtypes by CD3 ligation with examination of cytokines and CD69 expression).

NK cell number and signaling (activation following exposure to antibody immobilized plate as measured by IFN-γ release and CD69 expression)

• CD37 expression by flow cytometry

• Change in chemokine, cytokine and microvesicle MiRs

• Biomarkers: changes in proteins and genes that appear involved in signaling, apoptosis, and cell cycle regulation.

[00331] Response will be assessed (clinical signs and symptoms and CBC) monthly until the End of Treatment (EOT) visit, at the EOT visit, 8 weeks after the EOT visit, and subsequently every 3 months until progression of CLL, death, withdrawal from the study, initiation of new therapy, or completion of approximately 24 months of follow-up evaluations after the last treatment. Safety evaluations will include physical examination, assessment of adverse events and laboratory parameters (chemistries, hematology, and urinalysis). Blood samples for testing for antibody formation to TRU-016 will be collected pre-treatment and periodically post-treatment.

[00332] Inclusion Criteria:

• Patients with a diagnosis of CLL who have not received prior therapy for the disease

• Patients must demonstrate at least 1 of the criteria for active disease requiring

treatment:

o Progressive splenomegaly and/or lymphadenopathy

o Anemia (hemoglobin <1 1 g/dL) or thrombocytopenia (platelets <100,000/mm³) due to bone marrow involvement

o Progressive lymphocytosis with an increase of >50% over a 2-month period or an anticipated doubling time of less than 6 months

• Age≥65 years

• Eastern Cooperative Oncology Group (ECOG) performance status of < 2

• Serum creatinine, total bilirubin, alanine aminotransferase/serum glutamate pyruvate transaminase (ALT/SGPT) of≤ 2.0 x upper limit of normal (ULN)

• ANC≥ 800/mm³ (80Ό/μΙ_); patients with lymphocyte count >50,000/mm³ (50 x 10⁹/L) may be enrolled irrespective of ANC

• Platelets > 30,000/mm³

[00333] Exclusion Criteria:

• Known positive serology for human immunodeficiency virus (HIV) or hepatitis C virus

• Hepatitis B surface antigen or hepatitis B core antibody positive

• Active autoimmune disease requiring immunosuppressive therapy

[00334] The primary objective of Stage I is to evaluate the safety and tolerabiility of TRU-016 with obinutuzumab. The primary objective of Stage II is to compare the complete response rate (CR) and MRD negative rates among the 2 treatment arms.

[00335] The primary efficacy goal is MRD negative rate of 25% with the combination of TRU-016 with obinutuzumab. Secondary efficacy endpoints will be summarized with descriptive statistics and graphical techniques. Descriptive statistics will also be used to summarize demographic features, baseline characteristics, and safety endpoints including adverse events and laboratory results. Pharmacodynamic measurements will be summarized.

A sample size of 45 treatment patients provides greater than 90% power for a one-sample, one-sided exact binomial test against 8% with a 5% one-sided alpha level if one assumes a MRD negative rate for TRU-016 in combination with obinutuzumab of 25%. The sample size will be 50 subjects to provide 45 evaluable subjects in each cohort.

Example 18. A Phase 1 b study of an anti-CD37 antibody in combination with an anti-CD20 antibody and a BCR pathway antagonist

[00336] A study can be conducted to evaluate the efficacy and safety of an anti- CD37 antibody such as TRU-016 in combination with an anti-CD20 antibody such as obinutuzumab and in combination with a BTK inhibitor such as ibrutinib or a PI3K inhibitor such as idelalisib.

[00337] For example a study is conducted to evaluate efficacy and safety of TRU- 016 and obinutuzumab in combination with ibrutinib or idelalisib in elderly, treatment naive patients with CLL. The study is a multicenter, open label study with two stages. Stage II will be conducted if the response rate per IWCLL of the 50 patients in Stage I is >70% and the combination is tolerable. Treatment naive CLL patients will receive six 28 day cycles of treatment.

[00338] Stage I: 6 patients will receive TRU-016 (20mg/kg) in combination with obinutuzumab (1 ,000 mg) and either ibrutinib or idelalisib. If≤ 1 dose limiting toxicity (DLT) is observed, then 44 additional patients will be enrolled in Stage II.

[00339] If > 1 DLT occurs in the first 6 patients, then the dose of TRU-016 will be reduced to 10 mg/kg. If > 1 DLT occurs at this dose of TRU-016, then the dose of TRU-016 will be reduced to 6 mg/kg, for all patients going forward. If > 1 DLT occurs at this dose of TRU- 016, then the dose of obinutuzumab will be reduced to 500 mg, for all patients going forward. A total of 50 patients will be enrolled in Stage 1.

[00340] Stage II: An additional 100-350 subjects will be randomized (stratified by del17p) equally to 1 of 7 treatment arms provided Stage I supports such dosing as follows:

1. Obinutuzumab + TRU-016 (10mg/kg)

2. TRU-016 (10 mg/kg) + Idelalisib

3. TRU-016 (10 mg/kg) + Obinutuzumab + Idelalisib

4. TRU-016 (20 mg/kg) + Obinutuzumab + Idelalisib

5. TRU-016 (10 mg/kg) + Ibrutinib

6. TRU-016 (10 mg/kg) + Obinutuzumab + Ibrutinib

7. TRU-016 (20 mg/kg) + Obinutuzumab + Ibrutinib [00341] Dosing will be as follows:

• TRU-016 20 mg/kg will be dosed weekly for 3 weeks followed by 5 monthly

• In idelalisib groups, beginning Week 3, idelalisib (150 mg) will be taken twice daily by mouth until the end of treatment (EOT) visit or approximately 5.5 months.

• In ibrutinib groups, beginning on day 1 , ibrutinib (420 mg in 3 140-mg capsules) will be taken once daily by mouth until the end of treatment (EOT) visit or approximately 5.5 months.

[00342] All patients will receive pre-medication with acetaminophen 650-1 ,000 mg oral, diphenhydramine 25-50 mg IV or oral, and hydrocortisone 100 mg IV or equivalent. The hydrocortisone may be discontinued after the first cycle if the patient had no clinically significant infusion reactions. Dosing decisions will be made based on hematology values before each dose. Serum samples will be collected for serial pharmacokinetic assessment for TRU-016 drug levels, and TRU-016 antibody formation.

[00343] Patients will have response assessment monthly (clinical signs and symptoms and CBC), at the EOT visit, 8 weeks after EOT and then every 3 months until evidence of disease progression occurs, initiation of new therapy, or completion of 24 months of follow-up evaluations. CT scan will be performed at baseline and repeated 2 months after the EOT visit if the patient has stable disease (SD), a partial response (PR) or complete response (CR) by clinical evaluation and CBC. A bone marrow biopsy and aspirate will be performed at screening and repeated 2 months after the EOT visit (which is 3 months after last dose of study drugs), if a CT scan confirms stable disease (SD), PR, or CR. The bone marrow aspirate will be tested by sensitive flow cytometry (5 color) to detect minimal residual disease (MRD). If bone marrow aspirate is not available for flow cytometry then MRD status will be determined from peripheral blood.

[00344] The primary endpoint is the percentage of patients with minimal residual disease. Secondary endpoints will be:

• ORR by the 2008 International Workshop on CLL (IWCLL) Criteria

• CR rate by the 2008 IWCLL Criteria • Progression-free survival (PFS)

• Overall survival (OS)

• Duration of response (DOR)

• Resolution of disease-related symptoms

[00345] Safety assessments will include incidence and severity of adverse events; and changes from baseline in laboratory parameters, vital signs, and physical examinations.

[00346] Pharmacokinetic (PK) parameters will include C_max, C_min, AUC₀-_t and AUC₀-«, CL, V_d, and t_1/2; and development of antibodies to TRU-016.

[00347] Exploratory assessments will include:

mutational status, β2Μ and ZAP-70 methylation

• Serial Pharmacodynamic monitoring:

• CD37 expression by flow cytometry

• Change in chemokine, cytokine and microvesicle MiRs

[00348] Response will be assessed (clinical signs and symptoms and CBC) monthly until the End of Treatment (EOT) visit, at the EOT visit, 8 weeks after the EOT visit, and subsequently every 3 months until progression of CLL, death, withdrawal from the study, initiation of new therapy, or completion of approximately 24 months of follow-up evaluations after the last treatment. Safety evaluations will include physical examination, assessment of adverse events and laboratory parameters (chemistries, hematology, and urinalysis). Blood samples for testing for antibody formation to TRU-016 will be collected pre-treatment and periodically post-treatment.

[00349] Inclusion Criteria:

treatment: o Progressive splenomegaly and/or lymphadenopathy

• Age≥65 years

• Eastern Cooperative Oncology Group (ECOG) performance status of < 2

• Platelets > 30,000/mm³

[00350] Exclusion Criteria:

• Hepatitis B surface antigen or hepatitis B core antibody positive

• Active autoimmune disease requiring immunosuppressive therapy

[00351] The primary objective of Stage I is to evaluate the safety and tolerabiility of TRU-016 with obinutuzumab and either ibrutinib or idelalisib. The primary objective of Stage II is to compare the complete response rate (CR) and MRD negative rates among the treatment arms.

[00352] The primary efficacy goal is MRD negative rate of 25% with the combination of TRU-016 with obinutuzumab and either ibrutinib or idelalisib. Secondary efficacy endpoints will be summarized with descriptive statistics and graphical techniques. Descriptive statistics will also be used to summarize demographic features, baseline characteristics, and safety endpoints including adverse events and laboratory results. Pharmacodynamic measurements will be summarized. A sample size of 45 treatment patients provides greater than 90% power for a one-sample, one-sided exact binomial test against 8% with a 5% one-sided alpha level if one assumes a MRD negative rate for TRU-016 in combination with obinutuzumab of 25%. The sample size will be 50 subjects to provide 45 evaluable subjects in each cohort. Example 19: Combination of Otlertuzumab (anti-CD37 antibody) and Obinutuzumab (anti- CD20 antibody) Significantly Reduces Tumor Volume and Increases Survival in a Murine Tumor Xenograft Model

[00353] A mouse tumor xenograft study was performed to study the effect of the combination of obinutuzumab (Genentech, NDC 50242-070-01 ) with otlertuzumab (SEQ ID NO:1 ), also known as TRU-016 herein. The study was performed using CB-17 SCID mice (Charles River Laboratoties) and the DOHH2 human B cell lymphoma cell line. DOHH2 cells were grown in vitro, and 5x10⁶ cells were implanted subcutaneously into the right flank of each mouse. Tumors were allowed to grow until the mean tumor volume reached approximately 220 mm³ (7 days). At this time, mice were sorted based on tumor volume and assigned into seven treatment groups (1 to 7) of 10 mice each with equivalent mean tumor volume. The remaining mice were assigned into group 8 as human IgG control (Figure 5A). The body weights of mice in each group on the day of sorting into groups are shown in Figure 5B. Day 8 after tumor implantation was assigned the first day of dosing (and day 0 of study); dosing was performed according to the group assignments in Table 3.

Table 3: Study Design

[00354] Otlertuzumab and obinutuzumab treatments were administered by intraperitoneal (IP) injection at dosages of 10 μg or 30 μg in 200 μΙ_ PBS on Day 0, 4, and 8 of the study. Two treatments were performed by separate IP injection with an interval of at least 4 hours. Tumor volumes were determined with a pair of calipers every other day during the course of the study and calculated using the formula: V=½ [length x (width )2]. Mice were euthanized when tumor volume met or exceeded a volume of 1500 mm³ and other endpoint criteria according to ACUP 20. The experiment was terminated on Day 63 of the study at the time when most groups had reached >50% endpoint (with exception of otiertuzumab alone (30 μg) and otiertuzumab (βθμς) + obinutuzumab (30 μς).

[00355] The effective combination of otiertuzumab and obinutuzumab was first determined by Day 15 and Day 21 tumor volumes. Day 15 was the last time point when all study mice were alive, including human IgG control group, while Day 21 was the last time point when all mice treated with otiertuzumab or/and obinutuzumab were alive. Therefore, Day 15 and Day 21 tumor volumes were used to evaluate differences in tumor volume between the treatment groups. Significant differences in tumor volume were determined using JMP Oneway analysis of nonparametric comparison for Each Pair using Wilcoxon Method.

[00356] Figure 6 shows tumor volumes on Day 15 which was the last time point when all mice were alive in each study group. Figure 7 shows tumor volumes on Day 21 which was the last time point when all mice treated with otiertuzumab or/and obinutuzumab were alive in each group. Individual tumor volumes are plotted with group mean ± standard deviation for all groups on day 15 (Figure 6) or day 21 (Figure 7) of the study. Differences in tumor volumes between the human IgG control group vs. the treatment groups, and also between either otiertuzumab or obinutuzumab alone and the groups treated with combination of otiertuzumab and obinutuzumab were determined using JMP One-way analysis of nonparametric comparison for Each Pair using Wilcoxon Method. Values of p < 0.05 were considered significant. Figure 6 and Table 4 demonstrate that all otiertuzumab or/and obinutuzumab treatments significantly inhibited the tumor growth compared to human IgG control group. As shown in Figures 6-7 and Tables 4-5, both doses of otiertuzumab combined with obinutuzumab treatment at the same dose significantly inhibited the tumor growth compared to each of the agents alone;

otiertuzumab at 30 μg combined with obinutuzumab at 10 μg treatment significantly inhibited the tumor growth compared to obinutuzumab treatment alone, however it did not reach statistical significance compared to otiertuzumab treatment alone at the same dose.

Table 4: Statistical Com arison of Day 15 Tumor Volumes

Obinutuzumabl

0.0010* 0.0013* 10μ3

Table 5: Statistical Comparison of Day 21 Tumor Volumes

[00357] The effect of the combination of otlertuzumab and obinutuzumab was further evaluated by measuring tumor growth over time. The time was defined to the first day when the tumor volume reached the limits (≥ 1500 mm³) in comparing study groups. Day 15 was the first day when the tumor volume reached endpoint limits in the human IgG control group, while Day 21 was the first day when the first mouse treated with otlertuzumab or/and obinutuzumab reached endpoint limits. Therefore, the mean tumor volumes from Day -1 through Day 15 were used to assess the inhibitory effects of treatments on tumor growth compared to human IgG control group, and the mean tumor volumes from Day -1 through Day 21 were used to evaluate the effective combination treatment of otlertuzumab with obinutuzumab on tumor growth compared to either agent alone. Significant differences in the mean tumor volumes over time were determined using JMP repeated measures analysis with both MANOVA and ANOVA methods. Values of p < 0.05 were considered significant. Tumor volumes for each group are plotted as the mean + SEM until first mouse in group reached the endpoint (tumor volume≥ 1500 mm³) and was euthanized (Figures 8-1 1 ).

[00358] As shown in Figure 8 and Table 6, all otlertuzumab or/and obinutuzumab treatments showed significant delay of tumor growth compared to human IgG control group.

Table 6: Statistical Comparison of Mean Tumor Volumes through Day 15

p-Value p-Value

JMP Repeated Measures Analysis

(MANOVA) (ANOVA) hlgG control vs. Otlertuzumab 30μg O.0001* O.0001* hlgG control vs. Otlertuzumab 10μg 0.0040* O.0001*

[00359] A subset of groups treated with otiertuzumab and obinutuzumab at 30 μg dose from Figure 8 is plotted in Figure 9. A subset of groups treated with otiertuzumab and obinutuzumab at 10 μg dose from Figure 8 is plotted in Figure 10. Figures 9-10 and Tables 7-8 indicate the combination of otiertuzumab at 30 μg or 10 μg dose with obinutuzumab treatment at the same dose resulted in statistically significant delay of tumor growth compared to either agent alone.

Table 7: Statistical Comparison of Mean Tumor Volumes through Day 21 in the

Otiertuzumab and Obinutuzumab Treated Groups at 30 Dose

[00360] A subset of groups with otiertuzumab treatment at 30 μg and obinutuzumab treatmenst at 10 μg dose from Figure 8 is plotted in Figure 1 1. Figure 1 1 and Table 9 show the combination of otiertuzumab at 30 μg dose with obinutuzumab at 10 μg dose treatment resulted in statistically significant delay of tumor growth compared to obinutuzumab treatment alone, and it did not reach statistical significance compared to otlertuzumab treatment at the same dose alone.

Table 9: Statistical Comparison of Mean Tumor Volumes through Day 21 in the

Otlertuzumab at 30 and Obinutuzumab at 10 g Groups

[00361] Finally, survival was used as the indicator for effective combination treatment. Survival events were recorded each time a mouse reached an endpoint and was sacrificed. The experiment was terminated on study day 58. All remaining mice were sacrificed at that time when the experiment ended. Median survival and statistical significance was calculated using Prism® Kaplan-Meier survival analysis with a log-rank test for comparing survival curves. Values of p < 0.05 were considered significant. As illustrated in Figure 12 and summarized in Table 10, the survival of mice treated with otlertuzumab or/and obinutuzumab was significantly prolonged compared to human IgG control group. The survival of mice treated with otlertuzumab at 10 μg dose combined with obinutuzumab at the same dose was significantly prolonged relative to mice treated with either agent alone; otlertuzumab treatment at 30μg dose combined with obinutuzumab at 30 μg or 10 μg dose was significantly prolonged relative to mice treated with obinutuzumab at the same dose alone, however, it did not reach statistical significance compared to otlertuzumab at the same dose alone.

Table 10: Survival Statistics Comparison by Log-rank (Mantel-Cox) Test

Otiertuzumab

30μς +

5 Undefined < 0.0001* 0.5097 0.0001*

Obinutuzumab

30μς

Otiertuzumab

30μς +

6 54 < 0.0001* 0.2426 < 0.0001* Obinutuzumab

10_Mg

Otiertuzumab

10_Mg

7 + 40 < 0.0001* 0.0085* 0.0007*

Obinutuzumab

10_Mg

8 hlgG 30 g 16

[00362] Taken together, the combination of otiertuzumab and obinutuzumab in vivo resulted in greater efficacy relative to either agent alone in DOHH-2 xenograft tumor models. In addition, statistically significant increases in overall survival were observed in the animals treated with the combination of otiertuzumab and obinutuzumab at 10 μg doses compared to either agent alone, and the combination of otiertuzumab at 30 μg and obinutuzumab at 30 μg or 10μg compared to obinutuzumab at the same doses alone. These results indicate that the treatment of otiertuzumab in combination with obinutuzumab may be beneficial in treatment of human lymphoma.

Example 20: Triple Combination of Otiertuzumab (anti-CD37 antibody) with Obinutuzumab (anti-CD20 antibody) and PI3K inhibitor (LY2940002) Siqnificantlv Reduces Tumor Volume and Increases Survival in a Murine Tumor Xenograft Model

[00363] A mouse tumor xenograft study was performed to study the effect of the triple combination of otiertuzumab, obinutuzumab (Genentech, NDC 50242-070-01 ), and a pan- PI3K inhibitor, LY294002 (Selleckchen, #S1 105). Idelalisib, an inhibitor of the PI3K5 isoform, has been recently approved for the treatment of three B cell malignancies including chronic lymphocytic leukemia (CLL), relapsed follicular B-cell non-Hodgkin lymphoma (FL) and small lymphocytic lymphoma (SLL). However, the idelalisib molecule used in the clinic has a poor half-life in mice and there is no equivalent of the idelalisib molecule that can be used in vivo in mice. Therefore, a pan-PI3K inhibitor LY294002 was used in the present study to test the efficiacy of the triple combination of otiertuzumab, obinutuzumab and a PI3K inhibitor.

[00364] The study was conducted using CB-17 SCID mice (Charles River

Laboratoties) and the DOHH2 human B cell lymphoma cell line. DOHH2 cells were grown in vitro, and 5x10⁶ cells were implanted subcutaneously into the right flank of each mouse.

Tumors were allowed to grow until the mean tumor volume reached approximately 247 mm³ (7 days). At this time, mice were sorted based on tumor volume, and assigned into eight treatment groups of 10 mice each with equivalent mean tumor volume (Figure 13A). The body weights in each group on the day of sorting into groups are shown (Figure 13B). Day 8 after tumor implantation was assigned the first day of dosing (and day 0 of study); dosing was performed according to the group assignments in Table 1 1.

Table 11 : Study Design

[00365] Otlertuzumab and obinutuzumab treatments were administered by intraperitoneal (IP) injection at dosage of 10 μg in 200 μΙ_ PBS on Day 0, 4, and 8 of the study; LY294002 treatment was administered by intraperitoneal (IP) injection at dosage of 250 μg in 100 μΙ_ 50% DMSO-PBS on Day 0, 3, 6, and 9 of the study. Three treatments were performed by separate IP injection with an interval of at least 4 hours. Tumor volumes were determined with a pair of calipers every other day during the course of the study and calculated using the formula: V=½ [length x (width)²]. Mice were euthanized when tumor volume met or exceeded a volume of 1500 mm³ and other endpoint criteria according to ACUP 20. The experiment was terminated on Day 40 of the study when at least half the mice in all treatment groups reached the endpoint.

[00366] The effective combination of otlertuzumab with obinutuzumab and

LY294002 was first determined by Day 13 and Day 17 tumor volumes. Day 13 was the last time point when all study mice were alive, including human IgG control group, while Day 17 was the last time point when all mice treated with otlertuzumab, obinutuzumab or/and LY294002 were alive. Therefore, Day 13 and Day 17 tumor volumes were used to evaluate differences in tumor volume between the treatment groups.

[00367] Tumor volumes on Day 13 which was the last time point when all mice were alive in each study group are shown in Figure 14. Tumor volumes on Day 17 which was the last time point when all mice treated otiertuzumab, obinutuzumab, or/and LY294002 were alive in each study group are shown in Figure 15. Individual tumor volumes are plotted with group mean ± standard deviation for all groups on day 13 or 17 of the study. Differences in tumor volume between the treatment groups were determined using JMP One-way analysis of nonparametric comparison for Each Pair using Wilcoxon Method. Values of p < 0.05 were considered significant. Figure 14 and Table 12 demonstrate that all otiertuzumab,

obinutuzumab or/and LY294002 treatments significantly reduced the Day 13 tumor size compared to human IgG control group and the triple combination treatment of otiertuzumab with obinutuzumab and LY294002 significantly reduced the Day 13 tumor size compared to each of the agents alone and the dual combination treatments (Table 12). As shown in Figures 14-15 and Tables 12-13, the triple combination treatment of otiertuzumab with obinutuzumab and LY294002 significantly reduced the Day 17 tumor size compared to each of the agents alone and the dual combination treatments.

Table 12: Statistical Comparison of Day 13 Tumor Volumes

Table 13: Statistical Comparison of Day 17 Tumor Volumes

[00368] The effect of the triple combination of otlertuzumab with obinutuzumab and LY294002 was further evaluated by measuring tumor growth over time. The time was defined to the first day when the tumor volume reached endpoint limits (≥ 1500 mm³) in comparing study groups. Day 13 was the first day when the tumor volume reached endpoint limits in the human IgG control group, while Day 17 was the first day when the first mouse treated with LY294002 reached endpoint limits. Therefore, the mean tumor volumes from Day -1 through Day 13 were used to assess the inhibitory effects of treatments on tumor growth compared to human IgG control group, and the mean tumor volumes from Day -1 through Day 17 were used to evaluate the effective triple combination treatment of otlertuzumab with obinutuzumab and LY2940002 on tumor growth compared to each of the agents alone or the dual combination treatments.

[00369] Tumor volumes for each group are plotted as the mean + SEM until the first mouse in group reached the endpoint (tumor volume≥ 1500 mm³) and was euthanized.

Differences in mean tumor volume from day -1 through day 13 between the human IgG control group vs. the treatment groups and also from day-1 through day 17 between the treatment groups were determined using JMP repeated measures analysis with MANOVA method.

Values of p < 0.05 were considered significant. As shown in Figure 16 and Tables 14-15, most treatments showed significant delay of tumor growth compared to human IgG control group with exception of LY294002 alone (Tabel 14); the triple combination of otlertuzumab with obinutuzumab and LY294002 treatment resulted in statistically significant delay of tumor growth compared to otlertuzumab or LY294002 alone. However, while the delay of tumor growth was observed in triple combination treatment, it did not reach statistical significance compared to obinutuzumab alone and the dual combination treatments. Table 14: Statistical Comparison of Mean Tumor Volumes through Day 13

[00370] Finally, survival was used as the indicator for effective combination treatment. Survival events were recorded each time a mouse reached an endpoint and was sacrificed. The experiment ended on study day 40. All remaining mice were sacrificed at that time when the experiment ended. Median survival and statistical significance were determined using Prism® Kaplan-Meier survival analysis with a log-rank test for comparing survival curves. As illustrated in Figure 17 and summarized in Table 16, the survival of mice treated with otiertuzumab, obinutuzumab or/and LY294002 was significantly prolonged compared to human IgG control group. The survival of mice treated with the triple combination of otiertuzumab with obinutuzumab and LY294002 was significantly prolonged relative to mice treated with

LY294002 alone and the dual combination of LY294002 with otiertuzumab or with

obinutuzumab. However, while a median survival time was improved, the triple combination did not reach statistical significance compared to otiertuzumab or obinutuzumab alone, or to the dual combination of otiertuzumab with obinutuzumab.

Table 16: Survival Statistics Com arison by Log-rank (Mantel-Cox) Test

[00371] Taken together, the triple combination of otiertuzumab with obinutuzumab and LY294002 treatment in vivo resulted in greater efficacy relative to each of the agents alone or to the dual combination of these agents in DOHH-2 xenograft tumor model. In addition, improvement on overall median survival was observed in the animals treated with the triple combination compared to each of the agents alone and to the dual combination treatments. These results indicate that the treatment of the triple combination of otiertuzumab with obinutuzumab and a PI3K inhibitor may be beneficial in treatment of human lymphoma.

Example 21 : In Vivo Triple Combination Study of Otiertuzumab with Anti-CD20 Antibody - Obinutuzumab and Btk Inhibitor - Ibrutinib

[00372] This study was designed to examine the triple combination of an anti-CD37 molecule (otiertuzumab) with an anti-CD20 antibody (obinutuzumab (Genentech, NDC 50242- 070-01 )) and a Btk inhibitor (ibrutinib (PCI-32765, Selleckchen, #S2680)).

[00373] A mouse tumor xenograft study was performed using CB-17 SCID mice (Charles River Laboratoties) and the Mino human mantle cell lymphoma cell line (ATCC, CRL- 3000). Mino cells were grown in vitro, and 5x10⁶ cells in 50 μί growth medium were mixed with an equal volume of BD Matrigel and implanted subcutaneously into the right flank of each mouse. Tumors were allowed to grow until the mean tumor volume (without subtraction of the baseline Matrigel measurement) reached approximately 351 mm³ ( 10 days). At this time, mice were sorted based on tumor volume and assigned into treatment groups of 12 mice each with equivalent mean tumor volume (Figure 18A). Body weights in each treatment group are shown in Figure 18B). Day 1 1 post tumor implantation was assigned the first day of dosing (and day 0 of study); dosing was performed according to the group assignments in Table 17.

Table 17: Study Design

[00374] Otlertuzumab, obinutuzumab and human IgG (control) treatments were administered by intraperitoneal (IP) injection at 200 μg of otlertuzumab and 10 μg or 3μg of obinutuzumab in 200 μΙ_ DPBS on Day 0, 4, 8, 12, 16, and 20 of the study. Ibrutinib treatment was administered via oral gavage for consecutive 28 days at 150 μg per day in 200 μΙ_ of 1 % Methylcellulose + 0.4% Cremephor EL water (PO vehicle). Tumor volumes were determined with a pair of calipers on Monday, Wednesday, and Friday schedule during the course of the study and calculated using the formula: V=½ [length x (width)²]. Mice were euthanized when tumor volumes met or reached greater than 1500 mm³, or by other endpoint criteria defined in ACUP 20. The experiment was terminated on Day 57 of the study when at least half the mice in all treatment groups reached the endpoint. [00375] The effective combination of otlertuzumab with obinutuzumab and ibrutinib was first determined by Day 22 and Day 27 tumor volumes. Day 22 was the last time point when all study mice were alive, including human IgG control group, while Day 27 was the last time point when all mice treated with otlertuzumab, obinutuzumab or/and ibrutinib were alive. Therefore, Day 22 and Day 27 tumor volumes were used to evaluate differences in tumor volume between the treatment groups. Significant differences in tumor volume were determined using JMP One-way analysis of nonparametric comparison for Each Pair using Wilcoxon Method. Figure 19 & Table 18 demonstrate that all otlertuzumab, obinutuzumab or/and ibrutinib treatments significantly reduced the Day 22 tumor size compared to human IgG control group. As shown in Figures 19 & 20 and Tables 18 & 19, otlertuzumab treatment combined with ibrutinib or obintuzumab at 10 μg dose significantly reduced the Day 22 and Day 27 tumor sizes compared to each of the agents alone; there was no reduction of the Day 22 and Day 27 tumor sizes in obinutuzumab treatment combined with ibrutinib when compared to obinutuzumab alone.

Table 18: Statistical Comparison of Day 22 Tumor Volumes

^* Indicates p-value < 0.05

OtI = Otlertuzumab; Obi = Obinutuzumab; Ibr

** P-value displays that the dual combination of OtI with Obi resulted in greater anti-tumor efficacy than the triple combination of OtI with Obi and Ibr

Table 19: Statistical Comparison of Day 27 Tumor Volumes

Otl + Obi "Ι Ομς 0.0194**

Otl + Obi 3μg

Otl + Ibr 0.2366

Obi + Ibr 0.2855

^* Indicates p-value < 0.05

Otl = Otiertuzumab; Obi = Obinutuzumab; Ibr

** P-value displays that the dual combination of otl with obi resulted in greater anti-tumor efficacy than the triple combination of otl with obi and ibr

[00376] Although, the triple combination treatment of otiertuzumab with

obinutuzumab and ibrutinib significantly reduced the Day 22 and Day 27 tumor sizes compared to otiertuzumab or ibrutinib alone, no significant reduction of tumor size was observed when compared to obinutuzumab alone and the dual combination treatments. Furthermore, the triple combination of otiertuzumab with obinutuzumab and ibrutinib treatment resulted in statistically significant greater tumor size on the Day 22 and Day 27 compared to the dual combination treatment of otiertuzumab with obintuzumab at 10μg dose.

[00377] Next, the effect of the triple combination of otiertuzumab with obinutuzumab and ibrutinib was evaluated by tumor growth over time. The time was defined to the first day when the tumor volume reached endpoint limits (≥ 1500 mm³) in comparing study groups. Day 22 was the first day when the tumor volume reached endpoint limits in the human IgG control group, while Day 27 was the first day when the first mouse treated with ibrutinib reached endpoint limits. Therefore, the mean tumor volumes from Day -1 through Day 22 were used to assess the inhibitory effects of treatments on tumor growth compared to human IgG control group, and the mean tumor volumes from Day -1 through Day 27 were used to evaluate the effective triple combination treatment of otiertuzumab with obinutuzumab and ibrutinib on tumor growth compared to each of the agents alone or the dual combination treatments. Significant differences in the mean tumor volume over time were determined using JMP repeated measures analysis with ANOVA Greenhouse-Geisser Correction method. Values of p < 0.05 were considered significant. Figure 21 & Table 20 demonstrate all treatments showed significant delay of tumor growth compared to human IgG control group.

Table 20: Statistical Comparison of Mean Tumor Volumes through Day 22

JMP Repeated Measures Analysis

p-Value

ANOVA G-G Method

Otiertuzumab 200μg vs. hlgG control 0.0003*

Obinutuzumab 10μg vs. hlgG control O.0001*

Obinutuzumab 3μg vs. hlgG control O.0001*

Ibrutinib 150μg vs. hlgG control 0.0028*

Otiertuzumab 200μg + Obinutuzumab 10μg vs. hlgG O.0001*

^* Indicates p- value < 0.05

[00378] As shown in Figures 22 to 26 & Tables 21 to 25, otlertuzumab treatment combined with ibrutinib or obinutuzumab at 10 μg resulted in statistically significant delay of tumor growth compared to each of the agents alone, whereas obinutuzumab combined with ibrutinib treatment resulted in reduced effect on tumor growth compared to obinutuzumab alone (Figure 24).

Table 21: Statistical Comparison of Mean Tumor Volumes through Day 27

^* Indicates p- value < 0.05

Table 22: Statistical Comparison of Mean Tumor Volumes through Day 27

^* Indicates p- value < 0.05

Table 23: Statistical Comparison of Mean Tumor Volumes through Day 27

^* Indicates p- value < 0.05

Table 24: Statistical Comparison of Mean Tumor Volumes through Day 27

JMP Repeated Measures Analysis

p-Value

ANOVA G-G Method Otler + Obinu + Ibrut vs. Otler 0.0634

Otler + Obinu + Ibrut vs. Obinu 0.2167

Otler + Obinu + Ibrut vs. Ibrut 0.0041*

^* Indicates p- value < 0.05

Table 25: Statistical Comparison of Mean Tumor Volumes through Day 27

JMP Repeated Measures Analysis

p-Value

ANOVA G-G Method

Otler + Obinu + Ibrut vs. Otler + Obinu 0.0007**

Otler + Obinu + Ibrut vs. Otler + Ibrut 0.0918

Otler + Obinu + Ibrut vs. Obinu + Ibrut 0.5466

^* Indicates p- value < 0.05

^** P-value displays that the dual combination of otlertuzumab with obinutuzumab resulted in greater anti-tumor efficacy than the triple combination of otlertuzumab with obinutuzumab and ibrutinib

[00379] The triple combination of otlertuzumab with obinutuzumab and ibrutinib treatment resulted in a statistically significant delay of tumor growth compared to ibrutinib alone only; there was no significant delay of tumor growth in triple combination treatment compared to otlertuzumab or obinutuzumab alone, or to the dual combination treatments. In contrast, the triple combination of otlertuzumab with obinutuzumab and ibrutinib treatment displayed statistically significant reduction of anti-tumor efficacy compared to the dual combination of otlertuzumab with obintuzumab (Figure 26 & Table 25).

[00380] Survival was also used as an indicator for effective combination treatment. Significant differences in median survival of mice were determined using Prism® Kaplan-Meier survival analysis with a log-rank test for comparing survival curves. As illustrated in Figure 27 and summarized in Table 26, the survival of mice treated with otlertuzumab, obinutuzumab or/and ibrutinib was significantly prolonged compared to human IgG control group.

Table 26: Survival Statistics Comparison by Log-rank (Mantel-Cox) Test

3 Obinu Ι Ομς 50 < 0.0001* 0.7830 0.7378 0.7391

4 Obinu 3μς 38 0.0001* 0.0766

5 Ibrut "Ι δθμς 36 0.0139* 0.0001* 0.0002* < 0.0001*

Otler +

6 55 < 0.0001* 0.1890 Obinu 10μ9

Otler+

7 45 < 0.0001*

Obinu 3μ9

Otler+

8 46.5 < 0.0001* 0.3251 Ibrut

Obinu +

9 46.5 < 0.0001* 0.8583 Ibrut

Otler +

10 Obinu + 50 < 0.0001*

Ibrut

^* Indicates p- value < 0.05

[00381] The survival of mice treated with the triple combination of otiertuzumab with obinutuzumab and ibrutinib was significantly prolonged relative to mice treated with ibrutinib alone only; there was no significant improvement of survival time in triple combination treatment compared to otiertuzumab or obinutuzumab alone, or to the dual combination treatments.

[00382] This in vivo study demonstrated otiertuzumab combined with ibrutinib or obinutuzumab resulted in greater efficacy relative to each of the agents alone in the Mino xenograft tumor model. The triple combination of otiertuzumab with obinutuzumab and ibrutinib did not display greater anti-tumor efficacy than the dual combinations of otiertuzumab with obinutuzumab or ibrutinib. Adding either obinutuzumab or ibrutinib to otlertuzmab treatment may be beneficial in treating human cancers.

[00383] Numerous modifications and variations in the invention as set forth in the above illustrative examples are expected to occur to those skilled in the art. Consequently only such limitations as appear in the appended claims should be placed on the invention. All publications cited herein are incorporated herein by reference in their entireties for all purposes.

Claims

WHAT IS CLAIMED is:

1. A method of treating a patient with a B cell malignancy or disorder comprising administering to the patient a therapeutically effective amount of an anti-CD37 antibody or antibody fragment that binds human CD37 with specificity and a therapeutically effective amount of an anti-CD20 antibody or antibody fragment that binds human CD20 with specificity.

2. The method of claim 1 , wherein the anti-CD20 antibody is selected from the group consisting of ofatumumab, veltuzumab, ocrelizumab and obinutuzumab.

3. The method of any one of claims 1 and 2, wherein the anti-CD20 antibody is obinutuzumab.

4. The method of any one of claims 1-3, wherein the anti-CD37 antibody or antibody fragment comprises a humanized or chimeric antibody or antibody fragment that binds CD37 with specificity.

5. The method of claim 4, wherein the anti-CD37 antibody or antibody fragment comprises a humanized or chimeric antibody or antibody fragment derived from a monoclonal antibody selected from the group consisting of G28-1 , MB371 , BL14, NMN46, IP024, HH1 , WR17, HD28, BI14, F93G6, RFB-7, Y29/55, MB-1 , M-B371 , IPO-24, S-B3 and K7153A.

6. The method of any one of claims 4-5, wherein the anti-CD37 antibody or antibody fragment comprises a humanized or chimeric monoclonal antibody derived from G28-1.

7. The method of any one claims 4 and 6, wherein the humanized or chimeric antibody or antibody fragment binds to the same epitope as G28-1 or competes with binding to an epitope with G28-1.

8. The method of claim 4, wherein the humanized or chimeric antibody or antibody fragment comprises a variable heavy chain with a HCDR1 , HCDR2 and an HCRD3 and comprises a variable light chain with a LCDR1 , LCDR2, and LCDR3;

wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:8, HCDR2 comprises the amino acid sequence of SEQ ID NO:1 1 , and HCDR3 comprises the amino acid sequence of SEQ ID NO: 14;

wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:9 or SEQ ID NO:10, HCDR2 comprises the amino acid sequence of SEQ ID NO:12 or SEQ ID NO:13, and HCDR3 comprises the amino acid sequence of SEQ ID NO: 15, SEQ ID NO:16 or SEQ ID NO:17; or

wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:30, HCDR2 comprises the amino acid sequence of SEQ ID NO:31 , and HCDR3 comprises the amino acid sequence of SEQ ID NO:32.

9. The method of claim 4, wherein the humanized or chimeric antibody or antibody fragment comprises a variable heavy chain with a HCDR1 , HCDR2 and an HCRD3 and comprises a variable light chain with a LCDR1 , LCDR2, and LCDR3;

wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:8, HCDR2 comprises the amino acid sequence of SEQ ID NO:1 1 , HCDR3 comprises the amino acid sequence of SEQ ID NO: 14, LCDR1 comprises the amino acid sequence of SEQ ID NO: 18, LCDR2 comprises the amino acid sequence of SEQ ID NO:22, and LCDR3 comprises the amino acid sequence of SEQ ID NO:24;

wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:9 or SEQ ID NO:10, HCDR2 comprises the amino acid sequence of SEQ ID NO:12 or SEQ ID NO:13, and HCDR3 comprises the amino acid sequence of SEQ ID NO:15, SEQ ID NO:16 or SEQ ID NO:17, LCDR1 comprises the amino acid sequence of SEQ ID NO: 19 or SEQ ID NO:20, LCDR2 comprises the amino acid sequence of SEQ ID NO:23, and LCDR3 comprises the amino acid sequence of SEQ ID NO:25; or

wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:30, HCDR2 comprises the amino acid sequence of SEQ ID NO:31 , and HCDR3 comprises the amino acid sequence of SEQ ID NO:32, LCDR1 comprises the amino acid sequence of SEQ ID NO:33, LCDR2 comprises the amino acid sequence of SEQ ID NO:34, and LCDR3 comprises the amino acid sequence of SEQ ID NO:35.

10. The method of claim 4, wherein the anti-CD37 antibody or antibody fragment comprises a variable heavy chain comprising an amino acid with 90% identity to the amino acid of SEQ ID NO: 5 or SEQ ID NO:27.

1 1. The method of claim 4, wherein the anti-CD37 antibody or antibody fragment comprises a variable heavy chain comprising an amino acid with 95% identity to the amino acid of SEQ ID NO: 5 or SEQ ID NO:27.

12. The method of claim 4, wherein the anti-CD37 antibody or antibody fragment comprises a variable heavy chain of SEQ ID NO: 5 or SEQ ID NO:27.

13. The method of any one of claims 4 and 10-12, wherein the anti-CD37 antibody or antibody fragment comprises a variable light chain comprising an amino acid with 90% identity to the amino acid of SEQ ID NO:7 or SEQ ID NO:29.

14. The method of any one of claims 4 and 10-12, wherein the anti-CD37 antibody or antibody fragment comprises a variable light chain comprising an amino acid with 95% identity to the amino acid of SEQ ID NO:7 or SEQ ID NO:29.

15. The method of any one of claims 4 and 10-12, wherein the anti-CD37 antibody or antibody fragment comprises a variable light chain of SEQ ID NO:7 or SEQ ID NO:29.

16. The method of claim 4, wherein the anti-CD37 antibody or antibody fragment comprises a variable heavy chain comprising an amino acid with 90% identity to the amino acid of SEQ ID NO:38 or SEQ ID NO:39.

17. The method of claim 4, wherein the anti-CD37 antibody or antibody fragment comprises a variable heavy chain comprising an amino acid with 95% identity to the amino acid of SEQ ID NO:38 or SEQ ID NO:39.

18. The method of claim 4, wherein the anti-CD37 antibody or antibody fragment comprises a variable heavy chain of SEQ ID NO:38 or SEQ ID NO:39.

19. The method of any one claims 4 and 16-18, wherein the anti-CD37 antibody or antibody fragment comprises a variable light chain comprising an amino acid with 90% identity to the amino acid of SEQ ID NO:43.

20. The method of any one of claims 4 and 16-18, wherein the anti-CD37 antibody or antibody fragment comprises a variable light chain comprising an amino acid with 95% identity to the amino acid of SEQ ID NO:43

21. The method of any one of claims 4 and 16-18, wherein the anti-CD37 antibody or antibody fragment comprises SEQ ID NO:43.

22. The method of any one of claims 1-21 , wherein the anti-CD37 antibody comprises a monoclonal antibody or recombinant polypeptide.

23. The method of any one of claims 1-22, wherein the anti-CD37 antibody comprises a bispecific or multispecific binding molecule.

24. The method of claim 23, wherein the multispecific binding molecule comprises an amino acid sequence with at least about 90% identity to an amino acid of SEQ ID NO:46, SEQ ID NO:48, SEQ ID NO:50, SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:56, SEQ ID NO:58, SEQ ID NO:60, or SEQ ID NO:63.

25. The method of claim 23, wherein the multispecific binding molecule comprises an amino acid sequence with at least about 95% identity to an amino acid of SEQ ID NO:46, SEQ ID NO:48, SEQ ID NO:50, SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:56, SEQ ID NO:58, SEQ ID NO:60, or SEQ ID NO:63.

26. The method of claim 23, wherein the multispecific binding molecule comprises SEQ ID NO:46, SEQ ID NO:48, SEQ ID NO:50, SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:56, SEQ ID NO:58, SEQ ID NO:60, or SEQ ID NO:63.

27. The method of any one of claims 1-26, wherein the anti-CD37 antibody or antibody fragment comprises an antibody or antibody fragment fused or conjugated to a toxin or small molecule therapeutic.

28. The method of any one of claims 1-7, wherein the anti-CD37 antibody or antibody fragment comprises an amino acid with at least about 90% identity to the amino acid of SEQ ID NO:3 or amino acid s 21 to 503 of SEQ ID NO:1.

29. The method of any one of claims 1-7, wherein the anti-CD37 antibody or antibody fragment comprises an amino acid with at least about 95% identity to the amino acid of SEQ ID NO:3 or amino acid s 21 to 503 of SEQ ID NO:1.

30. The method of any one of claims 1-7, wherein the anti-CD37 antibody or antibody fragment comprises SEQ ID NO:3 or amino acid s 21 to 503 of SEQ ID NO:1.

31. The method of any one of claims 1-23, wherein the anti-CD37 antibody or antibody fragment comprises, from amino to carboxyl terminus, a CD37 binding domain, an

immunoglobulin hinge domain, and an immunoglobulin constant region.

32. The method of any one of claims 1-23, wherein the anti-CD37 antibody or antibody fragment comprises dimerized single chain polypeptides, each single chain polypeptide comprising, from amino to carboxyl terminus, a CD37 binding domain, an immunoglobulin hinge domain and an immunoglobulin constant region.

33. The method of any one of claims 4-7, wherein the anti-CD37 antibody or antibody fragment comprises, from amino to carboxyl terminus, a binding domain capable of binding CD37, an immunoglobulin hinge domain, an immunoglobulin CH2 region and an immunoglobulin CH3 region.

34. The method of claim 33, wherein the immunoglobulin hinge domain, immunoglobulin CH2 region and immunoglobulin CH3 region are derived from a human lgG1 immunoglobulin.

35. The method of any one of claims 4-14, wherein the anti-CD37 antibody or antibody fragment comprises a bispecific or multispecific antibody that binds CD37.

36. The method of any one of claims 1-35, wherein the human CD37 comprises an amino acid of SEQ ID NO:61.

37. The method of any one of claims 1-36, wherein the B cell malignancy or disorder is selected from the group consisting of Hodgkin's disease, non-Hodgkin's lymphoma (NHL), a central nervous system lymphoma, small lymphocytic lymphoma, a leukemia, prolymphocytic leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, chronic myoblastic leukemia, a myelomas (such as multiple myeloma), small lymphocytic lymphoma, B-cell prolymphocytic leukemia, a lymphoplasmacytic lymphoma (including Waldenstrom's macroglobulinemia), a marginal zone lymphoma (including splenic marginal zone lymphoma and nodal marginal zone B-cell lymphoma), a plasma cell myeloma/plasmacytoma, solitary plasmacytoma of bone, extraosseous plasmacytoma, nodal marginal zone lymphoma, extra-nodal marginal zone B-cell lymphoma of mucosa-associated (MALT) lymphoid tissue, follicular lymphoma, mantle cell lymphoma (MCL), diffuse large B-cell lymphoma, transforming large B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma/leukemia, B-cell proliferations of uncertain malignant potential, lymphomatoid granulomatosis, and post-transplant lymphoproliferative disorder.

38. The method of any one of claims 1-36, wherein the B cell malignancy or disorder is selected from the group consisting of arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, polychondritis, psoriatic arthritis, psoriasis, dermatitis,

polymyositis/dermatomyositis, inclusion body myostitis, inflammatory myositis, toxic epidermal necrolysis, systemic scleroderma and sclerosis, CREST syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, respiratory distress syndrome, meningitis, encephalitis, uveitis, colitis, glomerulonephritis, allergic conditions, eczema, asthma, conditions involving infiltration of T cells and chronic inflammatory responses, atherosclerosis, autoimmune myocarditis, leukocyte adhesion deficiency, systemic lupus erythematosus (SLE), subacute cutaneous lupus erythematosus, lupus, juvenile onset diabetes, multiple sclerosis, allergic encephalomyelitis, neuromyelitis, rheumatic fever, Sydenham's chorea, immune responses associated with acute and delayed hypersensitivity mediated by cytokines and T- lymphocytes, tuberculosis, sarcoidosis, granulomatosis including Wegener's granulomatosis and Churg-Strauss disease, agranulocytosis, vasculitis, (including hypersensitivity vasculitis/angiitis, ANCA and rheumatoid vasculitis), aplastic anemia, Diamond Blackfan anemia, immune hemolytic anemia including autoimmune hemolytic anemia (AIHA), pernicious anemia, pure red cell aplasia (PRCA), Factor VIII deficiency, hemophilia A, autoimmune neutropenia, pancytopenia, leukopenia, diseases involving leukocyte diapedesis, central nervous system (CNS) inflammatory disorders, multiple organ injury syndrome, myasthenia gravis, antigen-antibody complex mediated diseases, anti-glomerular basement membrane disease, anti-phospholipid antibody syndrome, allergic neuritis, Behcet disease, Castleman's syndrome, Goodpasture's syndrome, Lambert-Eaton Myasthenic Syndrome, Reynaud's syndrome, Sjorgen's syndrome, Stevens-Johnson syndrome, solid organ transplant rejection, graft versus host disease (GVHD), pemphigoid bullous, pemphigus, autoimmune

polyneuropathies or IgM mediated neuropathy, idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), Henoch-Schonlein purpura, autoimmune thrombocytopenia, autoimmune disease of the testis and ovary including autoimmune orchitis and oophoritis, primary hypothyroidism; autoimmune endocrine diseases including autoimmune thyroiditis, chronic thyroiditis (Hashimoto's Thyroiditis), subacute thyroiditis, idiopathic hypothyroidism, Addison's disease, Grave's disease, autoimmune polyglandular syndromes (or polyglandular endocrinopathy syndromes), Type I diabetes also referred to as insulin- dependent diabetes mellitus (IDDM) and Sheehan's syndrome; autoimmune hepatitis, lymphoid interstitial pneumonitis (HIV), bronchiolitis obliterans (non-transplant) vs NSIP, Guillain-Barre' Syndrome, large vessel vasculitis (including polymyalgia rheumatica and giant cell (Takayasu's) arteritis), medium vessel vasculitis (including Kawasaki's disease and polyarteritis nodosa), polyarteritis nodosa (PAN) ankylosing spondylitis, Berger's disease (IgA nephropathy), rapidly progressive glomerulonephritis, primary biliary cirrhosis, Celiac sprue (gluten enteropathy), cryoglobulinemia, cryoglobulinemia associated with hepatitis, chronic obstructive pulmonary disease (COPD), amyotrophic lateral sclerosis (ALS), coronary artery disease, familial

Mediterranean fever, microscopic polyangiitis, Cogan's syndrome, Whiskott-Aldrich syndrome and thromboangiitis obliterans, autoimmune thyroid disease (such as Graves' disease and Hashimoto's thyroiditis), Sjogren's syndrome, and idiopathic inflammatory myopathy (MM), including dermatomyositis (DM) and polymyositis (PM).

39. The method of any one of claims 1-38, wherein the anti-CD37 antibody or antibody fragment and the anti-CD20 antibody or antibody fragment are administered simultaneously or sequentially in a 24 hour period.

40. The method of any one of claims 1-38, wherein the anti-CD37 antibody or antibody fragment and the anti-CD20 antibody or antibody fragment are administered sequentially and further wherein the anti-CD37 antibody or antibody fragment and the anti-CD20 antibody or antibody fragment exert an overlapping therapeutic effect.

41. The method of any one of claims 1-40, wherein the anti-CD20 antibody or antibody fragment is administered prior to the anti-CD37 antibody or antibody fragment.

42. The method of any one of claims 1-41 , wherein the administration of the anti-CD37 antibody or antibody fragment and the anti-CD20 antibody or antibody fragment results in B cell reduction or B cell depletion.

43. The method of any one of claims 1-41 , wherein administration of the anti-CD37 antibody or antibody fragment and the anti-CD20 antibody or antibody fragment results in a synergistic reduction of tumor size or number of tumors.

44. The method of any one of claims 1-41 , wherein administration of the anti-CD37 antibody or antibody fragment and the anti-CD20 antibody or antibody fragment results in a synergistic survival time.

45. A method of reducing or depleting B cells comprising exposing B cells to a synergistic combination of at least one anti-CD37 antibody and at least one anti-CD20 antibody.

46. The method of claim 45, wherein the anti-CD20 antibody is selected from the group consisting of ofatumumab, veltuzumab, ocrelizumab and obinutuzumab.

47. The method of any one of claims 45 and 46, wherein the anti-CD20 antibody is

obinutuzumab.

48. The method of any one of claims 1-47, wherein the anti-CD37 antibody or antibody fragment is administered in a dose range of about 0.01 to about 50 mg/kg.

49. The method of any one of claims 1-47, wherein the anti-CD37 antibody or antibody fragment is administered in a dose range of about 0.015 to about 30 mg/kg.

50. The method of any one of claims 1-47, wherein the anti-CD37 antibody or antibody fragment is administered in a dose range of about 0.015, about 0.05, about 0.15, about 0.5, about 1.5, about 5, about 15 or about 30 mg/kg.

51. An anti-CD37 antibody or antibody fragment for the manufacture of a medicament for treatment of a B-cell malignancy or disorder, wherein said anti-CD37 antibody or antibody fragment is administered in combination with an anti-CD20 antibody.

52. An anti-CD37 antibody or antibody fragment for the manufacture of a medicament for treatment of a B-cell malignancy or disorder, wherein said anti-CD37 antibody or antibody fragment is administered in combination with an anti-CD20 antibody is selected from the group consisting of ofatumumab, veltuzumab, ocrelizumab and obinutuzumab.

53. An anti-CD37 antibody or antibody fragment for the manufacture of a medicament for treatment of a B-cell malignancy or disorder, wherein said anti-CD37 antibody or antibody fragment is administered in combination with an anti-CD20 antibody for treatment of a B-cell malignancy or disorder selected from the list consisting of Hodgkin's disease, non-Hodgkin's lymphoma (NHL), a central nervous system lymphoma, small lymphocytic lymphoma, a leukemia, prolymphocytic leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, chronic myoblastic leukemia, a myelomas (such as multiple myeloma), small lymphocytic lymphoma, B-cell prolymphocytic leukemia, a lymphoplasmacytic lymphoma (including Waldenstrom's macroglobulinemia), a marginal zone lymphoma (including splenic marginal zone lymphoma and nodal marginal zone B-cell lymphoma), a plasma cell myeloma/plasmacytoma, solitary plasmacytoma of bone, extraosseous plasmacytoma, nodal marginal zone lymphoma, extra- nodal marginal zone B-cell lymphoma of mucosa-associated (MALT) lymphoid tissue, follicular lymphoma, mantle cell lymphoma (MCL), diffuse large B-cell lymphoma, transforming large B- cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma/leukemia, B-cell proliferations of uncertain malignant potential, lymphomatoid granulomatosis, and post-transplant

lymphoproliferative disorder.

54. An anti-CD37 antibody or antibody fragment for the manufacture of a medicament for treatment of a B-cell malignancy or disorder, wherein said anti-CD37 antibody or antibody fragment is administered in combination with an anti-CD20 antibody for treatment of a B-cell malignancy or disorder selected from the list consisting of arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, polychondritis, psoriatic arthritis, psoriasis, dermatitis, polymyositis/dermatomyositis, inclusion body myostitis, inflammatory myositis, toxic epidermal necrolysis, systemic scleroderma and sclerosis, CREST syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, respiratory distress syndrome, meningitis, encephalitis, uveitis, colitis, glomerulonephritis, allergic conditions, eczema, asthma, conditions involving infiltration of T cells and chronic inflammatory responses, atherosclerosis,

55. An anti-CD37 antibody or antibody fragment and anti-CD20 antibody or antibody fragment for the manufacture of a medicament for treatment of a B-cell malignancy or disorder, wherein the anti-CD20 antibody is selected from the group consisting of ofatumumab, veltuzumab, ocrelizumab and obinutuzumab.

56. A composition comprising an anti-CD37 antibody or antibody fragment and an anti-CD20 antibody for treatment of a B cell malignancy, wherein the anti-CD20 antibody is selected from the group consisting of ofatumumab, veltuzumab, ocrelizumab and obinutuzumab.

57. A kit composition comprising a pharmaceutical composition comprising anti-CD37 antibody or antibody fragment and a pharmaceutically acceptable carrier, diluent, or excipient wherein said composition is packaged with written directions for use in combination with a BCR antagonist for treatment of a B cell malignancy.

58. A kit composition comprising a pharmaceutical composition comprising an anti-CD20 antibody and a pharmaceutically acceptable carrier, wherein said composition is packaged with written directions for use in combination with an anti-CD37 antibody or antibody fragment for treatment of a B cell malignancy.

59. An anti-CD37 antibody or antibody fragment for use in treating a B-cell malignancy or disorder, wherein the anti-CD37 antibody or antibody fragment comprises a variable heavy chain with a HCDR1 , HCDR2 and an HCRD3 and comprises a variable light chain with a LCDR1 , LCDR2, and LCDR3;

wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:30, HCDR2 comprises the amino acid sequence of SEQ ID NO:31 , and HCDR3 comprises the amino acid sequence of SEQ ID NO:32,

characterized in that the anti-CD37 antibody or antibody fragment is to be used in combination with an anti-CD20 antibody or antibody fragment.

60. An anti-CD37 antibody or antibody fragment for use in treating a B-cell malignancy or disorder, wherein the anti-CD37 antibody or antibody fragment comprises a variable heavy chain with a HCDR1 , HCDR2 and an HCRD3 and comprises a variable light chain with a LCDR1 , LCDR2, and LCDR3; wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:8, HCDR2 comprises the amino acid sequence of SEQ ID NO:1 1 , HCDR3 comprises the amino acid sequence of SEQ ID NO: 14, LCDR1 comprises the amino acid sequence of SEQ ID NO: 18, LCDR2 comprises the amino acid sequence of SEQ ID NO:22, and LCDR3 comprises the amino acid sequence of SEQ ID NO:24;

characterized in that the anti-CD37 antibody or antibody fragment is to be used in combination with an anti-CD20 antibody.

61. An anti-CD37 antibody or antibody fragment for use in treating a B-cell malignancy or disorder,

wherein the anti-CD37 antibody or antibody fragment binds human CD37 with specificity;

wherein the anti-CD37 antibody or antibody (i) is derived from derived from a monoclonal antibody selected from the group consisting of G28-1 , MB371 , BL14, NMN46, IP024, HH1 , WR17, HD28, BI14, F93G6, RFB-7, Y29/55, MB-1 , M-B371 , IPO- 24, S-B3 and K7153A,

or (ii) competes with an antibody from the list consisting of G28-1 , MB371 , BL14, NMN46, IP024, HH1 , WR17, HD28, BI14, F93G6, RFB-7, Y29/55, MB-1 , M-B371 , IPO- 24, S-B3 and K7153A for binding to human CD37,

characterized in that the anti-CD37 antibody is to be used in combination with an anti-CD20 antibody or antibody fragment.

62. The anti-CD37 antibody or antibody fragment of any one of claims 59-61 , wherein the anti- CD20 antibody is selected from the group consisting of ofatumumab, veltuzumab, ocrelizumab and obinutuzumab.

63. The anti-CD37 antibody or antibody fragment of any one of claims 59-62, wherein the anti- CD20 antibody is obinutuzumab.

64. The anti-CD37 antibody or antibody fragment of any one of claims 59-63, wherein the anti- CD37 antibody or antibody fragment is a humanized anti-CD37 antibody or antibody fragment.

65. The anti-CD37 antibody or antibody fragment of any one of claims 59-63, wherein the anti- CD37 antibody or antibody fragment comprises an amino acid sequence with at least 90% identity to the amino acid sequence of SEQ ID NO:46, SEQ ID NO: 48, SEQ ID NO:50, SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:56, SEQ ID NO:58, SEQ ID NO:60 or amino acids 21-503 of SEQ ID NO:1.

66. The anti-CD37 antibody or antibody fragment of any one of claims 59-64, wherein the anti- CD37 antibody or antibody fragment comprises an amino acid sequence with at least 95% identity to the amino acid sequence of SEQ ID NO:46, SEQ ID NO: 48, SEQ ID NO:50, SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:56, SEQ ID NO:58, SEQ ID NO:60 or amino acids 21-503 of SEQ ID NO:1.

67. The anti-CD37 antibody or antibody fragment of any one of claims 59-64, wherein the anti- CD37 antibody or antibody fragment comprises SEQ ID NO:46, SEQ ID NO: 48, SEQ ID NO:50, SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:56, SEQ ID NO:58, SEQ ID NO:60 or amino acids 21-503 of SEQ ID NO:1.

68. The anti-CD37 antibody or antibody fragment of any one of claims 59-67, for treatment or use as a medicament for treatment of a B-cell malignancy or disease selected from the list consisting of Hodgkin's disease, non-Hodgkin's lymphoma (NHL), a central nervous system lymphoma, small lymphocytic lymphoma, a leukemia, prolymphocytic leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, chronic myoblastic leukemia, a myelomas (such as multiple myeloma), small lymphocytic lymphoma, B-cell prolymphocytic leukemia, a lymphoplasmacytic lymphoma (including Waldenstrom's macroglobulinemia), a marginal zone lymphoma (including splenic marginal zone lymphoma and nodal marginal zone B-cell lymphoma), a plasma cell myeloma/plasmacytoma, solitary plasmacytoma of bone, extraosseous plasmacytoma, nodal marginal zone lymphoma, extra-nodal marginal zone B-cell lymphoma of mucosa-associated (MALT) lymphoid tissue, follicular lymphoma, mantle cell lymphoma (MCL), diffuse large B-cell lymphoma, transforming large B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma/leukemia, B-cell proliferations of uncertain malignant potential, lymphomatoid granulomatosis, and post- transplant lymphoproliferative disorder.

69. The anti-CD37 antibody or antibody fragment of any one of claims 59-67, for treatment or use as a medicament for treatment of a B-cell malignancy or disease selected from the list consisting of arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, polychondritis, psoriatic arthritis, psoriasis, dermatitis, polymyositis/dermatomyositis, inclusion body myostitis, inflammatory myositis, toxic epidermal necrolysis, systemic scleroderma and sclerosis, CREST syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, respiratory distress syndrome, meningitis, encephalitis, uveitis, colitis, glomerulonephritis, allergic conditions, eczema, asthma, conditions involving infiltration of T cells and chronic inflammatory responses, atherosclerosis, autoimmune myocarditis, leukocyte adhesion deficiency, systemic lupus erythematosus (SLE), subacute cutaneous lupus erythematosus, lupus, juvenile onset diabetes, multiple sclerosis, allergic encephalomyelitis, neuromyelitis, rheumatic fever, Sydenham's chorea, immune responses associated with acute and delayed hypersensitivity mediated by cytokines and T-lymphocytes, tuberculosis, sarcoidosis, granulomatosis including Wegener's granulomatosis and Churg-Strauss disease,

agranulocytosis, vasculitis, (including hypersensitivity vasculitis/angiitis, ANCA and rheumatoid vasculitis), aplastic anemia, Diamond Blackfan anemia, immune hemolytic anemia including autoimmune hemolytic anemia (AIHA), pernicious anemia, pure red cell aplasia (PRCA), Factor VIII deficiency, hemophilia A, autoimmune neutropenia, pancytopenia, leukopenia, diseases involving leukocyte diapedesis, central nervous system (CNS) inflammatory disorders, multiple organ injury syndrome, myasthenia gravis, antigen-antibody complex mediated diseases, anti- glomerular basement membrane disease, anti-phospholipid antibody syndrome, allergic neuritis, Behcet disease, Castleman's syndrome, Goodpasture's syndrome, Lambert-Eaton Myasthenic Syndrome, Reynaud's syndrome, Sjorgen's syndrome, Stevens-Johnson syndrome, solid organ transplant rejection, graft versus host disease (GVHD), pemphigoid bullous, pemphigus, autoimmune polyendocrinopathies, seronegative spondyloarthropathies, Reiter's disease, stiff-man syndrome, giant cell arteritis, immune complex nephritis, IgA nephropathy, IgM polyneuropathies or IgM mediated neuropathy, idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), Henoch-Schonlein purpura, autoimmune thrombocytopenia, autoimmune disease of the testis and ovary including autoimmune orchitis and oophoritis, primary hypothyroidism; autoimmune endocrine diseases including autoimmune thyroiditis, chronic thyroiditis (Hashimoto's Thyroiditis), subacute thyroiditis, idiopathic hypothyroidism, Addison's disease, Grave's disease, autoimmune polyglandular syndromes (or polyglandular endocrinopathy syndromes), Type I diabetes also referred to as insulin-dependent diabetes mellitus (IDDM) and Sheehan's syndrome;

autoimmune hepatitis, lymphoid interstitial pneumonitis (HIV), bronchiolitis obliterans (non- transplant) vs NSIP, Guillain-Barre' Syndrome, large vessel vasculitis (including polymyalgia rheumatica and giant cell (Takayasu's) arteritis), medium vessel vasculitis (including

Kawasaki's disease and polyarteritis nodosa), polyarteritis nodosa (PAN) ankylosing spondylitis, Berger's disease (IgA nephropathy), rapidly progressive glomerulonephritis, primary biliary cirrhosis, Celiac sprue (gluten enteropathy), cryoglobulinemia, cryoglobulinemia associated with hepatitis, chronic obstructive pulmonary disease (COPD), amyotrophic lateral sclerosis (ALS), coronary artery disease, familial Mediterranean fever, microscopic polyangiitis, Cogan's syndrome, Whiskott-Aldrich syndrome and thromboangiitis obliterans, autoimmune thyroid disease (such as Graves' disease and Hashimoto's thyroiditis), Sjogren's syndrome, and idiopathic inflammatory myopathy (MM), including dermatomyositis (DM) and polymyositis (PM).

70. The method of any one of claims 1-50, further comprising administering to the patient a therapeutic molecule that actively mobilizes an egress of B cells from lymphoid tissue into peripheral blood.

71. The method of claim 70, wherein the therapeutic molecule is a BCR antagonist.

72. The method of claim 71 , wherein the BCR antagonist is selected from the group consisting of BTK inhibitor, SYK inhibitor, PI3K inhibitor, and CXCR4 antagonist.

73. The method of claim 71 , wherein the BCR antagonist prevents down-regulation of CXCR4 expression.

74. The method of any one of claims 71-73, wherein the BCR antagonist is a SYK inhibitor.

75. The method of claim 74, wherein the BCR antagonist is a reversible SYK inhibitor.

76. The method of claim 74, wherein the SYK inhibitor comprises a SYK inhibitor selected from the group consisting of fostamatinib, PRT062607 and PRT-318.

77. The method of claim 71 , wherein the BCR antagonist is a Bruton's Tyrosine Kinase (BTK) inhibitor.

78. The method of claim 77, wherein the BTK inhibitor is an irreversible BTK inhibitor.

79. The method of claim 77, wherein the BTK inhibitor covalently binds a cysteine residue on BTK.

80. The method of claim 79, wherein the covalent bond is formed between a portion of a Michael acceptor moiety on the BTK inhibitor and a portion of a cysteine residue of a BTK.

81. The method of claim 80, wherein the Michael acceptor moiety is an acrylamide, vinyl sulfonamide or propargylamide.

82. The method of any one of claims 79-80, wherein the inhibitor has a covalent bond to cysteine residue 481.

83. The method of claim 77, wherein the BTK inhibitor comprises a BTK inhibitor selected from the group consisting of ibrutinib and AVL-292.

84. The method of claim 83, wherein the BTK inhibitor comprises ibrutinib.

85. The method of claim 83, wherein the BTK inhibitor comprises AVL-292.

86. The method of claim 77, wherein the BTK inhibitor non-covalently binds BTK.

87. The method of claim 77, wherein the BTK inhibitor stabilizes an inactive conformation of

BTK.

88. The method of claim 77, wherein the BTK inhibitor comprises a reversible BTK inhibitor.

89. The method of claim 77, wherein the BTK inhibitor comprises a BTK inhibitor selected from the group consisting of ibrutinib, AVL-292, ONO-WG-307 and GDC-0834.

90. The method of claim 71 , wherein the BCR antagonist comprises a CXCR4 antagonist.

91. The method of claim 90, wherein the CXCR4 antagonist is selected from a group consisting of plerixafor, T140 analog and KRH-3955.

92. The anti-CD37 antibody or antibody fragment of any one of claims 51-54, wherein said anti- CD37- antibody or antibody fragment is further administered in combination with a BCR antagonist.

93. The anti-CD37 antibody or antibody fragment of claim 92, wherein the BCR antagonist is selected from the group consisting of BTK inhibitor, SYK inhibitor, PI3K inhibitor, and CXCR4 antagonist.

94. The composition of claim 56, further comprising a BCR antagonist.

95. The composition of claim 94, wherein the BCR antagonist is selected from the group consisting of BTK inhibitor, SYK inhibitor, PI3K inhibitor, and CXCR4 antagonist.

96. The kit of any one of claims 57-58, wherein the kit is packaged with further written directions for use in combination with a BCR antagonist.

97. The kit of claim 96, wherein the BCR antagonist is selected from the group consisting of BTK inhibitor, SYK inhibitor, PI3K inhibitor, and CXCR4 antagonist.

98. The anti-CD37-antibody or antibody fragment of any one of claims 59-69, wherein the anti- CD37 antibody or antibody fragment to be used in combination with an anti-CD20 antibody or antibody fragment is to be further used in combination with a BCR antagonist.

99. The anti-CD37 antibody or antibody fragment of claim 98, wherein the BCR antagonist is selected from the group consisting of BTK inhibitor, SYK inhibitor, PI3K inhibitor, and CXCR4 antagonist.

100. The method of any one of claims 1-50, further comprising administering to the patient a kinase inhibitor.

101. The method of claim 100, wherein the kinase inhibitor is selected from the group consisting of BTK inhibitor, SYK inhibitor and PI3K inhibitor.

102. The method of claim 101 , wherein the kinase inhibitor is PI3K inhibitor.

103. The method of claim 102, wherein the PI3K inhibitor is idelalisib.

104. The anti-CD37 antibody or antibody fragment of any one of claims 51-54, wherein said anti-CD37- antibody or antibody fragment is further administered in combination with a kinase inhibitor.

105. The anti-CD37 antibody or antibody fragment of claim 104, wherein the kinase inhibitor is selected from the group consisting of BTK inhibitor, SYK inhibitor and PI3K inhibitor.

106. The composition of claim 56, further comprising a kinase inhibitor.

107. The composition of claim 106, wherein the kinase inhibitor is selected from the group consisting of BTK inhibitor, SYK inhibitor and PI3K inhibitor.

108. The kit of any one of claims 57-58, wherein the kit is packaged with further written directions for use in combination with a kinase inhibitor.

109. The kit of claim 108, wherein the kinase inhibitor is selected from the group consisting of BTK inhibitor, SYK inhibitor and PI3K inhibitor.

1 10. The anti-CD37-antibody or antibody fragment of any one of claims 59-69, wherein the anti- CD37 antibody or antibody fragment to be used in combination with an anti-CD20 antibody or antibody fragment is to be further used in combination with a kinase inhibitor.

1 1 1. The anti-CD37 antibody or antibody fragment of claim 1 10, wherein the kinase inhibitor is selected from the group consisting of BTK inhibitor, SYK inhibitor and PI3K inhibitor.