Combination therapy with anti-CD38 antibody and PARP or adenosine receptor inhibitor

Abstract

The present invention relates to methods and compositions for treating disease by administering to a subject (e.g., a human patient) in need thereof an anti-CD38 antibody and a poly ADP-ribose polymerase inhibitor (PARPi); an anti-CD38 antibody and an adenosine receptor antagonist; or a combination therapy comprising an anti-CD38 antibody, a PARPi, and an adenosine receptor antagonist.

Description

[Technical field]

[0001] (Reference to electronically submitted sequence listing) This application contains a Sequence Listing having a size of 43 KB that has been submitted electronically via EFS-Web as an ASCII formatted Sequence Listing with the filename "JBI6472WOPCT1SEQLIST.txt" created on February 2, 2022. The Sequence Listing submitted via EFS-Web is a part of the present specification and is incorporated herein by reference in its entirety. [Background technology]

[0002] CD38 is a multifunctional protein that has functions in receptor-mediated adhesion and signal transduction, as well as mediating calcium mobilization through its ectoenzymatic activity, catalyzing the formation of cyclic ADP-ribose (cADPR) and ADPR. CD38 mediates cytokine secretion and lymphocyte activation and proliferation (Funaro et al., J Immunol. 145(8):2390-96(1990); Terhorst et al., Cell 23(3):771-80(1981); Guse et al., Nature 398:70-73(1999)). Because CD38 is expressed on a variety of malignant cells, anti-CD38 antibodies have been developed for the treatment of malignancies such as multiple myeloma (MM) and light chain amyloidosis (AL). CD38 binds nicotinamide adenine dinucleotide (NAD + ) and regulates its extracellular levels. Thus, patients treated with anti-CD38 antibodies have + may experience accumulation of adenosine and depletion of adenosine.

[0003] NAD + NAD is an essential coenzyme and a central signaling molecule involved in redox homeostasis, efficient signaling, and maintaining mitochondrial metabolism. +The extracellular transformation of can vary significantly depending on the tissue environment or pathological state (Horenstein et al., Cells. 4(3):520-37(2015)).

[0004] As a substrate, NAD + Adenosine is converted to adenosine (ADO), which is taken up by cells, transformed, and reincorporated into the intracellular nucleotide pool (Id.). Adenosine is an important intermediate metabolic product and serves as a building block of nucleic acids and a component of the biological energy currency ATP (Chen et al., Nat Rev Drug Discov. 12(4):265-86(2013)). Adenosine is also expressed by four different adenosine receptors, A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21, A22, A23, A24, A25, A26, A27, A28, A29, A30, A31, A32, A33, A34, A35, A36 2A , A 2B and A3, which function as signaling molecules through activation of Aβ and Aβ. These receptors are widely expressed and are involved in cardiac rhythm, circulation, lipolysis, renal blood flow, immune function, sleep regulation, and angiogenesis, as well as inflammatory diseases, ischemia-reperfusion, and neurodegenerative disorders. Summary of the Invention [Means for solving the problem]

[0005] NAD + There is a great need to determine the tissue- and age-specific effects of CD38 reduction on adenosine levels and to identify therapeutic agents that benefit patients (e.g., patients with multiple myeloma (MM) or light chain amyloidosis (AL)) treated with anti-CD38 antibodies.

[0006] The invention disclosed herein is based, at least in part, on the ability to inhibit NAD in mammalian models. + The present invention is based on the ability to determine the tissue- and age-specific effects of CD38 on reducing cADPR and adenosine levels. In some embodiments, the present invention generally relates to methods of treating a disease or condition in a subject (e.g., a human patient) in need thereof.

[0007] In one aspect, the invention provides a method of treating a disease in a subject in need thereof, comprising administering to the subject an anti-CD38 antibody and a poly ADP ribose polymerase inhibitor (PARPi) for a time sufficient to treat the disease.

[0008] In some embodiments, the PARPi is a PARP1 inhibitor, a PARP2 inhibitor, a PARP3 inhibitor, a PARP4 inhibitor, a PARP5 inhibitor, a PARP6 inhibitor, a PARP7 inhibitor, a PARP8 inhibitor, a PARP9 inhibitor, a PARP10 inhibitor, a PARP11 inhibitor, a PARP12 inhibitor, a PARP13 inhibitor, a PARP14 inhibitor, a PARP15 inhibitor, a PARP16 inhibitor, or a PARP17 inhibitor, or a combination thereof. In some embodiments, the PARPi is a PARP1 inhibitor, a PARP2 inhibitor, or a PARP3 inhibitor, or a combination thereof. In some embodiments, the PARPi is AG-14361, AZD2461, CEP-8983, CEP-9722, E7016 (GPI21016), iniparib (BSI201), INO-1001, niraparib (MK-4827), NU1025, olaparib (AZD-2281), pamiparib (BGB-290), PJ34, PJ34HCl, RBN-2397, rucaparib (AG-014699, PF-01367338), talazoparib (BMN-673), or veliparib (ABT-888), or a pharma- ceutical acceptable salt thereof. In some embodiments, the PARPi is niraparib (MK-4827), olaparib (AZD-2281), rucaparib (AG-014699, PF-01367338), or talazoparib (BMN-673), or a pharma- ceutical acceptable salt thereof.

[0009] In another aspect, the invention provides a method of treating a disease in a subject in need thereof comprising administering to the subject an anti-CD38 antibody and an adenosine receptor antagonist for a time sufficient to treat the disease.

[0010] In some embodiments, the adenosine receptor antagonist is an A1 receptor (A1AR) antagonist, A2A Receptor (A 2A AR) antagonist, A 2B Receptor (A 2B The antagonist is an A3 receptor (A3AR) antagonist or an A3 receptor (A3AR) antagonist, or a combination thereof.

[0011] In some embodiments, the adenosine receptor antagonist is an A1AR antagonist. In some embodiments, the A1AR antagonist is BG9719, DPCPX, FK453, FR194921, N-0861, rolofylline (KW3902), tonapofylline (BG9928) or WRC-0571.

[0012] In some embodiments, the adenosine receptor antagonist is A 2A In some embodiments, the A 2A The AR antagonist is caffeine, 8-(-3-chlorostyryl)-caffeine (CSC), istradefylline (KW-6002), preladenant (SCH420814), the "Schering compound" (see, e.g., Jacobson & Gao, Nat Rev Drug Discov., 5(3):247-64 (2006)), SCH58261, SCH442416, SYN115, VER6947, VER7835, or ZM241,385.

[0013] In some embodiments, the adenosine receptor antagonist is A 2B In some embodiments, the A 2B The AR antagonist is "Eisai's compound" (see, e.g., Jacobson & Gao, Nat Rev Drug Discov., 5(3):247-64 (2006)), MRE2029-F20, MRS1754, or OSIP-339391.

[0014] In some embodiments, the adenosine receptor antagonist is an A3AR antagonist. In some embodiments, the A3AR antagonist is FA385, MRE3008-F20, MRS1292, MRS1334, MRS1523, MRS3777, "Novartis compound" (see, e.g., Jacobson & Gao, Nat Rev Drug Discov., 5(3):247-64 (2006)), OT-7999, PSB-11, or VUF5574.

[0015] In some embodiments, the anti-CD38 antibody comprises: a) the amino acid sequences of heavy chain complementarity determining region 1 (HCDR1), HCDR2 and HCDR3 of SEQ ID NOs: 6, 7 and 8, respectively; and b) The amino acid sequences of light chain complementarity determining region 1 (LCDR1), LCDR2 and LCDR3 of SEQ ID NOs: 9, 10 and 11, respectively.

[0016] In some embodiments, the anti-CD38 antibody comprises: a) the heavy chain variable region (VH) amino acid sequence of SEQ ID NO:4; and b) The light chain variable region (VL) amino acid sequence of SEQ ID NO:5.

[0017] In some embodiments, the anti-CD38 antibody comprises the heavy chain amino acid sequence of SEQ ID NO:12 and the light chain amino acid sequence of SEQ ID NO:13.

[0018] In some embodiments, the anti-CD38 antibody is of the IgG1, IgG2, IgG3, or IgG4 subtype. In some embodiments, the anti-CD38 antibody is of the IgG1 subtype.

[0019] In some embodiments, the anti-CD38 antibody is daratumumab.

[0020] In some embodiments, the anti-CD38 antibody is HexaBody-CD38 (GEN3014).

[0021] In some embodiments, the disease is cancer. In some embodiments, the cancer is a CD38-positive cancer. In some embodiments, the cancer is a CD38-negative cancer. In some embodiments, the cancer is a hematological cancer. In some embodiments, the hematological cancer is a CD38-positive hematological malignancy. In some embodiments, the hematological cancer is multiple myeloma (MM). In some embodiments, the cancer is light chain amyloidosis (AL). In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is a CD38-positive solid tumor. In some embodiments, the solid tumor is a CD38-negative solid tumor. In some embodiments, the solid tumor is a metastatic lesion of a cancer.

[0022] In some embodiments, the disease is a neurological disorder, hi some embodiments, the neurological disorder is Alzheimer's disease (AD) or multiple sclerosis (MS).

[0023] In some embodiments, the disease is a liver disease. In some embodiments, the liver disease is non-alcoholic steatohepatitis (NASH).

[0024] The foregoing will be apparent from the following more particular description of exemplary embodiments, as illustrated in the accompanying drawings, in which like reference characters represent the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the embodiments. [Brief description of the drawings]

[0025] [Figure 1A]Generation and validation of CD38-KO mouse lines on a C57BL / 6N background. FIG. 1A shows the generation of CD38-KO mouse lines. Mouse CD38 expression was abolished by inserting humanized CD38 flanked by loxP sites followed by Cre-mediated excision in vivo of the loxP-introduced region. FIG. 1B shows that mouse CD38 was not detected on immune subsets of CD38-KO mice. FIG. 1C shows that human CD38 was absent on B cells and NK cells of CD38-KO mice. PB: peripheral blood; SP: spleen; BM: bone marrow; FoB: follicular B cells; MZB: marginal zone B cells; iB: immature B cells. [Figure 1B] Generation and validation of CD38-KO mouse lines on a C57BL / 6N background. FIG. 1A shows the generation of CD38-KO mouse lines. Mouse CD38 expression was abolished by inserting humanized CD38 flanked by loxP sites followed by Cre-mediated excision in vivo of the loxP-introduced region. FIG. 1B shows that mouse CD38 was not detected on immune subsets of CD38-KO mice. FIG. 1C shows that human CD38 was absent on B cells and NK cells of CD38-KO mice. PB: peripheral blood; SP: spleen; BM: bone marrow; FoB: follicular B cells; MZB: marginal zone B cells; iB: immature B cells. [Figure 1C] Generation and validation of CD38-KO mouse lines on a C57BL / 6N background. FIG. 1A shows the generation of CD38-KO mouse lines. Mouse CD38 expression was abolished by inserting humanized CD38 flanked by loxP sites followed by Cre-mediated excision in vivo of the loxP-introduced region. FIG. 1B shows that mouse CD38 was not detected on immune subsets of CD38-KO mice. FIG. 1C shows that human CD38 was absent on B cells and NK cells of CD38-KO mice. PB: peripheral blood; SP: spleen; BM: bone marrow; FoB: follicular B cells; MZB: marginal zone B cells; iB: immature B cells. [Figure 2A]Characterization of CD38-KO lineages. Figure 2A shows that mature NK and Treg were modulated in CD38-KO mice. Figure 2B shows the percentage of T cells in CD38-KO mice. Figure 2C shows that the percentage of B cells was normal in CD38-KO mice. B220: total B220+ B cells; FoB: follicular B cells; MZB: marginal zone B cells; iB: immature B cells; T1B: transitional (bone marrow derived) B cells; mB: mature B cells. Figure 2D shows that the myeloid compartment was not affected in heterozygous (HT) and homozygous (HO) CD38-KO mice. CD38-KO mice. Figure 2E shows that macrophage populations of CD38-KO mice were altered in different organs. NS: not significant > 0.05; *: P ≤ 0.05; **: P ≤ 0.01; ****: P ≤ 0.0001 (unpaired two-tailed t-test). [Figure 2B] Characterization of CD38-KO lineages. Figure 2A shows that mature NK and Treg were modulated in CD38-KO mice. Figure 2B shows the percentage of T cells in CD38-KO mice. Figure 2C shows that the percentage of B cells was normal in CD38-KO mice. B220: total B220+ B cells; FoB: follicular B cells; MZB: marginal zone B cells; iB: immature B cells; T1B: transitional (bone marrow derived) B cells; mB: mature B cells. Figure 2D shows that the myeloid compartment was not affected in heterozygous (HT) and homozygous (HO) CD38-KO mice. CD38-KO mice. Figure 2E shows that macrophage populations of CD38-KO mice were altered in different organs. NS: not significant > 0.05; *: P ≤ 0.05; **: P ≤ 0.01; ****: P ≤ 0.0001 (unpaired two-tailed t-test). [Figure 2C]Characterization of CD38-KO lineages. Figure 2A shows that mature NK and Treg were modulated in CD38-KO mice. Figure 2B shows the percentage of T cells in CD38-KO mice. Figure 2C shows that the percentage of B cells was normal in CD38-KO mice. B220: total B220+ B cells; FoB: follicular B cells; MZB: marginal zone B cells; iB: immature B cells; T1B: transitional (bone marrow derived) B cells; mB: mature B cells. Figure 2D shows that the myeloid compartment was not affected in heterozygous (HT) and homozygous (HO) CD38-KO mice. CD38-KO mice. Figure 2E shows that macrophage populations of CD38-KO mice were altered in different organs. NS: not significant > 0.05; *: P ≤ 0.05; **: P ≤ 0.01; ****: P ≤ 0.0001 (unpaired two-tailed t-test). [Figure 2D] Characterization of CD38-KO lineages. Figure 2A shows that mature NK and Treg were modulated in CD38-KO mice. Figure 2B shows the percentage of T cells in CD38-KO mice. Figure 2C shows that the percentage of B cells was normal in CD38-KO mice. B220: total B220+ B cells; FoB: follicular B cells; MZB: marginal zone B cells; iB: immature B cells; T1B: transitional (bone marrow derived) B cells; mB: mature B cells. Figure 2D shows that the myeloid compartment was not affected in heterozygous (HT) and homozygous (HO) CD38-KO mice. CD38-KO mice. Figure 2E shows that macrophage populations of CD38-KO mice were altered in different organs. NS: not significant > 0.05; *: P ≤ 0.05; **: P ≤ 0.01; ****: P ≤ 0.0001 (unpaired two-tailed t-test). [Figure 2E]Characterization of CD38-KO lineages. Figure 2A shows that mature NK and Treg were modulated in CD38-KO mice. Figure 2B shows the percentage of T cells in CD38-KO mice. Figure 2C shows that the percentage of B cells was normal in CD38-KO mice. B220: total B220+ B cells; FoB: follicular B cells; MZB: marginal zone B cells; iB: immature B cells; T1B: transitional (bone marrow derived) B cells; mB: mature B cells. Figure 2D shows that the myeloid compartment was not affected in heterozygous (HT) and homozygous (HO) CD38-KO mice. CD38-KO mice. Figure 2E shows that macrophage populations of CD38-KO mice were altered in different organs. NS: not significant > 0.05; *: P ≤ 0.05; **: P ≤ 0.01; ****: P ≤ 0.0001 (unpaired two-tailed t-test). [Figure 3A] Figure 3 shows that genetic disruption of CD38 increased NAD+ levels in various tissues of naive non-tumor-bearing mice. Figure 3A compares young CD38-KO mice with young CD38-WT mice. Figure 3B compares old CD38-KO mice with old CD38-WT mice. NS: not significant > 0.05; *: P ≤ 0.05; **: P ≤ 0.01; ****: P ≤ 0.0001 (unpaired two-tailed t-test). [Figure 3B] Figure 3 shows that genetic disruption of CD38 increased NAD+ levels in various tissues of naive non-tumor-bearing mice. Figure 3A compares young CD38-KO mice with young CD38-WT mice. Figure 3B compares old CD38-KO mice with old CD38-WT mice. NS: not significant > 0.05; *: P ≤ 0.05; **: P ≤ 0.01; ****: P ≤ 0.0001 (unpaired two-tailed t-test). [Figure 4A]Figure 4 shows that genetic disruption of CD38-mediated increase in NAD+ levels was age-dependent. Figures 4A and 4B compare tissue-specific changes in NAD+ levels between young and old mice. Figure 4C compares NAD+ levels in old vs. young CD38-WT mice. Figure 4D compares NAD+ levels in old vs. young CD38-KO mice. NS: not significant > 0.05; *: P ≤ 0.05; **: P ≤ 0.01; ****: P ≤ 0.0001 (unpaired two-tailed t-test). [Figure 4B] Figure 4 shows that genetic disruption of CD38-mediated increase in NAD+ levels was age-dependent. Figures 4A and 4B compare tissue-specific changes in NAD+ levels between young and old mice. Figure 4C compares NAD+ levels in old vs. young CD38-WT mice. Figure 4D compares NAD+ levels in old vs. young CD38-KO mice. NS: not significant > 0.05; *: P ≤ 0.05; **: P ≤ 0.01; ****: P ≤ 0.0001 (unpaired two-tailed t-test). [Figure 4C] Figure 4 shows that genetic disruption of CD38-mediated increase in NAD+ levels was age-dependent. Figures 4A and 4B compare tissue-specific changes in NAD+ levels between young and old mice. Figure 4C compares NAD+ levels in old vs. young CD38-WT mice. Figure 4D compares NAD+ levels in old vs. young CD38-KO mice. NS: not significant > 0.05; *: P ≤ 0.05; **: P ≤ 0.01; ****: P ≤ 0.0001 (unpaired two-tailed t-test). [Figure 4D] Figure 4 shows that genetic disruption of CD38-mediated increase in NAD+ levels was age-dependent. Figures 4A and 4B compare tissue-specific changes in NAD+ levels between young and old mice. Figure 4C compares NAD+ levels in old vs. young CD38-WT mice. Figure 4D compares NAD+ levels in old vs. young CD38-KO mice. NS: not significant > 0.05; *: P ≤ 0.05; **: P ≤ 0.01; ****: P ≤ 0.0001 (unpaired two-tailed t-test). [Figure 5A]Figure 5 shows that genetic disruption of CD38 altered adenosine levels in various tissues of naive non-tumor-bearing mice. Figures 5A and 5B compare young CD38-KO mice with young CD38-WT mice. Figures 5C and 5D compare old CD38-KO mice with old CD38-WT mice. NS: not significant > 0.05; *: P ≤ 0.05; **: P ≤ 0.01; ***: P ≤ 0.001 (unpaired two-tailed t-test). [Figure 5B] Figure 5 shows that genetic disruption of CD38 altered adenosine levels in various tissues of naive non-tumor-bearing mice. Figures 5A and 5B compare young CD38-KO mice with young CD38-WT mice. Figures 5C and 5D compare old CD38-KO mice with old CD38-WT mice. NS: not significant > 0.05; *: P ≤ 0.05; **: P ≤ 0.01; ***: P ≤ 0.001 (unpaired two-tailed t-test). [Figure 5C] Figure 5 shows that genetic disruption of CD38 altered adenosine levels in various tissues of naive non-tumor-bearing mice. Figures 5A and 5B compare young CD38-KO mice with young CD38-WT mice. Figures 5C and 5D compare old CD38-KO mice with old CD38-WT mice. NS: not significant > 0.05; *: P ≤ 0.05; **: P ≤ 0.01; ***: P ≤ 0.001 (unpaired two-tailed t-test). [Figure 5D] Figure 5 shows that genetic disruption of CD38 altered adenosine levels in various tissues of naive non-tumor-bearing mice. Figures 5A and 5B compare young CD38-KO mice with young CD38-WT mice. Figures 5C and 5D compare old CD38-KO mice with old CD38-WT mice. NS: not significant > 0.05; *: P ≤ 0.05; **: P ≤ 0.01; ***: P ≤ 0.001 (unpaired two-tailed t-test). [Figure 6A]We show that gene disruption of CD38-mediated changes in adenosine levels was age-dependent. Figure 6A compares tissue-specific changes in adenosine levels between young and old mice. Figure 6B compares adenosine levels in old vs. young CD38-WT mice. Figure 6C compares adenosine levels in old vs. young CD38-KO mice. NS: not significant > 0.05; *: P ≤ 0.05; **: P ≤ 0.01; ***: P ≤ 0.001; ****: P ≤ 0.0001 (unpaired two-tailed t-test). [Figure 6B] We show that gene disruption of CD38-mediated changes in adenosine levels was age-dependent. Figure 6A compares tissue-specific changes in adenosine levels between young and old mice. Figure 6B compares adenosine levels in old vs. young CD38-WT mice. Figure 6C compares adenosine levels in old vs. young CD38-KO mice. NS: not significant > 0.05; *: P ≤ 0.05; **: P ≤ 0.01; ***: P ≤ 0.001; ****: P ≤ 0.0001 (unpaired two-tailed t-test). [Figure 6C] We show that gene disruption of CD38-mediated changes in adenosine levels was age-dependent. Figure 6A compares tissue-specific changes in adenosine levels between young and old mice. Figure 6B compares adenosine levels in old vs. young CD38-WT mice. Figure 6C compares adenosine levels in old vs. young CD38-KO mice. NS: not significant > 0.05; *: P ≤ 0.05; **: P ≤ 0.01; ***: P ≤ 0.001; ****: P ≤ 0.0001 (unpaired two-tailed t-test). [Figure 7] Figure 1 shows that genetic disruption of CD38 altered cADPR levels in various tissues of naive non-tumor-bearing young mice. ND: not detectable; *: P < 0.05; **: P < 0.01; ****: P < 0.0001 (unpaired two-tailed t-test). [Figure 8A]We show that anti-CD38 NIMR5 mouse IgG2a antibody efficiently depletes CD38 from splenic CD8 T cells (Figure 8A), splenic CD4 T cells (Figure 8B), tumor-infiltrating T cells (TILs, Figure 8C), and tumor cells (Figure 8D). [Figure 8B] We show that anti-CD38 NIMR5 mouse IgG2a antibody efficiently depletes CD38 from splenic CD8 T cells (Figure 8A), splenic CD4 T cells (Figure 8B), tumor-infiltrating T cells (TILs, Figure 8C), and tumor cells (Figure 8D). [Figure 8C] We show that anti-CD38 NIMR5 mouse IgG2a antibody efficiently depletes CD38 from splenic CD8 T cells (Figure 8A), splenic CD4 T cells (Figure 8B), tumor-infiltrating T cells (TILs, Figure 8C), and tumor cells (Figure 8D). [Figure 8D] We show that anti-CD38 NIMR5 mouse IgG2a antibody efficiently depletes CD38 from splenic CD8 T cells (Figure 8A), splenic CD4 T cells (Figure 8B), tumor-infiltrating T cells (TILs, Figure 8C), and tumor cells (Figure 8D). [Figure 9A]Figure 9 shows that treatment with anti-CD38 NIMR5 mouse IgG2a antibody significantly increased NAD+ levels in tissues and tumors. Figure 9A shows anti-CD38-mediated increase in NAD+ levels in bone marrow, femur, lymph node, spleen and tumor. Figure 9B shows that NAD+ levels increased approximately 4-fold in bone marrow isolated from the right (R) femur in response to isotype treatment (Iso), anti-CD38 NIMR5 mouse IgG2a antibody (αCD38) treatment or genetic disruption (KO) of CD38. Figure 9C shows that the increase in NAD+ levels in tumors was smaller in CD38-KO mice compared to mice treated with anti-CD38 antibody, and that active Fc (mouse IgG2a) was required for anti-CD38 antibody to increase NAD+ levels. Figure 9D shows that the increase in NAD+ levels in femurs and lymph nodes of mice treated with anti-CD38 NIMR5 mouse IgG2a antibody and CD38-KO mice was of similar magnitude. NS: not significant > 0.05; *: P ≤ 0.05; **: P ≤ 0.01; ***: P ≤ 0.001; ****: P ≤ 0.0001 (unpaired two-tailed t-test). [Figure 9B]Figure 9 shows that treatment with anti-CD38 NIMR5 mouse IgG2a antibody significantly increased NAD+ levels in tissues and tumors. Figure 9A shows anti-CD38-mediated increase in NAD+ levels in bone marrow, femur, lymph node, spleen and tumor. Figure 9B shows that NAD+ levels increased approximately 4-fold in bone marrow isolated from the right (R) femur in response to isotype treatment (Iso), anti-CD38 NIMR5 mouse IgG2a antibody (αCD38) treatment or genetic disruption (KO) of CD38. Figure 9C shows that the increase in NAD+ levels in tumors was smaller in CD38-KO mice compared to mice treated with anti-CD38 antibody, and that active Fc (mouse IgG2a) was required for anti-CD38 antibody to increase NAD+ levels. Figure 9D shows that the increase in NAD+ levels in femurs and lymph nodes of mice treated with anti-CD38 NIMR5 mouse IgG2a antibody and CD38-KO mice was of similar magnitude. NS: not significant > 0.05; *: P ≤ 0.05; **: P ≤ 0.01; ***: P ≤ 0.001; ****: P ≤ 0.0001 (unpaired two-tailed t-test). [Figure 9C]Figure 9 shows that treatment with anti-CD38 NIMR5 mouse IgG2a antibody significantly increased NAD+ levels in tissues and tumors. Figure 9A shows anti-CD38-mediated increase in NAD+ levels in bone marrow, femur, lymph node, spleen and tumor. Figure 9B shows that NAD+ levels increased approximately 4-fold in bone marrow isolated from the right (R) femur in response to isotype treatment (Iso), anti-CD38 NIMR5 mouse IgG2a antibody (αCD38) treatment or genetic disruption (KO) of CD38. Figure 9C shows that the increase in NAD+ levels in tumors was smaller in CD38-KO mice compared to mice treated with anti-CD38 antibody, and that active Fc (mouse IgG2a) was required for anti-CD38 antibody to increase NAD+ levels. Figure 9D shows that the increase in NAD+ levels in femurs and lymph nodes of mice treated with anti-CD38 NIMR5 mouse IgG2a antibody and CD38-KO mice was of similar magnitude. NS: not significant > 0.05; *: P ≤ 0.05; **: P ≤ 0.01; ***: P ≤ 0.001; ****: P ≤ 0.0001 (unpaired two-tailed t-test). [Figure 9D]Figure 9 shows that treatment with anti-CD38 NIMR5 mouse IgG2a antibody significantly increased NAD+ levels in tissues and tumors. Figure 9A shows anti-CD38-mediated increase in NAD+ levels in bone marrow, femur, lymph node, spleen and tumor. Figure 9B shows that NAD+ levels increased approximately 4-fold in bone marrow isolated from the right (R) femur in response to isotype treatment (Iso), anti-CD38 NIMR5 mouse IgG2a antibody (αCD38) treatment or genetic disruption (KO) of CD38. Figure 9C shows that the increase in NAD+ levels in tumors was smaller in CD38-KO mice compared to mice treated with anti-CD38 antibody, and that active Fc (mouse IgG2a) was required for anti-CD38 antibody to increase NAD+ levels. Figure 9D shows that the increase in NAD+ levels in femurs and lymph nodes of mice treated with anti-CD38 NIMR5 mouse IgG2a antibody and CD38-KO mice was of similar magnitude. NS: not significant > 0.05; *: P ≤ 0.05; **: P ≤ 0.01; ***: P ≤ 0.001; ****: P ≤ 0.0001 (unpaired two-tailed t-test). [Figure 10] Comparing NAD+ levels in intact femurs (L, left) and bones without BMA (R, right). Lower NAD+ levels were detected in empty bone tissue, indicating that the main difference comes from BMA. [Figure 11A] 13 shows that treatment with anti-CD38 NIMR5 mouse IgG2a antibody did not significantly alter adenosine levels in bone, femur, lymph nodes, spleen and tumors without BMA in young mice, consistent with the results in young naive CD38 KO mice. [Figure 11B] 13 shows that treatment with anti-CD38 NIMR5 mouse IgG2a antibody did not significantly alter adenosine levels in bone, femur, lymph nodes, spleen and tumors without BMA in young mice, consistent with the results in young naive CD38 KO mice. [Figure 11C]13 shows that treatment with anti-CD38 NIMR5 mouse IgG2a antibody did not significantly alter adenosine levels in bone, femur, lymph nodes, spleen and tumors without BMA in young mice, consistent with the results in young naive CD38 KO mice. [Figure 12] Figure 1 shows that treatment with anti-CD38 NIMR5 mouse IgG2a antibody reduced cADPR in all tissues tested, but did not reach statistical significance, except in tumors. **: P≦0.01 (unpaired two-tailed t-test). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] A description of exemplary embodiments follows below.

[0027] In one aspect, provided herein is a method of treating a disease in a subject in need thereof, comprising administering to the subject an anti-CD38 antibody and a poly ADP ribose polymerase inhibitor (PARPi) for a time sufficient to treat the disease.

[0028] In another aspect, provided herein is a method of treating a disease in a subject in need thereof, comprising administering to the subject an anti-CD38 antibody and an adenosine receptor antagonist for a time sufficient to treat the disease.

[0029] In another aspect, provided herein is a method of treating a disease in a subject in need thereof, comprising administering to the subject an anti-CD38 antibody, a PARPi and an adenosine receptor antagonist for a time sufficient to treat the disease.

[0030] Anti-CD38 antibody In some embodiments, the anti-CD38 antibodies of the invention bind to human CD38 (SEQ ID NO: 1). In some embodiments, the anti-CD38 antibodies bind to at least the region SKRNIQFSCKNIYR (SEQ ID NO: 2) and the region EKVQTLEAWVIHGG (SEQ ID NO: 3) of human CD38 (SEQ ID NO: 1). The amino acid sequences of SEQ ID NOs: 1-40 are provided in Table 1.

[0031] "CD38" refers to human CD38 protein (synonyms include: ADP ribosyl cyclase 1, cADPr hydrolase 1, cyclic ADP ribose hydrolase 1). Human CD38 has the amino acid sequence shown in GenBank Accession No. NP 001766 and in SEQ ID NO: 1. Human CD38 is a single-pass type II membrane protein, with amino acid residues 1-21 representing the cytoplasmic domain, amino acid residues 22-42 representing the transmembrane domain, and amino acid residues 43-300 representing the extracellular domain.

[0032] In some embodiments, the anti-CD38 antibody comprises the heavy chain variable region (VH) amino acid sequence of SEQ ID NO: 4. In some embodiments, the anti-CD38 antibody comprises a VH amino acid sequence that is at least 95% identical, e.g., about 95%, 96%, 97%, 98% or 99% identical, to SEQ ID NO: 4.

[0033] In some embodiments, the anti-CD38 antibody comprises the light chain variable region (VL) amino acid sequence of SEQ ID NO: 5. In some embodiments, the anti-CD38 antibody comprises a VL amino acid sequence that is at least 95% identical, e.g., about 95%, 96%, 97%, 98% or 99% identical, to SEQ ID NO:5.

[0034] [Table 1-1]

[0035] [Table 1-2]

[0036] In some embodiments, the anti-CD38 antibody comprises a VH amino acid sequence of SEQ ID NO: 4 or a VL amino acid sequence of SEQ ID NO: 5, or both. In some embodiments, the anti-CD38 antibody comprises a VH amino acid sequence of SEQ ID NO: 4 and a VL amino acid sequence of SEQ ID NO: 5. In some embodiments, the anti-CD38 antibody comprises a VH amino acid sequence that is at least 95% identical to SEQ ID NO: 4 and a VL amino acid sequence that is at least 95% identical to SEQ ID NO: 5.

[0037] In some embodiments, the anti-CD38 antibody comprises: a) the amino acid sequences of heavy chain complementarity determining region 1 (HCDR1), HCDR2 and HCDR3 of SEQ ID NOs: 6, 7 and 8, respectively; or b) the amino acid sequences of light chain complementarity determining region 1 (LCDR1), LCDR2 and LCDR3 of SEQ ID NOs: 9, 10 and 11, respectively; c) or both a) and b).

[0038] In some embodiments, the anti-CD38 antibody comprises: a) the amino acid sequences of HCDR1, HCDR2 and HCDR3 of SEQ ID NOs: 6, 7 and 8, respectively; and b) The amino acid sequences of LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 9, 10 and 11, respectively.

[0039] In some embodiments, the anti-CD38 antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 12. In some embodiments, the anti-CD38 antibody comprises a heavy chain amino acid sequence that is at least 90% identical, e.g., about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical, to SEQ ID NO: 12.

[0040] In some embodiments, the anti-CD38 antibody comprises a light chain amino acid sequence of SEQ ID NO: 13. In some embodiments, the anti-CD38 antibody comprises a light chain amino acid sequence that is at least 90% identical, e.g., about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical, to SEQ ID NO: 13.

[0041] In some embodiments, the anti-CD38 antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 12 or a light chain amino acid sequence of SEQ ID NO: 13, or both. In some embodiments, the anti-CD38 antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 12 and a light chain amino acid sequence of SEQ ID NO: 13. In some embodiments, the anti-CD38 antibody comprises a heavy chain amino acid sequence that is at least 95% identical to SEQ ID NO: 12 and a light chain amino acid sequence that is at least 95% identical to SEQ ID NO: 13.

[0042] In some embodiments, the anti-CD38 antibody is of the IgG1, IgG2, IgG3, or IgG4 subtype. In some embodiments, the anti-CD38 antibody is of the IgG1 subtype. In some embodiments, the anti-CD38 antibody is of the κ subtype. In some embodiments, the anti-CD38 antibody is of the IgG1 / κ subtype.

[0043] In some embodiments, the anti-CD38 antibody is daratumumab. Daratumumab is an IgG1 / kappa subtype and is described in U.S. Patent No. 7,829,673. Daratumumab comprises the HCDR1, HCDR2 and HCDR3 amino acid sequences of SEQ ID NOs: 6, 7 and 8, respectively; and LCDR1, LCDR2 and LCDR3 amino acid sequences of SEQ ID NOs: 9, 10 and 11, respectively. Daratumumab comprises the VH amino acid sequence of SEQ ID NO: 4 and the VL amino acid sequence of SEQ ID NO: 5. Daratumumab comprises the heavy chain amino acid sequence of SEQ ID NO: 12 and the light chain amino acid sequence of SEQ ID NO: 13.

[0044] In some embodiments, the anti-CD38 antibody comprises a mutation in at least one amino acid residue selected from those corresponding to E345, E430, S440, Q386, P247, 1253, S254, Q311, D / E356, T359, E382, Y436, and K447 in the Fc region of a human IgG1 heavy chain to increase effector function. Non-limiting examples of effector functions include antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), antibody-mediated binding of opsonized antibodies to complement receptors, C1q binding, complement activation, complement-dependent cytotoxicity (CDCC), complement-dependent cytotoxicity (CDC), complement-enhanced cytotoxicity, downregulation, Fcγ receptor binding, FcRn binding, induction of apoptosis, internalization, oligomer (e.g., hexamer) formation, oligomer (e.g., hexamer) stability, opsonization, protein A binding, and protein G binding. Non-limiting examples of mutations, for example, mutations that increase hexamer formation, hexamer stability, or both, can be found in WO 13 / 004842 and WO 20 / 012036, which are incorporated by reference in their entireties. In some embodiments, the anti-CD38 antibody is HexaBody-CD38 (GEN3014).

[0045] Other non-limiting examples of anti-CD38 antibodies that may be used in the methods of the invention include mAb003, mAb024, MOR-202 (MOR-03087), isatuximab, and anti-CD38 antibodies described in WO 05 / 103083, WO 06 / 125640, WO 07 / 042309, WO 08 / 047242, and WO 14 / 178820, etc. mAb003, which comprises the VH and VL amino acid sequences of SEQ ID NOs: 14 and 15, respectively, is described in U.S. Patent No. 7,829,673. mAb024, which comprises the VH and VL amino acid sequences of SEQ ID NOs: 16 and 17, respectively, is described in U.S. Patent No. 7,829,673. MOR-202 (MOR-03087), comprising the VH and VL amino acid sequences of SEQ ID NOs: 18 and 19, respectively, is described in U.S. Patent No. 8,088,896. Isatuximab, comprising the VH and VL amino acid sequences of SEQ ID NOs: 20 and 21, respectively, is described in U.S. Patent No. 8,153,765. The VH and VL of mAb003, mAb024, MOR-202 or isatuximab, or combinations thereof, can be expressed as IgG1 / κ.

[0046] In some embodiments, the anti-CD38 antibody comprises the following HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 amino acid sequences: a) a VH of SEQ ID NO: 14 and a VL of SEQ ID NO: 15; b) a VH of SEQ ID NO: 16 and a VL of SEQ ID NO: 17; c) a VH of SEQ ID NO: 18 and a VL of SEQ ID NO: 19; or d) VH of sequence number 20 and VL of sequence number 21.

[0047] In some embodiments, the anti-CD38 antibody comprises the following VH and VL amino acid sequences: a) SEQ ID NOs: 14 and 15, respectively; b) SEQ ID NOs: 16 and 17, respectively; c) SEQ ID NOs: 18 and 19, respectively; or d) SEQ ID NOs: 20 and 21, respectively.

[0048] In some embodiments, the anti-CD38 antibody is HexaBody-CD38 (GEN3014).

[0049] The anti-CD38 antibodies used in the methods of the invention may be selected de novo, for example from a phage display library, where phage are engineered to express human immunoglobulins or portions thereof, such as Fabs, single chain antibodies (scFvs), or unpaired or paired antibody variable regions (Knappik et al., J Mol Biol 296:57-86, 2000; Krebs et al., J. Immunol. Meth. 254:67-84(2001); Vaughan et al., Nature Biotechnology 14:309-14(1996); Sheets et al., PITAS (USA) 95:6157-62(1998); Hoogenboom & Winter, J. Mol. Biol. 227:381(1991); Marks et al., J. Mol. Biol. 222:581(1991)). CD38-binding variable domains can be isolated from phage display libraries expressing antibody heavy and light chain variable regions as fusion proteins with bacteriophage pIX coat protein, e.g., as described in Shi et al., J. Mol Biol. 397:385-96 (2010) and WO 09 / 085462. Antibody libraries are screened for binding to human CD38 extracellular domain; the resulting positive clones are further characterized; Fabs can be isolated from clonal lysates and subsequently cloned as full-length antibodies. Such phage display methods for isolating human antibodies are well established in the art. See, e.g., U.S. Patent Nos. 5,223,409, 5,403,484, 5,427,908, 5,571,698, 5,580,717, 5,885,793, 5,969,108, 6,172,197, 6,521,404, 6,544,731, 6,555,313, 6,582,915, and 6,593,081.

[0050] In some embodiments, the anti-CD38 antibody has a titer of about 1×10 as determined by surface plasmon resonance or KinExA methods, as performed by one of skill in the art. -7 M, 1×10 -8 M, 1×10 -9 M, 1×10 -10 M, 1×10 -11 M, 1×10 -12 M, 1×10 -13 M, 1×10 -14 M or 1×10 -15 Dissociation constant (K D In some embodiments, the antibody binds to human CD38 at about 1×10 -8 K less than M D In some embodiments, the antibody binds to human CD38 at about 1 x 10 -9 K less than M D It binds to human CD38 at 100 ng / mL.

[0051] KinExA instruments, ELISA or competitive binding assays are known to those skilled in the art. The measured affinity of a particular antibody / CD38 interaction may differ when measured under different conditions (e.g., osmolarity, pH). Thus, affinity and other binding parameters (e.g., K D , K on , K off Measurements of K are typically performed under standardized conditions and using standardized buffers. A person skilled in the art will appreciate that the internal error (measured as standard deviation (SD)) of affinity measurements using, for example, Biacore 3000 or ProteOn, can typically be in the range of 5-33% of the measurement result within the typical detection limit. Thus, K D The term "about" in the context of reflects the typical standard deviation in an assay. D is 1×10 -9 Typical SD for M is up to ±0.33×10 -9 It's M.

[0052] "Antibody" is meant in a broad sense and includes full-length antibodies, antigen-binding fragments, monospecific and multispecific (e.g., bispecific) antibodies, monoclonal antibodies (including murine, human, humanized, and chimeric antibodies), dimeric, tetrameric or multimeric antibodies, single-chain antibodies, domain antibodies, and any other modified configuration of immunoglobulin molecules that contain an antigen-binding site of the required specificity.

[0053] A "full-length antibody" comprises two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, and multimers thereof (e.g., IgM). Each heavy chain comprises a heavy chain variable region (VH) and a heavy chain constant region (comprising domains CH1, hinge, CH2, and CH3). Each light chain comprises a light chain variable region (VL) and a light chain constant region (CL). The VH and VL regions are further divided into hypervariable regions called complementarity determining regions (CDRs), which are interspersed with framework regions (FRs). Each VH and VL comprises three CDRs and four FRs, arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0054] The "complementarity determining region (CDR)" is the "antigen binding site" in an antibody. CDRs can be defined using a variety of terms: (i) based on sequence variability: HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 (Wu and Kabat, J. Exp. Med. 132:211-50 (1970); Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)); (ii) "hypervariable regions" (HVRs or HVs) H1, H2, H3, L1, L2 and L3 based on the structure defined by Chothia and Lesk (Chothia & Lesk, Mol. Biol. 196:901-17 (1987)); (iii) the International ImMunoGeneTics (IMGT) database (www_imgt_org) provides standard numbering and definitions for antigen binding sites. The correspondence between the descriptions of CDR, HV and IMGT is described in Lefranc et al., Dev. Comparat. Immunol. 27:55-77 (2003). As used herein, the terms "CDR", "HCDR1", "HCDR2", "HCDR3", "LCDR1", "LCDR2" and "LCDR3" include CDRs defined by any of the methods described by Kabat, Chothia and Lesk, supra, or IMGT, unless otherwise indicated.

[0055] Immunoglobulins can be assigned to five major classes, namely IgA, IgD, IgE, IgG, and IgM, depending on the amino acid sequence of the heavy chain constant domain. IgA is further subclassified into isotypes IgA1, IgA2. IgG is further subclassified into IgG1, IgG2, IgG3, and IgG4. Antibody light chains of any vertebrate species can be assigned to one of two clearly distinct types, kappa (κ) and lambda (λ), based on the amino acid sequence of their constant domain.

[0056] "Antigen-binding fragment" refers to a portion of an immunoglobulin molecule that retains the antigen-binding properties of the original full-length antibody. Non-limiting examples of antigen-binding fragments include heavy chain complementarity determining regions (HCDRs) 1, 2 and / or 3, light chain complementarity determining regions (LCDRs) 1, 2 and / or 3, heavy chain variable regions (VH) or light chain variable regions (VL), Fab, F(ab')2, Fd and Fv fragments, and domain antibodies (dAbs) consisting of either one VH domain or one VL domain. VH and VL domains can be linked together via synthetic linkers to form various types of single-chain antibody designs, where the VH / VL domains pair intramolecularly or intermolecularly when the VH and VL domains are expressed by separate chains to form monovalent antigen-binding sites such as single-chain Fvs (scFvs) or bispecific antibodies. See, for example, WO 1998 / 44001, WO 1988 / 01649, WO 1994 / 13804, and WO 1992 / 01047.

[0057] "Monoclonal antibody" refers to an antibody population having a single amino acid composition in each heavy and each light chain, except for possible known modifications such as removal of the C-terminal lysine from the antibody heavy chain. Monoclonal antibodies may have heterogeneous glycosylation within the antibody population. Monoclonal antibodies may be monovalent, bivalent or multivalent.

[0058] Monoclonal antibodies can be monospecific or polyspecific (e.g., bispecific). A monospecific antibody binds to one antigenic epitope.

[0059] "Multispecific" refers to an antibody that specifically binds to at least two different antigens, or at least two different epitopes within an antigen, for example, three, four or five different antigens or epitopes.

[0060] "Bispecific" refers to an antibody that specifically binds to two different antigens or two different epitopes on the same antigen.

[0061] An "isolated antibody" refers to an antibody or antigen-binding fragment that is substantially free of other antibodies having different antigen specificities (e.g., an isolated anti-CD38 antibody is substantially free of antibodies that specifically bind to antigens other than human CD38). In the case of a bispecific antibody, the bispecific antibody specifically binds to two antigens of interest and is substantially free of antibodies that specifically bind to antigens other than the two antigens of interest. In some embodiments, the anti-CD38 antibody is at least 80% pure, e.g., about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% pure.

[0062] In some embodiments, the anti-CD38 antibody is a humanized or human antibody. In some embodiments, the anti-CD38 antibody is a human antibody.

[0063] "Humanized antibody" refers to an antibody in which the antigen binding site is derived from a species other than human and the variable region framework is derived from a human immunoglobulin sequence. Because humanized antibodies may contain mutations intentionally introduced within the framework regions, such frameworks may not be exact copies of expressed human immunoglobulin or germline gene sequences.

[0064] "Human antibody" refers to an antibody having heavy and light chain variable regions in which both the framework and antigen binding sites are derived from sequences of human origin. If the antibody contains a constant region or a portion of a constant region, the constant region also is derived from sequences of human origin. Antibodies in which the antigen binding site is derived from a non-human species are not included in the definition of "human antibody."

[0065] A human antibody comprises a heavy or light chain variable region derived from a sequence of human origin when the variable region of the antibody is obtained from a system using human germline immunoglobulin or rearranged immunoglobulin genes. Non-limiting exemplary systems include human immunoglobulin gene libraries displayed on phage, and transgenic non-human animals carrying human immunoglobulin loci, such as mice or rats. Human antibodies typically contain amino acid differences compared to human germline or rearranged immunoglobulin sequences due to, for example, naturally occurring somatic mutations, deliberate substitutions in frameworks or antigen-binding sites, and substitutions introduced during cloning or VDJ recombination in the non-human animal. Typically, human antibodies are at least 80% identical in amino acid sequence to the amino acid sequences encoded by human germline or rearranged immunoglobulin genes. For example, about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. In some cases, the human antibody may contain consensus framework sequences obtained from human framework sequence analysis (see, e.g., Knappik et al., J Mol Biol 296:57-86 (2000)), or synthetic HCDR3s incorporated into a human immunoglobulin gene library displayed on phage (see, e.g., Shi et al., J Mol Biol 397:385-96 (2010), and WO 2009 / 085462).

[0066] "Recombinant" includes antibodies and other proteins that are prepared, expressed, produced, or isolated by recombinant techniques.

[0067] "Epitope" refers to a portion of an antigen to which an antibody specifically binds. Epitopes typically consist of surface groupings of chemically active (such as polar, non-polar or hydrophobic) moieties, such as amino acids or polysaccharide side chains, and may have specific three-dimensional structural characteristics as well as specific charge characteristics. Epitopes may be composed of contiguous and / or discontinuous amino acids that form a conformational spatial unit. In discontinuous epitopes, amino acids in different parts of the linear sequence of the antigen are brought into close proximity in three-dimensional space due to folding of the protein molecule.

[0068] "Variant" refers to a polypeptide or polynucleotide that differs from a reference polypeptide or polynucleotide by one or more modifications, such as, for example, a substitution, insertion, or deletion, or a combination thereof.

[0069] Administration / Pharmaceutical Compositions In the methods of the invention, the anti-CD38 antibody may be provided in a suitable pharmaceutical composition comprising the anti-CD38 antibody and a pharma- ceutically acceptable carrier.

[0070] "Pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical composition other than the active ingredient that is not toxic to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives. A carrier can be a diluent, adjuvant, excipient, or vehicle administered with an anti-CD38 antibody. Such vehicles can be liquids such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, mineral oil, sesame oil, and the like. For example, 0.4% saline and 0.3% glycine can be used. These solutions are sterile and generally free of particulate matter. They can be sterilized by conventional, well-known sterilization techniques (e.g., filtration). The compositions can contain pharma-ceutically acceptable auxiliary substances required to approximate physiological conditions, such as pH adjusting and buffering agents, stabilizers, thickeners, lubricants, and coloring agents. The concentration of anti-CD38 antibodies in such pharmaceutical formulations may vary widely, i.e., from less than about 0.5% by weight, to at least about 1% by weight, up to 15% or 20%, 25%, 30%, 35%, 40%, 45%, or 50% by weight. The concentration is selected primarily based on the required dose, fluid volumes, viscosities, etc., according to the mode of administration. Suitable vehicles and formulations, including other human proteins, such as human serum albumin, are described, for example, in Remington: The Science and Practice of Pharmacy, 21 st Edition, Troy, DB ed., Lipincott Williams and Wilkins, Philadelphia, PA 2006, Part 5, Pharmaceutical Manufacturing pp691-1092 (e.g., pages 958-89).

[0071] The mode of administration of the anti-CD38 antibody may be any suitable parenteral administration, including, but not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, pulmonary, transmucosal (oral, intranasal, intravaginal, rectal), etc.

[0072] In some embodiments, the anti-CD38 antibody is administered by intravenous infusion. In some embodiments, the intravenous infusion is administered over 15, 30, 45, or 60 minutes. In some embodiments, the intravenous infusion is administered over 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours.

[0073] The dose of anti-CD38 antibody administered to a patient is sufficient to ameliorate or at least partially prevent the disease being treated (a "therapeutically effective amount"). Non-limiting examples of therapeutically effective amounts include about 0.005 mg to about 100 mg / kg, such as about 0.05 to 30, 5 to 25, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 40, 50, 60, 70, 80, 90, or 100 mg / kg.

[0074] For example, fixed unit doses of 50, 100, 200, 500, or 1000 mg can be given. In some embodiments, the dose is based on the surface area of ​​the patient, e.g., 500, 400, 300, 250, 200, or 100 mg / m 2 The dosage may also depend on the disease. Typically, 1 to 8 doses, such as 1, 2, 3, 4, 5, 6, 7 or 8 doses, may be administered to treat AL. In some embodiments, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more doses may be administered.

[0075] The administration of anti-CD38 antibody may be repeated, for example after 1, 2, 3, 4, 5 or 6 days, 1, 2, 3, 4, 5, 6 or 7 weeks, or 1, 2, 3, 4, 5 or 6 months or more. Repeated courses of treatment are also possible as is administration over time. Repeated administration may be at the same dose or at different doses. For example, anti-CD38 antibody may be administered at 8 mg / kg or 16 mg / kg at weekly intervals for 8 weeks, followed by administration at 8 mg / kg or 16 mg / kg every 2 weeks for another 16 weeks, followed by administration by intravenous infusion at 8 mg / kg or 16 mg / kg every 4 weeks.

[0076] In some embodiments, the anti-CD38 antibody is administered at 16 mg / kg once per week for 8 weeks, then 16 mg / kg once every 2 weeks for 16 weeks, then 16 mg / kg once every 4 weeks until discontinued.

[0077] In some embodiments, the anti-CD38 antibody is administered at 8 mg / kg once per week for 8 weeks, then 8 mg / kg once every 2 weeks for 16 weeks, then 8 mg / kg once every 4 weeks until discontinued.

[0078] In some embodiments, the anti-CD38 antibody is administered at 16 mg / kg once weekly for 4 weeks, 16 mg / kg once every 2 weeks for 16 weeks, then 16 mg / kg once every 4 weeks until discontinued.

[0079] In some embodiments, the anti-CD38 antibody is administered at 8 mg / kg once per week for 4 weeks, then 8 mg / kg once every 2 weeks for 16 weeks, then 8 mg / kg once every 4 weeks until discontinued.

[0080] The anti-CD38 antibody may be administered as a maintenance therapy, for example, once a week for a period of six months or more.

[0081] For example, the anti-CD38 antibody can be administered as a daily dose in an amount of about 0.1 to 100 mg / kg, e.g., about 0.5, 0.9, 1.0, 1.1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90, or 100 mg / kg per day, using a single or divided dose every 24, 12, 8, 6, 4, or 2 hours, or using a combination thereof. It may be provided on at least one of the 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 days, or at least one of the 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks after initiation of treatment, or any combination thereof.

[0082] Daratumumab is indicated for the treatment of adult patients with multiple myeloma. For example, in combination with lenalidomide and dexamethasone in newly diagnosed patients ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy; in combination with bortezomib, melphalan and prednisone in newly diagnosed patients ineligible for autologous stem cell transplant; in combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients eligible for autologous stem cell transplant; in combination with bortezomib and dexamethasone in patients who have received at least one prior therapy; in combination with carfilzomib and dexamethasone in patients who have received 1 to 3 prior therapies; in combination with pomalidomide and dexamethasone in patients who have received at least two prior therapies including lenalidomide and a proteasome inhibitor; or as monotherapy in patients who have received at least three prior therapies including a proteasome inhibitor (PI) and an immunomodulatory agent or who are dual refractory to a PI and an immunomodulatory agent. Additional information regarding daratumumab can be found, for example, in the prescribing information of the DARZALEX® product insert (www.janssenlabels.com / package-insert / product-monograph / prescribing-information / DARZALEX-pi.pdf), which is incorporated herein by reference.

[0083] Anti-CD38 antibodies may also be administered prophylactically to reduce the risk of cancer progression, delay the onset of events in cancer progression, and / or reduce the risk of recurrence when the cancer goes into remission. This may be particularly useful in patients where it is difficult to locate a tumor known to be present due to other biological factors.

[0084] The anti-CD38 antibodies can be lyophilized for storage and dissolved in a suitable carrier prior to use. This technique has been shown to be effective with conventional protein preparations, and well-known lyophilization and reconstitution techniques can be used.

[0085] In some embodiments, the anti-CD38 antibody is administered intravenously.

[0086] In some embodiments, the anti-CD38 antibody is administered subcutaneously.

[0087] In some embodiments, the anti-CD38 antibody is administered subcutaneously in a pharmaceutical composition comprising the anti-CD38 antibody and hyaluronidase. In some embodiments, the hyaluronidase is rHuPH20 recombinant hyaluronidase. In some embodiments, the hyaluronidase is rHuPH20 having the amino acid sequence of SEQ ID NO:22.

[0088] Hyaluronidase is an enzyme that degrades hyaluronic acid (EC 3.2.1.35) and reduces the viscosity of hyaluronan in the extracellular matrix, thereby increasing tissue permeability. rHuPH20 is a recombinant hyaluronidase (HYLENEX® recombinant) and is described in WO 2004 / 078140.

[0089] Additional information regarding daratumumab and hyaluronidase can be found, for example, in the prescribing information of the DARZALEX FASPRO™ product insert (www.janssenlabels.com / package-insert / product-monograph / prescribing-information / DARZALEX+Faspro-pi.pdf), which is incorporated herein by reference.

[0090] Administration of the pharmaceutical composition comprising anti-CD38 antibody and hyaluronidase can be repeated after 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, or longer. Repeated courses of treatment are also possible as long-term administration. Repeated administrations can be at the same dose or at different doses. For example, the pharmaceutical composition comprising anti-CD38 antibody and hyaluronidase can be administered once a week for 8 weeks, then once every 2 weeks for 16 weeks, then once every 4 weeks. The administered pharmaceutical composition can include about 1,800 mg of anti-CD38 antibody and about 30,000 U of hyaluronidase. In some embodiments, the concentration of anti-CD38 antibody in the pharmaceutical composition is about 120 mg / ml. The pharmaceutical composition comprising anti-CD38 antibody and hyaluronidase can be administered subcutaneously in the abdomen. The pharmaceutical composition comprising an anti-CD38 antibody and hyaluronidase can be administered in a total volume of about 15 mL.

[0091] In some embodiments, the pharmaceutical composition comprising an anti-CD38 antibody and a hyaluronidase is a fixed combination. A "fixed combination" refers to a single pharmaceutical composition that comprises two or more compounds, e.g., an anti-CD38 antibody and a hyaluronidase, administered together in the form of a single entity or dosage.

[0092] In some embodiments, the pharmaceutical composition comprising an anti-CD38 antibody and a hyaluronidase is a non-fixed combination. A "non-fixed combination" refers to separate pharmaceutical compositions, each comprising one or more compounds, such as an anti-CD38 antibody and a hyaluronidase, or unit dosage forms, that are administered as separate entities either simultaneously, concurrently, or sequentially without specific time restrictions, such administration providing effective levels of the two compounds in the subject's body.

[0093] "Treating" or "treatment" refers to a therapeutic procedure whose purpose is to slow (reduce) the progression of an undesirable physiological change or disease, for example, to slow the development or spread of a tumor or tumor cells, or to provide a beneficial or desired clinical outcome during treatment. Beneficial or desired clinical outcomes include alleviation of symptoms, reduction in the extent of disease, stable (i.e., not worsening) disease state, delayed or slowed disease progression, lack of metastasis, improvement or mitigation of disease state, and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival compared to the expected survival if the subject is not receiving treatment. Subjects in need of treatment include those who already have an undesirable physiological change or disease, as well as those who are predisposed to having a physiological change or disease.

[0094] "Therapeutically effective amount" refers to an amount effective to achieve the desired therapeutic result at the dosage and duration required. The therapeutically effective amount may vary depending on factors such as the individual's condition, age, sex, and weight, and the ability of the therapeutic agent or combination of therapeutic agents to elicit a desired response in the individual. Exemplary indicators of an effective therapeutic agent or combination of therapeutic agents include, for example, an improvement in the patient's health status, a reduction in tumor burden, a halt or slowing of tumor growth, and / or the absence of metastasis of cancer cells to other locations in the body.

[0095] "Inhibiting proliferation" (e.g., when referring to tumor cells) refers to a measurable decrease in tumor cell proliferation or tumor tissue in vitro or in vivo when contacted with a therapeutic agent or combination of therapeutic agents compared to the proliferation of the same tumor cells or tumor tissue in the absence of the therapeutic agent or combination of therapeutic agents. Inhibition of tumor cell or tumor tissue proliferation in vitro or in vivo can be at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 99% or 100%.

[0096] "About" means within an acceptable range of error for a particular value as determined by one of ordinary skill in the art, which will depend in part on the limitations of the method by which the value is measured or determined, i.e., the measurement system. In the context of a particular assay, result, or embodiment, unless expressly stated otherwise in the examples or elsewhere in the specification, "about" means within one standard deviation per the practice of the art, or within a range of up to 5%, whichever is greater.

[0097] cancer In some embodiments, the disease is cancer. In some embodiments, the cancer is a CD38 positive cancer. In some embodiments, the cancer is a CD38 negative cancer. In some embodiments, the cancer is a metastatic cancer.

[0098] In some embodiments, the cancer is a hematological cancer.

[0099] In some embodiments, the hematological cancer is leukemia, hi some embodiments, the leukemia is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), hairy cell leukemia (HCL), or myelodysplastic syndrome (MDS), or a combination thereof.

[0100] In some embodiments, the hematological cancer is lymphoma.

[0101] In some embodiments, the lymphoma is Hodgkin's lymphoma. In some embodiments, the Hodgkin's lymphoma is nodular sclerosing Hodgkin's lymphoma (NSCHL), mixed cellularity Hodgkin's lymphoma (MCcHL), lymphocyte predominant Hodgkin's disease (LRCHL) or lymphocyte depletion Hodgkin's disease (LDHL), or a combination thereof.

[0102] In some embodiments, the lymphoma is non-Hodgkin's lymphoma (NHL).

[0103] In some embodiments, the non-Hodgkin's lymphoma is a B-cell lymphoma. In some embodiments, the B-cell lymphoma is diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), follicular lymphoma (FL), small lymphocytic lymphoma (SLL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia (WMG), or Burkitt's lymphoma (BL), or a combination thereof.

[0104] In some embodiments, the non-Hodgkin's lymphoma is a T-cell lymphoma. In some embodiments, the T-cell lymphoma is a peripheral T-cell lymphoma (PTCL), an anaplastic large cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AITL), or a cutaneous T-cell lymphoma, or a combination thereof.

[0105] In some embodiments, the hematological cancer is multiple myeloma. In some embodiments, the multiple myeloma is light chain multiple myeloma (LCMM), nonsecretory multiple myeloma (NSMM), monofocal plasmacytoma (SP), extramedullary plasmacytoma (EMP), monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), immunoglobulin D multiple myeloma (IgD MM), or immunoglobulin E (IgE) multiple myeloma, or a combination thereof.

[0106] In some embodiments, the hematological cancer is a CD38-positive hematological malignancy. In some embodiments, the CD38-positive hematological malignancy is multiple myeloma (MM), acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma (BL), follicular lymphoma (FL), mantle cell lymphoma (MCL), acute myeloid leukemia (AML), or chronic lymphocytic leukemia (CLL), or a combination thereof.

[0107] "CD38-positive hematological malignancies" refers to hematological malignancies characterized by the presence of tumor cells expressing CD38, including leukemias, lymphomas, and myelomas. Examples of such CD38-positive hematological malignancies include precursor B-cell lymphoblastic leukemia / lymphoma and B-cell non-Hodgkin's lymphoma, acute promyelocytic leukemia, acute lymphoblastic leukemia, and mature B-cell neoplasms, such as B-cell chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), B-cell acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, mantle cell lymphoma (MCL), follicular lymphoma (FL) (low-grade malignant lymphomas), and leukemias and tumors of the pulmonary artery and pulmonary stenosis. These include: cutaneous follicle center lymphoma, marginal zone B-cell lymphoma (MALT type, nodal and splenic types), hairy cell leukemia, diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma (BL), plasmacytoma, multiple myeloma, plasma cell leukemia, post-transplant lymphoproliferative disorder, light chain amyloidosis, Waldenstrom's macroglobulinemia, plasma cell leukemia and anaplastic large cell lymphoma (ALCL).

[0108] In some embodiments, the CD38-positive hematological malignancy is a plasma cell dyscrasia. In some embodiments, the plasma cell dyscrasia is light chain amyloidosis (AL), multiple myeloma (MM), or Waldenstrom's macroglobulinemia. In some embodiments, the plasma cell dyscrasia is MM or AL.

[0109] In some embodiments, the disease is MM. In some embodiments, the MM is relapsed or refractory. In some embodiments, the MM is newly diagnosed MM.

[0110] In some embodiments, the disease is AL. In some embodiments, the AL is cardiac stage I, cardiac stage II, or cardiac stage III. In some embodiments, the AL is relapsed or refractory AL. In some embodiments, the AL is newly diagnosed AL.

[0111] In some embodiments, subjects with AL are homozygous for phenylalanine at position 158 of CD16 (FcγRIIIa-158F / F genotype) or heterozygous for valine and phenylalanine at position 158 of CD16 (FcγRIIIa-158F / V genotype). CD16 is also known as Fc gamma receptor IIIa (FcγRIIIa) or low affinity immunoglobulin gamma Fc region receptor III-A isoform. The valine / phenylalanine (V / F) polymorphism at position 158 of the FcγRIIIa protein residue has been shown to affect FcγRIIIa affinity for human IgG. Receptors with FcγRIIIa-158F / F or FcγRIIIa-158F / V polymorphisms exhibit reduced Fc binding and therefore reduced ADCC when compared to FcγRIIIa-158V / V. The absence or low amount of fucose on human N-linked oligosaccharides improves the ability of antibodies to induce ADCC due to improved binding of the antibodies to human FcγRIIIa (CD16) (Shields et al., J Biol Chem. 277:26733-40 (2002)). Patients can be analyzed for FcγRIIIa polymorphisms using routine methods.

[0112] In some embodiments, the anti-CD38 antibody induces in vitro killing of CD38-expressing pathogenic plasma cells by antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), apoptosis, or in vitro modulation of CD38 enzymatic activity, and wherein the subject is homozygous for valine at position 158 of CD16.

[0113] In some embodiments, the cancer is a solid tumor.

[0114] In some embodiments, the solid tumor is a tumor of the breast, lung, prostate, colon, bladder, ovary, kidney, stomach, colon, rectum, testis, head and / or neck, pancreas, brain, skin, or a combination thereof.

[0115] In some embodiments, the solid tumor is bladder cancer, brain cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, fallopian tube cancer, gastric cancer, genitourinary cancer, head and neck cancer, liver cancer, lung cancer, melanoma, nasopharyngeal cancer, pancreatic cancer, prostate cancer, ovarian cancer, rectal cancer, kidney cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer, or urethral cancer, or a combination thereof.

[0116] In some embodiments, the solid tumor is squamous non-small cell lung cancer (NSCLC), non-squamous NSCLC, lung adenocarcinoma, mesothelioma, renal clear cell carcinoma, papillary renal cell carcinoma, castration-resistant prostate cancer, squamous cell carcinoma of the head and neck, cancer of the esophagus, cancer of the gastrointestinal tract, or endometriosis, or a combination thereof.

[0117] In some embodiments, the solid tumor is melanoma, lung cancer, squamous non-small cell lung cancer (NSCLC), non-squamous NSCLC, colorectal cancer, prostate cancer, castration-resistant prostate cancer, gastric cancer, ovarian cancer, stomach cancer, liver cancer, pancreatic cancer, thyroid cancer, squamous cell carcinoma of the head and neck, cancer of the esophagus or gastrointestinal tract, breast cancer, fallopian tube cancer, brain cancer, urethral cancer, genitourinary cancer, endometriosis, cervical cancer, or a metastatic lesion of cancer.

[0118] In some embodiments, the solid tumor is a CD38-positive solid tumor. In some embodiments, the solid tumor is a CD38-negative solid tumor.

[0119] In some embodiments, the solid tumor is a metastatic lesion of a cancer.

[0120] In some embodiments, the disease is an MDSC-associated disease. "MDSC-associated disease" refers to a disease or disorder associated with myeloid-derived suppressor cells (MDSCs). The MDSC-associated disease may be caused by MDSC function, for example, suppression of anti-tumor response or effector T cell proliferation. The MDSC-mediated disease may be cancer. "MDSC-associated disease" and "MDSC-mediated disease" are used interchangeably herein.

[0121] In some embodiments, the disease is a Breg-associated disease. "Breg-associated disease" refers to a disease or disorder associated with regulatory B cells. A Breg-associated disease can be caused, for example, by Breg-mediated suppression of anti-tumor responses or effector T cell proliferation. A Breg-mediated disease can be cancer. "Breg-associated disease" and "Breg-mediated disease" are used interchangeably herein.

[0122] Neuropathy In some embodiments, the disease is a neurological disorder.

[0123] In some embodiments, the neurological disorder is acute spinal cord injury (SCI), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), ataxia, Bell's palsy, brain tumor, cerebral aneurysm, epilepsy, Guillain-Barre syndrome (GBS), hydrocephalus, lumbar disc disease, meningitis, multiple sclerosis (MS), muscular dystrophy, neurocutaneous syndrome, Parkinson's disease (PD), stroke, cluster headache, tension headache, migraine, encephalitis, sepsis, or myasthenia gravis (MG), or a combination thereof. In some embodiments, the neurological disorder is AD or MS. In some embodiments, the neurological disorder is AD. In some embodiments, the neurological disorder is MS.

[0124] Liver disease In some embodiments, the disease is a liver disease.

[0125] In some embodiments, the liver disease is Alagille syndrome (ALGS), autoimmune hepatitis (AIH), biliary atresia, cirrhosis, hemochromatosis, hepatitis, nonalcoholic fatty liver disease (NAFLD), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) or Wilson's disease, or a combination thereof. In some embodiments, the NAFLD is nonalcoholic steatohepatitis (NASH).

[0126] Poly ADP-ribose polymerase inhibitors As used herein, "poly ADP ribose polymerase inhibitor" or "PARPi" refers to a substance that, when provided exogenously, results in the inhibition of poly ADP-ribose polymerase. PARPi includes any such substance, now known or discovered in the future, or a pharma- ceutically acceptable salt, tautomer, N-oxide, solvate, hydrate, or stereoisomer thereof.

[0127] In some embodiments, the PARPi is poly[ADP-ribose] polymerase 1 (PARP1, NAD +In some embodiments, the PARPi is a poly[ADP-ribose] polymerase 2 (PARP2) inhibitor. In some embodiments, the PARPi is a poly[ADP-ribose] polymerase 3 (PARP3) inhibitor. In some embodiments, the PARPi is a PARP1 inhibitor or a PARP2 inhibitor, or a combination thereof. In some embodiments, the PARPi is a PARP1 inhibitor, a PARP2 inhibitor, or a PARP3 inhibitor, or a combination thereof. In some embodiments, the PARPi is a PARP4 inhibitor. In some embodiments, the PARPi is a PARP7 inhibitor. In some embodiments, the PARPi is a PARP14 inhibitor. In some embodiments, the PARPi is a PARP1 inhibitor, a PARP2 inhibitor, a PARP3 inhibitor, a PARP7 inhibitor, or a PARP14 inhibitor, or a combination thereof. In some embodiments, the PARPi is a PARP1 inhibitor, a PARP2 inhibitor, a PARP3 inhibitor, a PARP4 inhibitor, a PARP7 inhibitor, or a PARP14 inhibitor, or a combination thereof. In some embodiments, the PARPi is a PARP1 inhibitor, a PARP2 inhibitor, a PARP3 inhibitor, a PARP4 inhibitor, a PARP5 inhibitor, a PARP6 inhibitor, a PARP7 inhibitor, a PARP8 inhibitor, a PARP9 inhibitor, a PARP10 inhibitor, a PARP11 inhibitor, a PARP12 inhibitor, a PARP13 inhibitor, a PARP14 inhibitor, a PARP15 inhibitor, a PARP16 inhibitor, or a PARP17 inhibitor, or a combination thereof.

[0128] In some embodiments, the PARPi is AG-14361 (CAS#328543-09-5), AZD2461 (CAS#1174043-16-3), CEP-8983 (CAS#374071-46-2), CEP-9722 (CAS#916574-83-9), E7016 (GPI21016, CAS#902128-9 2-1), iniparib (BSI201, CAS#160003-66-7), INO-1001 (B2186, CAS#3544-24-9), niraparib (MK-4827, CAS#1038915-60-4), NU1025 (CAS#90417-38-2), olaparib (AZD-2281, Ku-0059436, CAS#7 63113-22-0), pamiparib (BGB-290, CAS#1446261-44-4), PJ34 (CAS#344458-15-7), PJ34HCl, RBN-2397 (CAS#2381037-82-5), rucaparib (AG-014447, CAS#283173-50-2; rucaparib phosphate (AG-01 4699, PF-01367338, CAS#459868-92-9), talazoparib (BMN-673, CAS#1207456-01-6) or veliparib (ABT-888, CAS#912444-00-9), or a pharma- ceutically acceptable salt, tautomer, N-oxide, solvate, hydrate or stereoisomer thereof. CAS# refers to Chemical Abstracts Registry Number.

[0129] In some embodiments, the disease is bile duct cancer, bone cancer, breast cancer, colorectal cancer, endometrial cancer, fallopian tube cancer, blood cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, peritoneal cancer, prostate cancer, sarcoma, or skin cancer, or a combination thereof. See, e.g., Slade D., PARP and PARG inhibitors in cancer treatment, Genes Dev. 34(5-6): 360-94 (2020) and Mateo J et al., A decade of clinical development of PARP inhibitors in perspective, Ann Oncol. 30(9): 1437-47 (2019).

[0130] In some embodiments, the PARPi is NU1025 or a pharma- ceutically acceptable salt thereof and the disease is cancer or cerebral ischemia.

[0131] In some embodiments, the PARPi is PJ34 or PJ34HCl, and the disease is alcoholic fatty liver disease, cancer, neurodegenerative disease, retinal detachment, or subarachnoid hemorrhage (SAH). In some embodiments, the cancer is breast cancer, colorectal cancer, glioblastoma, ovarian cancer, or pancreatic cancer. In some embodiments, the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC).

[0132] In some embodiments, the PARPi is niraparib, olaparib, pamiparib, rucaparib, or talazoparib, or a pharma- ceutically acceptable salt thereof.

[0133] Niraparib is indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who have a complete or partial response to platinum-based chemotherapy. ZEJULA™ (niraparib) is an oral capsule. In some embodiments, the dose is 300 mg taken once daily with or without food. Additional information regarding niraparib can be found, for example, in the prescribing information of the ZEJULA™ product insert (www.gsksource.com / pharma / content / dam / GlaxoSmithKline / US / en / Prescribing_Information / Zejula / pdf / ZEJULA-PI-PIL.PDF), which is incorporated herein by reference in its entirety.

[0134] Olaparib is indicated in ovarian cancer for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who have a complete or partial response to platinum-based chemotherapy. Olaparib is indicated in ovarian cancer for the treatment of adult patients with adverse or suspected adverse germline BRCA mutation (gBRCAm) advanced ovarian cancer who have been treated with three or more prior chemotherapy regimens. Olaparib is also indicated in breast cancer in patients with adverse or suspected adverse gBRCAm, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have been previously treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with previous endocrine therapy or be considered ineligible for endocrine therapy. LYNPARZA® (olaparib) is an oral tablet. In some embodiments, the tablet dose is 300 mg taken orally twice daily with or without food. Additional information regarding olaparib can be found, for example, in the prescribing information of the LYNPARZA® product insert (www.azpicentral.com / pi.html?product=lynparza_tb&country=us&popup=no), which is incorporated herein by reference in its entirety.

[0135] Rucaparib is indicated in ovarian cancer for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who have a complete or partial response to platinum-based chemotherapy. Rucaparib is indicated in ovarian cancer for the treatment of adult patients with deleterious BRCA mutation (germline and / or somatic)-associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or more chemotherapy regimens. Rucaparib is also indicated in prostate cancer for the treatment of adult patients with deleterious BRCA mutation (germline and / or somatic)-associated metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy and taxane-based chemotherapy. Patients receiving rucaparib for mCRPC should also be receiving gonadotropin-releasing hormone (GnRH) analogs concomitantly or have had both testes removed. RUBRACA® (rucaparib) is an oral tablet. In some embodiments, the dose is 600 mg orally twice daily, with or without food. Additional information regarding rucaparib can be found, for example, in the prescribing information of the RUBRACA® product insert (clovisoncology.com / media / 1094 / rubraca-prescribing-info.pdf), which is incorporated herein by reference in its entirety.

[0136] Talazoparib is indicated for the treatment of adult patients with harmful or suspected harmful germline BRCA-mutated (gBRCAm) HER2-negative locally advanced or metastatic breast cancer. TALZENNA™ (talazoparib) is an oral capsule. In some embodiments, the dose of TALZENNA™ is 1 mg taken as a single oral daily dose with or without food. Additional information regarding talazoparib can be found, for example, in the prescribing information of the TALZENNA™ product insert (labeling.pfizer.com / ShowLabeling.aspx?id=11046), which is incorporated herein by reference in its entirety.

[0137] In some embodiments, a) the PARPi is niraparib, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or pharma- ceutically acceptable salt thereof, and the disease is bile duct cancer, endometrial cancer, fallopian tube cancer, ovarian cancer, pancreatic cancer, peritoneal cancer, prostate cancer, or skin cancer, or a combination thereof; b) the PARPi is olaparib, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or pharma- ceutically acceptable salt thereof, and the disease is bile duct cancer, breast cancer, colorectal cancer, endometrial cancer, fallopian tube cancer, melanoma, ovarian cancer, pancreatic cancer, primary peritoneal cancer, prostate cancer, or skin cancer, or a combination thereof; c) the PARPi is pamiparib, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or pharma- ceutically acceptable salt thereof, and the disease is esophageal cancer, glioma, head and neck cancer, non-small cell lung cancer (NSCLC), small cell gastric cancer, small cell lung cancer, soft tissue sarcoma, or multiple soft tissue sarcomas, or a combination thereof; d) the PARPi is rucaparib, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or pharma- ceutically acceptable salt thereof, and the disease is ovarian cancer; or e) the PARPi is talazoparib, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or pharma- ceutically acceptable salt thereof, and the disease is breast cancer, bile duct cancer, bone cancer, colorectal cancer, endometrial cancer, lung cancer, pancreatic cancer, prostate cancer, or skin cancer, or a combination thereof; or It is a combination of the above.

[0138] In some embodiments, the PARPi is Niraparib. In some embodiments, the disease is cholangiocarcinoma, endometrial cancer, fallopian tube cancer, ovarian cancer, pancreatic cancer, peritoneal cancer, prostate cancer, or skin cancer. In some embodiments, the disease is recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, and / or the subject is in a complete or partial response to platinum-based chemotherapy.

[0139] In some embodiments, the PARPi is olaparib. In some embodiments, the disease is cholangiocarcinoma, breast cancer, colorectal cancer, endometrial cancer, fallopian tube cancer, melanoma, ovarian cancer, pancreatic cancer, primary peritoneal cancer, prostate cancer, or skin cancer. In some embodiments, the disease is ovarian cancer. In some embodiments, the subject is an adult patient with recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, and / or the subject is in a complete or partial response to platinum-based chemotherapy. In some embodiments, the subject is an adult patient with deleterious or suspected deleterious germline BRCA mutation (gBRCAm) advanced ovarian cancer, and / or the subject has been treated with three or more prior chemotherapy regimens. In some embodiments, the disease is breast cancer, and the subject is a patient with deleterious or suspected deleterious gBRCAm, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer, and / or the subject has been previously treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. In some embodiments, the subject has hormone receptor (HR) positive breast cancer and / or the subject has been treated with previous endocrine therapy or is considered refractory to endocrine therapy.

[0140] In some embodiments, the PARPi is pamiparib and the disease is esophageal cancer, glioma, head and neck cancer, non-small cell lung cancer (NSCLC), small cell gastric cancer, small cell lung cancer, soft tissue sarcoma, or multiple soft tissue sarcomas.

[0141] In some embodiments, the PARPi is rucaparib. In some embodiments, the disease is ovarian cancer, and / or the subject is an adult patient with recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who has a complete or partial response to platinum-based chemotherapy. In some embodiments, the disease is ovarian cancer, and / or the subject is an adult patient with deleterious BRCA mutation (germline and / or somatic)-associated epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who has been treated with two or more chemotherapy regimens. In some embodiments, the disease is prostate cancer, and / or the subject is an adult patient with deleterious BRCA mutation (germline and / or somatic)-associated metastatic castration-resistant prostate cancer (mCRPC) who has been treated with androgen receptor-directed therapy and taxane-based chemotherapy.

[0142] In some embodiments, the PARPi is talazoparib. In some embodiments, the disease is breast cancer, cholangiocarcinoma, bone cancer, colorectal cancer, endometrial cancer, lung cancer, pancreatic cancer, prostate cancer, or skin cancer. In some embodiments, the subject is an adult patient with deleterious or suspected deleterious germline BRCA mutated (gBRCAm) HER2 negative locally advanced or metastatic breast cancer.

[0143] In some embodiments, the bone cancer is Ewing's sarcoma.

[0144] In some embodiments, the breast cancer is advanced breast cancer, BRCA1 / 2 mutated and human epidermal growth factor receptor type 2 (HER2) negative metastatic breast cancer, or triple negative breast cancer (TNBC).

[0145] In some embodiments, the lung cancer is small cell lung cancer.

[0146] In some embodiments, the ovarian cancer is advanced ovarian cancer, BRCA mutated ovarian cancer, high-grade epithelial ovarian cancer (HGOC), high-grade serous ovarian cancer, high-grade serous and undifferentiated ovarian cancer, platinum-sensitive newly diagnosed advanced ovarian cancer, platinum-sensitive recurrent ovarian cancer, platinum-sensitive recurrent ovarian cancer, sporadic platinum-resistant high-grade serous ovarian cancer, recurrent high-grade ovarian cancer, recurrent high-grade serous epithelial ovarian cancer or undifferentiated ovarian cancer.

[0147] In some embodiments, the pancreatic cancer is pancreatic adenocarcinoma or BRCA-mutated metastatic pancreatic cancer.

[0148] In some embodiments, the prostate cancer is sporadic prostate cancer or metastatic castration-resistant prostate cancer.

[0149] In some embodiments, the skin cancer is a non-melanoma skin cancer.

[0150] In some embodiments, the anti-CD38 antibody (e.g., daratumumab or HexaBody-CD38 (GEN3014)) is administered in combination with a PARPi, i.e., the anti-CD38 antibody and the PARPi are administered together as a mixture, simultaneously as a single agent, or sequentially in any order as a single agent. In some embodiments, the anti-CD38 antibody and the PARPi are administered in the same pharmaceutical composition.

[0151] In some embodiments, the anti-CD38 antibody and the PARPi are administered in different pharmaceutical compositions. In some embodiments, the anti-CD38 antibody and the PARPi are administered sequentially. In some embodiments, the PARPi is administered after administration of the anti-CD38 antibody. In some embodiments, the PARPi is administered before administration of the anti-CD38 antibody. In some embodiments, the anti-CD38 antibody and the PARPi are administered simultaneously.

[0152] Adenosine receptor antagonists The term "adenosine receptor antagonist" refers to a substance that acts on adenosine receptors and blocks the action of adenosine receptors when provided from the outside. Adenosine receptor antagonists include any such substance now known or discovered in the future, or its pharma- ceutically acceptable salt, tautomer, N-oxide, solvate, hydrate or stereoisomer. See, for example, Jacobson & Gao, Nat.Rev.Drug Discov.5(3):247-64(2006) and Chen et al., Nat.Rev.Drug Discov.12(4):265-86(2013).

[0153] In some embodiments, the adenosine receptor antagonist is an A1AR antagonist, A 2A AR antagonist, A 2B AR antagonists or A3AR antagonists, or a combination thereof.

[0154] In some embodiments, the adenosine receptor antagonist is selected from the group consisting of BG9719, DPCPX (CAS#102146-07-6), FK453 (CAS#121524-18-3), FR194921 (CAS#202646-80-8), N-0861 (CAS#121241-87-0), rolofylline (KW3902, CAS#136199-02-5), tonapofylline (BG9928, CAS#340021-17- 2) or WRC-0571 (CAS#501667-77-2), caffeine (CAS#58-08-2), 8-(-3-chlorostyryl)-caffeine (CSC, CAS#147700-11-6), istradefylline (KW-6002, CAS#155270-99-8), preladenant (SCH420814, CAS#377727-87-2), Schering's compound, SCH58261 (CAS#160098-96-4) ), SCH442416 (CAS#316173-57-6), SYN115 (CAS#870070-55-6), VER-6947, VER-7835, ZM241,385 (CAS#139180-30-6), Eisai's compounds, MRE2029-F20 (CAS#574753-99-4), MRS1754 (CAS#264622-58-4), OSIP-339391 (CAS#748136-54-1), FA385, M RE3008-F20 (CAS#252979-43-4), MRS1292, MRS1334 (CAS#192053-05-7), MRS1523 (CAS#212329-37-8), MRS3777 (CAS#1186195-57-2), Novartis compounds, OT-7999, PSB-11 (CAS#453591-58-7) or VUF5574 (CAS#280570-45-8), or combinations thereof.

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[0164] In some embodiments, the disease is anxiety, cerebral ischemia, dementia, heart failure (e.g., acute heart failure), liver damage, herniated disc, Parkinson's disease (PD), renal failure, restless legs syndrome, or a combination thereof.

[0165] In some embodiments, the adenosine receptor antagonist is an A1AR antagonist. In some embodiments, the A1AR antagonist is a human A1AR antagonist. 2A At least 5-fold selectivity for human A1AR compared to human A1AR, e.g., 2AIn some embodiments, the A1AR antagonists exhibit at least 10-fold, 15-fold, 20-fold, 50-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 550-fold, 600-fold, 650-fold, 700-fold, 750-fold, 800-fold, 850-fold, 900-fold, 950-fold, or 1000-fold selectivity for the human A1AR compared to the human A1AR. 2B At least 1.5-fold selectivity for human A1AR compared to human A1AR, e.g., 2B The A1AR antagonist exhibits at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 13-fold, 14-fold, 15-fold, 16-fold, 17-fold, 18-fold, 19-fold, 20-fold, 25-fold, or 30-fold selectivity for the human A1AR compared to the human A3AR. In some embodiments, the A1AR antagonist exhibits at least 5-fold selectivity for the human A1AR compared to the human A3AR, for example, at least 10-fold, 15-fold, 20-fold, 50-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 550-fold, 600-fold, 650-fold, 700-fold, 750-fold, 800-fold, 850-fold, 900-fold, 950-fold, or 1000-fold selectivity for the human A1AR compared to the human A3AR.

[0166] In some embodiments, the A1AR antagonist is BG9719, DPCPX (CAS#102146-07-6), FK453 (CAS#121524-18-3), FR194921 (CAS#202646-80-8), N-0861 (CAS#121241-87-0), rolofylline (KW3902, CAS#136199-02-5), tonapofylline (BG9928, CAS#340021-17-2) or WRC-0571 (CAS#501667-77-2), or a combination thereof.

[0167] In some embodiments, the disease is heart failure (eg, acute heart failure), renal failure, liver damage, dementia, anxiety, or a combination thereof.

[0168] In some embodiments, a) the adenosine receptor antagonist is BG9719, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or pharma- ceutically acceptable salt thereof, and the disease is renal failure or congestive heart failure, or a combination thereof; b) the adenosine receptor antagonist is FR194921, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or pharma- ceutically acceptable salt thereof, and the disease is dementia or anxiety, or a combination thereof; c) the adenosine receptor antagonist is rolofylline (KW-3902), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or pharma- ceutically acceptable salt thereof, and the disease is heart failure or renal failure, or a combination thereof; or d) the adenosine receptor antagonist is tonapofylline (BG9928), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or pharma- ceutically acceptable salt thereof, and the disease is heart failure, renal failure, or hepatic dysfunction, or a combination thereof; or It is a combination of the above.

[0169] In some embodiments, the heart failure is congestive heart failure or acute heart failure, hi some embodiments, the heart failure is acute heart failure.

[0170] In some embodiments, the adenosine receptor antagonist is BG9719, for example, and the disease is renal failure or congestive heart failure.

[0171] In some embodiments, the adenosine receptor antagonist is FR194921, for example, and the disease is dementia or anxiety.

[0172] In some embodiments, the adenosine receptor antagonist is rolofylline (KW-3902), for example, the condition is heart failure or renal failure, in some embodiments, the heart failure is congestive heart failure or acute heart failure.

[0173] In some embodiments, the adenosine receptor antagonist is tonapofylline (BG9928), for example, the disease is heart failure, renal failure, or liver failure, hi some embodiments, the heart failure is acute heart failure.

[0174] In some embodiments, the adenosine receptor antagonist is an A1AR or A 2A It is nonselective for AR.

[0175] In some embodiments, the adenosine receptor antagonist is A 2A In some embodiments, the A 2A AR antagonists are more specific to human A1AR than human A1AR. 2A At least 5-fold selectivity for the human A1AR, e.g., human A1AR compared to human A1AR 2A In some embodiments, the selectivity of the A is at least 10-fold, 15-fold, 20-fold, 50-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 1,000-fold, 2,000-fold, 4,000-fold, 5,000-fold, 10,000-fold, 20,000-fold, or 30,000-fold for A. 2A AR antagonists are human A 2B Human A compared with AR 2A At least 5-fold selectivity for AR, e.g., human A 2B Human A compared with AR 2A In some embodiments, the selectivity of the AR is at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 250, 300, 350, 400, 450, 500, 1,000, 2,000, 4,000, 5,000, 10,000, 20,000, 50,000, or 100,000 fold. 2A AR antagonists are more specific to human AAR than human A3AR. 2A At least 5-fold selectivity for the AR, e.g., human AAR compared to human A3AR 2AThe antibody exhibits at least 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 250, 300, 350, 400, 450, 500, 1,000, 2,000, 4,000, 5,000, 10,000, 20,000, 50,000 or 100,000 fold selectivity for AR.

[0176] In some embodiments, the adenosine receptor antagonist is caffeine (CAS#58-08-2), 8-(-3-chlorostyryl)-caffeine (CSC, CAS#147700-11-6), istradefylline (KW-6002, CAS#155270-99-8), preladenant (SCH420814, CAS#377727-87-2), Schering's compound, SCH58261 (CAS#160098-96-4), SCH442416 (CAS#316173-57-6), SYN115 (CAS#870070-55-6), VER-6947, VER-7835 or ZM241,385 (CAS#139180-30-6), or a combination thereof.

[0177] In some embodiments, the adenosine receptor antagonist is istradefylline.

[0178] Istradefylline is indicated as an adjunct treatment to levodopa / carbidopa in adult patients with Parkinson's disease (PD) experiencing "off" episodes. NOURIANZ™ (Istradefylline) is an oral tablet. In some embodiments, the dosage is 20 mg orally once daily. Dosage can be increased up to 40 mg once daily. Additional information regarding Istradefylline can be found, for example, in the NOURIANZ™ product insert prescribing information (https: / / www.nourianzhcp.com / assets / pdf / nourianz-full-prescribing-information.pdf), which is incorporated herein by reference in its entirety.

[0179] In some embodiments, the disease is selected from the group consisting of Parkinson's disease (PD), restless legs syndrome, cerebral ischemia, herniated disc, and combinations thereof.

[0180] In some embodiments, a) the adenosine receptor antagonist is caffeine, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or pharma- ceutically acceptable salt thereof, and the disease is Parkinson's disease (PD); e) the adenosine receptor antagonist is istradefylline (KW-6002), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or pharma- ceutically acceptable salt thereof, and the disease is Parkinson's disease (PD) or restless legs syndrome, or a combination thereof; f) the adenosine receptor antagonist is preladenant (SCH420814), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or pharma- ceutically acceptable salt thereof, and the disease is Parkinson's disease (PD); g) the adenosine receptor antagonist is a compound of Schering or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or pharma- ceutically acceptable salt thereof and the disease is a herniated intervertebral disc; h) the adenosine receptor antagonist is SCH58261, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or pharma- ceutically acceptable salt thereof, and the disease is cerebral ischemia; i) the adenosine receptor antagonist is SCH442416, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or pharma- ceutically acceptable salt thereof, and the disease is Parkinson's disease (PD); or j) the adenosine receptor antagonist is SYN115, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or pharma- ceutically acceptable salt thereof, and the disease is Parkinson's disease (PD); or It is a combination of the above.

[0181] In some embodiments, the adenosine receptor antagonist is caffeine.In some embodiments, the disease is Parkinson's disease (PD).

[0182] In some embodiments, the adenosine receptor antagonist is istradefylline. In some embodiments, the disease is Parkinson's disease (PD) or restless legs syndrome. In some embodiments, the subject is an adult patient with Parkinson's disease (PD) treated with levodopa / carbidopa and experiencing one or more "off" episodes.

[0183] In some embodiments, the adenosine receptor antagonist is preladenant (SCH420814). In some embodiments, the disease is Parkinson's disease (PD).

[0184] In some embodiments, the adenosine receptor antagonist is a compound from Schering Corp. In some embodiments, the disease is a herniated disc.

[0185] In some embodiments, the adenosine receptor antagonist is SCH 58261. In some embodiments, the disease is cerebral ischemia (i.e., ischemia).

[0186] In some embodiments, the adenosine receptor antagonist is SCH 442416. In some embodiments, the disease is Parkinson's disease (PD).

[0187] In some embodiments, the adenosine receptor antagonist is SYNl 15. In some embodiments, the disease is Parkinson's disease (PD).

[0188] In some embodiments, the adenosine receptor antagonist is A 2B In some embodiments, the A 2B AR antagonists are more specific to human A1AR than human A1AR. 2BAt least 5-fold selectivity for the human A1AR, e.g., human A1AR compared to human A1AR 2B In some embodiments, the A1A1A2A1B ... 2B AR antagonists are human A 2A Human A compared with AR 2B At least 5-fold selectivity for AR, e.g., human A 2A Human A compared with AR 2B In some embodiments, the A1A1A2A1B ... 2B AR antagonists are more specific to human AAR than human A3AR. 2B At least 5-fold selectivity for the AR, e.g., human AAR compared to human A3AR 2B The antibody exhibits at least 10-fold, 15-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 125-fold, 150-fold, 175-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 750-fold, or 1,000-fold selectivity for AR.

[0189] In some embodiments, the adenosine receptor antagonist is an Eisai compound, MRE2029-F20 (CAS#574753-99-4), MRS1754 (CAS#264622-58-4) or OSIP-339391 (CAS#748136-54-1), or a combination thereof.

[0190] In some embodiments, the adenosine receptor antagonist is an A3AR antagonist. In some embodiments, the A3AR antagonist exhibits at least 5-fold selectivity for human A3AR compared to human A1AR, for example, at least 10-fold, 15-fold, 20-fold, 50-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 1,000-fold, 2,000-fold, 4,000-fold, 5,000-fold, 10,000-fold, 20,000-fold or 30,000-fold selectivity for human A3AR compared to human A1AR. In some embodiments, the A3AR antagonist exhibits at least 5-fold selectivity for human A3AR compared to human A1AR. 2A At least 5-fold selectivity for human A3AR compared to human AAR, e.g., 2A In some embodiments, the A3AR antagonist exhibits at least 10-fold, 15-fold, 20-fold, 50-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 1,000-fold, 2,000-fold, 4,000-fold, 5,000-fold, 10,000-fold, 20,000-fold, or 30,000-fold selectivity for the human A3AR compared to the human A3AR. 2B At least 5-fold selectivity for human A3AR compared to human AAR, e.g., 2B The antibodies exhibit at least 10-fold, 15-fold, 20-fold, 50-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 1,000-fold, 2,000-fold, 4,000-fold, 5,000-fold, 10,000-fold, 20,000-fold or 30,000-fold selectivity for the human A3AR compared to the AR.

[0191] In some embodiments, the adenosine receptor antagonist is FA385, MRE3008-F20 (CAS#252979-43-4), MRS1292, MRS1334 (CAS#192053-05-7), MRS1523 (CAS#212329-37-8), MRS3777 (CAS#1186195-57-2), a Novartis compound, OT-7999, PSB-11 (CAS#453591-58-7) or VUF5574 (CAS#280570-45-8), or a combination thereof.

[0192] In some embodiments, the anti-CD38 antibody (e.g., daratumumab or HexaBody-CD38 (GEN3014)) is administered in combination with an adenosine receptor antagonist. In some embodiments, the anti-CD38 antibody and the adenosine receptor antagonist are administered in the same pharmaceutical composition. In some embodiments, the anti-CD38 antibody and the adenosine receptor antagonist are administered simultaneously as single agents.

[0193] In some embodiments, the anti-CD38 antibody and the adenosine receptor antagonist are administered in different pharmaceutical compositions. In some embodiments, the anti-CD38 antibody and the adenosine receptor antagonist are administered sequentially as single agents. In some embodiments, the adenosine receptor antagonist is administered prior to administration of the anti-CD38 antibody. In some embodiments, the adenosine receptor antagonist is administered after administration of the anti-CD38 antibody.

[0194] In some embodiments, the methods include administering to the subject an anti-CD38 antibody, a PARPi and an adenosine receptor antagonist for a time sufficient to treat the disease.

[0195] Also included is the use of one or more of the compounds (e.g., PARPi, adenosine receptor antagonist, or both and anti-CD38 antibodies) or compositions listed herein for treating, or for the manufacture of a medicament for treating, a disease or disorder provided herein.

[0196] Combination therapy In some embodiments of the invention, the subject has cancer (e.g., a solid tumor), and the PARPi, adenosine receptor antagonist, or both, and the anti-CD38 antibody are administered in combination with a chemotherapeutic agent, a targeted anti-cancer therapy, a standard of care for cancer treatment, or an immune checkpoint inhibitor.

[0197] In some embodiments, the PARPi and the chemotherapeutic agent, targeted anti-cancer therapy, standard of care for cancer treatment, or immune checkpoint inhibitor are administered simultaneously. In some embodiments, the PARPi and the chemotherapeutic agent, targeted anti-cancer therapy, standard of care for cancer treatment, or immune checkpoint inhibitor are administered sequentially or separately.

[0198] In some embodiments, the adenosine receptor antagonist and the chemotherapeutic agent, targeted anti-cancer therapy, standard of care for cancer treatment, or immune checkpoint inhibitor are administered simultaneously, hi some embodiments, the adenosine receptor antagonist and the chemotherapeutic agent, targeted anti-cancer therapy, standard of care for cancer treatment, or immune checkpoint inhibitor are administered sequentially or separately.

[0199] In some embodiments, the anti-CD38 antibody and the chemotherapeutic agent, targeted anti-cancer therapy, standard of care for cancer treatment, or immune checkpoint inhibitor are administered simultaneously, hi some embodiments, the anti-CD38 antibody and the chemotherapeutic agent, targeted anti-cancer therapy, standard of care for cancer treatment, or immune checkpoint inhibitor are administered sequentially or separately.

[0200] In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-PD-L2 antibody, an anti-LAG3 antibody, an anti-TIM3 antibody, or an anti-CTLA-4 antibody.

[0201] In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody comprises the following VH and VL amino acid sequences: a) SEQ ID NO:23 and SEQ ID NO:24, respectively; b) SEQ ID NO:25 and SEQ ID NO:26, respectively; c) SEQ ID NO: 33 and SEQ ID NO: 34, respectively; or d) SEQ ID NO: 35 and SEQ ID NO: 36, respectively.

[0202] In some embodiments, the immune checkpoint inhibitor is an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody comprises the following VH and VL amino acid sequences: a) SEQ ID NO:27 and SEQ ID NO:28, respectively; b) SEQ ID NO:29 and SEQ ID NO:30, respectively; or c) SEQ ID NO: 31 and SEQ ID NO: 32, respectively.

[0203] In some embodiments, the immune checkpoint inhibitor is an anti-PD-L2 antibody.

[0204] In some embodiments, the immune checkpoint inhibitor is an anti-LAG3 antibody. Non-limiting examples of anti-LAG-3 antibodies are described in WO 2010 / 019570.

[0205] In some embodiments, the immune checkpoint inhibitor is an anti-TIM-3 antibody. In some embodiments, the anti-TIM-3 antibody comprises the following VH and VL amino acid sequences: a) SEQ ID NO: 37 and SEQ ID NO: 38, respectively; or b) SEQ ID NO: 39 and SEQ ID NO: 40, respectively.

[0206] In some embodiments, the immune checkpoint inhibitor is an anti-CTLA-4 antibody. A non-limiting example of an anti-CTLA-4 antibody is ipilimumab.

[0207] Anti-PD-1, anti-PD-L1, anti-PD-L2, anti-LAG3, anti-TIM3 and anti-CTLA-4 antibodies may be generated de novo.

[0208] In some embodiments, the anti-CD38 antibody and the immune checkpoint inhibitor are administered simultaneously. In some embodiments, the anti-CD38 antibody and the immune checkpoint inhibitor are administered sequentially or separately.

[0209] In some embodiments, the methods of the present invention further comprise administering a form of radiation therapy, surgery, or a combination thereof. Non-limiting examples of radiation therapy include external beam radiation therapy, intensity modulated radiation therapy (IMRT), focused radiation therapy, and any form of radiosurgery, including Gamma Knife, CyberKnife, Linac, and interstitial radiation (e.g., radioactive seed implants, GliaSite balloon).

[0210] Focused radiation methods that may be used include stereotactic radiosurgery, fractionated stereotactic radiosurgery, and intensity-modulated radiation therapy (IMRT). It is clear that stereotactic radiosurgery delivers radiation precisely to tumor tissue, e.g., brain tumors, while avoiding surrounding nontumor normal tissue. The dose of radiation applied by stereotactic radiosurgery may vary, but is typically between 1 Gy and about 30 Gy, and may include intermediate ranges in dose, e.g., 1-5, 10, 15, 20, 25, up to 30 Gy. Thanks to the noninvasive fixation device, stereotactic radiation does not have to be delivered in a single treatment. The treatment plan can be reliably reproduced from day to day, thereby allowing multiple fractionated radiation doses to be delivered. When used to treat tumors over time, radiosurgery is called "fractionated stereotactic radiosurgery" or FSR (fractionated stereotactic radiosurgery). In contrast, stereotactic radiosurgery refers to treatment in a single session. Fractionated stereotactic radiosurgery can provide a high treatability ratio, i.e., a high percentage of tumor cells are killed and normal tissue is less affected. Tumor and normal tissue respond differently to a single high dose of radiation and multiple low doses of radiation. A single high dose of radiation can kill more normal tissue than multiple low doses of radiation. Thus, multiple low doses of radiation can kill more tumor cells while sparing normal tissue. The dose of radiation applied by fractionated stereotactic radiosurgery can vary from 1 Gy to about 50 Gy, including intermediate ranges of hypofractionated doses, including, for example, 1-5, 10, 15, 20, 25, 30, 40, and up to 50 Gy. Intensity-modulated radiation therapy (IMRT) can also be used. IMRT is an advanced mode of high-precision three-dimensional conformal radiation therapy (3DCRT) that uses a computer-controlled linear accelerator to deliver precise doses of radiation to a malignant tumor or to specific areas within the tumor. In 3DCRT, the profile of each radiation beam is shaped to fit the target profile from the beam vector image (BEV) using a multi-leaf collimator (MLC), thereby generating many beams.IMRT allows the radiation dose to be more precisely matched to the three-dimensional (3D) shape of the tumor by modulating the intensity of the radiation beam into multiple small doses. Thus, IMRT allows a higher radiation dose to be focused on an area inside the tumor while minimizing the dose to surrounding normal critical structures. IMRT improves the ability to match the treatment volume to the concave shape of the tumor, for example, when the tumor is covering vulnerable structures such as the spinal cord, major organs, or blood vessels.

[0211] In some embodiments of the invention, the subject has cancer (e.g., AL) and the subject undergoes hematopoietic stem cell transplantation (HSCT). "Hematopoietic stem cell transplantation" is the transplantation of peripheral blood stem cells derived from bone marrow (in this case known as bone marrow transplant), blood (e.g., peripheral blood and umbilical cord blood), or amniotic fluid. "Receiving a hematopoietic stem cell transplant" means that the patient has already undergone, is undergoing, or will undergo a HSCT.

[0212] In some embodiments, the HSCT is allogeneic. In some embodiments, the HSCT is autologous or syngeneic (i.e., the donor is a twin). Autologous HSCT involves extraction of HSCs from the subject and freezing the harvested HSCs. After bone marrow ablation, the subject's stored HSCs are transplanted into the subject. Allogeneic HSCT involves HSCs obtained from an allogeneic HSC donor with a compatible HLA type with the subject.

[0213] In some embodiments, the subject has completed chemotherapy and / or radiation therapy prior to HSCT.

[0214] Prior to HSCT, the patient may be treated with chemotherapy and / or radiation therapy (so-called pre-transplant preparation) to eradicate some or all of the patient's hematopoietic cells prior to transplantation. In the case of allogeneic HSCT, the patient may also be treated with immunosuppressants. An exemplary pre-transplant preparation therapy is high-dose melphalan (see, for example, Skinner et al., Ann. Intern. Med. 140:85-93 (2004); Gertz et al., Bone Marrow Transplant 34:1025-31 (2004); Perfetti et al., Haematologica 91:1635-43 (2006)). Radiation therapy that may be used in pre-transplantation therapy may be performed according to protocols commonly known in the art. Radiation therapy may be provided simultaneously, sequentially, or separately with the anti-CD38 antibody.

[0215] In some embodiments (e.g., treating AL), the method further comprises administering to the subject a proteasome inhibitor, a corticosteroid, and cyclophosphamide for a time sufficient to treat the disease or condition (e.g., AL). In some embodiments, the proteasome inhibitor is Velcade® (bortezomib) or a vinca alkaloid, such as vincristine, or an anthracycline, such as doxorubicin. In some embodiments, the proteasome inhibitor is Velcade® (bortezomib). In some embodiments, the corticosteroid is dexamethasone. In some embodiments, the corticosteroid is prednisone.

[0216] Cyclophosphamide is given IV (intermittent therapy): 40-50 mg / kg (400-1800 mg / m2) divided over 2-5 days; may be repeated at 2-4 week intervals; IV (continuous daily therapy): 60-120 mg / m2 / day (1-2.5 mg / kg / day); PO (intermittent therapy): 400-1000 mg / m2 2 divided over 4-5 days or PO (continuous daily therapy): 50-100 mg / m 2 / day or 1 to 5 mg / kg / day.

[0217] Bortezomib was administered twice weekly or once weekly at 1.3 mg / m 2 It may be administered SQ.

[0218] Dexamethasone may be administered at 40 mg / week, or 20 mg before and after administration of the anti-CD38 antibody.

[0219] In some embodiments, the methods include administering to a subject an anti-CD38 antibody (e.g., daratumumab) and CyBorD (cyclophosphamide, bortezomib, and dexamethasone) for a time sufficient to treat the disease or condition (e.g., AL). In some embodiments, cyclophosphamide is administered at a dose of 300 mg / m 2 (oral or IV), and bortezomib was 1.3 mg / m 2 (SC injection) with dexamethasone given at 20 mg (oral or IV) as premedication and 20 mg the day after daratumumab administration.

[0220] Although exemplary embodiments have been particularly shown and described, those skilled in the art will understand that various changes in form and details may be made therein without departing from the scope of the embodiments encompassed by the appended claims.

[0221] Embodiment 1. A method of treating a disease in a subject in need thereof comprising administering to the subject an anti-CD38 antibody and a poly ADP ribose polymerase inhibitor (PARPi) for a time sufficient to treat the disease. 2. Anti-CD38 antibody, a) the amino acid sequences of heavy chain complementarity determining region 1 (HCDR1), HCDR2 and HCDR3 of SEQ ID NOs: 6, 7 and 8, respectively; and b) The method of embodiment 1, comprising the amino acid sequences of light chain complementarity determining region 1 (LCDR1), LCDR2 and LCDR3 of SEQ ID NOs: 9, 10 and 11, respectively. 3. Anti-CD38 antibody, a) the heavy chain variable region (VH) sequence of SEQ ID NO:4; and b) The method of embodiment 1, comprising the light chain variable region (VL) sequence of SEQ ID NO:5. 4. The method of embodiment 1, wherein the anti-CD38 antibody comprises the heavy chain sequence of SEQ ID NO:12 and the light chain sequence of SEQ ID NO:13. 5. Anti-CD38 antibody, a) the amino acid sequences of heavy chain complementarity determining region 1 (HCDR1), HCDR2 and HCDR3 of the heavy chain variable region (VH) of SEQ ID NO: 14, and the amino acid sequences of light chain complementarity determining region 1 (LCDR1), LCDR2 and LCDR3 of the light chain variable region (VL) of SEQ ID NO: 15; b) the amino acid sequences of HCDR1, HCDR2 and HCDR3 of VH of SEQ ID NO: 16, and LCDR1, LCDR2 and LCDR3 of VL of SEQ ID NO: 17; c) the amino acid sequence of HCDR1, HCDR2 and HCDR3 of VH of SEQ ID NO: 18, and the amino acid sequence of LCDR1, LCDR2 and LCDR3 of VL of SEQ ID NO: 19; or d) The method of embodiment 1, comprising the amino acid sequences of HCDR1, HCDR2 and HCDR3 of VH of SEQ ID NO: 20, and the amino acid sequences of LCDR1, LCDR2 and LCDR3 of VL of SEQ ID NO: 21. 6. Anti-CD38 antibody, a) SEQ ID NOs: 14 and 15, respectively; b) SEQ ID NOs: 16 and 17, respectively; c) SEQ ID NOs: 18 and 19, respectively; or d) The method of embodiment 5, comprising SEQ ID NOs: 20 and 21, respectively. 7. The method of any one of embodiments 1-6, wherein the anti-CD38 antibody is of the IgG1, IgG2, IgG3 or IgG4 subtype. 8. The method of embodiment 7, wherein the anti-CD38 antibody is of the IgG1 subtype. 9. The method of embodiment 8, wherein the anti-CD38 antibody is of the IgG1 / κ subtype. 10. The method of embodiment 1, wherein the anti-CD38 antibody is daratumumab. 11. The method of any one of embodiments 1-10, wherein the anti-CD38 antibody is administered intravenously. 12. The method of any one of embodiments 1 to 10, wherein the anti-CD38 antibody is administered subcutaneously. 13. The method of embodiment 12, wherein the anti-CD38 antibody is administered in a pharmaceutical composition comprising an anti-CD38 antibody and hyaluronidase. 14. The method of embodiment 13, wherein the hyaluronidase is rHuPH20 and has the amino acid sequence of SEQ ID NO: 22. 15. The method of any one of embodiments 1 to 14, wherein the disease is cancer. 16. The method of embodiment 15, wherein the cancer is a blood cancer. 17. The method of embodiment 16, wherein the blood cancer is leukemia. 18. The method of embodiment 17, wherein the leukemia is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), hairy cell leukemia (HCL) or myelodysplastic syndrome (MDS). 19. The method of embodiment 16, wherein the blood cancer is lymphoma. 20. The method of embodiment 19, wherein the lymphoma is Hodgkin's lymphoma. 21. The method of embodiment 20, wherein the Hodgkin's lymphoma is nodular sclerosing Hodgkin's lymphoma (NSCHL), mixed cellularity Hodgkin's lymphoma (MCcHL), lymphocyte predominant Hodgkin's disease (LRCHL) or lymphocyte depletion Hodgkin's disease (LDHL). 22. The method of embodiment 19, wherein the lymphoma is non-Hodgkin's lymphoma (NHL). 23. The method of embodiment 22, wherein the non-Hodgkin's lymphoma is a B-cell lymphoma. 24. The method of embodiment 23, wherein the B-cell lymphoma is diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), follicular lymphoma (FL), small lymphocytic lymphoma (SLL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia (WMG) or Burkitt's lymphoma (BL). 25. The method of embodiment 22, wherein the non-Hodgkin's lymphoma is a T-cell lymphoma. 26. The method of embodiment 25, wherein the T-cell lymphoma is peripheral T-cell lymphoma (PTCL), anaplastic large cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AITL) or cutaneous T-cell lymphoma. 27. The method of embodiment 16, wherein the blood cancer is multiple myeloma. 28. The method of embodiment 27, wherein the multiple myeloma is light chain multiple myeloma (LCMM), nonsecretory multiple myeloma (NSMM), monofocal plasmacytoma (SP), extramedullary plasmacytoma (EMP), monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), immunoglobulin D multiple myeloma (IgD MM) or immunoglobulin E (IgE) multiple myeloma. 29. The method of embodiment 16, wherein the hematological cancer is a CD38-positive hematological malignancy. 30. The method of embodiment 29, wherein the CD38-positive hematological malignancy is multiple myeloma (MM), acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma (BL), follicular lymphoma (FL), mantle cell lymphoma (MCL), acute myeloid leukemia (AML), or chronic lymphocytic leukemia (CLL). 31. The method of embodiment 29, wherein the CD38-positive hematological malignancy is a plasma cell dyscrasia. 32. The method of embodiment 31, wherein the plasma cell dyscrasia is light chain amyloidosis (AL), multiple myeloma (MM), or Waldenström's macroglobulinemia. 33. The method of embodiment 32, wherein the plasma cell disorder is MM. 34. The method of embodiment 32, wherein the plasma cell disorder is AL. 35. The method of embodiment 15, wherein the cancer is a solid tumor. 36. The method of embodiment 35, wherein the solid tumor is a tumor of the breast, lung, prostate, colon, bladder, ovary, kidney, stomach, colon, rectum, testis, head and / or neck, pancreas, brain or skin. 37. The method of embodiment 35, wherein the solid tumor is bladder cancer, brain cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, fallopian tube cancer, gastric cancer, genitourinary cancer, head and neck cancer, liver cancer, lung cancer, melanoma, nasopharyngeal carcinoma (NPC), pancreatic cancer, prostate cancer, ovarian cancer, rectal cancer, kidney cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer or urethral cancer. 38. The method of embodiment 35, wherein the solid tumor is squamous non-small cell lung cancer (NSCLC), non-squamous NSCLC, lung adenocarcinoma, mesothelioma, renal clear cell carcinoma, renal papillary cell carcinoma, castration-resistant prostate cancer, squamous cell carcinoma of the head and neck, cancer of the esophagus, cancer of the gastrointestinal tract or endometriosis. 39. The method of any one of embodiments 35 to 38, wherein the solid tumor is a metastatic lesion of a cancer. 40. The method of any one of embodiments 1 to 14, wherein the disease is a neurological disorder. 41. The method of embodiment 40, wherein the neurological disorder is acute spinal cord injury (SCI), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), ataxia, Bell's palsy, brain tumor, cerebral aneurysm, epilepsy, Guillain-Barré syndrome (GBS), hydrocephalus, lumbar disc disease, meningitis, multiple sclerosis (MS), muscular dystrophy, neurocutaneous syndrome, Parkinson's disease (PD), stroke, cluster headache, tension headache, migraine, encephalitis, sepsis or myasthenia gravis (MG). 42. The method of embodiment 41, wherein the neurological disorder is Alzheimer's disease (AD) or multiple sclerosis (MS). 43. The method of any one of embodiments 1-14, wherein the disease is a liver disease. 44. The method of embodiment 43, wherein the liver disease is Alagille syndrome (ALGS), autoimmune hepatitis (AIH), biliary atresia, cirrhosis, hemochromatosis, hepatitis, nonalcoholic fatty liver disease (NAFLD), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) or Wilson's disease (WD). 45. The method of embodiment 44, wherein the NAFLD is nonalcoholic steatohepatitis (NASH). 46. ​​The method of any one of embodiments 1 to 45, wherein the PARPi is a PARP1 inhibitor, a PARP2 inhibitor or a PARP3 inhibitor. 47. The method of any one of embodiments 1 to 45, wherein the PARPi is AZD2461, CEP-8983, CEP-9722, E7016 (GPI21016), iniparib (BSI201), INO-1001, niraparib (MK-4827), olaparib (AZD-2281), pamiparib (BGB-290), rucaparib (AG-014699, PF-01367338), talazoparib (BMN-673) or veliparib (ABT-888). 48. The method of embodiment 47, wherein the PARPi is niraparib (MK-4827), olaparib (AZD-2281), rucaparib (AG-014699, PF-01367338), or talazoparib (BMN-673). 49. The method according to any one of embodiments 1 to 48, wherein the disease is bile duct cancer, bone cancer, breast cancer, colorectal cancer, endometrial cancer, fallopian tube cancer, blood cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, peritoneal cancer, prostate cancer, sarcoma or skin cancer. 50. a) the PARPi is niraparib and the disease is bile duct cancer, endometrial cancer, fallopian tube cancer, ovarian cancer, pancreatic cancer, peritoneal cancer, prostate cancer or skin cancer; b) the PARPi is olaparib and the disease is cholangiocarcinoma, breast cancer, colorectal cancer, endometrial cancer, fallopian tube cancer, melanoma, ovarian cancer, pancreatic cancer, primary peritoneal cancer, prostate cancer or skin cancer; c) the PARPi is Pamiparib (BGB-290) and the disease is esophageal cancer, glioma, head and neck cancer, non-small cell lung cancer (NSCLC), small cell gastric cancer, small cell lung cancer or soft tissue sarcoma; d) the PARPi is rucaparib and the disease is ovarian cancer; or e) The method according to any one of embodiments 1 to 47, wherein the PARPi is talazoparib and the disease is breast cancer, bile duct cancer, bone cancer, colorectal cancer, endometrial cancer, lung cancer, pancreatic cancer, prostate cancer or skin cancer. 51. a) the bone cancer is Ewing's sarcoma; b) The breast cancer is advanced breast cancer, BRCA1 / 2 mutated and human epidermal growth factor receptor type 2 (HER2) negative metastatic breast cancer, or triple-negative breast cancer (TNBC); c) the lung cancer is small cell lung cancer; d) The ovarian cancer is advanced ovarian cancer, BRCA-mutated ovarian cancer, high-grade epithelial ovarian cancer (HGOC), high-grade serous ovarian cancer, high-grade serous and undifferentiated ovarian cancer, platinum-sensitive newly diagnosed advanced ovarian cancer, platinum-sensitive recurrent ovarian cancer, platinum-sensitive recurrent ovarian cancer, sporadic platinum-resistant high-grade serous ovarian cancer, recurrent high-grade ovarian cancer, recurrent high-grade serous epithelial ovarian cancer or undifferentiated ovarian cancer; e) the pancreatic cancer is pancreatic adenocarcinoma or BRCA mutant metastatic pancreatic cancer; f) the prostate cancer is sporadic prostate cancer or metastatic castration-resistant prostate cancer; or g) The method of embodiment 49 or 50, wherein the skin cancer is non-melanoma skin cancer. 52. The method according to any one of embodiments 1 to 51, wherein the anti-CD38 antibody and the PARPi are administered simultaneously. 53. The method of any one of embodiments 1 to 51, wherein the anti-CD38 antibody and the PARPi are administered sequentially or separately. 54. A method of treating a disease in a subject in need thereof, comprising administering to the subject an anti-CD38 antibody and an adenosine receptor antagonist for a time sufficient to treat the disease. 55.Anti-CD38 antibody, a) the amino acid sequences of heavy chain complementarity determining region 1 (HCDR1), HCDR2 and HCDR3 of SEQ ID NOs: 6, 7 and 8, respectively; and b) The method of embodiment 54, comprising the amino acid sequences of light chain complementarity determining region 1 (LCDR1), LCDR2 and LCDR3 of SEQ ID NOs: 9, 10 and 11, respectively. 56.Anti-CD38 antibody, a) the heavy chain variable region (VH) sequence of SEQ ID NO:4; and b) The method of embodiment 54, comprising the light chain variable region (VL) sequence of SEQ ID NO:5. 57. The method of embodiment 54, wherein the anti-CD38 antibody comprises the heavy chain sequence of SEQ ID NO: 12 and the light chain sequence of SEQ ID NO: 13. 58.Anti-CD38 antibody, a) the amino acid sequences of heavy chain complementarity determining region 1 (HCDR1), HCDR2 and HCDR3 of the heavy chain variable region (VH) of SEQ ID NO: 14, and the amino acid sequences of light chain complementarity determining region 1 (LCDR1), LCDR2 and LCDR3 of the light chain variable region (VL) of SEQ ID NO: 15; b) the amino acid sequences of HCDR1, HCDR2 and HCDR3 of VH of SEQ ID NO: 16, and LCDR1, LCDR2 and LCDR3 of VL of SEQ ID NO: 17; c) the amino acid sequence of HCDR1, HCDR2 and HCDR3 of VH of SEQ ID NO: 18, and the amino acid sequence of LCDR1, LCDR2 and LCDR3 of VL of SEQ ID NO: 19; or d) The method described in embodiment 54, comprising the amino acid sequences of HCDR1, HCDR2 and HCDR3 of VH of SEQ ID NO: 20, and the amino acid sequences of LCDR1, LCDR2 and LCDR3 of VL of SEQ ID NO: 21. 59.Anti-CD38 antibody, a) SEQ ID NOs: 14 and 15, respectively; b) SEQ ID NOs: 16 and 17, respectively; c) SEQ ID NOs: 18 and 19, respectively; or d) The method of embodiment 58, comprising SEQ ID NOs: 20 and 21, respectively. 60. The method of any one of embodiments 54 to 59, wherein the anti-CD38 antibody is of the IgG1, IgG2, IgG3 or IgG4 subtype. 61. The method of embodiment 60, wherein the anti-CD38 antibody is of the IgG1 subtype. 62. The method of embodiment 61, wherein the anti-CD38 antibody is of the IgG1 / κ subtype. 63. The method of embodiment 54, wherein the anti-CD38 antibody is daratumumab. 64. The method of any one of embodiments 54 to 63, wherein the anti-CD38 antibody is administered intravenously. 65. The method of any one of embodiments 54 to 63, wherein the anti-CD38 antibody is administered subcutaneously. 66. The method of embodiment 65, wherein the anti-CD38 antibody is administered in a pharmaceutical composition comprising an anti-CD38 antibody and hyaluronidase. 67. The method of embodiment 66, wherein the hyaluronidase is rHuPH20 and has the amino acid sequence of SEQ ID NO: 22. 68. The method of any one of embodiments 54 to 67, wherein the disease is cancer. 69. The method of embodiment 68, wherein the cancer is a blood cancer. 70. The method of embodiment 69, wherein the blood cancer is leukemia. 71. The method of embodiment 70, wherein the leukemia is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), hairy cell leukemia (HCL) or myelodysplastic syndrome (MDS). 72. The method of embodiment 69, wherein the blood cancer is lymphoma. 73. The method of embodiment 72, wherein the lymphoma is Hodgkin's lymphoma. 74. The method of embodiment 73, wherein the Hodgkin lymphoma is nodular sclerosing Hodgkin lymphoma (NSCHL), mixed cellularity classical Hodgkin lymphoma (MCcHL), lymphocyte predominant Hodgkin's disease (LRCHL) or lymphocyte depletion Hodgkin's disease (LDHL). 75. The method of embodiment 72, wherein the lymphoma is non-Hodgkin's lymphoma (NHL). 76. The method of embodiment 75, wherein the non-Hodgkin's lymphoma is a B-cell lymphoma. 77. The method of embodiment 76, wherein the B-cell lymphoma is diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), follicular lymphoma (FL), small lymphocytic lymphoma (SLL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia (WMG) or Burkitt's lymphoma (BL). 78. The method of embodiment 75, wherein the non-Hodgkin's lymphoma is a T-cell lymphoma. 79. The method of embodiment 78, wherein the T-cell lymphoma is peripheral T-cell lymphoma (PTCL), anaplastic large cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AITL) or cutaneous T-cell lymphoma. 80. The method of embodiment 79, wherein the blood cancer is multiple myeloma. 81. The method of embodiment 80, wherein the multiple myeloma is light chain multiple myeloma (LCMM), nonsecretory multiple myeloma (NSMM), monofocal plasmacytoma (SP), extramedullary plasmacytoma (EMP), monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), immunoglobulin D multiple myeloma (IgD MM) or immunoglobulin E (IgE) multiple myeloma. 82. The method of embodiment 69, wherein the hematological cancer is a CD38-positive hematological malignancy. 83. The method of embodiment 82, wherein the CD38-positive hematological malignancy is multiple myeloma (MM), acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma (BL), follicular lymphoma (FL), mantle cell lymphoma (MCL), acute myeloid leukemia (AML), or chronic lymphocytic leukemia (CLL). 84. The method of embodiment 82, wherein the CD38-positive hematological malignancy is a plasma cell dyscrasia. 85. The method of embodiment 84, wherein the plasma cell dyscrasia is light chain amyloidosis (AL), multiple myeloma (MM), or Waldenström's macroglobulinemia. 86. The method of embodiment 85, wherein the plasma cell disorder is MM. 87. The method of embodiment 85, wherein the plasma cell disorder is AL. 88. The method of embodiment 68, wherein the cancer is a solid tumor. 89. The method of embodiment 88, wherein the solid tumor is a tumor of the breast, lung, prostate, colon, bladder, ovary, kidney, stomach, colon, rectum, testis, head and / or neck, pancreas, brain or skin. 90. The method of embodiment 88, wherein the solid tumor is bladder cancer, brain cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, fallopian tube cancer, gastric cancer, genitourinary cancer, head and neck cancer, liver cancer, lung cancer, melanoma, nasopharyngeal cancer (NPC), pancreatic cancer, prostate cancer, ovarian cancer, rectal cancer, kidney cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer or urethral cancer. 91. The method of embodiment 88, wherein the solid tumor is squamous non-small cell lung cancer (NSCLC), non-squamous NSCLC, lung adenocarcinoma, mesothelioma, renal clear cell carcinoma, renal papillary cell carcinoma, castration-resistant prostate cancer, squamous cell carcinoma of the head and neck, cancer of the esophagus, cancer of the gastrointestinal tract or endometriosis. 92. The method of any one of embodiments 88-91, wherein the solid tumor is a metastatic lesion of a cancer. 93. The method of any one of embodiments 54-67, wherein the disease is a neurological disorder. 94. The method of embodiment 93, wherein the neurological disorder is acute spinal cord injury (SCI), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), ataxia, Bell's palsy, brain tumor, cerebral aneurysm, epilepsy, Guillain-Barré syndrome (GBS), hydrocephalus, lumbar disc disease, meningitis, multiple sclerosis (MS), muscular dystrophy, neurocutaneous syndrome, Parkinson's disease (PD), stroke, cluster headache, tension headache, migraine, encephalitis, sepsis or myasthenia gravis (MG). 95. The method of embodiment 94, wherein the neurological disorder is Alzheimer's disease (AD) or multiple sclerosis (MS). 96. The method of any one of embodiments 54-67, wherein the disease is a liver disease. 97. The method of embodiment 96, wherein the liver disease is Alagille syndrome (ALGS), autoimmune hepatitis (AIH), biliary atresia, cirrhosis, hemochromatosis, hepatitis, nonalcoholic fatty liver disease (NAFLD), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) or Wilson's disease (WD). 98. The method of embodiment 97, wherein the NAFLD is nonalcoholic steatohepatitis (NASH). 99. Adenosine receptor antagonists are A1 receptor (A1AR) antagonists, A 2AReceptor (A 2A AR) antagonist, A 2B Receptor (A 2B The method of any one of embodiments 54-98, wherein the compound is an A3 receptor (A3AR) antagonist or an A3 receptor (A3AR) antagonist. 100. The method of embodiment 99, wherein the adenosine receptor antagonist is an A1AR antagonist. 101. The method of embodiment 100, wherein the adenosine receptor antagonist is BBG9719, DPCPX, FK453, FR194921, N-0861, rolofylline (KW3902), tonapofylline (BG9928) or WRC-0571. 102. The method of embodiment 101, wherein the disease is heart failure, renal failure, liver damage, dementia or anxiety. 103. The method of embodiment 102, wherein the heart failure is acute heart failure. 104. a) the adenosine receptor antagonist is BG9719 and the disease is renal failure or congestive heart failure; b) the adenosine receptor antagonist is FR194921 and the disease is dementia or anxiety; c) the adenosine receptor antagonist is rolofylline (KW-3902) and the disease is heart failure or renal failure; or d) The method of embodiment 101, wherein the adenosine receptor antagonist is tonapofylline (BG9928) and the disease is heart failure, renal failure or liver disorder. 105. The method of embodiment 104, wherein the heart failure is congestive heart failure. 106. The method of embodiment 104, wherein the heart failure is acute heart failure. 107. Adenosine receptor antagonists are 2A 100. The method of embodiment 99, wherein the compound is an AR antagonist. 108. The method of embodiment 107, wherein the adenosine receptor antagonist is caffeine, 8-(-3-chlorostyryl)-caffeine (CSC), istradefylline (KW-6002), preladenant (SCH420814), Schering's compound, SCH58261, SCH442416, SYN115, VER6947, VER7835 or ZM241,385. 109. The method of embodiment 108, wherein the disease is Parkinson's disease (PD), restless legs syndrome, cerebral ischemia or herniated disc. 110. a) the adenosine receptor antagonist is caffeine and the disease is Parkinson's disease (PD); b) the adenosine receptor antagonist is istradefylline (KW-6002) and the disease is Parkinson's disease (PD) or restless legs syndrome; c) the adenosine receptor antagonist is preladenant (SCH420814) and the disease is Parkinson's disease (PD); d) the adenosine receptor antagonist is SCH58261 and the disease is cerebral ischemia; e) the adenosine receptor antagonist is SCH442416 and the disease is Parkinson's disease (PD); f) the adenosine receptor antagonist is SYN115 and the disease is Parkinson's disease (PD); or g) The method of embodiment 108, wherein the adenosine receptor antagonist is a compound of formula I and the disease is a herniated disc.

[0222] [ka] 111. Adenosine receptor antagonists are 2B 100. The method of embodiment 99, wherein the compound is an AR antagonist. 112. The method of embodiment 111, wherein the adenosine receptor antagonist is MRE2029-F20, MRS1754, OSIP-339391 or a compound of formula II.

[0223] [ka] 113. The method of embodiment 99, wherein the adenosine receptor antagonist is an A3AR antagonist. 114. The method of embodiment 113, wherein the adenosine receptor antagonist is FA385, MRE3008-F20, MRS1292, MRS1334, MRS1523, MRS3777, OT-7999, PSB-11, VUF5574 or a compound of formula III.

[0224] [ka] 115. The method according to any one of embodiments 54 to 114, wherein the anti-CD38 antibody and the adenosine receptor antagonist are administered simultaneously. 116. The method according to any one of embodiments 54 to 114, wherein the anti-CD38 antibody and the adenosine receptor antagonist are administered sequentially or separately. 117. The method of any one of embodiments 54-116, further comprising administering to the subject a poly ADP ribose polymerase inhibitor (PARPi) for a time sufficient to treat the disease. EXAMPLES

[0225] It is important to understand the tissue- and age-specific effects of CD38 depletion in mammalian models.

[0226] CD38 is a NAD + Plays an important role in the consumption of extracellular NAD + is degraded by CD38 to generate nicotinamide (NAM) or nicotinamide mononucleotide (NMN), which is further degraded to nicotinamide riboside (NR). NR enters cells via nucleotide transporters and is transported to intracellular NAD + Involved in the biosynthesis of NR, which is converted to NMN, and NAM, which is converted to NMN. These pathways merge at the stage of NMN formation, which then converts to NAD+ Nicotinic acid (NA) is converted to NA mononucleotide (NAMN), NA adenine dinucleotide (NAAD), and then NAD + is converted to NAD + NAD is also used as a cofactor for S-adenosylhomocysteine ​​(SAH) hydrolase for the production of intracellular adenosine. + The net loss of ADP-ribose formation (NAD + It is involved in the enzymatic reactions that occur during glycohydrolases, poly ADP-ribosylation (PARPs), and protein deacetylation (sirtuins). See, e.g., Horenstein AL et al., Cells 4(3):520-37(2015).

[0227] NAD + NAD is an essential coenzyme and a central signaling molecule involved in redox homeostasis, efficient signaling, and maintaining mitochondrial metabolism. + The extracellular transformation of can vary significantly according to the tissue environment or pathological state (Horenstein et al., Cells. 4(3):520-37(2015)). Accumulating evidence suggests that tumor cells exploit such networks for migration and homing to protected areas and, more importantly, to evade immune responses (ibid.).

[0228] CD38 also plays a role in adenosine production and signaling. In some cancers, NAD released by the salvage pathway + is hydrolyzed to adenosine via the CD38-CD203a-CD73 pathway. Accumulated adenosine is further degraded to inosine in the presence of adenosine deaminase (ADA) through association with CD26. See, e.g., Vijayan D et al., Nat. Rev. Cancer 17(12):709-24(2017).

[0229] CD38 also regulates age-related NAD +It mediates changes in metabolism and adenosine production. Increased expression of CD38 with age is associated with increased NAD + It has been hypothesized that this leads to a decline in NAD and mitochondrial dysfunction, thereby affecting metabolism and brain and immune function. See, e.g., Camacho-Pereira J et al., Cell Metab. 23(6):1127-39 (2016). For example, CD38 is involved in the regulation of age-related NAD in the liver and spleen. + CD38-mediated pathways are also thought to accentuate adenosine production in the bone marrow niche during progression to multiple myeloma. Horenstein AL et al., Mol. Med. 22:694-704 (2016).

[0230] Example 1. Generation, validation and characterization of CD38-KO mice To generate CD38-KO C57BL / 6N mice, mouse CD38 expression was disrupted by inserting human CD38 (hCD38) flanked by loxP sites in frame with the start codon. The locus of the insertion region lacks known regulatory elements to prevent disruption of mouse regulatory sequences. The transgene was under the control of the endogenous mouse promoter, allowing preservation of the mouse CD38 expression pattern. The hCD38 transgene was subsequently deleted by in vivo Cre-mediated excision of the loxP-introduced region by mating hCD38 transgenic mice with Cre-expressing mice (Figure 1A). C57BL / 6N wild-type and CD38-KO mice were bred at Charles River Laboratories (Wilmington, MA). FACS analysis was used to validate the CD38-KO lineage. Mouse CD38 was not detectable on immune subsets in CD38-KO mice (FIG. 1B), and human CD38 was absent on B cells and NK cells in CD38-KO mice (FIG. 1C).

[0231] FACS analysis was also used to characterize the CD38-KO lineage. Mature natural killer cells (NK) and regulatory T cells (Treg) were modulated in CD38-KO mice. NK in peripheral blood was decreased (Figure 2A). Treg was decreased in spleen and bone marrow but increased in peripheral blood (Figure 2A). Except for Treg, T cells were present in CD38-KO mice at normal percentages (Figure 2B). These changes are consistent with the observations in the hCD38-knock-in lineage. Total T cell reduction was observed in the spleen, possibly due to a significant reduction in splenic CD4 Treg. Although the percentage of B cells was normal in CD38-KO mice (Figure 2C), a reduction in FoB cells was observed in hCD38-knock-in mice. The bone marrow compartment was not affected in CD38-KO mice (Figure 2D). Finally, macrophage populations in CD38-KO mice were altered in different organs (Figure 2E).

[0232] Example 2. NAD in CD38-WT and CD38-KO mice + Quantification of cADPR and adenosine CD38 - / - Using the CD38-KO mouse model, + We investigated the effect of therapeutic anti-CD38 antibodies on adenosine and cADPR levels in young and aged C57BL6 CD38-KO mice and age-matched CD38 + / + Tissues were collected from (CD38-wild type (WT)) mice. Specifically, the six young CD38-KO mice included three females aged 4-6 weeks, two females aged 8 weeks, and one male aged 4-6 weeks. The four young CD38-WT mice included two females and two males aged 4-6 weeks. The five aged CD38-KO mice included one female and four males aged approximately 6 months. The five aged CD38-WT mice included one female and four males aged approximately 6 months. NAD in flash-frozen tissues + Levels were measured by liquid chromatography and mass spectrometry.

[0233] The following chemicals were used: acetonitrile (HPLC grade, EMD Millipore, Burlington, MA), methanol (HPLC grade, EMD Millipore, Burlington, MA), formic acid (reagent grade, Honeywell Fluka, Charlotte, NC), trifluoroacetic acid (reagent grade, Thermo Fisher Scientific, Inc., Waltham, MA), and perchloric acid (certified ACS grade, Thermo Fisher Scientific, Inc., Waltham, MA).

[0234] A 50:50 methanol / water solution was prepared by thoroughly mixing equal volumes of methanol (HPLC grade, EMD Millipore, Burlington, MA) and nanopure water. A solution of 0.1% formic acid in methanol / water (50 / 50) was prepared by transferring 1 volume (e.g., 1 mL) of formic acid (reagent grade, Honeywell Fluka, Charlotte, NC) to 500 volumes (e.g., 500 mL) of 50:50 methanol / water and mixing thoroughly. A 0.5 M aqueous solution of perchloric acid (PCA) was prepared by thoroughly mixing 39 volumes (e.g., 39 mL) PCA (certified ACS grade, Thermo Fisher Scientific, Inc., Waltham, MA) with 1,000 volumes (e.g., 1,000 mL) of nanopure water. The solution was cooled on ice before use. A 0.1% aqueous solution of trifluoroacetic acid was prepared by thoroughly mixing 1 volume (e.g., 1 mL) of trifluoroacetic acid (reagent grade, Thermo Fisher Scientific, Inc., Waltham, MA) with 1,000 volumes (e.g., 1,000 mL) of water.

[0235] The following standards: adenosine (Sigma-Aldrich, St. Louis, MO), NAD +(Sigma-Aldrich, St. Louis, MO), cADPR (Toronto Research Chemicals Inc., Ontario, Canada), NAD + -d3 (Toronto Research Chemicals Inc., Ontario, Canada), Adenosine-13C (Toronto Research Chemicals Inc., Ontario, Canada) and AMP-15N5 (Toronto Research Chemicals Inc., Ontario, Canada) were used.

[0236] Working standards were prepared in 0.1% formic acid (reagent grade, Honeywell Fluka, Charlotte, NC) in methanol / water (50 / 50) by diluting the primary standard stock solutions as shown in Table 2 .

[0237] The primary internal standard stock solution was prepared at 1 mg / mL in methanol / water (50 / 50). NAD + A working internal solution was prepared in 0.1% formic acid in methanol / water (50 / 50) containing -d3, adenosine-13C5, and AMP-15N5 internal standards at 2,500 ng / mL each.

[0238] [Table 2]

[0239] For QC preparation, three control tissue samples (n=2 for each lot) were included in each batch and measured for endogenous levels of analytes for assessment of assay reproducibility.

[0240] Brain, liver, lung, lymph node, right femur, spleen and whole blood were collected from CD38-WT and CD38-KO mice. Immediately after collection, the tissues were flash frozen using liquid nitrogen. The tissues were then stored at -80 °C for 2 h. o C and shipped on dry ice.

[0241] Approximately 0.2 g or less of frozen tissue was placed on ice into a 2 mL homogenization vial pre-filled with mixed beads. 1.0 mL of ice-cold 0.5 M aqueous perchloric acid was added. Samples were homogenized at 6,500 rpm for two runs with 20 s intervals. The homogenate was centrifuged at 14,000 rpm in a microcentrifuge.

[0242] A 0.1 mL aliquot of homogenate supernatant or standard was placed in the corresponding conical test tube. 0.1 mL of working internal standard, i.e., 2,500 ng / mL adenosine-13C5, NAD, in 0.1% formic acid in methanol / water (50 / 50), was added. + -d3 and cAMP-13C5 were added. Each tube was vortexed and dried under nitrogen at 40°C for 10 minutes to remove organic matter. (Samples do not need to be completely dry after 10 minutes.) Each tube was reconstituted by adding 0.5 mL of 0.5 M perchloric acid. Each tube was vortexed and then centrifuged at 3,000 rpm for 5 minutes. Approximately 0.2 mL of the supernatant was transferred to an HPLC vial and capped.

[0243] Method 1, analytical conditions: The HPLC used two pumps: PUMP A (Shimadzu LC-20AD) and PUMP B (Shimadzu LC-20AD). The mobile phase contained A (0.1% trifluoroacetic acid in water) and B (acetonitrile). The flow rate was 0.5 mL / min.

[0244] [Table 3]

[0245] A Shimadzu SIL-20AC autosampler was used. The injection volume was 10 μL (5–20 μL) and the stop time was 5.5 min. Methanol was used for needle cleaning. The temperature was 5°C. An Imtakt Unison UK-100 analytical column (100×2 mm; ID: 3 μm; PN: UK024) was used. A Shimadzu CTO-20AC column oven was used, no switch valve was used. Temperature: not used.

[0246] The mass spectrometer used a PE SCIEX API 5000 MS / MS#01 as a detector. Data acquisition was performed using a PC MS-01.

[0247] [Table 4]

[0248] [Table 5]

[0249] Method 2, analytical conditions: The HPLC used two pumps: PUMP A (Shimadzu LC-20AD) and PUMP B (Shimadzu LC-20AD). The mobile phase contained A (0.1% trifluoroacetic acid in water) and B (acetonitrile). The flow rate was 0.5 mL / min.

[0250] [Table 6]

[0251] A Shimadzu SIL-20AC autosampler was used. The injection volume was 10 μL (5–20 μL) and the stop time was 5.0 min. Methanol was used for needle cleaning. The temperature was 5°C. A Thermo Hypercarb analytical column (50×3 mm; ID: 3 μm; PN: 35003-053030) was used. A Shimadzu CTO-20AC column oven was used, no switch valve was used. Temperature: Not used.

[0252] The mass spectrometer used a PE SCIEX API 5000 MS / MS#01 as a detector. Data acquisition was performed using a PC MS-01.

[0253] [Table 7]

[0254] [Table 8]

[0255] Chromatographic peaks were integrated using the Analyst version 1.6.2 software package. Weighted (1 / x 2 Linear regression analysis was used (where x corresponds to concentration). The peak area ratio of the analyte to the internal standard was plotted against the preparation concentration. The slope, intercept, and correlation coefficient were calculated. The unknown concentration (x) was then calculated by the following formula: x=(yb) / m, where y is the peak area ratio of the unknown analyte to the internal standard, b is the y-intercept, and m is the slope.

[0256] Revised M180701.02 and M180701.03. Revised M180701.02 with updates including use of API5000, column change for Method 1, gradient tweaks, and use of cAMP-13C5.

[0257] Example 3. Genetic disruption of CD38 inhibits NAD + levels were significantly increased. In young mice, genetic disruption of CD38 reduced NAD levels in the brain, femur, lung, and spleen. + In the brain, NAD levels were significantly increased (Figure 3A and Table 9). + The levels were 43.00±1.39μg / ml and 66.75±4.41μg / ml in CD38-WT and CD38-KO, respectively (p≦0.01). + The levels were 24.10±4.11 μg / ml and 50.65±7.77 μg / ml in CD38-WT and CD38-KO, respectively (p≦0.05). + The levels were 18.52±3.62 μg / ml and 29.30±2.47 μg / ml in CD38-WT and CD38-KO, respectively (p≦0.05). +Levels were 3.65±1.04 μg / ml and 14.55±0.87 μg / ml in CD38-WT and CD38-KO, respectively (p≦0.0001).

[0258] In young mice, genetic disruption of CD38 reduced NAD in the liver or lymph nodes (LNs). + In the liver, NAD + The levels were 34.01±7.67 μg / ml and 48.28±3.31 μg / ml in CD38-WT and CD38-KO, respectively. + Levels were 2.52±0.46 μg / ml and 3.40±0.68 μg / ml in CD38-WT and CD38-KO, respectively.

[0259] In aged mice, genetic disruption of CD38 significantly reduced NAD levels in the blood, brain, femur, liver, lung, lymph nodes, and spleen. + The levels of NAD increased significantly in the blood (Fig. 3B and Table 9). + The levels were 30.93±1.13 μg / ml and 38.21±2.38 μg / ml in CD38-WT and CD38-KO, respectively (p≦0.05). + The levels were 24.30±1.27μg / ml and 64.57±4.28μg / ml in CD38-WT and CD38-KO, respectively (p≦0.0001). + The levels were 40.00±3.12 μg / ml and 50.08±2.25 μg / ml in CD38-WT and CD38-KO, respectively (p≦0.05). + The levels were 10.34±1.51 μg / ml and 116.67±6.20 μg / ml in CD38-WT and CD38-KO, respectively (p≦0.0001). + The levels were 9.60±3.87μg / ml and 35.51±3.94μg / ml in CD38-WT and CD38-KO, respectively (p≦0.01). +The levels were 0.94±0.49μg / ml and 32.93±8.34μg / ml in CD38-WT and CD38-KO, respectively (p≦0.01). + Levels were 0.68±0.05 μg / ml and 40.53±1.86 μg / ml in CD38-WT and CD38-KO, respectively (p≦0.0001).

[0260] Results from old mice were also analyzed based on tissue weight. In the brain, NAD + The levels were 97.18 ± 5.08 μg / g and 258.27 ± 17.11 μg / g in CD38-WT and CD38-KO, respectively (p ≤ 0.0001). + The levels were 159.98±12.47μg / g and 250.42±11.24μg / g in CD38-WT and CD38-KO, respectively (p≦0.001). + The levels were 51.71 ± 7.57 μg / g and 583.37 ± 31.01 μg / g in CD38-WT and CD38-KO, respectively (p ≤ 0.0001). + The levels were 30.19 ± 10.93 μg / g and 177.54 ± 19.71 μg / g in CD38-WT and CD38-KO, respectively (p ≤ 0.001). + The levels were 4.69±2.46μg / g and 164.66±41.72μg / g in CD38-WT and CD38-KO, respectively (p≦0.01). + Levels were 3.42±0.24 μg / g and 202.64±9.29 μg / g in CD38-WT and CD38-KO, respectively (p≦0.0001).

[0261] These data suggest that decreased CD38 expression reduces NAD in both young and aged mice. + These findings demonstrate that therapeutic agents that decrease CD38 expression significantly increase NAD levels. +It has been shown that this can reduce the breakdown of NAD and induce tolerance in patients. + Combined with the knowledge that inhibits apoptosis of MM cells by activating PARP and myeloma DNA repair pathways, the significantly higher NAD in the femurs of CD38-KO mice + Levels of NAD + These results suggest that PARPi may mediate resistance mechanisms to anti-CD38 antibody (e.g., daratumumab or HexaBody-CD38 (GEN3014)) treatment in patients (e.g., cancer patients such as multiple myeloma). Thus, PARPi is likely to benefit patients who are receiving or have received therapeutic agents that reduce CD38 expression.

[0262] Example 4. NAD via CD38 destruction + The increase was more pronounced in old mice. NAD associated with gene disruption of CD38 + The increase in NAD levels was more pronounced in old mice compared to young mice in most tissues analyzed (Figures 4A-4B). + A 1.55-fold increase in NAD levels was observed in old mice and a 2.66-fold increase in femurs was observed in young mice. + A 2.10-fold increase in NAD levels was observed in young mice and a 1.25-fold increase in NAD levels in old mice. + A 1.42-fold increase in NAD levels was observed in young mice and an 11.28-fold increase in NAD levels in old mice. + A 1.58-fold increase in NAD levels was observed in young mice and a 3.70-fold increase in NAD levels in old mice. + A 1.35-fold increase in NAD levels was observed in young mice and a 35.03-fold increase in NAD levels in old mice. + A 3.99-fold increase in levels was observed in aged mice and a 59.60-fold increase in levels was observed in aged mice.

[0263] In CD38-WT mice, NAD + Levels significantly decreased with age in the brain (43.00±1.39 μg / ml vs. 24.30±1.27 μg / ml, p≦0.01), liver (34.01±7.67 μg / ml vs. 10.34±1.51 μg / ml, p≦0.05), and spleen (3.65±1.04 μg / ml vs. 0.68±0.05 μg / ml, p≦0.05) (FIG. 4C and Table 11). The results are consistent with published observations that CD38 expression increases with age. However, NAD + No age-dependent decrease in was observed in the femur or lungs of CD38-WT mice (Figure 4C and Table 11).

[0264] NAD + No age-dependent decrease in NAD levels was observed in any tissue of CD38-KO mice (Figure 4D and Table 11). In the liver, lymph nodes, and spleen, + Levels significantly increased with age in CD38-KO mice (Figure 4D and Table 11).

[0265] Example 5. Effect of gene disruption of CD38 on adenosine levels. In young mice, genetic disruption of CD38 significantly reduced adenosine levels in lymph nodes and spleens (Figure 5A and Table 10). In lymph nodes, adenosine levels were 0.18±0.04μg / ml and 0.08±0.02μg / ml in CD38-WT and CD38-KO, respectively (p≦0.05). In spleens, adenosine levels were 0.36±0.01μg / ml and 0.27±0.03μg / ml in CD38-WT and CD38-KO, respectively (p≦0.05).

[0266] In young mice, genetic disruption of CD38 did not result in significant changes in adenosine levels in the brain, femur, liver, or lung (Figures 5A-5B and Table 10). In the brain, adenosine levels were 29.35 ± 1.34 μg / ml and 27.05 ± 1.22 μg / ml in CD38-WT and CD38-KO, respectively. In the femur, adenosine levels were 1.64 ± 0.11 μg / ml and 1.75 ± 0.13 μg / ml in CD38-WT and CD38-KO, respectively. In the liver, adenosine levels were 0.77 ± 0.16 μg / ml and 0.73 ± 0.14 μg / ml in CD38-WT and CD38-KO, respectively. In the lungs, adenosine levels were 0.46±0.07 μg / ml and 0.33±0.06 μg / ml in CD38-WT and CD38-KO, respectively.

[0267] In aged mice, genetic disruption of CD38 significantly reduced femoral adenosine levels (Figure 5C and Table 10). In femora, adenosine levels were 2.08±0.27μg / ml and 0.61±0.14μg / ml in CD38-WT and CD38-KO, respectively (p≦0.01).

[0268] In aged mice, genetic disruption of CD38 significantly increased adenosine levels in lymph nodes (Figure 5C and Table 10). In lymph nodes, adenosine levels were 0.27±0.07μg / ml and 1.51±0.19μg / ml in CD38-WT and CD38-KO, respectively (p≦0.001).

[0269] In aged mice, genetic disruption of CD38 did not result in significant changes in adenosine levels in blood, brain, liver, lung, or spleen (Figures 5C-5D and Table 10). In blood, adenosine levels were 0.019 ± 0.002 μg / ml and 0.027 ± 0.003 μg / ml in CD38-WT and CD38-KO, respectively. In brain, adenosine levels were 46.11 ± 3.30 μg / ml and 47.45 ± 3.40 μg / ml in CD38-WT and CD38-KO, respectively. In liver, adenosine levels were 1.65 ± 0.25 μg / ml and 2.47 ± 0.53 μg / ml in CD38-WT and CD38-KO, respectively. In the lung, adenosine levels were 0.70±0.15 μg / ml and 0.73±0.24 μg / ml in CD38-WT and CD38-KO, respectively, and in the spleen, adenosine levels were 1.56±0.10 μg / ml and 1.97±0.29 μg / ml in CD38-WT and CD38-KO, respectively.

[0270] These data demonstrate that reduced CD38 expression significantly increased adenosine levels in lymph nodes of aged mice. This finding indicates that therapeutic agents that reduce CD38 expression may increase adenosine production in human patients. Coupled with the knowledge that adenosine is an immunosuppressive metabolite produced at high levels within the tumor microenvironment, the significantly higher adenosine levels in lymph nodes suggest that adenosine may also mediate resistance mechanisms to anti-CD38 antibody (e.g., daratumumab or HexaBody-CD38 (GEN3014)) treatment in patients. Thus, adenosine receptor antagonists may be beneficial for patients who are receiving or have received therapeutic agents that reduce CD38 expression.

[0271] Example 6. The effect of CD38 destruction on adenosine levels was age-dependent. The changes in adenosine levels associated with gene disruption of CD38 were age-dependent (Figures 6A-6C).

[0272] In the brain, an 8% decrease in adenosine levels was observed in young mice and a 3% increase in old mice. In the femur, a 7% increase in adenosine levels was observed in young mice and a 71% decrease in old mice. In the liver, a 5% decrease in adenosine levels was observed in young mice and a 50% increase in old mice. In the lungs, a 28% decrease in adenosine levels was observed in young mice and a 4% increase in old mice. In the lymph nodes, a 56% decrease in adenosine levels was observed in young mice and a 5.59-fold increase in old mice. In the spleen, a 25% decrease in adenosine levels was observed in young mice and a 26% increase in old mice.

[0273] In CD38-WT mice, adenosine levels increased significantly with age in the liver and spleen (Figure 6B and Table 12). However, the age-dependent increase did not reach statistical significance in the femur, lung, or lymph nodes of CD38-WT mice (Figure 6B and Table 13).

[0274] In CD38-KO mice, adenosine levels increased significantly with age in the liver, lymph nodes, and spleen (Figure 6C and Table 12). However, the age-dependent increase did not reach statistical significance in the lungs of CD38-KO mice (Figure 6C and Table 12). In CD38-KO mice, adenosine levels decreased significantly with age in the femur (Figure 6C and Table 12).

[0275] Example 7. Genetic disruption of CD38 resulted in decreased cADPR levels in young mice. In young mice, genetic disruption of CD38 significantly reduced cADPR levels in the brain, femur, liver, lung, and spleen (Figure 7 and Table 13). In the brain, cADPR levels were 42.10 ± 2.09 ng / ml and 31.73 ± 2.10 ng / ml in CD38-WT and CD38-KO, respectively (p ≤ 0.05). In the femur, cADPR levels were 7.33 ± 0.40 ng / ml and undetectable in CD38-WT and CD38-KO, respectively (p ≤ 0.0001). In the liver, cADPR levels were 21.55 ± 5.87 ng / ml and undetectable in CD38-WT and CD38-KO, respectively (p ≤ 0.01). In the lung, cADPR levels were 11.28 ± 1.22 ng / ml and undetectable in CD38-WT and CD38-KO, respectively (p ≤ 0.0001), and in the spleen, cADPR levels were 6.05 ± 2.11 ng / ml and undetectable in CD38-WT and CD38-KO, respectively (p ≤ 0.01).

[0276] In young mice, cADPR levels were undetectable in lymph nodes of CD38-WT and CD38-KO (Figure 7 and Table 13).

[0277] cADPR is NAD + As a downstream intermediate in metabolism, the decreased levels of cADPR in CD38-KO mice may be due to the increased NAD + This is consistent with increased levels of CD38. Thus, the data provide further support that PARPi are likely to benefit patients who are receiving or have received therapeutic agents that decrease CD38 expression.

[0278] Example 8. Evaluation of anti-CD38 surrogate immunomodulatory properties in the MC-38 model By removing cell surface CD38 using anti-CD38 daratumumab surrogate, NAD + Effect of CD38 regulation on metabolism (NAD + Experiments were designed to determine the levels of β-adrenergic receptor agonist (β-ADP) and cADPR and adenosine.

[0279] Daratumumab does not bind to mouse CD38. To obtain an anti-mouse CD38 surrogate monoclonal antibody, anti-CD38 NIMR5 mouse IgG2a was generated by appending sequences from the NIMR5 clone to an "active" mouse Fc, IgG2a (TeneoBio, Newark, CA). Mouse IgG2a is considered similar to the human IgG1 that constitutes the Fc region of daratumumab. To obtain a "silent" anti-CD38 mouse surrogate, anti-CD38 NIMR5 mouse IgG2σ antibody was generated in-house (Janssen Biologics (JBIO), Janssen Research and Development, LLC, Spring House, PA) by appending sequences from the NIMR5 clone to a "silent" mouse Fc, IgG2σ. The "silent" mouse Fc does not bind to Fc receptors on effector cells (e.g., NK cells and monocytes).

[0280] On day 0, 0.5 × 10 6 MC-38 murine colon adenocarcinoma cells were injected subcutaneously into the right hind flank of C57BL / 6 or CD38-KO female mice.

[0281] On day 7 after tumor implantation, mice were randomized into treatment groups and the mean tumor volume measured by calipers was approximately 52-72 mm. 3 (Table 14). C57BL / 6N mice were administered isotype control (anti-mouse IgG2a) (group 1), anti-CD38 mouse surrogate (group 2), or "silent" anti-CD38 mouse surrogate (groups 3 and 4) at a dose of 30 mg / kg (or 10 mg / kg for group 3) every 3-4 days (q3d or q4d). CD38 KO mice were treated intraperitoneally (IP) with isotype control (anti-mouse IgG2a) (group 5) at 30 mg / kg every 3-4 days (q3d or q4d). Each group received initial treatment at the indicated dose by IP injection on day 7.

[0282] A total of three doses were administered twice weekly by IP. Additionally, untreated C57BL / 6N control mice were randomized and tested for immunophenotyping.

[0283] On day 15, 24 hours after the third dose, a final sampling of fresh spleen, tumor, draining lymph nodes, bone marrow, corresponding bones and complete femurs were snap frozen to assess CD38 enzyme activity in response to anti-CD38 surrogate treatment by liquid chromatography-mass spectrometry. Except for bone marrow, which was eluted with 3 ml of RPMI 1640 medium, metabolite analysis (NADH) was performed. + , cADPR, adenosine) were performed as before. BMA was vortexed to a single cell suspension and 100 μl was used for metabolite analysis. Raw values ​​were plotted for the 100 μl used for analysis.

[0284] In groups 1 and 2, 1 / 4 of the spleen, 1 / 4 of the tumor, draining lymph nodes (DLN), and bone marrow were obtained by flushing the right femur, and the right femur and the complete left femur were snap frozen for measurement of CD38 metabolite levels. In group 3, the entire spleen and the entire tumor were placed in medium for flow cytometry to monitor the loss of CD38 from immune cells and tumor cells. In group 4, 1 / 4 of the tumor was snap frozen for measurement of CD38 metabolite levels, and the entire spleen was placed in medium for flow cytometry to monitor the loss of CD38 from immune cells and tumor cells. In group 5, half of the tumor, DLN, bone marrow obtained by flushing the right femur, and the right femur and the complete left femur were snap frozen for measurement of adenosine levels.

[0285] The effect of anti-CD38 NIMR5 mouse IgG2a antibody on cell surface CD38 was investigated using flow cytometry with an allophycocyanin (APC)-labeled monoclonal antibody (C38B680.004). C38B680.004 was generated in-house and confirmed to not compete with the NIMR5 clone. Spleens from naive WT mice and CD38-KO tumor-bearing mice were used to generate positive and negative controls, respectively. Treatment with anti-CD38 NIMR5 mouse IgG2a antibody efficiently depleted CD38 from splenic CD8 T cells (Figure 8A), splenic CD4 T cells (Figure 8B), tumor-infiltrating T cells (TILs, Figure 8C), and tumor cells (Figure 8D). Depletion of CD38 by anti-CD38 NIMR5 mouse IgG2α surrogate mAb required active Fc (mouse IgG2α), as no depletion was detected when silent Fc (anti-CD38 NIMR5 mouse IgG2σ mAb) was used (Figures 8A-8D).

[0286] Treatment with anti-CD38 NIMR5 mouse IgG2a antibody reduced NAD in bone marrow, femur, lymph nodes, spleen, and tumors. + NAD levels were significantly increased in bone marrow compared to a 1.3-fold increase in corresponding bones or a 1.6-fold increase in intact femurs (Figure 9A). + A four-fold increase in NAD between intact femurs (L, left) and bones without BMA (R, right) was observed (Figure 9B), suggesting that the bone marrow (BMA) was the primary site where metabolic changes occurred upon treatment with anti-CD38 surrogate monoclonal antibodies. + The levels were compared (Figure 10). Lower NAD + was detected in empty bone tissue. The same trends were observed in bone and intact femurs, although the main differences likely occurred in the BMA.

[0287] Activation Fc (mouse IgG2a) suppresses NAD mediated by anti-CD38 NIMR5 mouse IgG2a surrogate mAb NIMR-5 +When a silent Fc (anti-CD38 NIMR5 mouse IgG2σ) was used, no increase was detected (Figure 9C). Thus, NAD + Regulation of levels correlated with the removal of CD38 from the cell surface (Figures 8A-8D), and active Fc is required for both processes.

[0288] In femurs and lymph nodes, both anti-CD38 NIMR5 mouse IgG2a antibody treatment and genetic disruption of CD38 reduced NAD to a similar extent. + This resulted in increased levels of NAD in the tumors of CD38-KO mice (Figure 9D). + The accumulation (Figure 9C) is likely due to CD38 expression in tumor cells, as CD38-WT tumors expressed the greatest amount of NAD compared to immune cells. + This suggests that the consumption

[0289] Treatment with anti-CD38 NIMR5 mouse IgG2a antibody did not alter femur, lymph node, spleen, or tumor adenosine levels in young mice (Figures 11A-11B), consistent with findings in young CD38-KO mice. Adenosine values ​​slightly above the lower limit of quantification due to BMA dilution during extraction were considered uninterpretable (Figure 11C). Values ​​below the lower limit of quantification were not included in the analysis.

[0290] Finally, treatment with anti-CD38 NIMR5 mouse IgG2a antibody reduced cADPR in tumors (p<0.01) (Figure 12). Reductions in cADPR that did not reach statistical significance were also observed in femurs and spleens (Figure 12).

[0291] These data suggest that therapeutic agents that decrease CD38 expression may reduce NAD accumulation in mouse tissues and tumors. + Directly demonstrated to reduce metabolism and NAD +This provides further support that PARPi may mediate resistance mechanisms to anti-CD38 antibody (e.g., daratumumab or HexaBody-CD38 (GEN3014)) treatment in patients (e.g., multiple myeloma patients). Thus, PARPi are likely to benefit patients who are receiving or have received therapeutic agents that reduce CD38 expression.

[0292] [Table 9-1]

[0293] [Table 9-2]

[0294] [Table 10]

[0295] [Table 11]

[0296] [Table 12]

[0297] [Table 13]

[0298] [Table 14]

[0299] The teachings of all patents, published patents, and references cited herein are incorporated by reference in their entirety.

Claims

1. A pharmaceutical composition comprising an anti-CD38 antibody for use in a method for treating a CD38-positive hematological malignancy, wherein the anti-CD38 antibody is of the IgG1 / κ subtype; a) the heavy chain variable region (VH) sequence of SEQ ID NO:4; and b) comprising the light chain variable region (VL) sequence of SEQ ID NO:5; The pharmaceutical composition, wherein the pharmaceutical composition is administered in combination with a poly ADP ribose polymerase inhibitor (PARPi), an adenosine receptor antagonist, or both.

2. The pharmaceutical composition of claim 1 , wherein the anti-CD38 antibody comprises the heavy chain sequence of SEQ ID NO: 12 and the light chain sequence of SEQ ID NO:

13.

3. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition is administered intravenously or subcutaneously.

4. The pharmaceutical composition described in claim 1 or 2, wherein the pharmaceutical composition is administered subcutaneously.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition is administered in combination with PARPi.

6. 6. The pharmaceutical composition of claim 5, wherein the PARPi comprises a PARP1 inhibitor, a PARP2 inhibitor, a PARP3 inhibitor, or a combination thereof.

7. 6. The pharmaceutical composition of claim 5, wherein the PARPi comprises AZD2461, CEP-8983, CEP-9722, E7016 (GPI21016), iniparib (BSI201), INO-1001, niraparib (MK-4827), olaparib (AZD-2281), pamiparib (BGB-290), rucaparib (AG-014699, PF-01367338), talazoparib (BMN-673), veliparib (ABT-888), or a combination thereof.

8. 8. The pharmaceutical composition of claim 7, wherein the PARPi comprises niraparib (MK-4827), olaparib (AZD-2281), rucaparib (AG-014699, PF-01367338), talazoparib (BMN-673), or a combination thereof.

9. The pharmaceutical composition according to any one of claims 5 to 8, wherein said pharmaceutical composition and said PARPi are administered separately.

10. The pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition is administered in combination with an adenosine receptor antagonist.

11. The adenosine receptor antagonist is １ Receptor (A １ AR) antagonist; ２Ａ Receptor (A ２Ａ AR) antagonist; ２Ｂ Receptor (A ２Ｂ AR) antagonist; ３ Receptor (A ３ 11. The pharmaceutical composition of claim 10, comprising a medicament for treating or preventing rheumatoid arthritis, ...

12. The adenosine receptor antagonist a) A selected from the group consisting of BG9719, DPCPX, FK453, FR194921, N-0861, rolofylline (KW3902), tonaofylline (BG9928), WRC-0571, and combinations thereof. １ AR antagonists; b) caffeine, 8-(-3-chlorostyryl)-caffeine (CSC), istradefylline (KW 6002), preladenant (SCH420814), SCH58261, SCH442416, SYN115, VER6947, VER7835, ZM241,385, a compound having the following structure: 【Chemistry 1】 and combinations thereof. ２Ａ AR antagonists; c) MRE2029-F20, MRS1754, OSIP-339391, a compound having the following structure: 【Chemistry 2】 and combinations thereof. ２Ｂ AR antagonists; d) FA385, MRE3008-F20, MRS1292, MRS1334, MRS1523, MRS3777, OT-7999, PSB-11, VUF5574, a compound having the following structure: 【Chemistry 3】 and combinations thereof. ３ AR antagonists, or The pharmaceutical composition of claim 11 comprising a combination of a) to d).

13. The pharmaceutical composition according to any one of claims 10 to 12, wherein the pharmaceutical composition and the adenosine receptor antagonist are administered separately.

14. The pharmaceutical composition according to any one of claims 1 to 4, wherein said pharmaceutical composition is administered in combination with a PARPi and an adenosine receptor antagonist.

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein the CD38-positive hematological malignancy is multiple myeloma (MM), acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma (BL), follicular lymphoma (FL), mantle cell lymphoma (MCL), acute myeloid leukemia (AML), or chronic lymphocytic leukemia (CLL).

16. The pharmaceutical composition described in claim 15, wherein the CD38-positive hematologic malignancy is multiple myeloma (MM).

17. The pharmaceutical composition described in claim 16, wherein the multiple myeloma (MM) is newly diagnosed multiple myeloma (NDMM).

18. The pharmaceutical composition described in claim 16, wherein the multiple myeloma (MM) is relapsed or refractory multiple myeloma (RRMM).

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