Methods for treating cancer and enhancing the efficacy of T cell redirecting therapeutics

Abstract

The present disclosure provides a method for treating cancer and / or killing tumor cells in a subject, the method comprising administering a therapeutically effective amount of an anti-CD38 antibody and a T cell redirection therapeutic agent to the subject to treat the cancer. The present disclosure provides a method for enhancing the efficacy of a T cell redirection therapeutic agent in a subject suffering from cancer, the method comprising administering an anti-CD38 antibody to the subject. The present disclosure also provides a method for treating multiple myeloma in a subject, the method comprising administering a therapeutically effective amount of a BCMA×CDS bispecific antibody and an anti-CD38 antibody to the subject to treat the multiple myeloma. The present disclosure also provides a drug combination comprising a GPRC5D×CD3 bispecific antibody. The present disclosure also provides a kit comprising a pharmaceutical composition, the pharmaceutical composition comprising a BCMA×CD3 bispecific antibody and an anti-CD38 antibody.

Description

Technical Field

[0001] Disclosed herein are methods of treating cancer and enhancing the efficacy of T cell redirecting therapeutics. Background Art

[0002] Redirected killing T cells are the desired mode of action in many therapeutic areas. Generally speaking, T cell redirection molecules are engineered to have at least two antigen binding sites, one of which binds to the surface antigen on the target cell, and the other binds to the T cell surface antigen. Among the T cell surface antigens, the human CD3ε subunit of the TCR protein complex has always been the main target of redirecting T cell killing. In both preclinical studies and clinical studies, various bispecific antibody formats have been shown to mediate T cell redirection (May C et al., Biochem Pharmacol, Vol. 84: pp. 1105-1112, 2012; Frankel SR and Baeuerle PA, Curr Opin Chem Biol, Vol. 17 No. 3: pp. 385-392, 2013).

[0003] Tumors escape immune recognition by producing an immunosuppressive tumor microenvironment (TME). In the TME, under conditions of persistent antigens and inflammation, T cells are exhausted or dysfunctional, and gradually lose their effector functions and proliferation capacity. Functionally impaired and available number of T cells are engaged with therapeutic agents that mediate T cell redirection killing, which can impair the anti-tumor efficacy of the therapeutic agent. Therefore, it is necessary to enhance T cell function to achieve the optimal efficacy of therapeutic agents that mediate T cell redirection killing. Summary of the invention

[0004] The present disclosure provides a method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of an anti-CD38 antibody and a T cell redirecting therapeutic agent to treat the cancer.

[0005] The present disclosure also provides a method of killing tumor cells in a subject, comprising administering to the subject an anti-CD38 antibody and a T cell redirecting therapeutic agent that binds to an antigen on the tumor cells for a time sufficient to kill the tumor cells.

[0006] The present disclosure provides a method of enhancing the efficacy of a T cell redirecting therapeutic in a subject having cancer, comprising administering an anti-CD38 antibody to the subject.

[0007] The present disclosure also provides a method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a BCMA×CD3 bispecific antibody and an anti-CD38 antibody to treat the cancer.

[0008] The present disclosure also provides a method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a BCMA×CD3 bispecific antibody to treat the cancer, wherein the subject has been treated with an anti-CD38 antibody prior to administering the BCMA×CD3 bispecific antibody.

[0009] The present disclosure also provides a method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a BCMA×CD3 bispecific antibody to treat the cancer, wherein the subject is relapsed or refractory to treatment with a previous anti-cancer therapeutic.

[0010] The present disclosure also provides a method of treating multiple myeloma in a subject, comprising administering to the subject a therapeutically effective amount of a BCMA×CD3 bispecific antibody and an anti-CD38 antibody to treat the multiple myeloma.

[0011] The present disclosure also provides a method of treating multiple myeloma in a subject, comprising administering to the subject a therapeutically effective amount of a BCMA×CD3 bispecific antibody to treat the multiple myeloma, wherein the subject has been treated with an anti-CD38 antibody prior to administering the BCMA×CD3 bispecific antibody.

[0012] The present disclosure also provides a method of treating multiple myeloma in a subject, comprising administering to the subject a therapeutically effective amount of a BCMA×CD3 bispecific antibody to treat the multiple myeloma, wherein the subject is relapsed or refractory to treatment with a previous multiple myeloma therapeutic.

[0013] The present disclosure also provides a pharmaceutical composition comprising a BCMA×CD3 bispecific antibody and an anti-CD38 antibody, wherein the BCMA×CD3 bispecific antibody comprises a BCMA binding domain and a CD3 binding domain, the BCMA binding domain comprises the VH of SEQ ID NO:29 and the VL of SEQ ID NO:30, the CD3 binding domain comprises the VH of SEQ ID NO:39 and the VL of SEQ ID NO:40, and the anti-CD38 antibody comprises the VH of SEQ ID NO:4 and the VL of SEQ ID NO:5.

[0014] The present disclosure also provides a method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a T cell redirecting therapeutic that binds GPRC5D and an anti-CD38 antibody to treat the cancer.

[0015] The present disclosure also provides a method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a GPRC5D×CD3 bispecific antibody to treat the cancer, wherein the subject is relapsed or refractory to treatment with a previous anti-cancer therapeutic.

[0016] The present disclosure also relates to a drug combination comprising a GPRC5D×CD3 bispecific antibody and an anti-CD38 antibody, wherein the GPRC5D×CD3 bispecific antibody comprises a GPRC5D binding domain and a CD3 binding domain, the GPRC5D binding domain comprises the HCDR1 of SEQ ID NO:43, the HCDR2 of SEQ ID NO:44, the HCDR3 of SEQ ID NO:45, the LCDR1 of SEQ ID NO:46, the LCDR2 of SEQ ID NO:47, and the LCDR3 of SEQ ID NO:48, the CD3 binding domain comprises the HCDR1 of SEQ ID NO:33, the HCDR2 of SEQ ID NO:34, the HCDR3 of SEQ ID NO:35, the LCDR1 of SEQ ID NO:36, the LCDR2 of SEQ ID NO:37, and the LCDR3 of SEQ ID NO:38, and the anti-CD38 antibody comprises the HCDR1 of SEQ ID NO:6, the HCDR2 of SEQ ID NO:7, the HCDR3 of SEQ ID NO:8, the LCDR1 of SEQ ID NO:9, the LCDR2 of SEQ ID NO:10 LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10 and LCDR3 of SEQ ID NO:11.

[0017] The present disclosure also provides a method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a CD19-binding T cell redirecting therapeutic and an anti-CD38 antibody to treat the cancer.

[0018] The present disclosure also provides a method of enhancing the efficacy of a T cell redirecting therapeutic that binds CD19 in a subject having cancer, comprising administering an anti-CD38 antibody to the subject prior to administering the T cell redirecting therapeutic that binds CD19.

[0019] The present disclosure also provides a drug combination comprising a CD19×CD3 bispecific antibody and an anti-CD38 antibody, wherein the CD19×CD3 bispecific antibody comprises blinatumomab of SEQ ID NO:53, and the anti-CD38 antibody comprises HCDR1 of SEQ ID NO:6, HCDR2 of SEQ ID NO:7, HCDR3 of SEQ ID NO:8, LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10, and LCDR3 of SEQ ID NO:11.

[0020] The present invention also provides a kit comprising the pharmaceutical composition disclosed herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 JNJ-957-mediated lysis of the multiple myeloma (MM) cell line RPMI8226 is shown. Healthy donor peripheral blood mononuclear cells (PB MNCs) were used as effector cells.

[0022] Figure 2 JNJ-957-mediated lysis of the multiple myeloma (MM) cell line UM9 is shown. Healthy donor peripheral blood mononuclear cells (PB MNCs) were used as effector cells.

[0023] Figure 3 JNJ-957-mediated lysis of the multiple myeloma (MM) cell line U226 is shown. Healthy donor peripheral blood mononuclear cells (PB MNCs) were used as effector cells.

[0024] Figure 4 JNJ-957-mediated lysis of the multiple myeloma (MM) cell line MM1 is shown. Healthy donor peripheral blood mononuclear cells (PB MNCs) were used as effector cells.

[0025] Figure 5 JNJ-957-mediated lysis of MM cells is accompanied by CD4 + T cell activation and degranulation, as determined by increased surface expression of CD25 (activation).

[0026] Figure 6 JNJ-957-mediated lysis of MM cells is accompanied by CD4 + T cell activation and degranulation, as determined by increased surface expression of CD107a (degranulation).

[0027] Figure 7JNJ-957-mediated lysis of MM cells is accompanied by CD4 + T cell activation and degranulation, as determined by the proportion of CD25 and CD107a double positive CD4+ T cells.

[0028] Figure 8 JNJ-957-mediated lysis of MM cells is accompanied by CD8 + T cell activation and degranulation, as determined by increased surface expression of CD25 (activation).

[0029] Fig. 9 JNJ-957-mediated lysis of MM cells is accompanied by CD8 + T cell activation and degranulation, as determined by increased surface expression of CD107a (degranulation).

[0030] Fig.10 JNJ-957-mediated lysis of MM cells is accompanied by CD8 + T cell activation and degranulation, as determined by an increase in the proportion of CD4+ T cells double positive for CD25 and CD107a.

[0031] Fig.11 In vitro daratumumab-mediated lysis of MM cells from newly diagnosed multiple myeloma (NDMM) and relapsed / refractory MM (RRMM) patients who had not received daratumumab treatment (N = 2) is shown. Multiple myeloma cells from daratumumab-refractory RRMM patients were resistant to daratumumab-mediated lysis ****P < 0.0001

[0032] Fig.12 The dose response of JNJ-957-mediated lysis of plasma cells, T cells and NK cells in completely autologous bone marrow (BM) MNCs obtained from newly diagnosed multiple myeloma patients (NDMM, n=8) is shown. As shown, the percentage of lysis was measured at various antibody concentrations (0.0064 μg / mL to 4.0 μg / mL). Circles (top line): plasma cells; squares (middle line): T cells; triangles (bottom line): NK cells.

[0033] Fig.13The dose response of JNJ-957-mediated lysis of plasma cells, T cells and NK cells in fully autologous bone marrow (BM) MNCs obtained from multiple myeloma (MM) patients who are refractory to lenalidomide treatment (n=15) is shown. As shown, the percentage of lysis was measured at various antibody concentrations (0.0064 μg / mL to 4.0 μg / mL). Circles (top line): plasma cells; Squares (middle line): T cells; Triangles (bottom line): NK cells.

[0034] Fig.14 The dose response of JNJ-957-mediated lysis of plasma cells, T cells and NK cells in fully autologous bone marrow (BM) MNCs obtained from MM patients who were refractory to treatment with lenalidomide and daratumumab (n=11) is shown. The percentage of lysis was measured at various antibody concentrations (0.0064 μg / mL to 4.0 μg / mL) as shown. Circles (top line): plasma cells; squares (middle line): T cells; triangles (bottom line): NK cells.

[0035] Fig.15 JNJ-957-mediated lysis of MM cells was accompanied by CD4 + Activation of T cells (as assessed by increased CD25 surface expression). 3930: isotype control; BC3B4: BCMA x blank bispecific antibody; 7008: blank x CD3 bispecific antibody.

[0036] Fig.16 JNJ-957-mediated lysis of MM cells was accompanied by CD4 + Degranulation of T cells (as assessed by increased CD107a surface expression). 3930: isotype control; BC3B4: BCMA x blank bispecific antibody; 7008: blank x CD3 bispecific antibody.

[0037] Fig.17 Double positive CD25 + CD107a + Cells were used as CD4 T cells in BM samples from patients with NDMM treated with JNJ-957 at the indicated concentrations, RRMM naive to daratumumab (RRMM), and RRMM refractory to daratumumab (RRMM daraR). +Percentage of T cells. 3930: isotype control; BC3B4: BCMA×blank bispecific antibody; 7008: blank×CD3 bispecific antibody. Double positive: CD25 and CD107a double positive CD4 + T cells.

[0038] Fig.18 JNJ-957-mediated lysis of MM cells was accompanied by CD8 + Activation of T cells (as assessed by increased CD25 surface expression). 3930: isotype control; BC3B4: BCMA x blank bispecific antibody; 7008: blank x CD3 bispecific antibody.

[0039] Fig.19 JNJ-957-mediated lysis of MM cells was accompanied by CD8 + Degranulation of T cells (as assessed by increased CD107a surface expression). 3930: isotype control; BC3B4: BCMA x blank bispecific antibody; 7008: blank x CD3 bispecific antibody.

[0040] Fig. 20 Double positive CD25 + CD107a + Cells were used as CD8 + Percentage of T cells. 3930: isotype control; BC3B4: BCMA×blank bispecific antibody; 7008: blank×CD3 bispecific antibody. Double positive: CD25 and CD107a double positive CD8 + T cells.

[0041] Fig.21 BCMA expression levels on MM cells in NDMM, RRMM naive to daratumumab treatment, and daratumumab refractory RRMM subjects are shown (mean MFI±SEM). P values ​​between designated groups were calculated using the Mann-Whitney U test; *P<0.05; ns: not significant.

[0042] Fig. 22PD-L1 expression levels on MM cells in NDMM, RRMM naive to daratumumab treatment, and daratumumab refractory RRMM subjects are shown (mean MFI±SEM). P values ​​between designated groups were calculated using the Mann-Whitney U test; *P<0.05; ns: not significant.

[0043] Fig.23 Baseline percentages of Tregs in BM MNCs from NDMM, daratumumab-naive RRMM, and daratumumab-refractory RRMM are shown. **p<0.01; ns: not significant.

[0044] Fig.24 Shown are the baseline percentages of activated T cells (as assessed by HLA-DR positivity) in BM MNCs from NDMM, daratumumab-naive RRMM, and daratumumab-refractory RRMM. **p<0.01; ns: not significant.

[0045] Fig.25 Baseline percentages of various T cell subsets in BM MNCs from NDMM, RRMM naive to daratumumab, and RRMM refractory to daratumumab are shown. *p<0.05; **p<0.01; Ns: not significant. TEMRA: CD45RA + CCR7-T cells; EM: effector memory type CM: central memory type; N: naive T cells.

[0046] Fig.26 Shown is JNJ-957-mediated lysis of multiple myeloma cells from NDMM patients by autologous BM MNCs. Samples were dichotomized for the frequency of Tregs at baseline (low ≤ 50%, high > 50%). Ns: not significant.

[0047] Fig. 27 JNJ-957-mediated lysis of multiple myeloma cells from RRMM patients naive to daratumumab by autologous BM MNCs is shown. Samples were dichotomized for the frequency of Tregs at baseline (low ≤ 50%, high > 50%). *p<0.05; **p<0.01; Ns: not significant.

[0048] Fig.28 Shown is JNJ-957-mediated lysis of multiple myeloma cells from daratumumab-refractory RRMM patients by autologous BM MNCs. Samples were dichotomized for the frequency of Tregs at baseline (low ≤ 50%, high > 50%). *p<0.05; ns: not significant.

[0049] Fig.29JNJ-957-mediated lysis of MM cells from BM samples of patients with NDMM (n=9), RRMM (n=18) who had not received daratumumab treatment, and daratumumab-refractory RRMM (n=13) after 48 hours of incubation is shown. Data are shown as mean ± SEM, and P values ​​were calculated using Student's t-test. **P<0.01

[0050] Fig.30 JNJ-957-mediated lysis of MM cells from bone marrow (BM) samples obtained from relapsed / refractory multiple myeloma patients (RRMM) (n=8) is shown to be enhanced in samples from the same patients who had received daratumumab ("Dara-exposed") when compared to samples from patients before the start of daratumumab treatment ("Dara-naive"). Data are shown as mean ± SEM; P values ​​were calculated using paired t-tests. ns: not significant; *P<0.05, **P<0.01.

[0051] Fig.31 Shown are the percentages of Tregs in serial BM aspirates from RRMM patients before starting daratumumab (before dara treatment) and at the time of daratumumab-refractory disease development (exposure to dara). ns: not significant.

[0052] Fig.32 Figure 4 CD4+ in serial BM aspirates from RRMM patients before starting daratumumab (before dara treatment) and at the time of daratumumab refractory disease development (exposure to dara) + ns: not significant.

[0053] Fig.33 Figure 2 shows CD8 in serial BM aspirates from RRMM patients before starting daratumumab (before dara treatment) and at the time of daratumumab refractory disease development (exposure to dara). + The percentage of T cells.

[0054] Fig.34 JNJ-957-mediated lysis of RPMI8226 multiple myeloma cells using patient-derived PB MNCs as effector cells is shown to be enhanced by PB MNCs from the same patients who had received daratumumab ("PBMNCs during dara") when compared to samples from patients before the start of daratumumab treatment ("PBMNCs naive") (n=5). Data are shown as mean ± SEM; P values ​​were calculated using paired t-test. ns: not significant; *P<0.05.

[0055] Fig.35Shown are the percentages of Tregs in PB-MNC samples from daratumumab-naïve (before dara treatment) and daratumumab-refractory (during dara treatment) RRMM patients.

[0056] Fig.36 Figure 2 shows CD4+ T cells in PB-MNC samples from RRMM patients who were daratumumab-naïve (before daratumumab treatment) and daratumumab-refractory (during daratumumab treatment). + Percentage of T cells. ns: not significant.

[0057] Fig.37 Figure 2 shows CD8 in PB-MNC samples from RRMM patients who were daratumumab-naïve (before daratumumab treatment) and daratumumab-refractory (during daratumumab treatment). + Percentage of T cells. ns: not significant.

[0058] Fig.38 It is shown that the addition of daratumumab enhances JNJ-957-mediated MM cell lysis. BM mononuclear cells (MNCs) from NDMM (n=8) patients were treated with JNJ-957 (0.032 μg / mL to 0.8 μg / mL) alone or in combination with 10 μg / mL of daratumumab for 48 hours. The lysis levels of the observed (Obs) MM cells by JNJ-957 and daratumumab were compared with the expected (Exp) lysis levels, where these lysis levels were calculated under the assumption that the combined effect was achieved by the additive effect as shown in the method. The black bars show the group mean ± SEM. P values ​​were calculated using paired Student's t-tests. ns: not significant.

[0059] Fig.39 It is shown that the addition of daratumumab enhances JNJ-957-mediated MM cell lysis. BM MNCs of RRMM (n=17) patients who have not received daratumumab treatment were treated with JNJ-957 (0.032 μg / mL to 0.8 μg / mL) alone or in combination with 10 μg / mL of daratumumab for 48 hours. The lysis levels of (Obs) MM cells observed by JNJ-957 and daratumumab were compared with the expected (Exp) lysis levels, where these lysis levels were calculated under the assumption that the combined effect was achieved by an additive effect as shown in the method. The black bars show group mean ± SEM. P values ​​were calculated using paired Student's t-tests. ns: not significant.

[0060] Fig.40It is shown that the addition of daratumumab enhances the lysis of JNJ-957-mediated MM cells. BM MNCs of patients with daratumumab-refractory RRMM (n=14) were treated with JNJ-957 (0.032 μg / mL to 0.8 μg / mL) alone or in combination with 10 μg / mL of daratumumab for 48 hours. The observed lysis levels of (O) MM cells by JNJ-957 and daratumumab were compared with the expected (E) lysis levels, where these lysis levels were calculated under the assumption that the combined effect was achieved by the additive effect as shown in the method. The black bars show the group mean ± SEM. P values ​​were calculated using paired Student's t-tests. In the figure, JNJ-957 is referred to as JNJ-7957. Dara: daratumumab. ns: not significant.

[0061] Fig.41 Blinatumomab-mediated lysis of the Raji cell line using consecutive PB samples from 11 RRMM patients as effector cells (E:T of 10:1) is shown, which were obtained directly before the start of daratumumab treatment (black, bottom line) and during daratumumab treatment (gray, top line); the median duration of treatment was 7 months, ranging from 2 months to 14 months. In the presence of these PB-MNCs, Raji cells were incubated with blinatumomab (0.01 μg / mL to 10 μg / mL) for 48 hours before blinatumomab-based cytotoxicity assays were performed. Data are presented as mean ± SEM, and experiments were performed in duplicate. Statistical significance (P value) between indicated groups was calculated using nonlinear regression analysis.

[0062] Fig.42 The dose response of JNJ-957-mediated lysis of plasma cells, T cells and NK cells of BM-MNC cells obtained from six patients with primary plasma cell leukemia (pPCL) is shown. As shown, the lysis percentage was measured at various antibody concentrations (0.0064 μg / mL to 4.0 μg / mL). Top line: plasma cells; bottom line: overlapping lines of T cells and NK cells. JNJ-957 is referred to as JNJ-7957 in the figure.

[0063] Fig.43Anti-GPRC5D×CD3 antibody-mediated lysis of MM cell lines using serial PB samples from 11 RRMM patients as effector cells (E:T of 10:1) obtained directly before the start of daratumumab treatment (bottom line) and during daratumumab treatment (top line); median duration of treatment was 7 months, ranging from 2 months to 14 months. After incubation of Raji cells with blinatumomab (0.01 μg / mL to 10 μg / mL) for 48 hours in the presence of these PB-MNCs, blinatumomab-based cytotoxicity assays were performed. Data are presented as mean ± SEM, and experiments were performed in duplicate.

[0064] Fig.44 It is shown that the addition of daratumumab is additive to the MM cell lysis mediated by anti-GPRC5D×CD3 bispecific antibody (JNJ-7564). BM MNCs of RRMM (n=17) patients who had not received daratumumab treatment were treated with anti-GPRC5D×CD3 bispecific antibody (0.00128μg / mL to 0.8μg / mL) alone or in combination with 0.1μg / mL of daratumumab for 48 hours. The observed (O) lysis levels of MM cells by anti-GPRC5D×CD3 bispecific antibody and daratumumab were compared with the expected (E) lysis levels, where these lysis levels were calculated under the assumption that the combined effect was achieved by an additive effect as shown in the method. The black bars show the group mean ± SEM. P values ​​were calculated using a paired Student's t-test. ns: not significant. Dara: daratumumab. DETAILED DESCRIPTION

[0065] The methods disclosed herein may be more readily understood with reference to the following detailed description in conjunction with the accompanying drawings that form a part of the present disclosure. It should be understood that the methods disclosed herein are not limited to the specific methods described and / or illustrated herein, and that the terms used herein are only used to describe specific embodiments by way of example and are not intended to limit the methods protected by the claims. All patents, published patent applications, and publications cited herein are incorporated herein by reference as if fully set forth herein.

[0066] As used herein, the singular forms "a," "an," and "the" include plural forms.

[0067] Various terms related to various aspects of the specification are used throughout the specification and claims. Unless otherwise indicated, such terms are given the ordinary meaning of the art. Other specifically defined terms should be understood in a manner consistent with the definitions provided herein.

[0068] "About" when used in reference to a numerical range, critical value or a particular value means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. In the context of an assay, result or embodiment, unless otherwise expressly stated in the examples or elsewhere in the specification, "about" means within one standard deviation, or up to a range of 5% (whichever is greater) according to the convention in the art.

[0069] "Antibody" broadly means and includes immunoglobulin molecules, specifically including monoclonal antibodies (including murine monoclonal antibodies, human monoclonal antibodies, humanized monoclonal antibodies and chimeric monoclonal antibodies), antigen-binding fragments, multispecific antibodies (such as bispecific antibodies, trispecific antibodies, tetraspecific antibodies, etc.), dimers, tetramers or multimers, single-chain antibodies, domain antibodies, and any other modified configurations of immunoglobulin molecules containing antigen-binding sites with desired specificity. "Full-length antibodies" contain two heavy chains (HC) and two light chains (LC) interconnected by disulfide bonds, and multimers thereof (e.g., IgM). Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region (composed of domains CH1, hinge, CH2, and CH3). Each light chain consists of a light chain variable region (VL) and a light chain constant region (CL). The VH and VL regions can be further subdivided into hypervariable regions, called complementarity determining regions (CDRs), interspersed with framework regions (FRs). Each VH and VL comprises three CDRs and four FR segments, and is arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. Immunoglobulins can be assigned to five major classes, IgA, IgD, IgE, IgG, and IgM, based on the amino acid sequence of the heavy chain constant domain. IgA and IgG are further subclassified into isotypes IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. Based on the amino acid sequence of its constant domain, the antibody light chain of any vertebrate species can be assigned to one of two completely different types, kappa and lambda.

[0070] "Antigen binding fragment" or "antigen binding domain" refers to a part of an immunoglobulin molecule that binds to an antigen. Antigen binding fragments may be synthetic, enzymatically obtainable or genetically engineered polypeptides, including VH, VL, VH and VL, Fab, F(ab')2, Fd and Fv fragments, domain antibodies (dAbs) consisting of one VH domain or one VL domain, shark variable IgNAR domains, camelized VH domains, minimal recognition units consisting of amino acid residues that mimic the CDRs of antibodies such as FR3-CDR3-FR4 portions, HCDR1, HCDR2 and / or HCDR3 and LCDR1, LCDR2 and / or LCDR3. The VH and VL domains can be linked together via synthetic linkers to form various types of single chain antibody designs, in which the VH and VL domains are expressed by separate single chain antibody constructs, and the VH / VL domains can pair intramolecularly or intermolecularly to form a monovalent antigen binding site, such as a single chain Fv (scFv) or a diabody; for example, as described in International Patent Publications WO1998 / 44001, WO1988 / 01649, WO1994 / 13804, and WO1992 / 01047.

[0071] "BCMA" refers to human B-cell maturation antigen, also known as CD269 or TNFRSF17 (UniProt Q02223). The extracellular domain of BCMA encompasses residues 1-54 of Q02223. Human BCMA comprises the amino acid sequence of SEQ ID NO:2.

[0072] SEQ ID NO:2

[0073] MLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPLTCQRYCNASVTNSVKGTNAILWTCLGLSLIISLAVFVLMFLLRKINSEPLKDEFKNTGSGLLGMANIDLEKSRTGDEIILPRGLEYTVEECTCEDCIKSKPKVDSDHCFPLPAMEEGATILVTTKTNDYCKSLPAALSATEIEKSISAR

[0074] "Bispecific" refers to an antibody that specifically binds to two different antigens or two different epitopes within the same antigen. Bispecific antibodies may have cross-reactivity to other related antigens, for example, to the same antigen from other species (homologous) (such as humans or monkeys, e.g., Macaca cynomolgus (cynomolgus, cyno), chimpanzees (Pantroglodytes), or may bind to epitopes shared between two or more antigens.

[0075] "Cancer" refers to a broad variety of diseases characterized by the uncontrolled growth of abnormal cells in the body. Uncontrolled cell division and growth leads to the formation of malignant tumors that invade adjacent tissues and may also metastasize to distant parts of the body via the lymphatic system or bloodstream. "Cancer" or "cancer tissue" may include tumors.

[0076] "CD123" refers to human interleukin-3 receptor subunit alpha (IR3RA) having the amino acid sequence shown in SEQ ID NO: 57. The extracellular domain or CD123 spans residues 19-305 of SEQ ID NO:57.

[0077] CD123 (SEQ ID NO: 57)

[0078] MVLLWLTLLLIALPCLLQTKEDPNPPITNLRMKAKAQQLTWDLNRNVTDIECVKDADYSMPAVNNSYCQFGAISLCEVTNYTVRVANPPFSTWILFPENSGKPWAGAENLTCWIHDVDFLSCSWAVGPGAPADVQYDLYLNVANRRQQYECLHYKTDAQGTRIGCRFDDISRLSSGSQSSHILVRGRSA AFGIPCTDKFVVFSQIEILTPPNMTAKCNKTHSFMHWKMRSHFNRKFRYELQIQKRMQPVITEQVRDRTSFQLLNPGTYTVQIRARERVYEFLSAWSTPQRFECDQEEGANTRAWRTSLLIALGTLLALVCVFVICRRYLVMQRLFPRIPHMKDPIGDSFQNDKLVVWEAGKAGLEECLVTEVQVVQKT

[0079] "CD19" refers to the human B-lymphocyte antigen CD19 having the amino acid sequence of SEQ ID NO: 58. The extracellular domain of CD19 spans residues 20-291 of SEQ ID NO:58.

[0080] CD19 (SEQ ID NO:58)

[0081] MPPPRLLFFLLFLTPMEVRPEEPLVVKVEEGDNAVLQCLKGTSDGPTQQLTWSRESPLKPFLKLSLGLPGLGIHMRPLAIWLFIFNVSQQMGGFYLCQPGPPSEKAWQPGWTVNVEGSGELFRWNVSDLGGLGCGLKNR SSEGPSSPSGKLMSPKLYVWAKDRPEIWEGEPPCLPPRDSLNQSLSQDLTMAPGSTLWLSCGVPPDSVSRGPLSWTHVHPKGPKSLLSLELKDDRPARDMWVMETGLLLPRATAQDAGKYYCHRGNLTMSFHLEITARP VLWHWLLRTGGWKVSAVTLAYLIFCLCSLVGILHLQRALVLRRKRKRMTDPTRRFFKVTPPPGSGPQNQYGNVLSLPTPTSGLGRAQRWAAGLGGTAPSYGNPSSDVQADGALGSRSPPGVGPEEEEGEGYEEPDSEED SEFYENDSNLGQDQLSQDGSGYENPEDEPLGPEDEDSFSNAESYENEDEELTQPVARTMDFLSPHGSAWDPSREATSLGSQSYEDMRGILYAAPQLRSIRGQPGPNHEEDADSYENMDNPDGPDPAWGGGGRMGTWSTR

[0082] "CD3" refers to a human antigen expressed on T cells as part of a multimolecular T cell receptor (TCR) complex and composed of a homodimer or heterodimer formed by the association of two or four receptor chains: CD3ε, CD3δ, CD3ζ and CD3γ. Human CD3ε comprises the amino acid sequence of SEQ ID NO: 3. SEQ ID NO: 22 shows the extracellular domain of CD3ε.

[0083] SEQ ID NO:3

[0084] MQSGTHWRVLGLCLLSVGVWGQDGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENCMEMDVMSVATIVIVDICITGGLLLLVYYWSKNRKAKAKPVTRGAGAGGRQRGQNKERPPPVPNPDYEPIRKGQRDLYSGLNQRRI

[0085] SEQ ID NO:22

[0086] DGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENCMEMD

[0087] "CD33" refers to the myeloid cell surface antigen CD33 having the amino acid sequence of SEQ ID NO: 97. The extracellular domain of CD33 spans residues 18 - 259 of SEQ ID NO: 97.

[0088] CD33 (SEQ ID NO:97)

[0089] MPLLLLLPLLWAGALAMDPNFWLQVQESVTVQEGLCVLVPCTFFHPIPYYDKNSPVHGYWFREGAIISRDSPVATNKLDQEVQEETQGRFRLLGDPSRNNCSLSIVDARRRDNGSYFFRMERGSTKYSYKSPQLSVHVTDLTHRPKILIPGTLEPGHSKNLTCSVSWACEQGTPPIFSWLSAAPTSLGPRTTHSSVLIITPRPQDHGTNLTCQVKFAGAGVTTERTIQLNVTYVPQNPTTGIFPGDGSGKQETRAGVVHGAIGGAGVTALLALCLCLIFFIVKTHRRKAARTAVGRNDTHPTTGSASPKHQKKSKLHGPTETSSCSGAAPTVEMDEELHYASLNFHGMNPSKDTSTEYSEVRTQ

[0090] "CD38" refers to human CD38 protein (UniProt accession number P28907) (synonyms: ADP-ribosyl cyclase 1, cADPr hydrolase 1, cyclic ADP-ribose hydrolase 1). Human CD38 has the amino acid sequence shown in SEQ ID NO: 1. CD38 is a single-pass type II transmembrane protein having amino acid residues 1-21 representing a cytoplasmic domain, amino acid residues 22-42 representing a transmembrane domain, and residues 43-300 representing an extracellular domain.

[0091] SEQ ID NO:1

[0092] MANCEFSPVSGDKPCCRLSRRAQLCLGVSILVLILVVVLAVVVPRWRQQWSGPGTTKRFPETVLARCVKYTEIHPEMRHVDCQSVWDAFKGAFISKHPCNITEEDYQPLMKLGTQTVPCNKILLWSRIKDLAHQFTQVQRDMFTLEDTLL GYLADDLTWCGEFNTSKINYQSCPDWRKDCSNNPVSVFWKTVSRRFAEAACDVVHVMLNGSRSKIFDKNSTFGSVEVHNLQPEKVQTLEAWVIHGGREDSRDLCQDPTIKELESIISKRNIQFSCKNIYRPDKFLQCVKNPEDSSCTSEI

[0093] "CH3 region" or "CH3 domain" refers to the CH3 region of an immunoglobulin. The CH3 region of a human IgG1 antibody corresponds to amino acid residues 341-446. However, the CH3 region may also be any of the other antibody isotypes described herein.

[0094] "Chimeric antigen receptor" or "CAR" refers to an engineered T cell receptor that is specifically transplanted to a ligand or antigen onto a T cell (e.g., a naive T cell, a central memory T cell, an effector memory T cell, or a combination thereof). CAR is also referred to as an artificial T cell receptor, a chimeric T cell receptor, or a chimeric immune receptor. CAR comprises an extracellular domain, a transmembrane domain, and at least one intracellular domain that can bind to an antigen. The CAR intracellular domain comprises a polypeptide known to be used as a domain for transmitting a signal to cause activation or inhibition of a biological process in a cell. The transmembrane domain comprises any peptide or polypeptide known to span the cell membrane and can act to connect the extracellular domain and the signaling domain. The chimeric antigen receptor may optionally include a hinge domain that serves as a connector between the extracellular domain and the transmembrane domain.

[0095] "In combination" means that two or more therapeutic agents are administered to a subject together as a mixture, simultaneously as a single agent, or sequentially in any order as a single agent.

[0096] "Complementarity determining region" (CDR) is the region of an antibody that binds to an antigen. CDRs can be defined using various delineations, such as Kabat (Wu et al., J Exp Med Vol. 132: pp. 211-250, 1970) (Kabat et al., "Sequences of Proteins of Immunological Interest", 5th ed., Public Health Service, National Institutes of Health, Bethesda, Md., 1991), Chothia (Chothia et al., J Mol Biol Vol. 196: pp. 901-917, 1987), IMGT (Lefranc et al., Dev Comp Immunol, Vol. 27, pp. 55-77, 2003), and AbM (Martin and Thornton, J Bmol Biol, Vol. 263: pp. 800-815, 1996). The correspondence between various delineations and variable region numbers is described (see, e.g., Lefranc et al., Dev Comp Immunol, Vol. 27: pp. 55-77, 2003; Honegger and Pluckthun, J Mol Biol, Vol. 309: pp. 657-670, 2001; International Immunogenetics (IMGT) database; Web resource, http: / / www_imgt_org). Available programs (such as abYsis of UCL Business PLC) can be used to delineate CDRs. Unless otherwise expressly stated in the specification, as used herein, the terms "CDR", "HCDR1", "HCDR2", "HCDR3", "LCDR1", "LCDR2" and "LCDR3" include CDRs defined by any of the above methods (Kabat, Chothia, IMGT or AbM).

[0097] The term "comprising" is intended to include examples encompassed by the terms "consisting essentially of" and "consisting of; similarly, the term "consisting essentially of" is intended to include examples encompassed by the term "consisting of. Unless the context clearly requires otherwise, throughout the specification and claims, the words "comprising," "including," and the like should be understood to have an inclusive sense, rather than an exclusive or exhaustive sense; that is, in the sense of "including, but not limited to."

[0098] "Enhancement" or "enhanced"Refers to one or more functions of the test molecule when compared to a control molecule, or when compared to one or more control molecules, the combined functions of the test molecule are enhanced. Exemplary measurable functions are tumor cell killing, T cell activation, relative or absolute T cell numbers, Fc-mediated effector functions (e.g., ADCC, CDC, and / or ADCP), or binding to Fcγ receptors (FcγRs) or FcRn. "Enhanced" can be an enhancement of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% or more, or an enhancement that is statistically significant.

[0099] "Fcγ receptor" (FcγR) refers to the well-known FcγRI, FcγRIIa, FcγRIIb or FcγRIII. Activating FcγRs include FcγRI, FcγRIIa and FcγRIII.

[0100] “GPRC5D” refers to human G protein coupled receptor family C group 5 member D having the amino acid sequence shown in SEQ ID NO:98.

[0101] GPRC5D (SEQ ID NO:98)

[0102] MYKDCIESTGDYFLLCDAEGPWGIILESLAILGIVVTILLLLAFLFLMRKIQDCSQWNVLPTQLLFLLSVLGLFGLAFAFIIELNQQTAPVRYFLFGVLFALCFSCLLAHASNLVKLVRGCVSFSWTTILCIAIGCSLLQIIIATEYVTLIMTRGMMFVNMTPCQLNVDFVV LLVYVLFLMALTFFVSKATFCGPCENWKQHGRLIFITVLFSIIIWVVWISMLLRGNPQFQRQPQWDDPVVCIALVTNAWVFLLLYIVPELCILYRSCRQECPLQGNACPVTAYQHSFQVENQELSRARDSDGAEEDVALTSYGTPIQPQTVDPTQECFIPQAKLSPQQDAGGV

[0103] "Human antibody" refers to an antibody optimized to have a minimal immune response when applied to a human subject. The variable region of a human antibody is derived from a human immunoglobulin sequence. If a human antibody comprises a constant region or a part of a constant region, the constant region is also derived from a human immunoglobulin sequence. If the variable region of a human antibody is derived from a system using human germline immunoglobulins or rearranged immunoglobulin genes, the human antibody comprises a heavy chain variable region and a light chain variable region "derived from" a sequence of human origin. Such exemplary systems are human immunoglobulin gene libraries displayed on phages, and transgenic non-human animals, such as mice or rats carrying human immunoglobulin loci. Due to the differences between the systems for obtaining human antibodies and human immunoglobulin loci, the introduction of somatic mutations, the intentional introduction of substitutions into frameworks or CDRs, "human antibodies" generally contain amino acid differences when compared with immunoglobulins expressed in humans. Typically, the amino acid sequence of a "human antibody" is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence encoded by a human germline immunoglobulin gene or a rearranged immunoglobulin gene. In some cases, a "human antibody" may comprise a consensus framework sequence derived from human framework sequence analysis (e.g., as described in Knappik et al., (2000) J Mol Biol, Vol. 296: 57-86); or a synthetic HCDR3 bound to a human immunoglobulin gene library displayed on phage (e.g., as described in Shi et al., (2010) J Mol Biol, Vol. 397: 385-396 and International Patent Publication No. WO2009 / 085462). The definition of "human antibody" does not include antibodies in which at least one CDR is derived from a non-human species.

[0104] "Humanized antibody" refers to an antibody in which at least one CDR is derived from a non-human species and at least one framework is derived from a human immunoglobulin sequence. A humanized antibody may comprise substitutions in the framework so that the framework may not be an exact copy of an expressed human immunoglobulin or human immunoglobulin germline gene sequence.

[0105] "Isolated" refers to a homogenous population of molecules (such as synthetic polynucleotides or proteins, such as antibodies) that have been substantially separated and / or purified from other components of a system (such as a recombinant cell) in which the molecules were produced, as well as proteins that have been subjected to at least one purification or separation step. "Isolated antibody" refers to an antibody that is substantially free of other cellular material and / or chemicals, and encompasses antibodies isolated to a higher degree of purity, such as 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% purity.

[0106] "Monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibody molecules, i.e., the individual antibodies comprising the population are identical, except for possible well-known changes, such as removal of the C-terminal lysine from the antibody heavy chain or post-translational modifications such as amino acid isomerization or deamidation, methionine oxidation, or asparagine or glutamine deamidation. Monoclonal antibodies generally bind to one antigenic epitope. Bispecific monoclonal antibodies bind to two different antigenic epitopes. Monoclonal antibodies may have heterogeneous glycosylation within the antibody population. Monoclonal antibodies may be monospecific or multispecific, such as bispecific, monovalent, bivalent or multivalent.

[0107] "Mutation" refers to an engineered or naturally occurring change in a polypeptide or polynucleotide sequence when compared to a reference sequence. The change can be a substitution, insertion or deletion of one or more amino acids or polynucleotides.

[0108] "Non-fixed combination" refers to separate pharmaceutical compositions wherein the T cell redirecting therapeutic and the anti-CD38 antibody are administered simultaneously, concurrently or sequentially as separate entities with no specific time interval constraints, wherein such administration provides effective levels of both compounds in the subject.

[0109] "Multispecific" refers to an antibody that specifically binds to at least two different antigens or at least two different epitopes within the same antigen. A multispecific antibody can bind, for example, to two, three, four or five different antigens or different epitopes within the same antigen.

[0110] "Pharmaceutical composition" refers to a composition comprising an active ingredient and a pharmaceutically acceptable carrier.

[0111] "Pharmaceutically acceptable carrier" or "excipient" refers to an ingredient in a pharmaceutical composition other than the active ingredient, which is non-toxic to the subject.

[0112] "Philadelphia chromosome" or "Ph" refers to the well-known chromosomal translocation between chromosomes 9 and 22, resulting in an oncogenic BCR-ABL gene fusion with constitutively active tyrosine kinase activity. The translocation results in a fusion of a portion of the BCR gene from chromosome 22q11 with a portion of the ABL gene from chromosome 9q34 and is named t(9;22)(q34;q11) according to the International System for Human Cytogenetic Nomenclature (ISCN). Depending on the precise location of the fusion, the molecular weight of the resulting fusion protein can range from 185 kDa to 210 kDa. "Philadelphia chromosome" refers to all BCR-ABL fusion proteins formed as a result of the (9;22)(q34;q11) translocation.

[0113] "PSMA" refers to human prostate-specific membrane antigen having the amino acid sequence of SEQ ID NO: 99. The extracellular domain spans residues 44 to 750 of SEQ ID NO:99.

[0114] PSMA (SEQ ID NO:99)

[0115] MWNLLHETDSAVATARRPRWLCAGALVLAGGFFLLGFLFGWFIKSSNEATNITPKHNMKAFLDELKAENIKKFLYNFTQIPHLAGTEQNFQLAKQIQSQWKEFGLDSVELAHYDVLLSYPNKTHPNYISIINEDGNEIFNTSLFEPPPPGYENVSDIVPPFSAFSPQGMPEGDLVYVNYARTEDFFK LERDMKINCSGKIVIARYGKVFRGNKVKNAQLAGAKGVILYSDPADYFAPGVKSYPDGWNLPGGGVQRGNILNLNGAGDPLTPGYPANEYAYRRGIAEAVGLPSIPVHPIGYYDAQKLLEKMGGSAPPDSSWRGSLKVPYNVGPGFTGNFSTQKVKMHIHSTNEVTRIYNVIGTLRGAVEPDRYVILG GHRDSWVFGGIDPQSGAAVVHEIVRSFGTLKKEGWRPRRTILFASWDAEEFGLLGSTEWAEENSRLLQERGVAYINADSSIEGNYTLRVDCTPLMYSLVHNLTKELKSPDEGFEGKSLYESWTKKSPSPEFSGMPRISKLGSGNDFEVFFQRLGIASGRARYTKNWETNKFSGYPLYHSVYETYELV EKFYDPMFKYHLTVAQVRGGMVFELANSIVLPFDCRDYAVVLRKYADKIYSISMKHPQEMKTYSVSFDSLFSAVKNFTEIASKFSERLQDFDKSNPIVLRMMNDQLMFLERAFIDPLGLPDRPFYRHVIYAPSSHNKYAGESFPGIYDALFDIESKVDPSKAWGEVKRQIYVAAFTVQAAAETLSEVA

[0116] "Recombinant" refers to DNA, antibodies and other proteins that are prepared, expressed, produced or isolated by recombinant means when fragments from different sources are joined to produce the recombinant DNA, antibody or protein.

[0117] "Reduction" or "reduced" refers to a reduction in one or more functions of the test molecule when compared to a control molecule, or a reduction in the combined functions of the test molecule when compared to one or more control molecules. Exemplary measurable functions are tumor cell killing, T cell activation, relative or absolute T cell numbers, Fc-mediated effector functions (e.g., ADCC, CDC, and / or ADCP), or binding to Fcγ receptors (FcγRs) or FcRn. "Reduced" can be a reduction of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% or more, or a statistically significant reduction.

[0118] "rHuPh20" refers to a recombinant human hyalurodinase having an amino acid sequence of SEQ ID NO: 105, which is a recombinant hyaluronidase described in International Patent Publication No. WO2004 / 078140 ( recombinant).

[0119] rHuPH20 (SEQ ID NO: 105)

[0120] MGVLKFKHIFFRSFVKSSGVSQIVFTFLLIPCCLTLNFRAPPVIPNVPFLWAWNAPSEFCLGKFDEPLDMSLFSFIGSPINATGQGVTIFYVDRLGYYPYIDSITGVTVNGGIPQKISLQDHLDKA KKDITFYMPVDNLGMAVIDWEEWRPTWARNWKPKDVYKNRSIELVQQQNVQLSLTEATEKAKQEFEKAGKDFLVETIKLGKLLRPNHLWGYYLFPDCYNHHYKKPGYNGSCFNVEIKRNDDLSWLWN ESTALYPSIYLNTQQSPVAATLYVRNRVREAIRVSKIPDAKSPLPVFAYTRIVFTDQVLKFLSQDELVYTFGETVALGASGIVIWGTLSIMRSMKSCLLLDNYMETILNPYIINVTLAAKMCSQVLC QEQGVCIRKNWNSSDYLHLNPDNFAIQLEKGGKFTVRGKPTLEDLEQFSEKFYCSCYSTLSCKEKADVKDTDAVDVCIADGVCIDAFLKPPMETEEPQIFYNASPSTLSATMFIVSILFLIISSVASL

[0121] "Refractory" refers to cancer that is not amenable to surgical intervention and does not initially respond to treatment.

[0122] "Recurrent" refers to cancer that has responded to treatment but has subsequently come back.

[0123] "Subject" includes any human or non-human animal. "Non-human animals" include all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc. Unless otherwise indicated, the terms "patient" or "subject" are used interchangeably.

[0124] "T cell redirecting therapeutic agent" refers to a molecule comprising two or more binding regions, wherein one of the binding regions specifically binds to a cell surface antigen on a target cell or tissue (such as a tumor-associated antigen), and wherein a second binding region of the molecule specifically binds to a T cell antigen (such as CD3). This dual / multi-target binding capability recruits T cells to the target cell or tissue, thereby eradicating the target cell or tissue.

[0125] "TMEFF2" refers to a human transmembrane protein with EGF-like and two follistatin-like domains 2, also known as brain tumor suppressor protein 2. The amino acid sequence of full-length human TMEFF2 is shown in SEQ ID NO: 101. The extracellular domain of TMEFF2 spans residues 40-374 of SEQ ID NO:101.

[0126] TMEFF2 (SEQ ID NO: 101)

[0127] MVLWESPRQCSSWTLCEGFCWLLLLLPVMLLIVARPVKLAAFPTSLSDCQTPTGWNCSGYDDRENDLFLCDTNTCKFDGECLRIGDTVTCVCQFKCNNDYVPVCGSNGESYQNECYLRQAACKQQSEILVVSEGSCATDAGSGSGDGVHEGSGETSQKETSTCDICQFGAECDEDAEDVWCVCNIDCS QTNFNPLCASDGKSYDNACQIKEASCQKQEKIEVMSLGRCQDNTTTTTKSEDGHYARTDYAENANKLEESAREHHIPCPEHYNGFCMHGKCEHSINMQEPSCRCDAGYTGQHCEKKDYSVLYVVPGPVRFQYVLIAAVIGTIQIAVICVVVLCITRKCPRSNRIHRQKQNTGHYSSDNTTRASTRLI

[0128] A "therapeutically effective amount" refers to an amount effective to achieve the desired therapeutic outcome at the required dosage and time period. A therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the 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, improving the health of the patient.

[0129] "Treatment" refers to both therapeutic treatment and preventive or defensive measures, wherein the goal is to prevent or slow down (mitigate) undesirable physiological changes or disorders. Beneficial or desired clinical outcomes include alleviation of symptoms, attenuation of disease extent, stable (i.e., non-exacerbated) state of disease, delay or slowing of disease progression, improvement or alleviation of the disease state, and relief (whether partial or complete), whether detectable or undetectable. "Treatment" may also mean prolonging survival compared to the expected survival of the subject if he or she is not receiving treatment. Individuals in need of treatment include individuals who already have a disease or disorder and individuals who are susceptible to a disease or disorder or individuals in whom a disease or disorder is to be prevented.

[0130] "Tumor cell" or "cancer cell" refers to a cancerous, precancerous or transformed cell in vivo, in vitro or in tissue culture, which has spontaneous or induced phenotypic changes. These changes do not necessarily involve the uptake of new genetic material. However, transformation can occur by infection with transforming viruses and binding of new genomic nucleic acids, uptake of exogenous nucleic acids, or it can also occur spontaneously or after exposure to carcinogens, thereby mutating endogenous genes. Transformation / cancer is exemplified by morphological changes, cell immortality, abnormal growth control, lesion formation, proliferation, malignant tumors, adjustment of tumor-specific marker levels, invasion, tumor growth in vitro, in vivo and in vitro in suitable animal hosts (such as nude mice, etc.).

[0131] Unless otherwise specifically stated, throughout the specification, the amino acid residues in the antibody constant region are numbered according to the EU index as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Edition Public Health Service, National Institutes of Health, Bethesda, MD. (1991). Antibody constant chain numbering can be found, for example, on the ImMunoGeneTics website, IMGT Web resources of IMGT Scientific charts.

[0132] The substitution in the CH3 region is expressed as a modification position in the first CH3 domain of the first heavy chain / a modification position in the second CH3 domain of the second heavy chain. For example, F405L / K409R refers to a F405L mutation in the first CH3 region and a K09R mutation in the second CH3 region. L351Y_F405A_Y407V / T394W refers to a L351Y, F40FA and Y407V mutation in the first CH3 region and a T394W mutation in the second CH3 region. D399FHKRQ / K409AGRH refers to a mutation in which D399 can be replaced by F, H, K, R or Q and K409 can be replaced by A, G, R or H.

[0133] Conventional one-letter and three-letter amino acid codes are used herein, as shown in Table 1.

[0134] Table 1 .

[0135] Amino Acids Three letter code Single letter code Alanine Ala A Arginine Arg R Asparagine Asn N Aspartic acid Asp D Cysteine Cys C Glutamate Gln E Glutamine Glu Q Glycine Gly G Histidine His H Isoleucine Ile I Leucine Leu L Lysine Lys K Methionine Met M Phenylalanine Phe F Proline Pro P Serine Ser S Threonine Thr T Tryptophan Trp W Tyrosine Tyr Y Valine Val V

[0136] Combination of anti-CD38 antibody and T cell redirecting therapeutic agent and use thereof

[0137] The present invention is based, at least in part, on the discovery that the therapeutic agents JNJ-957 or GPRC5D×CD3 antibody and anti-CD38 antibody (daratumumab), each of which mediates killing of multiple myeloma cells when the target is engaged on the same cell, does not antagonize each other in terms of competing for binding to or acting on MM cells or mutual downregulation of the target, and is therefore suitable for use as a combination therapy. The present invention is also based, at least in part, on the discovery that: (daratumumab) treatment before treatment enhanced JNJ-957-mediated killing of multiple myeloma cells obtained from heavily treated relapsed / refractory multiple myeloma subjects. The present invention is also based at least in part on the following findings: (Daratumumab) enhances killing of tumor cells other than multiple myeloma cells by targeting T cell redirecting therapeutics that are not multiple myeloma tumor cells. Therefore, the combination of anti-CD38 antibodies and T cell redirecting therapeutics and / or pre-treatment of subjects with anti-CD38 antibodies prior to administration of T cell redirecting therapeutics can enhance the anti-tumor efficacy of monotherapy. Also given that cancer is often a heterogeneous disease, portions of the cancer may uniquely have sufficient expression of one target relative to another, and combination therapy will help to more deeply eradicate the disease.

[0138] CD38 is a multifunctional protein that functions as receptor-mediated adhesion and signal transduction, as well as calcium mobilization via its extracellular enzyme 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 Vol. 145: pp. 2390-2396, 1990; Terhorst et al., Cell, pp. 771-780, 1981; Guse et al., Nature, Vol. 398: pp. 70-73, 1999). CD38 also regulates extracellular NAD via its NAD glycohydrolase activity. + levels, which is involved in regulating the regulatory T cell compartment (Adriouch et al., Microbes infect, Vol. 14: pp. 1284-1292, 2012; Chiarugi et al., Nature Reviews, Vol. 12: pp. 741-752, 2012). 2+ In addition to signal transduction by , CD38 signaling also occurs through cross-responses with antigen-receptor complexes or other types of receptor complexes (such as MHC molecules) on T cells and B cells, so that CD38 is not only involved in several cellular responses, but also in the conversion and secretion of IgG1. Anti-CD38 antibodies have been identified herein (daratumumab) enhances the anti-tumor effect of T cell redirecting therapeutics. Without being bound by any particular theory, it can be hypothesized that (daratumumab) through its immunomodulatory activity in human subjects (i.e., reducing the number of immunosuppressive Tregs, MDSCs, and Bregs, increasing CD8 + The number of T cells and CD8 + ratio to Treg, promoting CD8 + Central memory cell formation and increased T cell clonality) or may even lead to an enhanced immune response in a subject, thus facilitating T cell engagement with T cell redirecting therapeutics.

[0139] The present disclosure provides a method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of an anti-CD38 antibody and a T cell redirecting therapeutic agent to treat the cancer.

[0140] The present disclosure also provides a method of killing tumor cells in a subject, comprising administering to the subject an anti-CD38 antibody and a T cell redirecting therapeutic agent that binds to an antigen on a tumor cell for a time sufficient to kill the tumor cell.

[0141] The present disclosure also provides a method of enhancing the efficacy of a T cell redirecting therapeutic in a subject having cancer, comprising administering an anti-CD38 antibody to the subject.

[0142] In some embodiments, the anti-CD38 antibody is administered prior to administration of the T cell redirecting therapeutic.

[0143] The T cell redirecting therapeutic can be administered one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, one month, five weeks, six weeks, seven weeks, two months, three months, four months, five months, six months, or more prior to administration of the anti-CD38 antibody.

[0144] In some embodiments, the T cell redirecting therapeutic binds to an antigen on a tumor cell.

[0145] In some embodiments, the antigen on the tumor cell is BCMA, GPRC5D, CD33, CD123, CD19, PSMA, TMEFF2, CD20, CD10, CD21, CD22, CD25, CD30, CD34, CD37, CD44v6, CD45, CD52, CD133, ROR1, B7-H6, B7-H3, HM1.24, SLAMF7, Fms-like tyrosine kinase 3 (FLT-3, CD135), chondroitin sulfate proteoglycan 4 (CSP G4, melanoma-associated chondroitin sulfate proteoglycan), epidermal growth factor receptor (EGFR), Her2, Her3, IGFR, IL3R, fibroblast activation protein (FAP), CDCP1, Derlin1, tenascin, Frizzled 1-10, VEGFR2 (KDR / FLK1), VEGFR3 (FLT4, CD309), PDGFR-α (CD140a), PDGFR-β (CD140b), endoglin, CLEC14, Tem1-8 or Tie2. Additional exemplary antigens on tumor cells include A33, CAMPATH-1 (CDw52), carcinoembryonic antigen (CEA), carbonic anhydrase IX (MN / CA IX), de2-7, EGFRvIII, EpCAM, Ep-CAM, folate binding protein, G250, c-Kit (CD117), CSF1R (CD115), HLA-DR, IGFR, IL-2 receptor, IL3R, MCSP (melanoma-associated cell surface chondroitin sulfate proteoglycan), Muc-1, prostate stem cell antigen (PSCA), prostate specific antigen (PSA), hK2, TAG-72, or tumor cell neoantigens.

[0146] In some embodiments, the T cell redirecting therapeutic binds BCMA, GPRC5D, CD33, CD123, CD19, PSMA, TMEFF2, CD20, CD22, CD25, CD52, ROR1, HM1.24, CD38, or SLAMF7.

[0147] In some embodiments, the T cell redirecting therapeutic binds CD3 epsilon (CD3ε).

[0148] In some embodiments, the T cell redirecting therapeutic binds CD3.

[0149] In some embodiments, the T cell redirecting therapeutic binds to CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, BTNL8, PD-1, CD195, or NKG2C. When compared to CD3, these antigens have a significant effect on CD8. + T cells are more specific (see, e.g., International Patent Publication WO2018 / 187215).

[0150] In some embodiments, the T cell redirecting therapeutic comprises a CD3 binding domain comprising:

[0151] heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO:33, HCDR2 of SEQ ID NO:34, HCDR3 of SEQ ID NO:35, light chain complementarity determining region 1 (LCDR1) of SEQ ID NO:36, LCDR2 of SEQ ID NO:37, and LCDR3 of SEQ ID NO:38;

[0152] The heavy chain variable region (VH) of SEQ ID NO:39 and the light chain variable region (VL) of SEQ ID NO:40;

[0153] HCDR1 of SEQ ID NO:74, HCDR2 of SEQ ID NO:75, HCDR3 of SEQ ID NO:76, LCDR1 of SEQ ID NO:77, LCDR2 of SEQ ID NO:78, and LCDR3 of SEQ ID NO:79;

[0154] VH of SEQ ID NO:80 and VL of SEQ ID NO:81;

[0155] HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of the CD3 binding domain of SEQ ID NO:53; or

[0156] VH and VL of the CD3 binding domain of SEQ ID NO:53.

[0157] In some embodiments, the T cell redirecting therapeutic binds BCMA.

[0158] In some embodiments, the T cell redirecting therapeutic comprises

[0159] a BCMA binding domain and a CD3 binding domain, the BCMA binding domain comprising HCDR1 of SEQ ID NO:23, HCDR2 of SEQ ID NO:24, HCDR3 of SEQ ID NO:25, LCDR1 of SEQ ID NO:26, LCDR2 of SEQ ID NO:27, and LCDR3 of SEQ ID NO:28, and the CD3 binding domain comprising HCDR1 of SEQ ID NO:33, HCDR2 of SEQ ID NO:34, HCDR3 of SEQ ID NO:35, LCDR1 of SEQ ID NO:36, LCDR2 of SEQ ID NO:37, and LCDR3 of SEQ ID NO:38; and / or

[0160] The BCMA binding domain comprises the VH of SEQ ID NO:29 and the VL of SEQ ID NO:30, and the CD3 binding domain comprises the VH of SEQ ID NO:39 and the VL of SEQ ID NO:40.

[0161] In some embodiments, the BCMA-binding T cell redirecting therapeutic comprises a first heavy chain (HC1) of SEQ ID NO:31, a first light chain (LC1) of SEQ ID NO:32, a second heavy chain (HC2) of SEQ ID NO:41, and a second light chain (LC2) of SEQ ID NO:42.

[0162] In some embodiments, T cell redirecting therapeutics that bind to BCMA include ACTR cancer therapy from Seattle Genetics, AFM-26, ALLO-715, anti-BCMA allogeneic CAR-T cell therapy from CRISPR Therapeutics, anti-BCMA CAR-T therapy from Sorrento Therapeutics, anti-CD19 / BCMACAR-T cell therapy from Hrain Biotechnology, BCMA CAR-T therapy from Chineo Med (Beijing), BCMATAC-T cell therapy from Triumvira Immunologics, BCMA-CAR-T cell therapy from Shanghai Unicar-Therapy Biomed. T cell therapy, Regeneron's BCMA / CD3 antibody, NantKwest's CAR-NK cell therapy, CC-93629, CMD-505, CTX-4419, CYAD-211, HDP-101, HPN-217, P-BCMA-ALLO1, TNB-383B, bb-2121, AUTO-2, Pregene's BCMA chimeric antigen receptor therapy, Shanghai Bioray Laboratory's BCMA-CAR T cells, CARsgen Therapeutics' BCMA-CAR-T cells, Shenzhen BinDeBio's CAR-T / TCR-T cell immunotherapy, ET-140, P-BCMA-101, REGN-5458, AMG-701, Cellular Biomedicine Group's anti-BCMA CAR-T cell therapy, bb-21217, BI-836909, CC-93269, Descartes-08, IM-21, JNJ-64007957, MEDI-2228, or PF-06863135.

[0163] In some embodiments, the T cell redirecting therapeutic comprises any of the BCMA binding domains described in International Patent Publication No. WO2017 / 031104.

[0164] In some embodiments, the T cell redirecting therapeutic binds to GPRC5D.

[0165] In some embodiments, the T cell redirecting therapeutic comprises

[0166] a GPRC5D binding domain and a CD3 binding domain, the GPRC5D binding domain comprising HCDR1 of SEQ ID NO:43, HCDR2 of SEQ ID NO:44, HCDR3 of SEQ ID NO:45, LCDR1 of SEQ ID NO:46, LCDR2 of SEQ ID NO:47, and LCDR3 of SEQ ID NO:48, and the CD3 binding domain comprising HCDR1 of SEQ ID NO:33, HCDR2 of SEQ ID NO:34, HCDR3 of SEQ ID NO:35, LCDR1 of SEQ ID NO:36, LCDR2 of SEQ ID NO:37, and LCDR3 of SEQ ID NO:38; and / or

[0167] The GPRC5D binding domain comprises the VH of SEQ ID NO:49 and the VL of SEQ ID NO:50, and the CD3 binding domain comprises the VH of SEQ ID NO:39 and the VL of SEQ ID NO:40.

[0168] In some embodiments, a T cell redirecting therapeutic that binds GPRC5D comprises HC1 of SEQ ID NO:51, LC1 of SEQ ID NO:52, HC2 of SEQ ID NO:41, and LC2 of SEQ ID NO:42.

[0169] In some embodiments, the T cell redirecting therapeutic comprises the GPRC5D antibody of Eureka Therapeutics.

[0170] In some embodiments, the T cell redirecting therapeutic comprises any of the GPRC5D binding domains described in International Patent Publication No. WO2018 / 0037651.

[0171] In some embodiments, the T cell redirecting therapeutic binds CD33.

[0172] In some embodiments, the T cell redirecting therapeutic comprises

[0173] A CD33 binding domain and a CD3 binding domain, the CD33 binding domain comprises HCDR1 of SEQ ID NO:84, HCDR2 of SEQ ID NO:85, HCDR3 of SEQ ID NO:86, LCDR1 of SEQ ID NO:87, LCDR2 of SEQ ID NO:88, and LCDR3 of SEQ ID NO:89, and the CD3 binding domain comprises HCDR1 of SEQ ID NO:74, HCDR2 of SEQ ID NO:75, HCDR3 of SEQ ID NO:76, LCDR1 of SEQ ID NO:77, LCDR2 of SEQ ID NO:78, and LCDR3 of SEQ ID NO:79; and / or

[0174] The CD33 binding domain comprises the VH of SEQ ID NO:90 and the VL of SEQ ID NO:91, and the CD3 binding domain comprises the VH of SEQ ID NO:80 and the VL of SEQ ID NO:81.

[0175] In some embodiments, the CD33-binding T cell redirecting therapeutic comprises HC1 of SEQ ID NO:92, LC1 of SEQ ID NO:93, HC2 of SEQ ID NO:82, and LC2 of SEQ ID NO:83.

[0176] In some embodiments, T cell redirecting therapeutics that bind CD33 include Shenzhen BinDeBio's CAR-T / TCR-T cell immunotherapy, AMG-330, AMV-564, JNJ-67571244, ICG-144, AMG-673, Ziopharm's CD33 CAR-T therapy INXN 3004, huCD33-BsAb, VOR-33, HMBD-004A, GEM-333, TGB-3550, or CD33.taNK.

[0177] In some embodiments, the T cell redirecting therapeutic binds CD123.

[0178] In some embodiments, the T cell redirecting therapeutic comprises

[0179] A CD123 binding domain and a CD3 binding domain, the CD123 binding domain comprises the HCDR1 of SEQ ID NO:94, the HCDR2 of SEQ ID NO:95, the HCDR3 of SEQ ID NO:96, the LCDR1 of SEQ ID NO:9, the LCDR2 of SEQ ID NO:10, and the LCDR3 of SEQ ID NO:59, and the CD3 binding domain comprises the HCDR1 of SEQ ID NO:33, the HCDR2 of SEQ ID NO:34, the HCDR3 of SEQ ID NO:35, the LCDR1 of SEQ ID NO:36, the LCDR2 of SEQ ID NO:37, and the LCDR3 of SEQ ID NO:38; and / or

[0180] The CD123 binding domain comprises the VH of SEQ ID NO: 100 and the VL of SEQ ID NO: 61, and the CD3 binding domain comprises the VH of SEQ ID NO: 39 and the VL of SEQ ID NO: 40.

[0181] In some embodiments, the T cell redirecting therapeutic that binds CD123 comprises HC1 of SEQ ID NO: 102, LC1 of SEQ ID NO: 63, HC2 of SEQ ID NO: 41, and LC2 of SEQ ID NO: 42.

[0182] In some embodiments, T cell redirecting therapeutics that bind CD123 include TheraVectys' acute myeloid leukemia therapy, APVO-437, Nanjing Legend Biotech's anti-CD123 CAR-T cell therapy, APVO-436, Hebei Senlang Biotechnology's CD123 CAR-T cell therapy, vortuzumab, IM-23, JNJ-63709178, Mustang Bio's MB-102, UCART-123, XmAb-14045, or Sanofi's CD3-CD123 bispecific T cell engager.

[0183] In some embodiments, the T cell redirecting therapeutic comprises any of the CD123 binding domains as described in International Patent Publication No. WO2016 / 036937.

[0184] In some embodiments, the T cell redirecting therapeutic binds CD19.

[0185] In some embodiments, the T cell redirecting therapeutic comprises

[0186] A CD19 binding domain and a CD3 binding domain, the CD19 binding domain comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of the CD19 binding domain of SEQ ID NO:53, and the CD3 binding domain comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of the CD3 binding domain of SEQ ID NO:53; and / or

[0187] The amino acid sequence of SEQ ID NO:53.

[0188] In some embodiments, T cell redirecting therapeutics that bind to CD19 include axicabtageneciloleucel, blinatumomab, tisagenlecleucel-t, AMG-562, Cellular Biomedicine Group's AUTO-1 CAR-T CD19, Ziopharm's CD19 chimeric antigen receptor T cell therapy, ioceltech Therapeutics' CD19-CAR-T cell therapy, Marino Biotechnology's CD19-CAR-T cell therapy, Guangdong Zhaotai InVivo's CD19-CAR-T2 cell therapy, Juno Therapeutics' CD19 / 4-1BBL armored CAR T cell therapy, CSG-CD19, DI-B4, ET-190, GC-007F, GC-022, HRAIN Biotechnology's human CD19 T cell therapy, Kite Pharma's humanized anti-CD19 control CAR (3rd generation), Immune Cell Therapy's ICAR-19CAR-T cells, ICTCAR-003, Marino Biotechnology's iPD1 CD19 eCAR T cells, JWCAR029, PTG-01, PZ01, Senl_1904A, Senl_1904B, UCART-19, UWC-19, AUTO-3, BinD-19, Shanghai Unicar-Therapy Biomed's CAR-T cell therapy, Shenzhen BinDeBio's CAR-T / TCR-T cell immunotherapy, Miltenyi Biotec's CD-19CAR-T cell therapy, Miltenyi Biotec's CD19 CAR-T cells, ShanghaiUnicar-Therapy Biomed's CD19-CART cell therapy, Takara Bio's CD19-CAR T cell therapy, Shanghai Bioray Laboratory's CD19-CART, Sinobioway's CD19-targeted chimeric antigen receptor T cells, Shanghai Longyao Biotechnology's CD19 / CD20 CAR-T cell therapy, CIK-CAR.CD19, ICTCAR-011, IM-19, JCAR-014, loncastuximab tesirine, MB-CART2019.1. OXS-1550, PBCAR-0191, PCAR-019, PCAR-119, Senl-001, TI-1007, XmAb-5871, inebilizumab, lisocabtagene maraleucel, XmAb-5574, Eden BioCell's third-generation CD19-CART cells + mbIL15, A-329, ALLO-501, Beijing Doing Biomedical Co's anti-CD19 anti-CD20 bispecific CAR redirected autologous T cells, Allife Medical Science's anti-CD19 CAR NK cell therapy, Hrain Biotechnology's anti-CD19 / BCMA CAR-T cell therapy, ATA-2431, Celularity's ATA-3219.AVA-008.CD19 CAR-T cell therapy, Ziopharm's third-generation CD19 chimeric antigen receptor T cell therapy, Inovio's CD19 dBiTE, Bellicum's CD19 TCR cell therapy, Wilex's CD19-ATAC, Chineo Med (Beijing)'s CD19 / 20 CAR-T therapy, Eureka Therapeutics' CD19 / CD22 dual-targeted therapy, Helix BioPharma's chimeric antigen receptor T cell (CAR-T) therapy, CMD-502, CTX-110, CYAD-04, CYAD-221, ET-019002, FT-596, FT-819, TC Biopharm's γ-δ CAR-T therapy, ICT CAR-014, iDD-002, KITE-037, NI-2201, RB-1916, Senl_002, TAC01-CD19, TC-110, TC-310, TCB-003, or TI-7007. .

[0189] In some embodiments, the T cell redirecting therapeutic binds to PSMA.

[0190] In some embodiments, the T cell redirecting therapeutic comprises

[0191] a PSMA binding domain and a CD3 binding domain, the PSMA binding domain comprising HCDR1 of SEQ ID NO:54, HCDR2 of SEQ ID NO:55, HCDR3 of SEQ ID NO:56, LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10, and LCDR3 of SEQ ID NO:59, and the CD3 binding domain comprising HCDR1 of SEQ ID NO:33, HCDR2 of SEQ ID NO:34, HCDR3 of SEQ ID NO:35, LCDR1 of SEQ ID NO:36, LCDR2 of SEQ ID NO:37, and LCDR3 of SEQ ID NO:38; and / or

[0192] The PSMA binding domain comprises the VH of SEQ ID NO:60 and the VL of SEQ ID NO:61, and the CD3 binding domain comprises the VH of SEQ ID NO:39 and the VL of SEQ ID NO:40.

[0193] In some embodiments, the PSMA-binding T cell redirecting therapeutic comprises HC1 of SEQ ID NO:62, LC1 of SEQ ID NO:63, HC2 of SEQ ID NO:41, and LC2 of SEQ ID NO:42.

[0194] In some embodiments, the T cell redirecting therapeutic binds TMEFF2.

[0195] In some embodiments, the T cell redirecting therapeutic comprises

[0196] TMEFF2 binding domain and CD3 binding domain, TMEFF2 binding domain contains

[0197] SEQ ID NO:64 HCDR1, SEQ ID NO:65 HCDR2, SEQ ID NO:66 HCDR3, SEQ ID NO:67 LCDR1, SEQ ID NO:68 LCDR2 and SEQ ID NO:69 LCDR3, and the CD3 binding domain comprises SEQ ID NO:74 HCDR1, SEQ ID NO:75 HCDR2, SEQ ID NO:76 HCDR3, SEQ ID NO:77 LCDR1, SEQ ID NO:78 LCDR2 and SEQ ID NO:79 LCDR3; and / or

[0198] The TMEFF2 binding domain comprises the VH of SEQ ID NO:70 and the VL of SEQ ID NO:71, and the CD3 binding domain comprises the VH of SEQ ID NO:80 and the VL of SEQ ID NO:81.

[0199] In some embodiments, a T cell redirecting therapeutic that binds TMEFF2 comprises HC1 of SEQ ID NO:72, LC1 of SEQ ID NO:73, HC2 of SEQ ID NO:82, and LC2 of SEQ ID NO:83.

[0200] In some embodiments, the T cell redirecting therapeutic binds CD20.

[0201] In some embodiments, the T cell redirecting therapeutic binds CD22.

[0202] In some embodiments, the T cell redirecting therapeutic binds CD25.

[0203] In some embodiments, the T cell redirecting therapeutic binds CD52.

[0204] In some embodiments, the T cell redirecting therapeutic binds ROR1.

[0205] In some embodiments, the T cell redirecting therapeutic is bound to HM1.24.

[0206] In some embodiments, the T cell redirecting therapeutic binds SLAMF7.

[0207] In some embodiments, the T cell redirecting therapeutic is a multispecific antibody, a chimeric antigen receptor (CAR), or a T cell comprising a CAR.

[0208] In some embodiments, the T cell redirecting therapeutic is a CAR.

[0209] In some embodiments, the T cell redirecting therapeutic is a T cell expressing a CAR.

[0210] In some embodiments, the T cell redirecting therapeutic is a multispecific antibody.

[0211] In some embodiments, the multispecific antibody is of the IgG1, IgG2, IgG3, or IgG4 isotype.

[0212] In some embodiments, the multispecific antibody is of the IgG1 isotype.

[0213] In some embodiments, the multispecific antibody is of the IgG2 isotype.

[0214] In some embodiments, the multispecific antibody is of the IgG3 isotype.

[0215] In some embodiments, the multispecific antibody is of the IgG4 isotype.

[0216] Multispecific antibodies can be any allotype. It is expected that allotype has no effect on the properties of multispecific antibodies (such as binding function or Fc-mediated effector function). The immunogenicity of therapeutic antibodies is associated with increased risk of infusion reactions and reduced duration of therapeutic response (Baert et al., (2003) NEngl J Med 348:602-08). The extent to which therapeutic antibodies induce immune responses in hosts can be determined in part by the allotype of antibodies (Stickler et al., (2011) Genes and Immunity 12:213-21). Antibody allotypes are related to amino acid sequence variations at specific positions in the constant region sequence of antibodies. Table 2 shows selected IgG1, IgG2 and IgG4 allotypes.

[0217] Table 2 .

[0218]

[0219] In some embodiments, the multispecific antibody comprises one or more Fc substitutions that reduce the binding of the multispecific antibody to Fcγ receptors (FcγRs). Substitutions that reduce the binding of the multispecific antibody to FcγRs reduce Fc effector functions such as ADCC, ADCP, and / or CDC of the multispecific antibody. Specific substitutions can be made compared to the wild-type IgG1 of SEQ ID NO: 103 or the wild-type IgG4 of SEQ ID NO: 104.

[0220] In some embodiments, the one or more Fc substitutions are selected from F234A / L235A on IgG4, L234A / L235A on IgG1, V234A / G237A / P238S / H268A / V309L / A330S / P331S on IgG2, F234A / L235A on IgG4, S228P / F234A / L235A on IgG4, N297A on all Ig isotypes, V234A / G237A on IgG2, K214T / E233P / L234V / L235A / G236-deletion / A327G / P331S on IgG1. A / D365E / L358M on IgG2, H268Q / V309L / A330S / P331S on IgG2, S267E / L328F on IgG1, L234F / L235E / D265A on IgG1, L234A / L235A / G237A / P238S / H268A / A330S / P331S on IgG1, S228P / F234A / L235A / G237A / P238S on IgG4, and S228P / F234A / L235A / G236-deletion / G237A / P238S on IgG4, where the residues are numbered according to the EU index.

[0221] In some embodiments, the one or more Fc substitutions are F234A / L235A on IgG4.

[0222] In some embodiments, the one or more Fc substitutions are L234A / L235A on IgG1.

[0223] In some embodiments, the one or more Fc substitutions are V234A / G237A / P238S / H268A / V309L / A330S / P331S on IgG2.

[0224] In some embodiments, the one or more Fc substitutions are F234A / L235A on IgG4.

[0225] In some embodiments, the one or more Fc substitutions are S228P / F234A / L235A on IgG4.

[0226] In some embodiments, the one or more Fc substitutions is N297A on all Ig isotypes.

[0227] In some embodiments, the one or more Fc substitutions are V234A / G237A on IgG2.

[0228] In some embodiments, the one or more Fc substitutions are K214T / E233P / L234V / L235A / G236-deletion / A327G / P331A / D365E / L358M on IgG1.

[0229] In some embodiments, the one or more Fc substitutions are H268Q / V309L / A330S / P331S on IgG2.

[0230] In some embodiments, the one or more Fc substitutions are S267E / L328F on IgG1. In some embodiments, the one or more Fc substitutions are L234F / L235E / D265A on IgG1.

[0231] In some embodiments, the one or more Fc substitutions are L234A / L235A / G237A / P238S / H268A / A330S / P331S on IgG1.

[0232] In some embodiments, the one or more Fc substitutions are S228P / F234A / L235A / G237A / P238S on IgG4 and S228P / F234A / L235A / G236-deletion / G237A / P238S on IgG4.

[0233] In some embodiments, the multispecific antibody further comprises an S228P substitution.

[0234] In some embodiments, the multispecific antibody comprises one or more asymmetric substitutions in the first CH3 domain or the second CH3 domain, or in both the first CH3 domain and the second CH3 domain.

[0235] In some embodiments, the one or more asymmetric substitutions are selected from F450L / K409R, wild type / F409L_R409K, T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S, and T366W / T366S_L368A_Y407V, L351Y_F405A_Y407V / T394S. 94W, T366I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F and T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W.

[0236] In some embodiments, the one or more asymmetric substitutions are F450L / K409R.

[0237] In some embodiments, the one or more asymmetric substitutions are wild type / F409L_R409K.

[0238] In some embodiments, the one or more asymmetric substitutions are T366Y / F405A.

[0239] In some embodiments, the one or more asymmetric substitutions are T366W / F405W.

[0240] In some embodiments, the one or more asymmetric substitutions are F405W / Y407A.

[0241] In some embodiments, the one or more asymmetric substitutions are T394W / Y407T.

[0242] In some embodiments, the one or more asymmetric substitutions are T394S / Y407A.

[0243] In some embodiments, the one or more asymmetric substitutions are T366W / T394S.

[0244] In some embodiments, the one or more asymmetric substitutions are F405W / T394S.

[0245] In some embodiments, the one or more asymmetric substitutions are T366W / T366S_L368A_Y407V.

[0246] In some embodiments, the one or more asymmetric substitutions are L351Y_F405A_Y407V / T394W.

[0247] In some embodiments, the one or more asymmetric substitutions are T366I_K392M_T394W / F405A_Y407V.

[0248] In some embodiments, the one or more asymmetric substitutions are T366L_K392M_T394W / F405A_Y407V.

[0249] In some embodiments, the one or more asymmetric substitutions are L351Y_Y407A / T366A_K409F.

[0250] In some embodiments, the one or more asymmetric substitutions are L351Y_Y407A / T366V_K409F.

[0251] In some embodiments, the one or more asymmetric substitutions are Y407A / T366A_K409F.

[0252] In some embodiments, the one or more asymmetric substitutions are T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W.

[0253] In some embodiments, the cancer is a hematological malignancy or a solid tumor.

[0254] In some embodiments, the hematological malignancy is multiple myeloma, smoldering multiple myeloma, monoclonal gammopathy of undetermined significance (MGUS), acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma (BL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, plasma cell leukemia, light chain amyloidosis (AL), precursor B-cell lymphoblastic leukemia, precursor B-cell lymphoblastic leukemia, Myeloid leukemia, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic lymphocytic leukemia (CLL), B-cell malignancies, chronic myeloid leukemia (CML), hairy cell leukemia (HCL), blastic plasmacytoid dendritic cell neoplasm, Hodgkin lymphoma, non-Hodgkin lymphoma, marginal zone B-cell lymphoma (MZL), mucosa-associated lymphoid tissue lymphoma (MALT), plasma cell leukemia, anaplastic large cell lymphoma (ALCL), leukemia or lymphoma.

[0255] In some embodiments, the hematological malignancy is multiple myeloma.

[0256] In some embodiments, the multiple myeloma is newly diagnosed multiple myeloma.

[0257] In some embodiments, the multiple myeloma is relapsed or refractory multiple myeloma.

[0258] In some embodiments, multiple myeloma is high-risk multiple myeloma. It is known that subjects with high-risk multiple myeloma relapse early and have poor prognosis and outcome. If the subject has one or more of the following cytogenetic abnormalities, the subject can be classified as having high-risk multiple myeloma: t(4;14)(p16;q32), t(14;16)(q32;q23), del17p, 1qAmp, t(4;14)(p16;q32) and t(14;16)(q32;q23), t(4;14)(p16;q32) and del17p, t(14;16)(q32;q23) and del17p, or t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p.

[0259] In some embodiments, the subject with high-risk multiple myeloma has one or more chromosomal abnormalities comprising: t(4;14)(p16;q32), t(14;16)(q32;q23), del17p, 1qAmp, t(4;14)(p16;q32) and t(14;16)(q32;q23), t(4;14)(p16;q32) and del17p, t(14;16)(q32;q23) and del17p; or t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p, or any combination thereof.

[0260] Various qualitative and / or quantitative methods can be used to determine the relapse or refractory nature of the disease. Symptoms that may be relevant are, for example: a decline or stabilization of the patient's health status, or the re-establishment or worsening of various symptoms associated with solid tumors, and / or the spread of cancer cells from one site in the body to other organs, tissues or cells.

[0261] Cytogenetic abnormalities can be detected, for example, by fluorescence in situ hybridization (FISH). In chromosomal translocations, oncogenes are translocated to the IgH region on chromosome 14q32, resulting in these gene disorders. t(4; 14)(p16; q32) involves translocations of fibroblast growth factor receptor 3 (FGFR3) and multiple myeloma SET domain-containing protein (MMSET) (also referred to as WHSC1 / NSD2), and t(14; 16)(q32; q23) involves translocations of MAF transcription factor C-MAF. The loss of 17p (del17p) involves the loss of the p53 locus.

[0262] In some embodiments, the multiple myeloma is relapsed or refractory to treatment with an anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotozumab, ixazomib, melphalan, or thalidomide, or any combination thereof.

[0263] In some embodiments, multiple myeloma is relapsed or refractory to treatment with an anti-CD38 antibody. In some embodiments, multiple myeloma is relapsed or refractory to treatment with lenalidomide. In some embodiments, multiple myeloma is relapsed or refractory to treatment with bortezomib. In some embodiments, multiple myeloma is relapsed or refractory to treatment with pomalidomide. In some embodiments, multiple myeloma is relapsed or refractory to treatment with carfilzomib. In some embodiments, multiple myeloma is relapsed or refractory to treatment with elotozumab. In some embodiments, multiple myeloma is relapsed or refractory to treatment with ixazomib. In some embodiments, multiple myeloma is relapsed or refractory to treatment with melphalan. In some embodiments, multiple myeloma is relapsed or refractory to treatment with thalidomide.

[0264] In some embodiments, the hematological malignancy is AML.

[0265] In some embodiments, AML is AML with at least one genetic abnormality, AML with multilineage dysplasia, therapy-related AML, undifferentiated AML, AML with minimal maturity, AML with maturity, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, acute megakaryoblastic leukemia, acute basophilic leukemia, acute panmyelosis with fibrosis, or myeloid sarcoma.

[0266] In some embodiments, AML is AML with at least one genetic abnormality. In some embodiments, AML is AML with multilineage dysplasia. In some embodiments, AML is treatment-related AML. In some embodiments, AML is undifferentiated AML. In some embodiments, AML is AML with minimal maturity. In some embodiments, AML is AML with maturity. In some embodiments, AML is acute myelomonocytic leukemia. In some embodiments, AML is acute monocytic leukemia. In some embodiments, AML is acute erythroleukemia. In some embodiments, AML is acute megakaryoblastic leukemia. In some embodiments, AML is acute basophilic leukemia. In some embodiments, AML is acute panmyelosis with fibrosis. In some embodiments, AML is myeloid sarcoma.

[0267] In some embodiments, the at least one genetic abnormality is a translocation between chromosomes 8 and 21, a translocation or inversion in chromosome 16, a translocation between chromosomes 15 and 17, an alteration in chromosome 11, or a mutation in fms-related tyrosine kinase 3 (FLT3), nucleolar phosphatidylcholine (NPM1), isocitrate dehydrogenase 1 (IDH1), isocitrate dehydrogenase 2 (IDH2), DNA (cytosine-5)-methyltransferase 3 (DNMT3A), CCAAT / enhancer binding protein alpha (CEBPA), U2 small nuclear RNA accessory factor 1 (U2AF1), enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), structural maintenance of chromosome 1A (SMC1A), or structural maintenance of chromosome 3 (SMC3).

[0268] In some embodiments, the at least one genetic abnormality is a translocation between chromosomes 8 and 21. In some embodiments, the at least one genetic abnormality is a translocation or inversion in chromosome 16. In some embodiments, the at least one genetic abnormality is a translocation between chromosomes 15 and 17. In some embodiments, the at least one genetic abnormality is an alteration of chromosome 11. In some embodiments, the at least one genetic abnormality is a mutation of fms-related tyrosine kinase 3 (FLT3). In some embodiments, the at least one genetic abnormality is a mutation of nucleolar phosphatidylcholine (NPM1). In some embodiments, the at least one genetic abnormality is a mutation of isocitrate dehydrogenase 1 (IDH1). In some embodiments, the at least one genetic abnormality is a mutation of isocitrate dehydrogenase 2 (IDH2). In some embodiments, the at least one genetic abnormality is a mutation of DNA (cytosine-5)-methyltransferase 3 (DNMT3A). In some embodiments, the at least one genetic abnormality is a mutation of CCAAT / enhancer binding protein alpha (CEBPA). In some embodiments, the at least one genetic abnormality is a mutation in U2 small nuclear RNA auxiliary factor 1 (U2AF1). In some embodiments, the at least one genetic abnormality is a mutation in enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2). In some embodiments, the at least one genetic abnormality is a mutation in structural maintenance of chromosome 1A (SMC1A). In some embodiments, the at least one genetic abnormality is a mutation in structural maintenance of chromosome 3 (SMC3).

[0269] In some embodiments, the at least one genetic abnormality is translocation t(8;21)(q22;q22), inversion inv(16)(p13;q22), translocation t(16;16)(p13;q22), translocation t(15;17)(q22;q12), mutation FLT3-ITD in IDH1, mutation R132H or R100Q / R104V / F108L / R119Q / I130V, or mutation R140Q or R172 in IDH2.

[0270] In some embodiments, the at least one genetic abnormality is a translocation t(8;21)(q22;q22). In some embodiments, the at least one genetic abnormality is an inversion inv(16)(p13;q22). In some embodiments, the at least one genetic abnormality is a translocation t(16;16)(p13;q22). In some embodiments, the at least one genetic abnormality is a translocation t(15;17)(q22;q12). In some embodiments, the at least one genetic abnormality is a mutation FLT3-ITD. In some embodiments, the at least one genetic abnormality is a mutation R132H in IDH1. In some embodiments, the at least one genetic abnormality is a mutation R100Q / R104V / F108L / R119Q / I130V in IDH1. In some embodiments, the at least one genetic abnormality is a mutation R140Q in IDH2. In some embodiments, the at least one genetic abnormality is a mutation R172 in IDH2.

[0271] In some embodiments, the hematological malignancy is ALL.

[0272] In some embodiments, the ALL is B-cell lineage ALL, T-cell lineage ALL, adult ALL, or pediatric ALL.

[0273] In some embodiments, ALL is B cell lineage ALL. In some embodiments, ALL is T cell lineage ALL. In some embodiments, ALL is adult ALL. In some embodiments, ALL is pediatric ALL.

[0274] In some embodiments, the subject with ALL has a Philadelphia chromosome or exhibits or has acquired resistance to treatment with a BCR-ABL kinase inhibitor.

[0275] In some embodiments, the subject with ALL has a Philadelphia chromosome. In some embodiments, the subject with ALL exhibits or has acquired resistance to treatment with a BCR-ABL kinase inhibitor.

[0276] Ph chromosomes are present in about 20% of adults with ALL and a small portion of children with ALL and are associated with a poor prognosis. At relapse, Ph+ positive ALL patients may take a tyrosine kinase inhibitor (TKI) regimen and may therefore become resistant to TKIs. Therefore, anti-CD38 antibodies may be administered to subjects who have become resistant to selective or partially selective BCR-ABL inhibitors. Exemplary BCR-ABL inhibitors are, for example, imatinib, dasatinib, nilotinib, bosutinib, ponatinib, barfitinib, sacatinib, tauzacer or daruselta.

[0277] Other chromosomal rearrangements identified in patients with B-lineage ALL are t(v;11q23)(MLL rearrangement), t(1;19)(q23;p13.3); TCF3-PBX1(E2A-PBX1), t(12;21)(p13;q22); ETV6-RUNX1(TEL-AML1), and t(5;14)(q31;q32); IL3-IGH.

[0278] In some embodiments, the subject with ALL has t(v;11q23)(MLL rearrangement), t(1;19)(q23;p13.3); TCF3-PBX1(E2A-PBX1), t(12;21)(p13;q22); ETV6-RUNX1(TEL-AML1), or t(5;14)(q31;q32); IL3-IGH chromosome rearrangement.

[0279] Chromosomal rearrangements can be identified using well-known methods, such as fluorescence in situ hybridization, karyotyping, pulsed-field gel electrophoresis, or sequencing.

[0280] In some embodiments, the hematological malignancy is smoldering multiple myeloma.

[0281] In some embodiments, the hematological malignancy is MGUS.

[0282] In some embodiments, the hematological malignancy is ALL.

[0283] In some embodiments, the hematological malignancy is DLBLC.

[0284] In some embodiments, the hematological malignancy is BL.

[0285] In some embodiments, the hematological malignancy is FL.

[0286] In some embodiments, the hematological malignancy is MCL.

[0287] In some embodiments, the hematological malignancy is Waldenstrom's macroglobulinemia.

[0288] In some embodiments, the hematological malignancy is plasma cell leukemia.

[0289] In some embodiments, the hematological malignancy is AL.

[0290] In some embodiments, the hematological malignancy is precursor B-cell lymphoblastic leukemia.

[0291] In some embodiments, the hematological malignancy is precursor B-cell lymphoblastic leukemia.

[0292] In some embodiments, the hematological malignancy is myelodysplastic syndrome (MDS).

[0293] In some embodiments, the hematological malignancy is CLL.

[0294] In some embodiments, the hematological malignancy is a B-cell malignancy.

[0295] In some embodiments, the hematological malignancy is CML.

[0296] In some embodiments, the hematological malignancy is HCL.

[0297] In some embodiments, the hematological malignancy is blastic plasmacytoid dendritic cell neoplasm.

[0298] In some embodiments, the hematological malignancy is Hodgkin's lymphoma.

[0299] In some embodiments, the hematological malignancy is non-Hodgkin's lymphoma.

[0300] In some embodiments, the hematological malignancy is MZL.

[0301] In some embodiments, the hematological malignancy is MALT.

[0302] In some embodiments, the hematological malignancy is plasma cell leukemia.

[0303] In some embodiments, the hematological malignancy is ALCL.

[0304] In some embodiments, the hematological malignancy is leukemia.

[0305] In some embodiments, the hematological malignancy is lymphoma.

[0306] In some embodiments, the solid tumor is prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), liver cancer, cervical cancer, colon cancer, breast cancer, ovarian cancer, endometrial cancer, pancreatic cancer, melanoma, esophageal cancer, gastric cancer, stomach cancer, kidney cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, urothelial carcinoma, head and neck cancer, glioma, glioblastoma, colorectal cancer, thyroid cancer, epithelial cancer, adenocarcinoma, or an advanced solid tumor.

[0307] In some embodiments, the solid tumor is prostate cancer.

[0308] In some embodiments, the solid tumor is lung cancer.

[0309] In some embodiments, the solid tumor is non-small cell lung cancer (NSCLC).

[0310] In some embodiments, the solid tumor is liver cancer.

[0311] In some embodiments, the solid tumor is cervical cancer.

[0312] In some embodiments, the solid tumor is colon cancer.

[0313] In some embodiments, the solid tumor is breast cancer.

[0314] In some embodiments, the solid tumor is ovarian cancer.

[0315] In some embodiments, the solid tumor is endometrial cancer.

[0316] In some embodiments, the solid tumor is pancreatic cancer.

[0317] In some embodiments, the solid tumor is melanoma.

[0318] In some embodiments, the solid tumor is esophageal cancer.

[0319] In some embodiments, the solid tumor is gastric cancer.

[0320] In some embodiments, the solid tumor is gastric cancer.

[0321] In some embodiments, the solid tumor is renal cancer.

[0322] In some embodiments, the solid tumor is bladder cancer.

[0323] In some embodiments, the solid tumor is hepatocellular carcinoma.

[0324] In some embodiments, the solid tumor is renal cell carcinoma.

[0325] In some embodiments, the solid tumor is urothelial carcinoma.

[0326] In some embodiments, the solid tumor is head and neck cancer.

[0327] In some embodiments, the solid tumor is a glioma.

[0328] In some embodiments, the solid tumor is a glioblastoma.

[0329] In some embodiments, the solid tumor is colorectal cancer.

[0330] In some embodiments, the solid tumor is thyroid cancer.

[0331] In some embodiments, the solid tumor is an epithelial cancer.

[0332] In some embodiments, the solid tumor is an adenocarcinoma.

[0333] In some embodiments, the solid tumor is an advanced solid tumor.

[0334] In some embodiments, the prostate cancer is recurrent prostate cancer, refractory prostate cancer, malignant prostate cancer, or castration-resistant prostate cancer, or any combination thereof.

[0335] In some embodiments, the prostate cancer is recurrent prostate cancer. In some embodiments, the prostate cancer is refractory prostate cancer. In some embodiments, the prostate cancer is malignant prostate cancer. In some embodiments, the prostate cancer is castration-resistant prostate cancer.

[0336] In some embodiments, the anti-CD38 antibody comprises HCDR1 of SEQ ID NO:6, HCDR2 of SEQ ID NO:7, HCDR3 of SEQ ID NO:8, LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10, and LCDR3 of SEQ ID NO:11.

[0337] In some embodiments, the anti-CD38 antibody comprises the VH of SEQ ID NO:4 and the VL of SEQ ID NO:5.

[0338] In some embodiments, the anti-CD38 antibody is of the IgG1 isotype.

[0339] In some embodiments, the anti-CD38 antibody comprises the HC of SEQ ID NO:12 and the LC of SEQ ID NO:13.

[0340] Other anti-CD38 antibodies used in the methods of the present invention may be known antibodies, such as mAb003, which comprises the VH and VL sequences of SEQ ID NOs: 14 and 15, respectively, and is described in U.S. Pat. No. 7,829,673. The VH and VL of mAb003 may be expressed as IgG1 / κ; mAb024, which comprises the VH and VL sequences of SEQ ID NOs: 16 and 17, respectively, and is described in U.S. Pat. No. 7,829,673. The VH and VL of mAb024 may be expressed as IgG1 / κ; MOR-202 (MOR-03087), which comprises the VH and VL sequences of SEQ ID NOs: 18 and 19, respectively, and is described in U.S. Pat. No. 8,088,896. The VH and VL of MOR-202 may be expressed as IgG1 / κ; or isatuximab; comprising the VH and VL sequences of SEQ ID NOs: 20 and 21, respectively, described in U.S. Patent No. 8,153,765. The VH and VL of isatuximab may be expressed as IgG1 / κ.

[0341] SEQ ID NO:4 (Daratumumab VH)

[0342] EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQAPGKGLEWVSAISGSGGGTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCAKDKILWFGEPVFDYWGQGTLVTVSS

[0343] SEQ ID NO: 5 (Daratumumab VL)

[0344] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPTFGQGTKVEIK

[0345] SEQ ID NO:6 (Daratumumab HCDR1)

[0346] SFAMS

[0347] SEQ ID NO:7 (Daratumumab HCDR2)

[0348] AISGSGGGTYYADSVKG

[0349] SEQ ID NO: 8 (Daratumumab HCDR3)

[0350] DKILWFGEPVFDY

[0351] SEQ ID NO:9 (Daratumumab LCDR1)

[0352] RASQSVSSYLA

[0353] SEQ ID NO: 10 (Daratumumab LCDR2)

[0354] DASNRAT

[0355] SEQ ID NO: 11 (Daratumumab LCDR3)

[0356] QQRSNWPPTF

[0357] SEQ ID NO: 12 (Daratumumab HC)

[0358] EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQAPGKGLEWVSAISGSGGGTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCAKDKILWFGEPVFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0359] SEQ ID NO: 13 (Daratumumab LC)

[0360] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0361] SEQ ID NO:14

[0362] QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAFSWVRQAPGQGLEWMGRVIPFLGIANSAQKFQGRVTITADKSTSTAYMDLSSLRSEDTAVYYCARDDIAALGPFDYWGQGTLVTVSSAS

[0363] SEQ ID NO:15

[0364] DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQKPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPRTFGQGTKVEIK

[0365] SEQ ID NO:16

[0366] EVQLVQSGAEVKKPGESLKISCKGSGYSFSNYWIGWVRQMPGKGLEWMGIIYPHDSDARYSPSFQGQVTFSADKSISTAYLQWSSLKASDTAMYYCARHVGWGSRYWYFDLWGRGTLVTVSS

[0367] SEQ ID NO:17

[0368] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPGLLIYDASNRASGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK

[0369] SEQ ID NO:18

[0370] QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMNWVRQAPGKGLEWVSGISGDPSNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDLPLVYTGFAYWGQGTLVTVSS

[0371] SEQ ID NO:19

[0372] DIELTQPPSVSVAPGQTARISCSGDNLRHYYVYWYQQKPGQAPVLVIYGDSKRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQTYTGGASLVFGGGTKLTVLGQ

[0373] SEQ ID NO:20 :

[0374] QVQLVQSGAEVAKPGTSVKLSCKASGYTFTDYWMQWVKQRPGQGLEWIGTIYPGDGDTGYAQKFQGKATLTADKSSKTVYMHLSSLASEDSAVYYCARGDYYGSNSLDYWGQGTSVTVSS

[0375] SEQ ID NO:21 :

[0376] DIVMTQSHLSMSTSLGDPVSITCKASQDVSTVVAWYQQKPGQSPRRLIYSASYRYIGVPDRFTGSGAGTDFTFTISSVQAEDLAVYYCQQHYSPPYTFGGGTKLEIK

[0377] In some embodiments, the anti-CD38 antibody comprises:

[0378] VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15;

[0379] VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17;

[0380] VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19; or

[0381] VH of SEQ ID NO:20 and VL of SEQ ID NO:21.

[0382] In some embodiments, the anti-CD38 antibody is of the IgG1 isotype.

[0383] In some embodiments, the T cell redirecting therapeutic is a BCMA×CD3 bispecific antibody, a GPRC5D×CD3 bispecific antibody, a CD33×CD3 bispecific antibody, a CD19×CD3 bispecific antibody, a CD123×CD3 bispecific antibody, a PSMA×CD3 bispecific antibody, or a TMEFF2×CD3 bispecific antibody.

[0384] In some embodiments, the T cell redirecting therapeutic is a BCMA×CD3 bispecific antibody.

[0385] In some embodiments, the T cell redirecting therapeutic is a GPRC5D×CD3 bispecific antibody.

[0386] In some embodiments, the T cell redirecting therapeutic is a CD33×CD3 bispecific antibody,

[0387] In some embodiments, the T cell redirecting therapeutic is a CD19×CD3 bispecific antibody.

[0388] In some embodiments, the T cell redirecting therapeutic is a CD123×CD3 bispecific antibody.

[0389] In some embodiments, the T cell redirecting therapeutic is a PSMA×CD3 bispecific antibody.

[0390] In some embodiments, the T cell redirecting therapeutic is a TMEFF2×CD3 bispecific antibody.

[0391] In some embodiments, the method further comprises administering to the subject one or more anti-cancer therapies.

[0392] In some embodiments, the one or more anti-cancer therapies are selected from autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulators, and targeted cancer therapies.

[0393] In some embodiments, the one or more anticancer therapies are autologous stem cell transplantation (ASCT). In some embodiments, the one or more anticancer therapies are radiation. In some embodiments, the one or more anticancer therapies are surgery. In some embodiments, the one or more anticancer therapies are chemotherapeutic agents. In some embodiments, the one or more anticancer therapies are immunomodulators. In some embodiments, the one or more anticancer therapies are targeted cancer therapies.

[0394] In some embodiments, the one or more anti-cancer therapies are selected from lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, elotozumab, ixazomib, melphalan, dexamethasone, vincristine, cyclophosphamide, hydroxydaunorubicin, prednisone, rituximab, imatinib, dasatinib, nilotinib, bosutinib, ponatinib, bafitinib, sacatinib, tauzerti or darusertib, cytarabine, daunorubicin, idarubicin, mitoxantrone, hydroxyurea, decitabine, cladribine, fludarabine, topotecan, etoposide 6-thioguanine, corticosteroids, methotrexate, 6-mercaptopurine, azacitidine, arsenic trioxide and all-trans retinoic acid, or any combination thereof.

[0395] In some embodiments, the anti-CD38 antibody is administered at a dose of between about 8 mg / kg to about 16 mg / kg.

[0396] In some embodiments, the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising between about 20 mg / mL to about 120 mg / mL of the anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mannitol, and about 0.04% w / v polysorbate-20 (PS-20); pH is about 5.5.

[0397] In some embodiments, the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising about 1,800 mg of the anti-CD38 antibody and about 30,000 U of rHuPH20.

[0398] In some embodiments, the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising about 120 mg / mL of the anti-CD38 antibody and about 2,000 U / mL of rHuPH20.

[0399] In some embodiments, the CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising

[0400] between about 5 mM to about 15 mM histidine;

[0401] between about 100 mM and about 300 mM sorbitol;

[0402] Between about 0.01% w / v to about 0.04% w / v PS-20; and

[0403] Between about 1 mg / mL to about 2 mg / mL methionine, pH about 5.5 to 5.6.

[0404] In some embodiments, the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising

[0405] About 1,800 mg of anti-CD38 antibody;

[0406] About 30,000U of rHuPH20;

[0407] About 10 mM histidine;

[0408] About 300 mM sorbitol;

[0409] About 0.04% (w / v) PS-20; and

[0410] About 1 mg / mL of methionine, pH about 5.6.

[0411] In some embodiments, the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising

[0412] about 120 mg / mL of anti-CD38 antibody;

[0413] About 2,000 U / mL of rHuPH20;

[0414] About 10 mM histidine;

[0415] About 300 mM sorbitol;

[0416] About 0.04% (w / v) PS-20; and

[0417] About 1 mg / mL of methionine, pH about 5.6.

[0418] Combination of anti-CD38 antibody and BCMA×CD3 bispecific antibody

[0419] The present disclosure also provides a method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a BCMA×CD3 bispecific antibody and an anti-CD38 antibody to treat the cancer.

[0420] The present disclosure also provides a method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a BCMA×CD3 bispecific antibody to treat the cancer, wherein the subject has been treated with an anti-CD38 antibody prior to administering the BCMA×CD3 bispecific antibody.

[0421] The present disclosure also provides a method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a BCMA×CD3 bispecific antibody to treat the cancer, wherein the subject is relapsed or refractory to treatment with a previous anti-cancer therapeutic.

[0422] T cell redirecting therapeutics such as BCMA×CD3 bispecific antibodies (such as JNJ-957) redirect T cells to BCMA-positive tumor cells (such as multiple myeloma cells), followed by perforin / granzyme release or activation of the FASL / FAS pathway, and ultimately leading to BCMA-positive tumor cell death. Therefore, the efficacy of T cell redirecting therapeutics such as BCMA×CD3 bispecific antibodies may be affected by the availability and activity of recruited T cells, as well as by the possible regulated expression of tumor-associated antigens such as BCMA on tumor cells.

[0423] In some embodiments, the cancer is a BCMA-expressing cancer.

[0424] B cell maturation antigen (BCMA) is a cell membrane-bound tumor necrosis factor receptor family member that participates in the differentiation of B cells into plasma cells. The expression of BCMA is limited to the B cell lineage, where BCMA is mainly expressed in the interfollicular region of the germinal center and expressed on differentiated plasma cells and plasmablasts. BCMA is almost absent on naive and memory B cells (Tai and Anderson, Immunotherapy, Vol. 7, pp. 1187-1199, 2015).

[0425] In some embodiments, the cancer is a hematological malignancy.

[0426] In some embodiments, the cancer is multiple myeloma, smoldering myeloma, monoclonal gammopathy of undetermined significance (MGUS), B-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, mantle cell lymphoma, Waldenstrom's macroglobulinemia, plasma cell leukemia, light chain amyloidosis, or non-Hodgkin's lymphoma. An experienced physician will make the diagnosis of cancer.

[0427] In some embodiments, the subject is relapsed or refractory to treatment with an anti-CD38 antibody or lenalidomide, or a combination thereof.

[0428] In some embodiments, the subject is relapsed or refractory to treatment with an anti-CD38 antibody. In some embodiments, the subject is relapsed or refractory to treatment with lenalidomide.

[0429] In some embodiments, the subject is relapsed or refractory to treatment with a prior anti-cancer therapeutic, such as a therapeutic used to treat multiple myeloma or other hematological malignancies.

[0430] In some embodiments, the subject is (thalidomide), (lenalidomide), (Pomalidomide), (bortezomib), NINLARO (esazomib), (Carfilzomib), (Pabinostat), (pamidronic acid), (zoledronic acid), Patients with relapsed or refractory disease have been treated with daratumumab, elotozumab, and melphalan.

[0431] In some embodiments, the subject is (daratumumab) for treatment is recurrent.

[0432] In some embodiments, the BCMA×CD3 bispecific antibody and the anti-CD38 antibody are antigen-binding fragments. Exemplary antigen-binding fragments are Fab, F(ab')2, Fd, and Fv fragments.

[0433] In some embodiments, the BCMA×CD3 bispecific antibody is chimeric, humanized, or human.

[0434] In some embodiments, the BCMA×CD3 bispecific antibody is of IgG1, IgG2, IgG3, or IgG4 isotype.

[0435] In some embodiments, the BCMA×CD3 bispecific antibody is of the IgG4 isotype.

[0436] In some embodiments, the BCMA×CD3 bispecific antibody comprises a BCMA binding domain comprising HCDR1 of SEQ ID NO:23, HCDR2 of SEQ ID NO:24, HCDR3 of SEQ ID NO:25, LCDR1 of SEQ ID NO:26, LCDR2 of SEQ ID NO:27, and LCDR3 of SEQ ID NO:28, and the CD3 binding domain comprises HCDR1 of SEQ ID NO:33, HCDR2 of SEQ ID NO:34, HCDR3 of SEQ ID NO:35, LCDR1 of SEQ ID NO:36, LCDR2 of SEQ ID NO:37, and LCDR3 of SEQ ID NO:38.

[0437] In some embodiments, the BCMA binding domain comprises the VH of SEQ ID NO:29 and the VL of SEQ ID NO:30, and the CD3 binding domain comprises the VH of SEQ ID NO:39 and the VL of SEQ ID NO:40.

[0438] In some embodiments, the BCMA×CD3 bispecific antibody is of the IgG4 isotype and comprises a phenylalanine at position 405 and an arginine at position 409 in the first heavy chain (HC1) and a leucine at position 405 and a lysine at position 409 in the second heavy chain (HC2), wherein the residues are numbered according to the EU index.

[0439] In some embodiments, the BCMA×CD3 bispecific antibody further comprises a proline at position 228, an alanine at position 234, and an alanine at position 235 in both HC1 and HC2.

[0440] In some embodiments, the BCMA×CD3 bispecific antibody comprises HC1 of SEQ ID NO:31, a first light chain (LC1) of SEQ ID NO:32, HC2 of SEQ ID NO:41, and a second light chain (LC2) of SEQ ID NO:42.

[0441] In some embodiments, the BCMA×CD3 bispecific antibody is BI 836909, PF-06863135, AMG-701, or CC-93269.

[0442] In some embodiments, the anti-CD38 antibody comprises HCDR1 of SEQ ID NO:6, HCDR2 of SEQ ID NO:7, HCDR3 of SEQ ID NO:8, LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10, and LCDR3 of SEQ ID NO:11.

[0443] In some embodiments, the anti-CD38 antibody comprises the VH of SEQ ID NO:4 and the VL of SEQ ID NO:5.

[0444] In some embodiments, the anti-CD38 antibody comprises the heavy chain (HC) of SEQ ID NO:12 and the light chain (LC) of SEQ ID NO:13.

[0445] In some embodiments, the anti-CD38 antibody is (Daratumumab).

[0446] In some embodiments, the anti-CD38 antibody comprises:

[0447] VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15;

[0448] VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17;

[0449] VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19; or

[0450] VH of SEQ ID NO:20 and VL of SEQ ID NO:21.

[0451] In some embodiments, the anti-CD38 antibody is chimeric, humanized, or human.

[0452] In some embodiments, the anti-CD38 antibody is of the IgG1, IgG2, IgG3, or IgG4 isotype.

[0453] In some embodiments, the anti-CD38 antibody is of the IgG1 isotype.

[0454] In some embodiments, the anti-CD38 antibody is administered at a dose of between about 8 mg / kg to about 16 mg / kg.

[0455] In some embodiments, the BCMA×CD3 bispecific antibody and the anti-CD38 antibody are administered by intravenous injection.

[0456] In some embodiments, the BCMA×CD3 bispecific antibody is administered by intravenous injection and the anti-CD38 antibody is administered by subcutaneous injection.

[0457] In some embodiments, the BCMA×CD3 bispecific antibody and the anti-CD38 antibody are administered by subcutaneous injection.

[0458] In some embodiments, the method further comprises administering to the subject one or more anti-cancer therapies.

[0459] In some embodiments, the one or more anti-cancer therapies are selected from autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulators, and targeted cancer therapies.

[0460] In some embodiments, the one or more anti-cancer therapies are selected from lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, elotozumab, ixazomib, melphalan, prednisone, or dexamethasone, or any combination thereof.

[0461] In some embodiments, the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising between about 20 mg / mL to about 120 mg / mL of the anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mannitol, and about 0.04% w / v polysorbate-20 (PS-20); pH is about 5.5.

[0462] In some embodiments, the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising about 1,800 mg of the anti-CD38 antibody and about 30,000 U of rHuPH20.

[0463] In some embodiments, the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising about 120 mg / mL of the anti-CD38 antibody and about 2,000 U / mL of rHuPH20.

[0464] In some embodiments, the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising

[0465] between about 5 mM to about 15 mM histidine;

[0466] between about 100 mM and about 300 mM sorbitol;

[0467] Between about 0.01% w / v to about 0.04% w / v PS-20; and

[0468] Between about 1 mg / mL to about 2 mg / mL methionine, pH about 5.5 to 5.6.

[0469] In some embodiments, the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising

[0470] About 1,800 mg of anti-CD38 antibody;

[0471] About 30,000U of rHuPH20;

[0472] About 10 mM histidine;

[0473] About 300 mM sorbitol;

[0474] About 0.04% (w / v) PS-20; and

[0475] About 1 mg / mL of methionine, pH about 5.6.

[0476] In some embodiments, the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising

[0477] about 120 mg / mL of anti-CD38 antibody;

[0478] About 2,000 U / mL of rHuPH20;

[0479] About 10 mM histidine;

[0480] About 300 mM sorbitol;

[0481] About 0.04% (w / v) PS-20; and

[0482] About 1 mg / mL of methionine, pH about 5.6.

[0483] The dose of the BCMA×CD3 bispecific antibody and the anti-CD38 antibody administered to a subject having cancer (such as multiple myeloma) is sufficient to alleviate or at least partially inhibit the disease being treated (a "therapeutically effective amount") and includes about 0.005 mg / kg to about 100 mg / kg of the antibody, for example, about 0.05 mg / kg to about 30 mg / kg, or about 5 mg / kg to about 25 mg / kg, or about 4 mg / kg, about 8 mg / kg, about 16 mg / kg, or about 24 mg / kg. Suitable dosages include, for example, about 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 30 mg / kg, 40 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, or 100 mg / kg.

[0484] A fixed unit dose of BCMA×CD3 bispecific antibody and / or anti-CD38 antibody may also be administered, such as 50 mg, 100 mg, 200 mg, 500 mg, or 1000 mg, or the dose may be based on the surface area of ​​the patient, such as 500 mg / m 2 , 400mg / m 2 , 300mg / m 2 , 250mg / m 2 , 200mg / m 2 or 100 mg / m 2 Typically between 1 and 8 doses (e.g., 1, 2, 3, 4, 5, 6, 7, or 8) may be administered to treat cancers such as multiple myeloma, but 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more doses may be given.

[0485] The BCMA×CD3 bispecific antibody and / or anti-CD38 antibody can be administered repeatedly after one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, one month, five weeks, six weeks, seven weeks, two months, three months, four months, five months, six months or more. The course of treatment can also be repeated, as in chronic administration. Repeated administration can be the same dose or different doses. For example, the BCMA×CD3 bispecific antibody and anti-CD38 antibody can be administered by intravenous infusion at 8 mg / kg or at 16 mg / kg at weekly intervals for 8 weeks, followed by 8 mg / kg or at 16 mg / kg once every two weeks for another 16 weeks, and then 8 mg / kg or at 16 mg / kg once every four weeks.

[0486] The BCMA×CD3 bispecific antibody and the anti-CD38 antibody can be administered by maintenance therapy, such as, for example, once a week for 6 months or longer. For example, the BCMA×CD3 bispecific antibody and the anti-CD38 antibody can be administered on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 13, day 14, day 15, day 16, day 17, day 18, day 19, day 20, day 21, day 22, day 23, day 24, day 25, day 26, day 27, day 28, day 29, day 30, day 31, day 32, day 33, day 34, day 35, day 36, day 37, day 38, day 39, day 40, day 41, day 42, day 43, day 44, day 45, day 46, day 47, day 48, day 49, day 50, day 51, day 52, day 53, day 54, day 55 or any combination thereof, in a single dose or in a regimen of once every 24 hours, every 12 hours, every 8 hours, every 6 hours, every 4 hours, or every 2 hours. The invention can be used in divided doses or any combination thereof in an amount of about 0.1 mg / kg to about 100 mg / kg as a daily dose (such as 0.5 mg / kg, 0.9 mg / kg, 1.0 mg / kg, 1.1 mg / kg, 1.5 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg per day). kg, 16mg / kg, 17mg / kg, 18mg / kg, 19mg / kg, 20mg / kg, 21mg / kg, 22mg / kg, 23mg / kg, 24mg / kg, 25mg / kg, 26mg / kg, 27mg / kg, 28mg / kg, 29mg / kg, 30mg / kg, 40mg / kg, 45mg / kg, 50mg / kg, 60mg / kg, 70mg / kg, 80mg / kg, 90mg / kg or 100mg / kg).

[0487] The BCMA×CD3 bispecific antibody and anti-CD38 antibody can also be administered prophylactically to reduce the risk of developing cancer (such as multiple myeloma), delay the onset of an event in cancer progression, and / or reduce the risk of relapse after cancer remission.

[0488] In some embodiments, the BCMA×CD3 bispecific antibody is administered to the subject after the anti-CD38 antibody is administered to the subject. The BCMA×CD3 bispecific antibody can be administered one week, two weeks, three weeks, one month, five weeks, six weeks, seven weeks, two months, three months, four months, five months, six months, or more after the administration of the anti-CD38 antibody. In some embodiments, the subject administered the BCMA×CD3 antibody is resistant and / or refractory to treatment with the anti-CD38 antibody.

[0489] The present invention also provides a pharmaceutical composition comprising a BCMA×CD3 bispecific antibody and an anti-CD38 antibody, the BCMA×CD3 bispecific antibody comprising a BCMA binding domain and a CD3 binding domain, the BCMA binding domain comprising VH of SEQ ID NO:29 and VL of SEQ ID NO:30, the CD3 binding domain comprising VH of SEQ ID NO:39 and VL of SEQ ID NO:40, and the anti-CD38 antibody comprising VH of SEQ ID NO:4 and VL of SEQ ID NO:5.

[0490] In some embodiments, the pharmaceutical composition comprises a BCMA×CD3 bispecific antibody and an anti-CD38 antibody, the BCMA×CD3 bispecific antibody comprising HC1 of SEQ ID NO:31, LC1 of SEQ ID NO:32, HC2 of SEQ ID NO:41, and LC2 of SEQ ID NO:42, and the anti-CD38 antibody comprises HC of SEQ ID NO:12 and LC of SEQ ID NO:13.

[0491] In some embodiments, the pharmaceutical composition is a non-fixed combination.

[0492] In some embodiments, the pharmaceutical composition comprises about 20 mg / mL to about 120 mg / mL of anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mannitol, and about 0.04% w / v polysorbate-20 (PS-20); pH is about 5.5.

[0493] The BCMA×CD3 bispecific antibody can be formulated as a pharmaceutical composition comprising about 20 mg / mL to about 120 mg / mL of the antibody, acetic acid, histidine, sodium chloride, mannitol, and / or polysorbate-20.

[0494] In some embodiments, the pharmaceutical composition comprises about 1,800 mg of an anti-CD38 antibody and about 30,000 U of rHuPH20.

[0495] In some embodiments, the pharmaceutical composition comprises about 120 mg / mL of an anti-CD38 antibody and about 2,000 U / mL of rHuPH20.

[0496] In some embodiments, the pharmaceutical composition further comprises one or more excipients.

[0497] In some embodiments, the one or more excipients are histidine, methionine, sorbitol, or polysorbate-20 (PS-20), or any combination thereof.

[0498] In some embodiments, the pharmaceutical composition comprises

[0499] between about 100 mg / mL to about 120 mg / mL of an anti-CD38 antibody formulated in between about 5 mM to about 15 mM histidine;

[0500] between about 100 mM and about 300 mM sorbitol;

[0501] Between about 0.01% w / v to about 0.04% w / v PS-20; and

[0502] Between about 1 mg / mL to about 2 mg / mL methionine, pH about 5.5 to 5.6.

[0503] In some embodiments, the pharmaceutical composition comprises about 10 mM histidine.

[0504] In some embodiments, the pharmaceutical composition comprises about 300 mM sorbitol.

[0505] In some embodiments, the pharmaceutical composition comprises about 0.04% (w / v) PS-20.

[0506] In some embodiments, the pharmaceutical composition comprises about 1 mg / mL of methionine.

[0507] In some embodiments, the pharmaceutical composition comprises

[0508] About 1,800 mg of anti-CD38 antibody;

[0509] About 30,000U of rHuPH20;

[0510] About 10 mM histidine;

[0511] About 300 mM sorbitol;

[0512] About 0.04% (w / v) PS-20; and

[0513] About 1 mg / mL of methionine, pH about 5.6.

[0514] In some embodiments, the pharmaceutical composition comprises

[0515] about 120 mg / mL of anti-CD38 antibody;

[0516] About 2,000 U / mL of rHuPH20;

[0517] About 10 mM histidine;

[0518] About 300 mM sorbitol;

[0519] About 0.04% (w / v) PS-20; and

[0520] About 1 mg / mL of methionine, pH about 5.6.

[0521] The present disclosure also provides a kit comprising a pharmaceutical composition comprising a BCMA×CD3 bispecific antibody and an anti-CD38 antibody.

[0522] Treatment of relapsed or refractory subjects with BCMA×CD3 bispecific antibody

[0523] The present disclosure also provides a method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a BCMA×CD3 bispecific antibody to treat the cancer, wherein the subject is relapsed or refractory to treatment with a previous anti-cancer therapeutic.

[0524] In some embodiments, the BCMA×CD3 bispecific antibody comprises a BCMA binding domain comprising HCDR1 of SEQ ID NO:23, HCDR2 of SEQ ID NO:24, HCDR3 of SEQ ID NO:25, LCDR1 of SEQ ID NO:26, LCDR2 of SEQ ID NO:27, and LCDR3 of SEQ ID NO:28, and the CD3 binding domain comprises HCDR1 of SEQ ID NO:33, HCDR2 of SEQ ID NO:34, HCDR3 of SEQ ID NO:35, LCDR1 of SEQ ID NO:36, LCDR2 of SEQ ID NO:37, and LCDR3 of SEQ ID NO:38.

[0525] In some embodiments, the BCMA binding domain comprises the VH of SEQ ID NO:29 and the VL of SEQ ID NO:30, and the CD3 binding domain comprises the VH of SEQ ID NO:39 and the VL of SEQ ID NO:40.

[0526] In some embodiments, the BCMA×CD3 bispecific antibody is of the IgG4 isotype and comprises a phenylalanine at position 405 and an arginine at position 409 in HC1 and a leucine at position 405 and a lysine at position 409 in HC2, wherein the residues are numbered according to the EU index.

[0527] In some embodiments, the BCMA×CD3 bispecific antibody further comprises a proline at position 228, an alanine at position 234, and an alanine at position 235 in both HC1 and HC2.

[0528] In some embodiments, the BCMA×CD3 bispecific antibody comprises HC1 of SEQ ID NO:31, LC1 of SEQ ID NO:32), HC2 of SEQ ID NO:41, and LC2 of SEQ ID NO:42.

[0529] In some embodiments, the cancer is a hematological malignancy.

[0530] In some embodiments, the hematological malignancy is multiple myeloma.

[0531] In some embodiments, the multiple myeloma is high-risk multiple myeloma.

[0532] In some embodiments, the subject with high-risk multiple myeloma has one or more chromosomal abnormalities comprising:

[0533] t(4;14)(p16;q32);

[0534] t(14;16)(q32;q23);

[0535] del17p;

[0536] 1qAmp;

[0537] t(4;14)(p16;q32) and t(14;16)(q32;q23);

[0538] t(4;14)(p16;q32) and del17p;

[0539] t(14;16)(q32;q23) and del17p; or

[0540] t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p or any combination thereof.

[0541] In some embodiments, the subject is relapsed or refractory to treatment with an anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotozumab, ixazomib, melphalan, or thalidomide, or any combination thereof.

[0542] In some embodiments, the subject is relapsed or refractory to treatment with lenalidomide. In some embodiments, the subject is relapsed or refractory to treatment with bortezomib. In some embodiments, the subject is relapsed or refractory to treatment with pomalidomide. In some embodiments, the subject is relapsed or refractory to treatment with carfilzomib. In some embodiments, the subject is relapsed or refractory to treatment with elotozumab. In some embodiments, the subject is relapsed or refractory to treatment with ixazomib. In some embodiments, the subject is relapsed or refractory to treatment with melphalan. In some embodiments, the subject is relapsed or refractory to treatment with thalidomide.

[0543] In some embodiments, the subject is relapsing for treatment with an anti-CD38 antibody.

[0544] In some embodiments, the anti-CD38 antibody comprises HCDR1 of SEQ ID NO:6, HCDR2 of SEQ ID NO:7, HCDR3 of SEQ ID NO:8, LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10, and LCDR3 of SEQ ID NO:11.

[0545] In some embodiments, the anti-CD38 antibody comprises the VH of SEQ ID NO:4 and the VL of SEQ ID NO:5.

[0546] In some embodiments, the anti-CD38 antibody is of the IgG1 isotype.

[0547] In some embodiments, the anti-CD38 antibody comprises the HC of SEQ ID NO:12 and the LC of SEQ ID NO:13.

[0548] In some embodiments, the anti-CD38 antibody comprises:

[0549] VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15;

[0550] VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17;

[0551] VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19; or

[0552] VH of SEQ ID NO:20 and VL of SEQ ID NO:21.

[0553] In some embodiments, the anti-CD38 antibody is of the IgG1 isotype.

[0554] In some embodiments, the subject is a human.

[0555] In some embodiments, the method further comprises administering to the subject one or more anti-cancer therapies.

[0556] In some embodiments, the one or more anti-cancer therapies are selected from autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulators, and targeted cancer therapies.

[0557] In some embodiments, the one or more anti-cancer therapies are selected from lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, elotozumab, ixazomib, melphalan, prednisone, or dexamethasone, or any combination thereof.

[0558] Combination therapy with a T cell redirecting therapeutic agent that binds GPRC5D and an anti-CD38 antibody

[0559] The present disclosure also provides a method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a T cell redirecting therapeutic agent that binds GPRC5D and an anti-CD38 antibody to treat the cancer.

[0560] In some embodiments, an anti-CD38 antibody is administered to a subject prior to administration of a T cell redirecting therapeutic that binds GPRC5D.

[0561] In some embodiments, the subject is relapsed or refractory to treatment with a prior anti-cancer therapeutic.

[0562] In some embodiments, the cancer is a GPRC5D-expressing cancer.

[0563] In some embodiments, the GPRC5D-expressing cancer is a hematological malignancy or a solid tumor.

[0564] In some embodiments, the hematological malignancy is leukemia, lymphoma, or multiple myeloma.

[0565] In some embodiments, the hematological malignancy is a leukemia. In some embodiments, the hematological malignancy is a lymphoma. In some embodiments, the hematological malignancy is multiple myeloma.

[0566] In some embodiments, the solid tumor is ovarian cancer, lung cancer, stomach cancer, prostate cancer, kidney cancer, liver cancer, pancreatic cancer, colon cancer, esophageal cancer, bladder cancer, cervical tumor, or malignant melanoma.

[0567] GPRC5D has been disclosed as being expressed in these tumors, see, e.g., International Patent Publication No. WO2018 / 147245.

[0568] In some embodiments, the subject is relapsed or refractory to treatment with an anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotozumab, ixazomib, melphalan, or thalidomide, or any combination thereof.

[0569] In some embodiments, the subject is relapsed or refractory to treatment with lenalidomide. In some embodiments, the subject is relapsed or refractory to treatment with bortezomib. In some embodiments, the subject is relapsed or refractory to treatment with pomalidomide. In some embodiments, the subject is relapsed or refractory to treatment with carfilzomib. In some embodiments, the subject is relapsed or refractory to treatment with elotozumab. In some embodiments, the subject is relapsed or refractory to treatment with ixazomib. In some embodiments, the subject is relapsed or refractory to treatment with melphalan. In some embodiments, the subject is relapsed or refractory to treatment with thalidomide. In some embodiments, the subject is relapsed or refractory to treatment with an anti-CD38 antibody.

[0570] In some embodiments, the multiple myeloma is newly diagnosed multiple myeloma.

[0571] In some embodiments, the multiple myeloma is relapsed or refractory multiple myeloma.

[0572] In some embodiments, the multiple myeloma is high-risk multiple myeloma.

[0573] In some embodiments, the subject with high-risk multiple myeloma has one or more chromosomal abnormalities comprising:

[0574] t(4;14)(p16;q32);

[0575] t(14;16)(q32;q23);

[0576] del17p;

[0577] 1qAmp;

[0578] t(4;14)(p16;q32) and t(14;16)(q32;q23);

[0579] t(4;14)(p16;q32) and del17p;

[0580] t(14;16)(q32;q23) and del17p; or

[0581] t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p or any combination thereof.

[0582] In some embodiments, the T cell redirecting therapeutic binds CD3, CD3ε (CD3ε), CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, BTNL8, PD-1, CD195, or NKG2C.

[0583] In some embodiments, the T cell redirecting therapeutic comprises a GPRC5D binding domain and a CD3 binding domain, the GPRC5D binding domain comprising HCDR1 of SEQ ID NO:43, HCDR2 of SEQ ID NO:44, HCDR3 of SEQ ID NO:45, LCDR1 of SEQ ID NO:46, LCDR2 of SEQ ID NO:47, and LCDR3 of SEQ ID NO:48, and the CD3 binding domain comprises HCDR1 of SEQ ID NO:33, HCDR2 of SEQ ID NO:34, HCDR3 of SEQ ID NO:35, LCDR1 of SEQ ID NO:36, LCDR2 of SEQ ID NO:37, and LCDR3 of SEQ ID NO:38.

[0584] In some embodiments, the GPRC5D binding domain comprises the VH of SEQ ID NO:49 and the VL of SEQ ID NO:50, and the CD3 binding domain comprises the VH of SEQ ID NO:39 and the VL of SEQ ID NO:40.

[0585] In some embodiments, the T cell redirecting therapeutic that binds GPRC5C is a multispecific antibody, a CAR, or a T cell expressing a CAR.

[0586] In some embodiments, the multispecific antibody is of the IgG1, IgG2, IgG3, or IgG4 isotype.

[0587] In some embodiments, the multispecific antibody is of IgG1 isotype. In some embodiments, the multispecific antibody is of IgG2 isotype. In some embodiments, the multispecific antibody is of IgG3 isotype. In some embodiments, the multispecific antibody is of IgG4 isotype.

[0588] In some embodiments, the multispecific antibody comprises one or more Fc substitutions that reduce binding of the multispecific antibody to an Fc gamma receptor (FcγR).

[0589] In some embodiments, the one or more Fc substitutions are selected from F234A / L235A on IgG4, L234A / L235A on IgG1, V234A / G237A / P238S / H268A / V309L / A330S / P331S on IgG2, F234A / L235A on IgG4, S228P / F234A / L235A on IgG4, N297A on all Ig isotypes, V234A / G237A on IgG2, K214T / E233P / L234V / L235A / G236-deletion / A327G / P331S on IgG1. A / D365E / L358M on IgG2, H268Q / V309L / A330S / P331S on IgG2, S267E / L328F on IgG1, L234F / L235E / D265A on IgG1, L234A / L235A / G237A / P238S / H268A / A330S / P331S on IgG1, S228P / F234A / L235A / G237A / P238S on IgG4, and S228P / F234A / L235A / G236-deletion / G237A / P238S on IgG4, where the residues are numbered according to the EU index.

[0590] In some embodiments, the multispecific antibody further comprises an S228P substitution.

[0591] In some embodiments, the multispecific antibody comprises one or more asymmetric substitutions in the first CH3 domain or the second CH3 domain, or in both the first CH3 domain and the second CH3 domain.

[0592] In some embodiments, the one or more asymmetric substitutions are selected from F450L / K409R, wild type / F409L_R409K, T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S, and T366W / T366S_L368A_Y407V, L351Y_F405A_Y407V / T394S. 94W, T366I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F and T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W.

[0593] In some embodiments, the multispecific antibody comprises HC1 of SEQ ID NO:51, LC1 of SEQ ID NO:52), HC2 of SEQ ID NO:41, and LC2 of SEQ ID NO:42.

[0594] In some embodiments, the anti-CD38 antibody comprises HCDR1 of SEQ ID NO:6, HCDR2 of SEQ ID NO:7, HCDR3 of SEQ ID NO:8, LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10, and LCDR3 of SEQ ID NO:11.

[0595] In some embodiments, the anti-CD38 antibody comprises the VH of SEQ ID NO:4 and the VL of SEQ ID NO:5.

[0596] In some embodiments, the anti-CD38 antibody is of the IgG1 isotype.

[0597] In some embodiments, the anti-CD38 antibody comprises the HC of SEQ ID NO:12 and the LC of SEQ ID NO:13.

[0598] In some embodiments, the anti-CD38 antibody comprises:

[0599] VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15;

[0600] VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17;

[0601] VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19; or

[0602] VH of SEQ ID NO:20 and VL of SEQ ID NO:21.

[0603] In some embodiments, the anti-CD38 antibody is of the IgG1 isotype.

[0604] In some embodiments, the anti-CD38 antibody is administered at a dose of between about 8 mg / kg to about 16 mg / kg.

[0605] In some embodiments, the T cell redirecting therapeutic that binds GPRC5D and the anti-CD38 antibody are administered by intravenous injection.

[0606] In some embodiments, the T cell redirecting therapeutic that binds GPRC5D is administered by intravenous injection and the anti-CD38 antibody is administered by subcutaneous injection.

[0607] In some embodiments, the T cell redirecting therapeutic that binds GPRC5D and the anti-CD38 antibody are administered by subcutaneous injection.

[0608] In some embodiments, the subject is a human.

[0609] In some embodiments, the T cell redirecting therapeutic that binds GPRC5D is a GPRC5D×CD3 bispecific antibody.

[0610] In some embodiments, the method further comprises administering to the subject one or more anti-cancer therapies.

[0611] In some embodiments, the one or more anti-cancer therapies are selected from autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulators, and targeted cancer therapies.

[0612] In some embodiments, the one or more anti-cancer therapies are selected from lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, elotozumab, ixazomib, melphalan, dexamethasone, or prednisone.

[0613] In some embodiments, the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising between about 20 mg / mL to about 120 mg / mL of the anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mannitol, and about 0.04% w / v polysorbate-20 (PS-20); pH is about 5.5.

[0614] In some embodiments, the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising about 1,800 mg of the anti-CD38 antibody and about 30,000 U of rHuPH20.

[0615] In some embodiments, the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising about 120 mg / mL of the anti-CD38 antibody and about 2,000 U / mL of rHuPH20.

[0616] In some embodiments, the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising

[0617] between about 100 mg / mL to about 120 mg / mL of an anti-CD38 antibody;

[0618] between about 5 mM to about 15 mM histidine;

[0619] between about 100 mM and about 300 mM sorbitol;

[0620] Between about 0.01% w / v to about 0.04% w / v PS-20; and

[0621] Between about 1 mg / mL to about 2 mg / mL methionine, pH about 5.5 to 5.6.

[0622] In some embodiments, the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising

[0623] About 1,800 mg of anti-CD38 antibody;

[0624] About 30,000U of rHuPH20;

[0625] About 10 mM histidine;

[0626] About 300 mM sorbitol;

[0627] About 0.04% (w / v) PS-20; and

[0628] About 1 mg / mL of methionine, pH about 5.6.

[0629] In some embodiments, the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising

[0630] about 120 mg / mL of anti-CD38 antibody;

[0631] About 2,000 U / mL of rHuPH20;

[0632] About 10 mM histidine;

[0633] About 300 mM sorbitol;

[0634] About 0.04% (w / v) PS-20; and

[0635] About 1 mg / mL of methionine, pH about 5.6.

[0636] The present disclosure also relates to a drug combination comprising a GPRC5D×CD3 bispecific antibody and an anti-CD38 antibody, wherein the GPRC5D×CD3 bispecific antibody comprises a GPRC5D binding domain and a CD3 binding domain, the GPRC5D binding domain comprises HCDR1 of SEQ ID NO:43, HCDR2 of SEQ ID NO:44, HCDR3 of SEQ ID NO:45, LCDR1 of SEQ ID NO:46, LCDR2 of SEQ ID NO:47, and LCDR3 of SEQ ID NO:48, the CD3 binding domain comprises HCDR1 of SEQ ID NO:33, HCDR2 of SEQ ID NO:34, HCDR3 of SEQ ID NO:35, LCDR1 of SEQ ID NO:36, LCDR2 of SEQ ID NO:37, and LCDR3 of SEQ ID NO:38, and the anti-CD38 antibody comprises HCDR1 of SEQ ID NO:6, HCDR2 of SEQ ID NO:7, HCDR3 of SEQ ID NO:8, LCDR1 of SEQ ID NO:9, HCDR2 of SEQ ID NO:10, HCDR3 of SEQ ID NO:11, LCDR2 of SEQ ID NO:12, and LCDR3 of SEQ ID NO:13. LCDR2 of SEQ ID NO:10 and LCDR3 of SEQ ID NO:11.

[0637] In some embodiments, the GPRC5D binding domain comprises the VH of SEQ ID NO:49 and the VL of SEQ ID NO:50, and the CD3 binding domain comprises the VH of SEQ ID NO:39 and the VL of SEQ ID NO:40, and the anti-CD38 antibody comprises the VH of SEQ ID NO:4 and the VL of SEQ ID NO:5.

[0638] In some embodiments, the GPRC5D×CD3 bispecific antibody comprises HC1 of SEQ ID NO:51, LC1 of SEQ ID NO:52, HC2 of SEQ ID NO:41, and LC2 of SEQ ID NO:42, and the anti-CD38 antibody comprises HC of SEQ ID NO:12 and LC of SEQ ID NO:13.

[0639] In some embodiments, the drug combination is a non-fixed combination.

[0640] In some embodiments, the pharmaceutical combination comprises about 20 mg / mL to about 120 mg / mL of an anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mannitol, and about 0.04% w / v polysorbate-20 (PS-20); pH is about 5.5.

[0641] In some embodiments, the pharmaceutical combination comprises about 1,800 mg of an anti-CD38 antibody and about 30,000 U of rHuPH20.

[0642] In some embodiments, the drug combination comprises about 120 mg / mL of an anti-CD38 antibody and about 2,000 U / mL of rHuPH20.

[0643] In some embodiments, the pharmaceutical composition further comprises one or more excipients.

[0644] In some embodiments, the one or more excipients are histidine, methionine, sorbitol, or polysorbate-20 (PS-20), or any combination thereof.

[0645] In some embodiments, the pharmaceutical composition comprises

[0646] between about 100 mg / mL to about 120 mg / mL of an anti-CD38 antibody;

[0647] between about 5 mM to about 15 mM histidine;

[0648] between about 100 mM and about 300 mM sorbitol;

[0649] Between about 0.01% w / v to about 0.04% w / v PS-20; and

[0650] Between about 1 mg / mL to about 2 mg / mL methionine, pH about 5.5 to 5.6.

[0651] In some embodiments, the pharmaceutical composition comprises about 10 mM histidine.

[0652] In some embodiments, the pharmaceutical combination comprises about 300 mM sorbitol.

[0653] In some embodiments, the pharmaceutical combination comprises about 0.04% (w / v) PS-20.

[0654] In some embodiments, the pharmaceutical combination comprises about 1 mg / mL of methionine.

[0655] In some embodiments, the drug combination comprises

[0656] About 1,800 mg of anti-CD38 antibody;

[0657] About 30,000U of rHuPH20;

[0658] About 10 mM histidine;

[0659] About 300 mM sorbitol;

[0660] About 0.04% (w / v) PS-20; and

[0661] About 1 mg / mL of methionine, pH about 5.6.

[0662] In some embodiments, the drug combination comprises

[0663] about 120 mg / mL of anti-CD38 antibody;

[0664] About 2,000 U / mL of rHuPH20;

[0665] About 10 mM histidine;

[0666] About 300 mM sorbitol;

[0667] About 0.04% (w / v) PS-20; and

[0668] About 1 mg / mL of methionine, pH about 5.6.

[0669] The present disclosure also provides a pharmaceutical combination comprising a T cell redirecting therapeutic agent that binds to GPRC5D and an anti-CD38 antibody.

[0670] Treatment of relapsed or refractory subjects with GPRC5D×CD3 bispecific antibody

[0671] The present disclosure also provides a method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a GPRC5D×CD3 bispecific antibody to treat the cancer, wherein the subject is relapsed or refractory to treatment with a previous anti-cancer therapeutic.

[0672] In some embodiments, the GPRC5D×CD3 bispecific antibody comprises a GPRC5D binding domain and a CD3 binding domain, the GPRC5D binding domain comprising HCDR1 of SEQ ID NO:43, HCDR2 of SEQ ID NO:44, HCDR3 of SEQ ID NO:45, LCDR1 of SEQ ID NO:46, LCDR2 of SEQ ID NO:47, and LCDR3 of SEQ ID NO:48, and the CD3 binding domain comprising HCDR1 of SEQ ID NO:33, HCDR2 of SEQ ID NO:34, HCDR3 of SEQ ID NO:35, LCDR1 of SEQ ID NO:36, LCDR2 of SEQ ID NO:37, and LCDR3 of SEQ ID NO:38.

[0673] In some embodiments, the GPRC5D binding domain comprises the VH of SEQ ID NO:49 and the VL of SEQ ID NO:50, and the CD3 binding domain comprises the VH of SEQ ID NO:39 and the VL of SEQ ID NO:40.

[0674] In some embodiments, the GPRC5D×CD3 bispecific antibody is of the IgG4 isotype and comprises a phenylalanine at position 405 and an arginine at position 409 in HC1 and a leucine at position 405 and a lysine at position 409 in HC2, wherein the residues are numbered according to the EU index.

[0675] In some embodiments, the GPRC5D×CD3 bispecific antibody further comprises a proline at position 228, an alanine at position 234, and an alanine at position 235 in both HC1 and HC2.

[0676] In some embodiments, the GPRC5D×CD3 bispecific antibody comprises HC1 of SEQ ID NO:51, LC1 of SEQ ID NO:52), HC2 of SEQ ID NO:41, and LC2 of SEQ ID NO:42.

[0677] In some embodiments, the cancer is a hematological malignancy or a solid tumor.

[0678] In some embodiments, the cancer is multiple myeloma, lymphoma, melanoma, breast cancer, endometrial cancer, ovarian cancer, lung cancer, stomach cancer, prostate cancer, kidney cancer, liver cancer, pancreatic cancer, colon cancer, esophageal cancer, bladder cancer, or a cervical tumor.

[0679] In some embodiments, the multiple myeloma is high-risk multiple myeloma.

[0680] In some embodiments, the subject with high-risk multiple myeloma has one or more chromosomal abnormalities comprising:

[0681] t(4;14)(p16;q32);

[0682] t(14;16)(q32;q23);

[0683] del17p;

[0684] 1qAmp;

[0685] t(4;14)(p16;q32) and t(14;16)(q32;q23);

[0686] t(4;14)(p16;q32) and del17p;

[0687] t(14;16)(q32;q23) and del17p; or

[0688] t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p or any combination thereof.

[0689] In some embodiments, the subject is refractory or relapsed to treatment with an anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotozumab, ixazomib, melphalan, or thalidomide, or any combination thereof.

[0690] In some embodiments, the subject is relapsed or refractory to treatment with an anti-CD38 antibody.

[0691] In some embodiments, the anti-CD38 antibody comprises HCDR1 of SEQ ID NO:6, HCDR2 of SEQ ID NO:7, HCDR3 of SEQ ID NO:8, LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10, and LCDR3 of SEQ ID NO:11.

[0692] In some embodiments, the anti-CD38 antibody comprises the VH of SEQ ID NO:4 and the VL of SEQ ID NO:5.

[0693] In some embodiments, the anti-CD38 antibody is of the IgG1 isotype.

[0694] In some embodiments, the anti-CD38 antibody comprises the HC of SEQ ID NO:12 and the LC of SEQ ID NO:13.

[0695] In some embodiments, the anti-CD38 antibody comprises:

[0696] VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15;

[0697] VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17;

[0698] VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19; or

[0699] VH of SEQ ID NO:20 and VL of SEQ ID NO:21.

[0700] In some embodiments, the anti-CD38 antibody is of the IgG1 isotype.

[0701] In some embodiments, the subject is a human.

[0702] In some embodiments, the method further comprises administering to the subject one or more anti-cancer therapies.

[0703] In some embodiments, the one or more anti-cancer therapies are selected from autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulators, and targeted cancer therapies.

[0704] In some embodiments, the one or more anti-cancer therapies are selected from lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, elotozumab, ixazomib, melphalan, dexamethasone, vincristine, cyclophosphamide, hydroxydaunorubicin, prednisone, rituximab, imatinib, dasatinib, nilotinib, bosutinib, ponatinib, bafitinib, sacatinib, tauzerti or darusertib, cytarabine, daunorubicin, idarubicin, mitoxantrone, hydroxyurea, decitabine, cladribine, fludarabine, topotecan, etoposide 6-thioguanine, corticosteroids, methotrexate, 6-mercaptopurine, azacitidine, arsenic trioxide and all-trans retinoic acid, or any combination thereof.

[0705] Combination therapy with CD19-binding T cell redirecting therapeutics and anti-CD38 antibodies

[0706] The present disclosure also provides a method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a CD19-binding T cell redirecting therapeutic and an anti-CD38 antibody to treat the cancer.

[0707] In some embodiments, the subject has been treated with an anti-CD38 antibody prior to administration of the T cell redirecting therapeutic that binds CD19.

[0708] The present disclosure also provides a method of enhancing the efficacy of a CD19-binding T cell redirecting therapeutic in a subject having cancer, comprising administering an anti-CD38 antibody to the subject prior to administering the CD19-binding T cell redirecting therapeutic.

[0709] In some embodiments, the subject is relapsed or refractory to treatment with a prior anti-cancer therapeutic.

[0710] In some embodiments, the cancer is a hematological malignancy or a solid tumor.

[0711] In some embodiments, the hematological malignancy is a lymphoma, a B-cell malignancy, Hodgkin's lymphoma, non-Hodgkin's lymphoma, DLBLC, FL, MCL, marginal zone B-cell lymphoma (MZL), mucosa-associated lymphoid tissue lymphoma (MALT), CLL, ALL, AML, Waldenstrom's macroglobulinemia, or a T-cell lymphoma.

[0712] In some embodiments, the solid tumor is lung cancer, liver cancer, cervical cancer, colon cancer, breast cancer, ovarian cancer, pancreatic cancer, melanoma, glioblastoma, prostate cancer, esophageal cancer or gastric cancer. WO2019057124A1 discloses cancers that are susceptible to treatment with T cell redirecting therapeutic agents that bind CD19.

[0713] In some embodiments, the T cell redirecting therapeutic binds CD3 epsilon (CD3ε), CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, BTNL8, PD-1, CD195, or NKG2C.

[0714] In some embodiments, the CD19-binding T cell redirecting therapeutic comprises a CD19 binding domain of blinatumomab, axicabtagene ciloleucel, tisagenlecleucel-t, inebilizumab, lisocabtagene maraleucel, XmAb-5574, CIK-CAR.CD19, ICTCAR-011, IM-19, JCAR-014, loncastuximab tesirine, MB-CART2019.1, OXS-1550, PBCAR-0191, PCAR-019, PCAR-119, Senl-001, TI-1007, XmAb-5 871, PTG-01, PZ01, Senl_1904A, Senl_1904B, UCART-19, CSG-CD19, DI-B4, ET-190, GC-007F or GC-022.

[0715] In some embodiments, the T cell redirecting therapeutic that binds to CD19 comprises: blinatumomab, axicabtagene ciloleucel, tisagenlecleucel-t, inebilizumab, lisocabtagene maraleucel, XmAb-5574, CIK-CAR.CD19, ICTCAR-011, IM-19, JCAR-014, loncastuximab tesirine, MB-CART2019.1, OXS-1550, PBCAR-0191, PCAR-019, PCAR-119, Senl-001, TI-1007, XmAb-5871, PTG-01, PZ01, Senl_1904A, Senl_1904B, UCART-19, CSG-CD19, DI-B4, ET-190, GC-007F or GC-022.

[0716] In some embodiments, the T cell redirecting therapeutic that binds CD19 is a multispecific antibody, a CAR, or a T cell expressing a CAR.

[0717] In some embodiments, the anti-CD38 antibody comprises HCDR1 of SEQ ID NO:6, HCDR2 of SEQ ID NO:7, HCDR3 of SEQ ID NO:8, LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10, and LCDR3 of SEQ ID NO:11.

[0718] In some embodiments, the anti-CD38 antibody comprises the VH of SEQ ID NO:4 and the VL of SEQ ID NO:5.

[0719] In some embodiments, the anti-CD38 antibody is of the IgG1 isotype.

[0720] In some embodiments, the anti-CD38 antibody comprises the HC of SEQ ID NO:12 and the LC of SEQ ID NO:13.

[0721] In some embodiments, the anti-CD38 antibody comprises:

[0722] VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15;

[0723] VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17;

[0724] VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19; or

[0725] VH of SEQ ID NO:20 and VL of SEQ ID NO:21.

[0726] In some embodiments, the anti-CD38 antibody is of the IgG1 isotype.

[0727] In some embodiments, the anti-CD38 antibody is administered at a dose of between about 8 mg / kg to about 16 mg / kg.

[0728] In some embodiments, the CD19 binding T cell redirecting therapeutic and the anti-CD38 antibody are administered by intravenous injection.

[0729] In some embodiments, the CD19-binding T cell redirecting therapeutic is administered by intravenous injection and the anti-CD38 antibody is administered by subcutaneous injection.

[0730] In some embodiments, the CD19 binding T cell redirecting therapeutic and the anti-CD38 antibody are administered by subcutaneous injection.

[0731] In some embodiments, the subject is a human.

[0732] In some embodiments, the T cell redirecting therapeutic that binds CD19 is a CD19×CD3 bispecific antibody.

[0733] In some embodiments, the method further comprises administering to the subject one or more anti-cancer therapies.

[0734] In some embodiments, the one or more anti-cancer therapies are selected from autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulators, and targeted cancer therapies.

[0735] The present disclosure also provides a drug combination comprising a CD19×CD3 bispecific antibody and an anti-CD38 antibody, wherein the CD19×CD3 bispecific antibody comprises blinatumomab of SEQ ID NO:53, and the anti-CD38 antibody comprises HCDR1 of SEQ ID NO:6, HCDR2 of SEQ ID NO:7, HCDR3 of SEQ ID NO:8, LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10, and LCDR3 of SEQ ID NO:11.

[0736] In some embodiments, the anti-CD38 antibody comprises the VH of SEQ ID NO:4 and the VL of SEQ ID NO:5.

[0737] In some embodiments, the anti-CD38 antibody comprises the HC of SEQ ID NO:12 and the LC of SEQ ID NO:13.

[0738] In some embodiments, the drug combination is a non-fixed combination.

[0739] In some embodiments, the pharmaceutical combination comprises about 20 mg / mL to about 120 mg / mL of an anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mannitol, and about 0.04% w / v polysorbate-20 (PS-20); pH is about 5.5.

[0740] In some embodiments, the pharmaceutical combination comprises about 1,800 mg of an anti-CD38 antibody and about 30,000 U of rHuPH20.

[0741] In some embodiments, the drug combination comprises about 120 mg / mL of an anti-CD38 antibody and about 2,000 U / mL of rHuPH20.

[0742] In some embodiments, the pharmaceutical composition further comprises one or more excipients.

[0743] In some embodiments, the one or more excipients are histidine, methionine, sorbitol, or polysorbate-20 (PS-20), or any combination thereof.

[0744] In some embodiments, the drug combination comprises

[0745] between about 100 mg / mL to about 120 mg / mL of an anti-CD38 antibody;

[0746] between about 5 mM to about 15 mM histidine;

[0747] between about 100 mM and about 300 mM sorbitol;

[0748] Between about 0.01% w / v to about 0.04% w / v PS-20; and

[0749] Between about 1 mg / mL to about 2 mg / mL methionine, pH about 5.5 to 5.6.

[0750] In some embodiments, the drug combination comprises

[0751] About 10 mM histidine.

[0752] In some embodiments, the pharmaceutical combination comprises about 300 mM sorbitol.

[0753] In some embodiments, the pharmaceutical combination comprises about 0.04% (w / v) PS-20.

[0754] In some embodiments, the pharmaceutical combination comprises about 1 mg / mL of methionine.

[0755] In some embodiments, the drug combination comprises

[0756] About 1,800 mg of anti-CD38 antibody;

[0757] About 30,000U of rHuPH20;

[0758] About 10 mM histidine;

[0759] About 300 mM sorbitol;

[0760] About 0.04% (w / v) PS-20; and

[0761] About 1 mg / mL of methionine, pH about 5.6.

[0762] In some embodiments, the drug combination comprises

[0763] about 120 mg / mL of anti-CD38 antibody;

[0764] About 2,000 U / mL of rHuPH20;

[0765] About 10 mM histidine;

[0766] About 300 mM sorbitol;

[0767] About 0.04% (w / v) PS-20; and

[0768] About 1 mg / mL of methionine, pH about 5.6.

[0769] In some embodiments, the drug combination comprises 35 meg of blinatumomab formulated with citric acid monohydrate (3.35 mg), lysine hydrochloride (23.23 mg), polysorbate 80 (0.64 mg), trehalose dihydrate (95.5 mg), and sodium hydroxide to adjust the pH to 7.0.

[0770] In some embodiments, blinatumomab is reconstituted with 3 mL of preservative-free Sterile Water for Injection, USP.

[0771] The present disclosure provides a kit comprising a drug combination comprising blinatumomab of SEQ ID NO:53 and an anti-CD38 antibody comprising HCDR1 of SEQ ID NO:6, HCDR2 of SEQ ID NO:7, HCDR3 of SEQ ID NO:8, LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10, and LCDR3 of SEQ ID NO:11.

[0772] T cell redirecting therapeutics

[0773] Multispecific Antibodies

[0774] T cell redirection therapeutic agents can be multispecific molecules, such as bispecific antibodies. Various multispecific and / or bispecific formats include the formats described herein and recombinant IgG-like dual-targeting molecules, wherein the two sides of the molecule each contain a Fab fragment or a portion of a Fab fragment of at least two different antibodies; IgG fusion molecules, wherein a full-length IgG antibody is fused with an additional Fab fragment or a portion of a Fab fragment; Fc fusion molecules, wherein a single-chain Fv molecule or a stable diabody is fused with a heavy chain constant domain, an Fc region or a portion thereof; Fab fusion molecules, wherein different Fab fragments are fused together; ScFv- and diabody-based heavy chain antibodies (e.g., domain antibodies, nanobodies), wherein different single-chain Fv molecules or different diabodies or different heavy chain antibodies (e.g., domain antibodies, nanobodies) are fused to each other or to another protein or carrier molecule, or multispecific antibodies generated by arm exchange. Exemplary multispecific and / or bispecific formats include dual targeting molecules, including dual targeting (DT)-Ig (GSK / Domantis), 2-in-1 antibodies (Genentech) and mAb2 (F-Star), dual variable domain (DVD)-Ig (Abbott), Ts2Ab (MedImmune / AZ) and BsAb (Zymogenetics), HERCULES (BiogenIdec) and TvAb (Roche), ScFv / Fc fusions (Academic Institution), SCORPION (Emergent BioSolutions / Trubion, Zymogenetics / BMS) and dual affinity blocking technology (Fc-DART) (MacroGenics), F(ab)2 (Medarex / AMGEN), dual-acting or Bis-Fab (Genentech), Dock-and-Lock (DNL) (ImmunoMedics), bivalent bispecific (Biotecnol) and Fab-Fv (UCB-Celltech), bispecific T cell engager (BITE) (Micromet), Tandem Diabody (Tandab) (Affimed), dual affinity retargeting technology (DART) (MacroGenics), single-chain diabody (Academic), TCR-like antibody (AIT, ReceptorLogics), human serum albumin ScFv fusion (Merrimack) and COMBODY (Epigen Biotech), dual-targeting nanobody (Ablynx), dual-targeting heavy chain domain-only antibody.Various formats of bispecific antibodies have been described, for example in Chames and Baty (2009) Curr Opin Drug Disc Dev, Vol. 12: p. 276 and in Nunez-Prado et al., (2015) Drug Discovery Today, Vol. 20 No. 5: pp. 588-594.

[0775] Methods for producing antibodies in the methods of the invention

[0776] Antibodies that bind to a specific antigen used in the methods of the invention can also be selected de novo, for example, from phage display libraries, in which phage are engineered to express human immunoglobulins or portions thereof, such as Fab, single chain antibodies (scFv), or unpaired or paired antibody variable regions (Knappik et al., J Mol Biol Vol. 296: 57-86, 2000; Krebs et al., J Immunol Meth 254: 67-84, 2001; Vaughan et al., Nature Biotechnology, Vol. 14, 309-314, 1996; Sheets et al., PITAS (USA), Vol. 95: 6157-6162, 1998; Hoogenboom and Winter, J Mol Biol, Vol. 227, 381, 1991; Marks et al., J Mol Biol, Vol. 222: 581, 1991). The antibody heavy chain variable region and light chain variable region are expressed as a phage display library of fusion proteins with phage pIX coat protein, as described in Shi et al. (2010) J. Mol. Biol. Vol. 397: pp. 385-396 and International Patent Publication WO2009 / 085462. Antibodies that bind to the desired antigen such as BCMA, CD3, CD38, CD123, CD19, CD33, PSMA or TMEFF2 extracellular domain can be screened from the antibody library, and the obtained positive clones can be further characterized, Fabs are isolated from the clone lysate, and then cloned as full-length antibodies. Such phage display methods for isolating human antibodies are established in the art. See, for example: U.S. Patent 5,223,409; U.S. Patent 5,403,484; U.S. Patent 5,571,698; U.S. Patent 5,427,908; U.S. Patent 5,580,717; U.S. Patent 5,969,108; U.S. Patent 6,172,197; U.S. Patent 5,885,793; U.S. Patent 6,521,404; U.S. Patent 6,544,731; U.S. Patent 6,555,313; U.S. Patent 6,582,915; and U.S. Patent 6,593,081.

[0777] T cell redirecting bispecific antibodies can be produced in vitro in a cell-free environment by the following process: introducing asymmetric mutations in the CH3 region of two monospecific homodimeric antibodies according to the method described in International Patent Publication WO2011 / 131746, and forming a bispecific heterodimeric antibody from two parental monospecific homodimeric antibodies under reducing conditions that allow disulfide bond isomerization. In this method, two monospecific bivalent antibodies are engineered to have certain substitutions at the CH3 domain that promote heterodimer stability; these antibodies are incubated together under reducing conditions sufficient to cause disulfide bond isomerization of cysteine ​​in the hinge region; thereby generating bispecific antibodies by Fab arm exchange. The incubation conditions can ideally be restored to non-reducing conditions. Exemplary reducing agents that can be used are 2-mercaptoethylamine (2-MEA), dithiothreitol (DTT), dithioerythritol (DTE), glutathione, tris (2-carboxyethyl) phosphine (TCEP), L-cysteine ​​and β-mercaptoethanol, preferably a reducing agent selected from 2-mercaptoethylamine, dithiothreitol and tris (2-carboxyethyl) phosphine. For example, the following conditions can be used: in the presence of at least 25 mM 2-MEA or at least 0.5 mM dithiothreitol, at a pH of 5-8, such as pH 7.0 or pH 7.4, at a temperature of at least 20° C., incubated for at least 90 minutes.

[0778] Exemplary CH3 mutations that can be used in the first and second heavy chains of the bispecific antibody are K409R and / or F405L.

[0779] Additional CH3 mutations that may be used include techniques such as mutations (Genmab), Knob-in-Hole mutations (Genentech), electrostatic matching mutations (Amgen, NovoNordisk, Oncomed), strand exchange engineered domain bodies (SEEDbody) (EMD Serono), and other asymmetric mutations (e.g., Zymeworks).

[0780] Mutations (Genmab) are disclosed in e.g. US9150663 and US2014 / 0303356, and including mutations F405L / K409R, wild type / F405L_R409K, T350I_K370T_F405L / K409R, K370W / K409R, D399AFGHILMNRSTVWY / K409R, T366ADEFGHILMQVY / K409R, L368ADEGHNRSTVQ / K409AGRH, D399FHKRQ / K409AGRH, F405IKLSTVW / K409AGRH and Y407LWQ / K409AGRH.

[0781] Knob-in-hole mutations are disclosed in, for example, WO1996 / 027011, and include mutations on the interface of the CH3 region, wherein an amino acid with a small side chain (hole) is introduced into the first CH3 region, and an amino acid with a large side chain (knob) is introduced into the second CH3 region, resulting in preferential interactions between the first CH3 region and the second CH3 region. Exemplary CH3 region mutations that form knobs and holes are T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S, and T366W / T366S_L368A_Y407V.

[0782] The formation of heavy chain heterodimers can be promoted by using electrostatic interactions by replacing positively charged residues on the first CH3 region with negatively charged residues on the second CH3 region as described in US2010 / 0015133, US2009 / 0182127, US2010 / 028637 or US2011 / 0123532.

[0783] Other asymmetric mutations that can be used to promote heavy chain heterodimerization are L351Y_F405A_Y407V / T394W, T366I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F, or T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W, as described in US2012 / 0149876 or US2013 / 0195849.

[0784] SEEDbody mutagenesis involves replacing selected IgG residues with IgA residues to promote heavy chain heterodimerization as described in US20070287170.

[0785] Other exemplary mutations that can be used are R409D_K370E / D399K_E357K, S354C_T366W / Y349C_T366S_L368A_Y407V, Y349C_T366W / S354C_T366S_L368A_Y407 as described in WO2007 / 147901, WO2011 / 143545, WO2013157954, WO2013096291, and US2018 / 0118849. V, T366K / L351D, L351K / Y349E, L351K / Y349D, L351K / L368E, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V _K409F, K392D / D399K, K392D / E356K, K253E_D282K_K322D / D239K_E240K_K292D, K392D_K409D / D356K_D399K.

[0786] Additional bispecific or multispecific structures that can be used as T cell redirecting therapeutics include dual variable domain immunoglobulins (DVDs) (International Patent Publication No. WO2009 / 134776; DVDs are full-length antibodies comprising a heavy chain having the structure VH1-linker-VH2-CH and a light chain having the structure VL1-linker-VL2-CL; the linker is optional), structures comprising various dimerization domains to connect two antibody arms with different specificities (such as leucine zippers or collagen dimerization domains (International Patent Publication No. WO2012 / 022811, U.S. Pat. No. 5,932,448; U.S. Pat. No. 6,833,441)), two or more domain antibodies (dAbs) conjugated together, diabodies, heavy chain-only antibodies (such as camelid antibodies and engineered camelid antibodies), dual targeting (DT)-Ig (GSK / Domantis), two-in-one antibodies (Genentech), cross-linked Mabs (Karmanos CancerCenter), mAb2 (F-Star) and CovX-body (CovX / Pfizer), IgG-like bispecific antibodies (InnClone / EliLilly), Ts2Ab (MedImmune / AZ) and BsAb (Zymogenetics), HERCULES (Biogen Idec) and TvAb (Roche), ScFv / Fc fusion (Academic Institution), SCORPION (Emergent BioSolutions / Trubion, Zymogenetics / BMS), dual affinity redirection technology (Fc-DART) (MacroGenics) and bis(ScFv)2-Fab (China National Antibody Medical Research Center), dual-acting or Bis-Fab (Genentech), Dock-and-Lock (DNL) (ImmunoMedics), bivalent bispecific (Biotecnol) and Fab-Fv (UCB-Celltech). ScFv-based, diabody-based domain antibodies include, but are not limited to, bispecific T cell engagers (BiTE) (Micromet), tandem diabodies (Tandab) (Affimed), dual affinity retargeting molecules (DART) (MacroGenics), single-chain diabodies (Academic), TCR-like antibodies (AIT, Receptor Logics), human serum albumin ScFv fusions (Merrimack) and COMBODY (Epigen Biotech), dual-targeting nanobodies (Ablynx), and dual-targeting heavy chain domain antibodies only.

[0787] Antibody Fc Engineering

[0788] The Fc region of a T cell redirecting therapeutic, such as a bispecific or multispecific antibody or an anti-CD38 antibody, may comprise at least one substitution in the Fc region that reduces binding of the T cell redirecting therapeutic to an activating Fcγ receptor (FcγR) and / or reduces Fc effector function, such as C1q binding, complement dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), or phagocytosis (ADCP).

[0789] The Fc positions that can be substituted to reduce Fc binding to activating FcγRs and subsequently reduce effector function are the substitutions L234A / L235A on IgG1, V234A, / G237A / P238S / H268A / V309L / A330S / P331S on IgG2, F234A / L235A on IgG4, S228P / F234A / L235A on IgG4, N297A on all Ig isotypes, V234A / G237A on IgG2, K214T / E233P / L234V / L235A / G236-deletion on IgG1. 7G / P331A / D365E / L358M, H268Q / V309L / A330S / P331S on IgG2, S267E / L328F on IgG1, L234F / L235E / D265A on IgG1, L234A / L235A / G237A / P238S / H268A / A330S / P331S on IgG1, S228P / F234A / L235A / G237A / P238S on IgG4, and S228P / F234A / L235A / G236-deletion / G237A / P238S on IgG4.

[0790] An Fc substitution that may be used to reduce CDC is the K322A substitution.

[0791] The well-known S228P substitution can also be made in IgG4 antibodies to enhance IgG4 stability.

[0792] An exemplary wild-type IgG1 comprises the amino acid sequence of SEQ ID NO:103.

[0793] SEQ ID NO:103 :

[0794] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0795] Exemplary wild-type IgG4 contains the amino acid sequence of SEQ ID NO: 104.

[0796] SEQ ID NO:104 :

[0797] ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0798] "Antibody-dependent cellular cytotoxicity," "antibody-dependent cell-mediated cytotoxicity," or "ADCC" is a mechanism of inducing cell death that relies on the interaction of antibody-coated target cells with effector cells with lytic activity, such as natural killer cells (NK), monocytes, macrophages, and neutrophils, via Fcγ receptors (FcγRs) expressed on effector cells. For example, NK cells express FcγRIIIa, while monocytes express FcγRI, FcγRII, and FcγRIIIa. The ADCC activity of an antibody can be assessed using an in vitro assay using cells expressing the protein to which the antibody binds as target cells and NK cells as effector cells. Cell lysis is detected based on a marker (e.g., a radioactive substrate, a fluorescent dye, or a native intracellular protein) released from the lysed cells. In an exemplary assay, target cells can be used at a ratio of 1 target cell to 4 effector cells. Target cells are pre-labeled with BATDA and combined with effector cells and a test antibody. The samples are incubated for 2 hours, and cell lysis is measured by measuring the BATDA released into the supernatant. Data were normalized to maximal cytotoxicity using 0.67% Triton X-100 (Sigma Aldrich) and to a minimal control determined by spontaneous release of BATDA from target cells in the absence of any antibody.

[0799] "Antibody-dependent cellular phagocytosis" ("ADCP") refers to a mechanism by which antibody-coated target cells are eliminated by internalization by phagocytic cells, such as macrophages or dendritic cells. ADCP can be evaluated by using monocyte-derived macrophages as effector cells and cells expressing the protein to which the antibody binds as target cells that are also engineered to express GFP or another marker molecule. In an exemplary assay, the effector cell: target cell ratio can be, for example, 4:1. The effector cells can be incubated with the target cells for 4 hours with or without the antibodies of the invention. After incubation, the cells can be separated using accutase. Anti-CD11b antibodies and anti-CD14 antibodies coupled to fluorescent markers can be used to identify macrophages, and standard methods can be used to identify macrophages based on CD11 + CD14 + The % GFP fluorescence in macrophages determined the percentage of phagocytosis.

[0800] "Complement-dependent cytotoxicity" (CDC) refers to a mechanism of inducing cell death in which the Fc effector domain of a target-binding antibody binds and activates complement component C1q, which in turn activates the complement cascade, leading to target cell death. Activation of complement can also lead to the deposition of complement components on the surface of target cells, which promote CDC by binding to complement receptors (e.g., CR3) on leukocytes. CDC of cells can be measured, for example, by incubating Daudi cells at 1×10 5 Cells / well (50 μL / well) were seeded in RPMI-B (RPMI supplemented with 1% BSA), 50 μL of test antibody was added to the well at a final concentration between 0 μg / mL and 100 μg / mL, the reaction was incubated for 15 minutes at room temperature, 11 μL of pooled human serum was added to the well, and the reaction was incubated for 45 minutes at 37° C. The % of propidium iodide-stained cells can be detected in a FACS assay as the percentage (%) of lysed cells using standard methods.

[0801] Binding of antibodies to FcγR or FcRn can be assessed using flow cytometry on cells engineered to express each receptor. In an exemplary binding assay, 2×10 5 Cells / well were seeded into 96-well plates and blocked at 4°C for 30 minutes in BSA staining buffer (BD Biosciences, San Jose, USA). The cells were incubated on ice with the test antibody at 4°C for 1.5 hours. After washing twice with BSA staining buffer, the cells were incubated with R-PE labeled anti-human IgG secondary antibodies (Jackson Immunoresearch Laboratories) at 4°C for 45 minutes. The cells were washed twice in staining buffer and then resuspended in 150 μL of staining buffer (Cell Signaling Technology, Danvers, USA) containing a 1:200 dilution of DRAQ7 live / dead stain. The PE and DRAQ7 signals of the stained cells were detected by a Miltenyi MACSQuant flow cytometer (Miltenyi Biotec, Auburn, USA) using the B2 and B4 channels, respectively. Live cells were gated based on DRAQ7 exclusion, and the geometric mean fluorescence signal of at least 10,000 live events collected was determined. Analysis was performed using FlowJo software (Tree Star). Data were plotted as log of antibody concentration versus mean fluorescence signal. Perform nonlinear regression analysis .

[0802] Chimeric Antigen Receptor (CAR)

[0803] Chimeric antigen receptor (CAR) is a genetically engineered receptor. These engineered receptors can be easily inserted into immune cells (including T cells) and expressed by them according to techniques known in the art. For CAR, a single receptor can be programmed to recognize a specific antigen, and when bound to the antigen, activate immune cells to attack and destroy cells carrying the antigen. When these antigens are present on tumor cells, immune cells expressing CAR can target and kill tumor cells.

[0804] CARs typically comprise an extracellular domain that binds an antigen (e.g., prostate neoantigen), an optional linker, a transmembrane domain, and a cytoplasmic domain comprising a co-stimulatory domain and / or a signaling domain.

[0805] The extracellular domain of CAR may contain any polypeptide that binds to a desired antigen (e.g., a prostate neoantigen). The extracellular domain may include a portion of an scFv, an antibody, or an alternative scaffold. CAR may also be engineered to bind to two or more desired antigens, which may be arranged in series and separated by a linker sequence. For example, one or more domain antibodies, scFvs, schma VHH antibodies, or other VH-only antibody fragments may be organized in tandem via a linker to provide bispecific or multispecific CAR.

[0806] The transmembrane domain of CAR can be derived from CD8, α, β or ζ chain of T cell receptor, CD28, CD3ε, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, KIRDS2, OX40, CD2, CD27, LFA-1 (CDI la, CD18), ICOS (CD278), 4-1BB (CD137), 4-1BBL, GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRFI), CD160, CD19, IL2Rβ, IL2Rγ, IL7R a, ITGA1, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CDI Id, ITGAE, CD103, ITGAL, CDIla, LFA-1, ITGAM, CDI lb, ITGAX, CDI lc, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, TNFR2, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRT AM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​PAG / Cbp, NKp44, NKp30, NKp46, the transmembrane domain of NKG2D and / or NKG2C.

[0807] The intracellular costimulatory domain of CAR can be derived from the intracellular domain of one or more costimulatory molecules.Costimulatory molecules are well-known cell surface molecules other than antigen receptors or Fc receptors, which provide T lymphocytes to effectively activate and function when combined with antigens. The exemplary costimulatory domains that can be used for CAR are 4-1BB, CD2, CD7, CD27, CD28, CD30, CD40, CD54 (ICAM), CD83, CD134 (OX40), CD150 (SLAMF1), CD152 (CTLA4), CD223 (LAG3), CD270 (HVEM), CD278 (ICOS), DAP10, LAT, NKD2C SLP76, TRIM and ZAP70 intracellular domains.

[0808] The intracellular signaling domain of CAR can be derived from, for example, the signaling domain of O'O3ζ, CD3ε, CD22, CD79a, CD66d or CD39. "Intracellular signaling domain" refers to the part of the CAR polypeptide involved in transducing the information of effective CAR binding to the target antigen to the inside of the immune effector cell to induce effector cell function, for example, activation, cytokine production, proliferation and cytotoxic activity, including the release of cytotoxic factors to the target cells bound by CAR, or other cellular responses triggered after the antigen is bound to the extracellular CAR domain.

[0809] The optional linker of the CAR positioned between the extracellular domain and the transmembrane domain can be a polypeptide of about 2 to 100 amino acids in length. The linker may include flexible residues (such as glycine and serine) or be composed of flexible residues so that adjacent protein domains move freely relative to each other. When it is desired to ensure that two adjacent domains do not interfere with each other spatially, a longer linker can be used. The linker may be cleavable or non-cleavable. Examples of cleavable linkers include 2A linkers (e.g., T2A), 2A-like linkers, or their functional equivalents and combinations thereof. The linker may also be derived from a hinge region or a portion of a hinge region of any immunoglobulin.

[0810] Exemplary CARs that can be used are, for example, CARs that include an extracellular domain that binds to the prostate neoantigens of the present invention, a CD8 transmembrane domain, and a CD3ζ signaling domain. Other exemplary CARs include an extracellular domain that binds to the prostate neoantigens of the present invention, a CD8 or CD28 transmembrane domain, a CD28, 41BB or OX40 costimulatory domain, and a CD3ζ signaling domain.

[0811] CARs are generated by standard molecular biology techniques. The extracellular domain that binds to the desired antigen can be derived from an antibody or antigen-binding fragment thereof generated using the techniques described herein.

[0812]

[0066] While the present invention has been generally described, embodiments of the present invention will be further disclosed in the following examples, which should not be construed as limiting the scope of the claims.

[0813] Other embodiments of the present invention

[0814] Certain further embodiments of the invention are set out below in light of the disclosure elsewhere herein. Features of embodiments of the invention set out above as being relevant to the invention disclosed herein also relate to each of all such further numbered embodiments.

[0815] Embodiment 1. An anti-CD38 antibody for use in combination with a T cell redirecting therapeutic agent in treating a subject having cancer.

[0816] Embodiment 2. An anti-CD38 antibody for use in enhancing the efficacy of a T cell redirecting therapeutic in a subject suffering from cancer.

[0817] Embodiment 3. Use of an anti-CD38 antibody in combination with a T cell redirecting therapeutic agent for the preparation of a medicament or pharmaceutical composition for treating a patient suffering from cancer.

[0818] Embodiment 4. Use of an anti-CD38 antibody in combination with a T cell redirecting therapeutic agent, characterized in that it is used to prepare a combination that can be used to treat a subject suffering from cancer in a patient in need thereof.

[0819] Embodiment 5. The anti-CD38 antibody for use according to any one of embodiments 1 to 4, wherein the anti-CD38 antibody is administered prior to administration of the T cell redirecting therapeutic agent.

[0820] Embodiment 6. The anti-CD38 antibody for use according to any one of embodiments 1 to 5, wherein the T cell redirecting therapeutic binds to BCMA, GPRC5D, CD33, CD123, CD19, PSMA, TMEFF2 or CD20.

[0821] Embodiment 7. The anti-CD38 antibody for use according to any one of Embodiments 1 to 6, wherein the T cell redirecting therapeutic binds to CD3, CD3ε (CD3ε), CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, BTNL8, PD-1, CD195 or NKG2C.

[0822] Embodiment 8. The anti-CD38 antibody for use according to any one of Embodiments 1 to 7, wherein the T cell redirecting therapeutic comprises a CD3 binding domain comprising

[0823] heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO:33, HCDR2 of SEQ ID NO:34, HCDR3 of SEQ ID NO:35, light chain complementarity determining region 1 (LCDR1) of SEQ ID NO:36, LCDR2 of SEQ ID NO:37, and LCDR3 of SEQ ID NO:38;

[0824] The heavy chain variable region (VH) of SEQ ID NO:39 and the light chain variable region (VL) of SEQ ID NO:40;

[0825] HCDR1 of SEQ ID NO:74, HCDR2 of SEQ ID NO:75, HCDR3 of SEQ ID NO:76, LCDR1 of SEQ ID NO:77, LCDR2 of SEQ ID NO:78, and LCDR3 of SEQ ID NO:79;

[0826] VH of SEQ ID NO:80 and VL of SEQ ID NO:81;

[0827] HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of the CD3 binding domain of SEQ ID NO:53; or

[0828] VH and VL of the CD3 binding domain of SEQ ID NO:53.

[0829] Embodiment 9. The anti-CD38 antibody for use according to any one of embodiments 1 to 8, wherein the T cell redirecting therapeutic agent comprises

[0830] a BCMA binding domain and a CD3 binding domain, the BCMA binding domain comprising HCDR1 of SEQ ID NO:23, HCDR2 of SEQ ID NO:24, HCDR3 of SEQ ID NO:25, LCDR1 of SEQ ID NO:26, LCDR2 of SEQ ID NO:27, and LCDR3 of SEQ ID NO:28, and the CD3 binding domain comprising HCDR1 of SEQ ID NO:33, HCDR2 of SEQ ID NO:34, HCDR3 of SEQ ID NO:35, LCDR1 of SEQ ID NO:36, LCDR2 of SEQ ID NO:37, and LCDR3 of SEQ ID NO:38; and / or

[0831] The BCMA binding domain comprises the VH of SEQ ID NO:29 and the VL of SEQ ID NO:30, and the CD3 binding domain comprises the VH of SEQ ID NO:39 and the VL of SEQ ID NO:40.

[0832] Embodiment 10. The anti-CD38 antibody for use according to any one of Embodiments 1 to 9, wherein the T cell redirecting therapeutic comprises a first heavy chain (HC1) of SEQ ID NO:31, a first light chain (LC1) of SEQ ID NO:32, a second heavy chain (HC2) of SEQ ID NO:41, and a second light chain (LC2) of SEQ ID NO:42.

[0833] Embodiment 11. The anti-CD38 antibody for use according to any one of embodiments 1 to 10, wherein the T cell redirecting therapeutic agent comprises

[0834] a GPRC5D binding domain and a CD3 binding domain, the GPRC5D binding domain comprising HCDR1 of SEQ ID NO:43, HCDR2 of SEQ ID NO:44, HCDR3 of SEQ ID NO:45, LCDR1 of SEQ ID NO:46, LCDR2 of SEQ ID NO:47, and LCDR3 of SEQ ID NO:48, and the CD3 binding domain comprising HCDR1 of SEQ ID NO:33, HCDR2 of SEQ ID NO:34, HCDR3 of SEQ ID NO:35, LCDR1 of SEQ ID NO:36, LCDR2 of SEQ ID NO:37, and LCDR3 of SEQ ID NO:38; and / or

[0835] The GPRC5D binding domain comprises the VH of SEQ ID NO:49 and the VL of SEQ ID NO:50, and the CD3 binding domain comprises the VH of SEQ ID NO:39 and the VL of SEQ ID NO:40.

[0836] Embodiment 12. The anti-CD38 antibody for use according to any one of Embodiments 111, wherein the T cell redirecting therapeutic comprises HC1 of SEQ ID NO:51, LC1 of SEQ ID NO:52, HC2 of SEQ ID NO:41, and LC2 of SEQ ID NO:42.

[0837] Embodiment 13. The anti-CD38 antibody for use according to any one of embodiments 1 to 12, wherein the T cell redirecting therapeutic agent comprises

[0838] A CD33 binding domain and a CD3 binding domain, wherein the CD33 binding domain comprises the HCDR1 of SEQ ID NO:84, the HCDR2 of SEQ ID NO:85, the HCDR3 of SEQ ID NO:86, the LCDR1 of SEQ ID NO:87, the LCDR2 of SEQ ID NO:88 and the LCDR3 of SEQ ID NO:89, and the CD3 binding domain comprises the HCDR1 of SEQ ID NO:74, the HCDR2 of SEQ ID NO:75, the HCDR3 of SEQ ID NO:76, the LCDR1 of SEQ ID NO:77, the LCDR2 of SEQ ID NO:78 and the LCDR3 of SEQ ID NO:79; and / or

[0839] The CD33 binding domain comprises the VH of SEQ ID NO:90 and the VL of SEQ ID NO:91, and the CD3 binding domain comprises the VH of SEQ ID NO:80 and the VL of SEQ ID NO:81.

[0840] Embodiment 14. The anti-CD38 antibody for use according to any one of Embodiments 1 to 13, wherein the T cell redirecting therapeutic comprises HC1 of SEQ ID NO:92, LC1 of SEQ ID NO:93, HC2 of SEQ ID NO:82, and LC2 of SEQ ID NO:83.

[0841] Embodiment 15. The anti-CD38 antibody for use according to any one of embodiments 1 to 14, wherein the T cell redirecting therapeutic agent comprises

[0842] A CD123 binding domain and a CD3 binding domain, wherein the CD123 binding domain comprises the HCDR1 of SEQ ID NO:94, the HCDR2 of SEQ ID NO:95, the HCDR3 of SEQ ID NO:96, the LCDR1 of SEQ ID NO:9, the LCDR2 of SEQ ID NO:10, and the LCDR3 of SEQ ID NO:59, and the CD3 binding domain comprises the HCDR1 of SEQ ID NO:33, the HCDR2 of SEQ ID NO:34, the HCDR3 of SEQ ID NO:35, the LCDR1 of SEQ ID NO:36, the LCDR2 of SEQ ID NO:37, and the LCDR3 of SEQ ID NO:38; and / or

[0843] The CD123 binding domain comprises the VH of SEQ ID NO: 100 and the VL of SEQ ID NO: 61, and the CD3 binding domain comprises the VH of SEQ ID NO: 39 and the VL of SEQ ID NO: 40.

[0844] Embodiment 16. The anti-CD38 antibody for use according to any one of Embodiments 1 to 15, wherein the T cell redirecting therapeutic comprises HC1 of SEQ ID NO: 102, LC1 of SEQ ID NO: 63, HC2 of SEQ ID NO: 41, and LC2 of SEQ ID NO: 42.

[0845] Embodiment 17. The anti-CD38 antibody for use according to any one of Embodiments 1 to 16, wherein the T cell redirecting therapeutic agent comprises

[0846] A CD19 binding domain and a CD3 binding domain, wherein the CD19 binding domain comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of the CD19 binding domain of SEQ ID NO:53, and the CD3 binding domain comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of the CD3 binding domain of SEQ ID NO:53; and / or the amino acid sequence of SEQ ID NO:53.

[0847] Embodiment 18. The anti-CD38 antibody for use according to any one of Embodiments 1 to 17, wherein the T cell redirecting therapeutic agent comprises

[0848] a PSMA binding domain comprising HCDR1 of SEQ ID NO:54, HCDR2 of SEQ ID NO:55, HCDR3 of SEQ ID NO:56, LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10, and LCDR3 of SEQ ID NO:59, and a CD3 binding domain comprising HCDR1 of SEQ ID NO:33, HCDR2 of SEQ ID NO:34, HCDR3 of SEQ ID NO:35, LCDR1 of SEQ ID NO:36, LCDR2 of SEQ ID NO:37, and LCDR3 of SEQ ID NO:38; and / or

[0849] The PSMA binding domain comprises the VH of SEQ ID NO:60 and the VL of SEQ ID NO:61, and the CD3 binding domain comprises the VH of SEQ ID NO:39 and the VL of SEQ ID NO:40.

[0850] Embodiment 19. The anti-CD38 antibody for use according to any one of Embodiments 1 to 18, wherein the T cell redirecting therapeutic comprises HC1 of SEQ ID NO:62, LC1 of SEQ ID NO:63, HC2 of SEQ ID NO:41, and LC2 of SEQ ID NO:42.

[0851] Embodiment 20. The anti-CD38 antibody for use according to any one of embodiments 1 to 19, wherein the T cell redirecting therapeutic agent comprises

[0852] a TMEFF2 binding domain and a CD3 binding domain, wherein the TMEFF2 binding domain comprises the HCDR1 of SEQ ID NO:64, the HCDR2 of SEQ ID NO:65, the HCDR3 of SEQ ID NO:66, the LCDR1 of SEQ ID NO:67, the LCDR2 of SEQ ID NO:68, and the LCDR3 of SEQ ID NO:69, and the CD3 binding domain comprises the HCDR1 of SEQ ID NO:74, the HCDR2 of SEQ ID NO:75, the HCDR3 of SEQ ID NO:76, the LCDR1 of SEQ ID NO:77, the LCDR2 of SEQ ID NO:78, and the LCDR3 of SEQ ID NO:79; and / or

[0853] The TMEFF2 binding domain comprises the VH of SEQ ID NO:70 and the VL of SEQ ID NO:71, and the CD3 binding domain comprises the VH of SEQ ID NO:80 and the VL of SEQ ID NO:81.

[0854] Embodiment 21. The anti-CD38 antibody for use according to any one of Embodiments 1 to 20, wherein the T cell redirecting therapeutic comprises HC1 of SEQ ID NO:72, LC1 of SEQ ID NO:73, HC2 of SEQ ID NO:82, and LC2 of SEQ ID NO:83.

[0855] Embodiment 22. The anti-CD38 antibody for use according to any one of Embodiments 1 to 21, wherein the T cell redirecting therapeutic agent is a multispecific antibody, a chimeric antigen receptor (CAR), or a T cell comprising the CAR.

[0856] Embodiment 23. The anti-CD38 antibody for use according to Embodiment 22, wherein the multispecific antibody is of IgG1, IgG2, IgG3 or IgG4 isotype.

[0857] Embodiment 24. The anti-CD38 antibody for use according to embodiment 22 or 23, wherein the multispecific antibody comprises one or more Fc substitutions that reduce binding of the multispecific antibody to an Fc gamma receptor (FcγR).

[0858] Embodiment 25. The anti-CD38 antibody for use according to any one of Embodiments 22 to 24, wherein the one or more Fc substitutions are selected from F234A / L235A on IgG4, L234A / L235A on IgG1, V234A / G237A / P238S / H268A / V309L / A330S / P331S on IgG2, F234A / L235A on IgG4, S228P / F234A / L235A on IgG4, N297A on all Ig isotypes, V234A / G237A on IgG2, K214T / E233P / L234V / L235A / G236 on IgG1. -deletion / A327G / P331A / D365E / L358M on IgG2, H268Q / V309L / A330S / P331S on IgG2, S267E / L328F on IgG1, L234F / L235E / D265A on IgG1, L234A / L235A / G237A / P238S / H268A / A330S / P331S on IgG1, S228P / F234A / L235A / G237A / P238S on IgG4, and S228P / F234A / L235A / G236-deletion / G237A / P238S on IgG4, where the residues are numbered according to the EU index.

[0859] Embodiment 26. The anti-CD38 antibody for use according to Embodiment 25, wherein the multispecific antibody further comprises an S228P substitution.

[0860] Embodiment 27. The anti-CD38 antibody for use according to any one of Embodiments 22 to 26, wherein the multispecific antibody comprises one or more asymmetric substitutions in the first CH3 domain or in the second CH3 domain or in both the first CH3 domain and the second CH3 domain.

[0861] Embodiment 28. The anti-CD38 antibody for use according to any one of Embodiments 27, wherein the one or more asymmetric substitutions are selected from F450L / K409R, wild type / F409L_R409K, T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S and T366W / T366S_L368A_Y407V, L351Y_F 405A_Y407V / T394W, T366I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F and T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W.

[0862] Embodiment 29. The anti-CD38 antibody for use according to any one of embodiments 1 to 28, wherein the subject has a newly diagnosed cancer.

[0863] Embodiment 30. The anti-CD38 antibody for use according to any one of embodiments 1 to 29, wherein the subject is relapsed or refractory to previous anti-cancer therapy.

[0864] Embodiment 31. The anti-CD38 antibody for use according to any one of embodiments 1 to 30, wherein the cancer is a hematological malignancy or a solid tumor.

[0865] Embodiment 32. The anti-CD38 antibody for use according to any one of embodiments 1 to 31, wherein the hematological malignancy is multiple myeloma, smoldering multiple myeloma, monoclonal gammopathy of undetermined significance (MGUS), acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma (BL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, plasma cell leukemia, light chain amyloidosis (AL), precursor B-cell lymphoblastoid Myeloid leukemia, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic lymphocytic leukemia (CLL), B-cell malignancies, chronic myeloid leukemia (CML), hairy cell leukemia (HCL), blastic plasmacytoid dendritic cell neoplasm, Hodgkin lymphoma, non-Hodgkin lymphoma, marginal zone B-cell lymphoma (MZL) or mucosa-associated lymphoid tissue lymphoma (MALT), plasma cell leukemia, anaplastic large cell lymphoma (ALCL), leukemia or lymphoma.

[0866] Embodiment 33. The anti-CD38 antibody for use according to any one of Embodiments 1 to 32, wherein the multiple myeloma is newly diagnosed multiple myeloma.

[0867] Embodiment 34. The anti-CD38 antibody for use according to any one of Embodiments 1 to 32, wherein the multiple myeloma is relapsed or refractory multiple myeloma.

[0868] Embodiment 35. The anti-CD38 antibody for use according to any one of Embodiments 1 to 34, wherein the multiple myeloma is high-risk multiple myeloma.

[0869] Embodiment 36. The anti-CD38 antibody for use according to Embodiment 35, wherein the subject suffering from the high-risk multiple myeloma has one or more chromosomal abnormalities, the one or more chromosomal abnormalities comprising:

[0870] t(4;14)(p16;q32);

[0871] t(14;16)(q32;q23);

[0872] del17p;

[0873] 1qAmp;

[0874] t(4;14)(p16;q32) and t(14;16)(q32;q23);

[0875] t(4;14)(p16;q32) and del17p;

[0876] t(14;16)(q32;q23) and del17p; or

[0877] t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p or any combination thereof.

[0878] Embodiment 37. The anti-CD38 antibody for use according to any one of Embodiments 1 to 36, wherein the multiple myeloma is relapsed or refractory to treatment with the anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotozumab, ixazomib, melphalan or thalidomide, or any combination thereof.

[0879] Embodiment 38. The anti-CD38 antibody for use according to any one of Embodiments 1 to 37, wherein the solid tumor is prostate cancer, lung cancer, liver cancer, cervical cancer, colon cancer, breast cancer, ovarian cancer, endometrial cancer, pancreatic cancer, melanoma, glioblastoma, esophageal cancer, gastric cancer, stomach cancer, kidney cancer, colon cancer, bladder cancer, cervical tumor, melanoma, hepatocellular carcinoma, renal cell carcinoma, urothelial carcinoma, head and neck cancer, glioma or glioblastoma.

[0880] Embodiment 39. The anti-CD38 antibody for use according to Embodiment 38, wherein the prostate cancer is recurrent prostate cancer, refractory prostate cancer, malignant prostate cancer or castration-resistant prostate cancer or any combination thereof.

[0881] Embodiment 40. The anti-CD38 antibody for use according to Embodiment 32, wherein the AML is AML with at least one genetic abnormality, AML with multilineage dysplasia, therapy-related AML, undifferentiated AML, AML with minimal maturity, AML with maturity, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, acute megakaryoblastic leukemia, acute basophilic leukemia, acute panmyelosis with fibrosis, or myeloid sarcoma.

[0882] Embodiment 41. The anti-CD38 antibody for use according to Embodiment 40, wherein the at least one genetic abnormality is a translocation between chromosomes 8 and 21, a translocation or inversion in chromosome 16, a translocation between chromosomes 15 and 17, an alteration in chromosome 11, or a mutation in fms-related tyrosine kinase 3 (FLT3), nucleolar phosphatidylcholine (NPM1), isocitrate dehydrogenase 1 (IDH1), isocitrate dehydrogenase 2 (IDH2), DNA (cytosine-5)-methyltransferase 3 (DNMT3A), CCAAT / enhancer binding protein alpha (CEBPA), U2 small nuclear RNA accessory factor 1 (U2AF1), enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), structural maintenance of chromosome 1A (SMC1A) or structural maintenance of chromosome 3 (SMC3).

[0883] Embodiment 42. The anti-CD38 antibody for use according to Embodiment 41, wherein the at least one genetic abnormality is translocation t(8;21)(q22;q22), inversion inv(16)(p13;q22), translocation t(16;16)(p13;q22), translocation t(15;17)(q22;q12), mutation FLT3-ITD in IDH1, mutation R132H or R100Q / R104V / F108L / R119Q / I130V or mutation R140Q or R172 in IDH2.

[0884] Embodiment 43. The anti-CD38 antibody for use according to Embodiment 32, wherein the ALL is B-cell lineage ALL, T-cell lineage ALL, adult ALL, or pediatric ALL.

[0885] Embodiment 44. The anti-CD38 antibody for use according to embodiment 43, wherein the subject suffering from ALL has a Philadelphia chromosome or exhibits or has acquired resistance to treatment with a BCR-ABL kinase inhibitor.

[0886] Embodiment 45. The anti-CD38 antibody for use according to any one of Embodiments 1 to 44, wherein the anti-CD38 antibody comprises HCDR1 of SEQ ID NO:6, HCDR2 of SEQ ID NO:7, HCDR3 of SEQ ID NO:8, LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10 and LCDR3 of SEQ ID NO:11.

[0887] Embodiment 46. The anti-CD38 antibody for use according to any one of Embodiments 1 to 45, wherein the anti-CD38 antibody comprises the VH of SEQ ID NO:4 and the VL of SEQ ID NO:5.

[0888] Embodiment 47. The anti-CD38 antibody for use according to any one of embodiments 1 to 46, wherein the anti-CD38 antibody is of IgG1 isotype.

[0889] Embodiment 48. The anti-CD38 antibody for use according to any one of Embodiments 1 to 47, wherein the anti-CD38 antibody comprises the HC of SEQ ID NO:12 and the LC of SEQ ID NO:13.

[0890] Embodiment 49. The anti-CD38 antibody for use according to any one of embodiments 1 to 44, wherein the anti-CD38 antibody comprises

[0891] VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15;

[0892] VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17;

[0893] VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19; or

[0894] VH of SEQ ID NO:20 and VL of SEQ ID NO:21.

[0895] Embodiment 50. The anti-CD38 antibody for use according to Embodiment 49, wherein the anti-CD38 antibody is of IgG1 isotype.

[0896] Embodiment 51. The anti-CD38 antibody for use according to any one of Embodiments 1 to 50, wherein the T cell redirecting therapeutic agent is a BCMA×CD3 bispecific antibody, a GPRC5D×CD3 bispecific antibody, a CD33×CD3 bispecific antibody, a CD19×CD3 bispecific antibody, a CD123×CD3 bispecific antibody, a PSMA×CD3 bispecific antibody or a TMEFF2×CD3 bispecific antibody.

[0897] Embodiment 52. The anti-CD38 antibody for use according to any one of Embodiments 1 to 51, further comprising administering one or more anti-cancer therapies to the subject.

[0898] Embodiment 53. The anti-CD38 antibody for use according to any one of Embodiments 1 to 52, wherein the one or more anti-cancer therapies are selected from autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulators and targeted cancer therapies.

[0899] Embodiment 54. The anti-CD38 antibody for use according to any one of Embodiments 1 to 53, wherein the one or more anti-cancer therapies are selected from lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, elotozumab, ixazomib, melphalan, dexamethasone, vincristine, cyclophosphamide, hydroxydaunorubicin, prednisone, rituximab, imatinib, dasatinib, nilotinib, bosutinib, ponatinib, bafitinib, sacatinib, tauzerti or darusertib, cytarabine, daunorubicin, idarubicin, mitoxantrone, hydroxyurea, decitabine, cladribine, fludarabine, topotecan, etoposide 6-thioguanine, corticosteroids, methotrexate, 6-mercaptopurine, azacitidine, arsenic trioxide and all-trans retinoic acid or any combination thereof.

[0900] Embodiment 55. The anti-CD38 antibody for use according to any one of embodiments 1 to 54, wherein the anti-CD38 antibody is administered at a dose of between about 8 mg / kg to about 16 mg / kg.

[0901] Embodiment 56. The anti-CD38 antibody for use according to any one of embodiments 1 to 55, wherein the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising between about 20 mg / mL to about 120 mg / mL of the anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mannitol, and about 0.04% w / v polysorbate-20 (PS-20); pH is about 5.5.

[0902] Embodiment 57. The anti-CD38 antibody for use according to any one of embodiments 1 to 53, wherein the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising about 1,800 mg of the anti-CD38 antibody and about 30,000 U of rHuPH20.

[0903] Embodiment 58. The anti-CD38 antibody for use according to Embodiment 57, wherein the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising about 120 mg / mL of the anti-CD38 antibody and about 2,000 U / mL of rHuPH20.

[0904] Embodiment 59. The anti-CD38 antibody for use according to any one of Embodiments 57 to 58, wherein the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising

[0905] between about 5 mM to about 15 mM histidine;

[0906] between about 100 mM and about 300 mM sorbitol;

[0907] Between about 0.01% w / v to about 0.04% w / v PS-20; and

[0908] Between about 1 mg / mL to about 2 mg / mL methionine, pH about 5.5 to 5.6.

[0909] Embodiment 60. The anti-CD38 antibody for use according to any one of Embodiments 57 to 59, wherein the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising

[0910] about 1,800 mg of the anti-CD38 antibody;

[0911] About 30,000U of rHuPH20;

[0912] About 10 mM histidine;

[0913] About 300 mM sorbitol;

[0914] About 0.04% (w / v) PS-20; and

[0915] About 1 mg / mL of methionine, pH about 5.6.

[0916] Embodiment 61. The anti-CD38 antibody for use according to any one of Embodiments 57 to 60, wherein the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising

[0917] about 120 mg / mL of the anti-CD38 antibody;

[0918] About 2,000 U / mL of rHuPH20;

[0919] About 10 mM histidine;

[0920] About 300 mM sorbitol;

[0921] About 0.04% (w / v) PS-20; and

[0922] About 1 mg / mL of methionine, pH about 5.6.

[0923] Embodiment 62. A BCMA×CD3 bispecific antibody for use in combination with an anti-CD38 antibody in treating a subject suffering from cancer.

[0924] Embodiment 63. The BCMA×CD3 bispecific antibody for use according to Embodiment 62, wherein said subject has been treated with an anti-CD38 antibody prior to administration of said BCMA×CD3 bispecific antibody.

[0925] Embodiment 64. The BCMA×CD3 bispecific antibody for use according to Embodiment 62 or 63, wherein the BCMA×CD3 bispecific antibody comprises a BCMA binding domain and a CD3 binding domain, the BCMA binding domain comprising HCDR1 of SEQ ID NO:23, HCDR2 of SEQ ID NO:24, HCDR3 of SEQ ID NO:25, LCDR1 of SEQ ID NO:26, LCDR2 of SEQ ID NO:27, and LCDR3 of SEQ ID NO:28, and the CD3 binding domain comprises HCDR1 of SEQ ID NO:33, HCDR2 of SEQ ID NO:34, HCDR3 of SEQ ID NO:35, LCDR1 of SEQ ID NO:36, LCDR2 of SEQ ID NO:37, and LCDR3 of SEQ ID NO:38.

[0926] Embodiment 65. The BCMA×CD3 bispecific antibody for use according to any one of Embodiments 62 to 64, wherein the BCMA binding domain comprises the VH of SEQ ID NO:29 and the VL of SEQ ID NO:30, and the CD3 binding domain comprises the VH of SEQ ID NO:39 and the VL of SEQ ID NO:40.

[0927] Embodiment 66. The BCMA×CD3 bispecific antibody for use according to any one of Embodiments 62 to 65, wherein the BCMA×CD3 bispecific antibody is of IgG4 isotype and comprises phenylalanine at position 405 and arginine at position 409 in HC1 and leucine at position 405 and lysine at position 409 in HC2, wherein the residues are numbered according to the EU index.

[0928] Embodiment 67. The BCMA×CD3 bispecific antibody for use according to any one of Embodiments 62 to 66, wherein the BCMA×CD3 bispecific antibody further comprises a proline at position 228, an alanine at position 234, and an alanine at position 235 in both HC1 and HC2.

[0929] Embodiment 68. The BCMA×CD3 antibody for use according to any one of Embodiments 62 to 67, wherein the BCMA×CD3 bispecific antibody comprises HC1 of SEQ ID NO:31, LC1 of SEQ ID NO:32, HC2 of SEQ ID NO:41, and LC2 of SEQ ID NO:42.

[0930] Embodiment 69. The BCMA×CD3 bispecific antibody for use according to any one of Embodiments 62 to 68, wherein the cancer is a BCMA-expressing cancer.

[0931] Embodiment 70. The BCMA×CD3 bispecific antibody for use according to any one of Embodiments 62 to 69, wherein the cancer is a hematological malignancy.

[0932] Embodiment 71. The BCMA×CD3 bispecific antibody for use according to any one of Embodiments 62 to 70, wherein the subject is relapsed or refractory to treatment with the anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotozumab, ixazomib, melphalan or thalidomide or any combination thereof.

[0933] Embodiment 72. The BCMA×CD3 bispecific antibody for use according to any one of Embodiments 62 to 71, wherein the subject is relapsed or refractory to treatment with said anti-CD38 antibody.

[0934] Embodiment 73. The BCMA×CD3 bispecific antibody for use according to any one of Embodiments 62 to 72, wherein the hematological malignancy is multiple myeloma, myeloma, DLBLC, CLL, Waldenstrom's hypergammaglobulinemia or non-Hodgkin's lymphoma.

[0935] Embodiment 74. The BCMA×CD3 bispecific antibody for use according to Embodiment 73, wherein the multiple myeloma is newly diagnosed multiple myeloma.

[0936] Embodiment 75. The BCMA×CD3 bispecific antibody for use according to Embodiment 74, wherein the multiple myeloma is relapsed or refractory multiple myeloma.

[0937] Embodiment 76. The BCMA×CD3 bispecific antibody for use according to Embodiment 74, wherein the multiple myeloma is high-risk multiple myeloma.

[0938] Embodiment 77. The BCMA×CD3 bispecific antibody for use according to Embodiment 76, wherein the subject suffering from the high-risk multiple myeloma has one or more chromosomal abnormalities, the one or more chromosomal abnormalities comprising:

[0939] t(4;14)(p16;q32);

[0940] t(14;16)(q32;q23);

[0941] del17p;

[0942] 1qAmp;

[0943] t(4;14)(p16;q32) and t(14;16)(q32;q23);

[0944] t(4;14)(p16;q32) and del17p;

[0945] t(14;16)(q32;q23) and del17p; or

[0946] t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p or any combination thereof.

[0947] Embodiment 78. The BCMA×CD3 bispecific antibody for use according to any one of Embodiments 62 to 77, wherein the anti-CD38 antibody comprises HCDR1 of SEQ ID NO:6, HCDR2 of SEQ ID NO:7, HCDR3 of SEQ ID NO:8, LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10 and LCDR3 of SEQ ID NO:11.

[0948] Embodiment 79. The BCMA×CD3 bispecific antibody for use according to any one of Embodiments 62 to 78, wherein the anti-CD38 antibody comprises the VH of SEQ ID NO:4 and the VL of SEQ ID NO:5.

[0949] Embodiment 80. The BCMA×CD3 bispecific antibody for use according to any one of Embodiments 62 to 79, wherein the anti-CD38 antibody is of IgG1 isotype.

[0950] Embodiment 81. The BCMA×CD3 bispecific antibody for use according to any one of Embodiments 62 to 80, wherein the anti-CD38 antibody comprises the HC of SEQ ID NO:12 and the LC of SEQ ID NO:13.

[0951] Embodiment 82. The BCMA×CD3 bispecific antibody for use according to any one of Embodiments 62 to 77, wherein the anti-CD38 antibody comprises

[0952] VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15;

[0953] VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17;

[0954] VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19; or

[0955] VH of SEQ ID NO:20 and VL of SEQ ID NO:21.

[0956] Embodiment 83. The BCMA×CD3 bispecific antibody for use according to Embodiment 82, wherein the anti-CD38 antibody is of IgG1 isotype.

[0957] Embodiment 84. The BCMA×CD3 bispecific antibody for use according to any one of Embodiments 62 to 83, wherein the anti-CD38 antibody is administered at a dose of between about 8 mg / kg to about 16 mg / kg.

[0958] Embodiment 85. The BCMA×CD3 bispecific antibody for use according to any one of Embodiments 62 to 84, wherein the BCMA×CD3 bispecific antibody and the anti-CD38 antibody are administered by intravenous injection.

[0959] Embodiment 86. The BCMA×CD3 bispecific antibody for use according to any one of Embodiments 62 to 84, wherein the BCMA×CD3 bispecific antibody is administered by intravenous injection and the anti-CD38 antibody is administered by subcutaneous injection.

[0960] Embodiment 87. The BCMA×CD3 bispecific antibody for use according to any one of Embodiments 62 to 86, wherein the subject is a human.

[0961] Embodiment 88. The BCMA×CD3 bispecific antibody for use according to any one of Embodiments 62 to 87, further comprising administering one or more anti-cancer therapies to the subject.

[0962] Embodiment 89. The BCMA×CD3 bispecific antibody for use according to Embodiment 88, wherein the one or more anti-cancer therapies are selected from autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulators and targeted cancer therapies.

[0963] Embodiment 90. The BCMA×CD3 bispecific antibody for use according to any one of Embodiments 88 to 89, wherein the one or more anti-cancer therapies are selected from lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, elotozumab, ixazomib, melphalan, prednisone or dexamethasone or any combination thereof.

[0964] Embodiment 91. The BCMA×CD3 bispecific antibody for use according to any one of Embodiments 62 to 90, wherein the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising between about 20 mg / mL to about 120 mg / mL of the anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mannitol and about 0.04% w / v polysorbate-20 (PS-20); pH is about 5.5.

[0965] Embodiment 92. The BCMA×CD3 bispecific antibody for use according to any one of Embodiments 62 to 90, wherein the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising about 1,800 mg of the anti-CD38 antibody and about 30,000 U of rHuPH20.

[0966] Embodiment 93. The BCMA×CD3 bispecific antibody for use according to Embodiment 92, wherein the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising about 120 mg / mL of the anti-CD38 antibody and about 2,000 U / mL of rHuPH20.

[0967] Embodiment 94. The BCMA×CD3 bispecific antibody for use according to any one of Embodiments 92 to 93, wherein the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising

[0968] between about 5 mM to about 15 mM histidine;

[0969] between about 100 mM and about 300 mM sorbitol;

[0970] Between about 0.01% w / v to about 0.04% w / v PS-20; and

[0971] Between about 1 mg / mL to about 2 mg / mL methionine, pH about 5.5 to 5.6.

[0972] Embodiment 95. The BCMA×CD3 bispecific antibody for use according to any one of Embodiments 92 to 94, wherein the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising

[0973] about 1,800 mg of the anti-CD38 antibody;

[0974] About 30,000U of rHuPH20;

[0975] About 10 mM histidine;

[0976] About 300 mM sorbitol;

[0977] About 0.04% (w / v) PS-20; and

[0978] About 1 mg / mL of methionine, pH about 5.6.

[0979] Embodiment 96. The BCMA×CD3 bispecific antibody for use according to any one of Embodiments 92 to 95, wherein the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising

[0980] about 120 mg / mL of the anti-CD38 antibody;

[0981] About 2,000 U / mL of rHuPH20;

[0982] About 10 mM histidine;

[0983] About 300 mM sorbitol;

[0984] About 0.04% (w / v) PS-20; and

[0985] About 1 mg / mL of methionine, pH about 5.6.

[0986] Embodiment 97. A BCMA×CD3 bispecific antibody for use in treating a subject having cancer, wherein the subject is relapsed or refractory to treatment with a prior anti-cancer therapeutic.

[0987] Embodiment 98. The BCMA×CD3 bispecific antibody for use according to Embodiment 97, wherein the BCMA×CD3 bispecific antibody comprises a BCMA binding domain and a CD3 binding domain, the BCMA binding domain comprising HCDR1 of SEQ ID NO:23, HCDR2 of SEQ ID NO:24, HCDR3 of SEQ ID NO:25, LCDR1 of SEQ ID NO:26, LCDR2 of SEQ ID NO:27, and LCDR3 of SEQ ID NO:28, and the CD3 binding domain comprising HCDR1 of SEQ ID NO:33, HCDR2 of SEQ ID NO:34, HCDR3 of SEQ ID NO:35, LCDR1 of SEQ ID NO:36, LCDR2 of SEQ ID NO:37, and LCDR3 of SEQ ID NO:38.

[0988] Embodiment 99. The BCMA×CD3 bispecific antibody for use according to Embodiment 97 or 98, wherein the BCMA binding domain comprises the VH of SEQ ID NO:29 and the VL of SEQ ID NO:30, and the CD3 binding domain comprises the VH of SEQ ID NO:39 and the VL of SEQ ID NO:40.

[0989] Embodiment 100. The BCMA×CD3 bispecific antibody for use according to any one of Embodiments 97 to 99, wherein the BCMA×CD3 bispecific antibody is of IgG4 isotype and comprises phenylalanine at position 405 and arginine at position 409 in HC1 and leucine at position 405 and lysine at position 409 in HC2, wherein the residues are numbered according to the EU index.

[0990] Embodiment 101. The BCMA×CD3 bispecific antibody for use according to Embodiment 100, wherein the BCMA×CD3 bispecific antibody further comprises a proline at position 228, an alanine at position 234, and an alanine at position 235 in both HC1 and HC2.

[0991] Embodiment 102. The BCMA×CD3 antibody for use according to any one of Embodiments 97 to 101, wherein the BCMA×CD3 bispecific antibody comprises HC1 of SEQ ID NO:31, LC1 of SEQ ID NO:32, HC2 of SEQ ID NO:41, and LC2 of SEQ ID NO:42.

[0992] Embodiment 103. The BCMA×CD3 bispecific antibody for use according to any one of Embodiments 97 to 102, wherein the cancer is a hematological malignancy.

[0993] Embodiment 104. The BCMA×CD3 bispecific antibody for use according to Embodiment 103, wherein the hematological malignancy is high-risk multiple myeloma.

[0994] Embodiment 105. The BCMA×CD3 bispecific antibody for use according to Embodiment 104, wherein the multiple myeloma is high-risk multiple myeloma.

[0995] Embodiment 106. The BCMA×CD3 bispecific antibody for use according to Embodiment 105, wherein the subject suffering from the high-risk multiple myeloma has one or more chromosomal abnormalities, the one or more chromosomal abnormalities comprising:

[0996] t(4;14)(p16;q32);

[0997] t(14;16)(q32;q23);

[0998] del17p;

[0999] 1qAmp;

[1000] t(4;14)(p16;q32) and t(14;16)(q32;q23);

[1001] t(4;14)(p16;q32) and del17p;

[1002] t(14;16)(q32;q23) and del17p; or

[1003] t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p or any combination thereof.

[1004] Embodiment 107. The BCMA×CD3 bispecific antibody for use according to any one of Embodiments 97 to 106, wherein the subject is refractory or relapsed to treatment with the anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotozumab, ixazomib, melphalan or thalidomide or any combination thereof.

[1005] Embodiment 108. The BCMA×CD3 bispecific antibody for use according to any one of Embodiments 97 to 107, wherein the subject is a relapse to treatment with said anti-CD38 antibody.

[1006] Embodiment 109. The BCMA×CD3 bispecific antibody for use according to any one of Embodiments 97 to 108, wherein the anti-CD38 antibody comprises HCDR1 of SEQ ID NO:6, HCDR2 of SEQ ID NO:7, HCDR3 of SEQ ID NO:8, LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10 and LCDR3 of SEQ ID NO:11.

[1007] Embodiment 110. The BCMA×CD3 bispecific antibody for use according to any one of Embodiments 97 to 109, wherein the anti-CD38 antibody comprises the VH of SEQ ID NO:4 and the VL of SEQ ID NO:5.

[1008] Embodiment 111. The BCMA×CD3 bispecific antibody for use according to any one of Embodiments 97 to 110, wherein the anti-CD38 antibody is of IgG1 isotype.

[1009] Embodiment 112. The BCMA×CD3 bispecific antibody for use according to any one of Embodiments 97 to 111, wherein the anti-CD38 antibody comprises the HC of SEQ ID NO:12 and the LC of SEQ ID NO:13.

[1010] Embodiment 113. The BCMA×CD3 bispecific antibody for use according to any one of Embodiments 97 to 108, wherein the anti-CD38 antibody comprises

[1011] VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15;

[1012] VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17;

[1013] VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19; or

[1014] VH of SEQ ID NO:20 and VL of SEQ ID NO:21.

[1015] Embodiment 114. The BCMA×CD3 bispecific antibody for use according to Embodiment 113, wherein the anti-CD38 antibody is of IgG1 isotype.

[1016] Embodiment 115. The BCMA×CD3 bispecific antibody for use according to any one of Embodiments 97 to 114, wherein the subject is a human.

[1017] Embodiment 116. The BCMA×CD3 bispecific antibody for use according to any one of Embodiments 97 to 115, further comprising administering one or more anti-cancer therapies to the subject.

[1018] Embodiment 117. The BCMA×CD3 bispecific antibody for use according to Embodiment 116, wherein the one or more anti-cancer therapies are selected from autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulators and targeted cancer therapies.

[1019] Embodiment 118. The BCMA×CD3 bispecific antibody for use according to Embodiment 116, wherein the one or more anti-cancer therapies are selected from lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, elotozumab, ixazomib, melphalan, prednisone or dexamethasone or any combination thereof.

[1020] Embodiment 119. A pharmaceutical composition comprising a BCMA×CD3 bispecific antibody and an anti-CD38 antibody, wherein the BCMA×CD3 bispecific antibody comprises a BCMA binding domain and a CD3 binding domain, wherein the BCMA binding domain comprises the VH of SEQ ID NO:29 and the VL of SEQ ID NO:30, wherein the CD3 binding domain comprises the VH of SEQ ID NO:39 and the VL of SEQID NO:40, and wherein the anti-CD38 antibody comprises the VH of SEQ ID NO:4 and the VL of SEQ ID NO:5.

[1021] Embodiment 120. A pharmaceutical composition according to Embodiment 119, wherein the BCMA×CD3 bispecific antibody comprises HC1 of SEQ ID NO:31, LC1 of SEQ ID NO:32, HC2 of SEQ ID NO:41, and LC2 of SEQ ID NO:42, and the anti-CD38 antibody comprises HC of SEQ ID NO:12 and LC of SEQ ID NO:13.

[1022] Embodiment 121. The pharmaceutical composition according to embodiment 119 or 120, which is a non-fixed combination.

[1023] Embodiment 122. A pharmaceutical composition according to Embodiment 121, comprising about 20 mg / mL to about 120 mg / mL of the anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mannitol and about 0.04% w / v polysorbate-20 (PS-20); pH is about 5.5.

[1024] Embodiment 123. The pharmaceutical composition of Embodiment 121, comprising about 1,800 mg of the anti-CD38 antibody and about 30,000 U of rHuPH20.

[1025] Embodiment 124. The pharmaceutical composition of Embodiment 123, comprising about 120 mg / mL of the anti-CD38 antibody and about 2,000 U / mL of rHuPH20.

[1026] Embodiment 125. The pharmaceutical composition of embodiment 124, further comprising one or more excipients.

[1027] Embodiment 126. The pharmaceutical composition of embodiment 125, wherein the one or more excipients are histidine, methionine, sorbitol or polysorbate-20 (PS-20), or any combination thereof.

[1028] Embodiment 127. The pharmaceutical composition according to embodiment 126, wherein the pharmaceutical composition comprises

[1029] between about 100 mg / mL to about 120 mg / mL of said anti-CD38 antibody;

[1030] between about 5 mM to about 15 mM histidine;

[1031] between about 100 mM and about 300 mM sorbitol;

[1032] Between about 0.01% w / v to about 0.04% w / v PS-20; and

[1033] Between about 1 mg / mL to about 2 mg / mL methionine, pH about 5.5 to 5.6.

[1034] Embodiment 128. The pharmaceutical composition of Embodiment 127, comprising about 10 mM histidine.

[1035] Embodiment 129. The pharmaceutical composition of embodiment 127 or 128, comprising about 300 mM sorbitol.

[1036] Embodiment 130. The pharmaceutical composition of any one of Embodiments 127 to 129, comprising about 0.04% (w / v) PS-20.

[1037] Embodiment 131. The pharmaceutical composition of any one of Embodiments 127 to 130, comprising about 1 mg / mL methionine.

[1038] Embodiment 132. A pharmaceutical composition according to any one of Embodiments 127 to 131, comprising

[1039] about 1,800 mg of the anti-CD38 antibody;

[1040] About 30,000U of rHuPH20;

[1041] About 10 mM histidine;

[1042] About 300 mM sorbitol;

[1043] About 0.04% (w / v) PS-20; and

[1044] About 1 mg / mL of methionine, pH about 5.6.

[1045] Embodiment 133. A pharmaceutical composition according to any one of Embodiments 127 to 132, comprising

[1046] about 120 mg / mL of the anti-CD38 antibody;

[1047] About 2,000 U / mL of rHuPH20;

[1048] About 10 mM histidine;

[1049] About 300 mM sorbitol;

[1050] About 0.04% (w / v) PS-20; and

[1051] About 1 mg / mL of methionine, pH about 5.6.

[1052] Embodiment 134. A kit comprising a pharmaceutical composition according to any one of Embodiments 119 to 133.

[1053] Embodiment 135. A T cell redirecting therapeutic that binds GPRC5D for use in combination with an anti-CD38 antibody to treat a subject having cancer.

[1054] Embodiment 136. The GPRC5D-binding T cell redirecting therapeutic for use according to Embodiment 135, wherein the anti-CD38 antibody is administered to the subject prior to administration of the GPRC5D-binding T cell redirecting therapeutic.

[1055] Embodiment 137. The GPRC5D-binding T cell redirecting therapeutic for use according to Embodiment 135 or 136, wherein the subject is relapsed or refractory to treatment with a previous anti-cancer therapeutic.

[1056] Embodiment 138. The GPRC5D-binding T cell redirecting therapeutic for use according to any one of Embodiments 135 to 137, wherein the cancer is a GPRC5D-expressing cancer.

[1057] Embodiment 139. The GPRC5D-binding T cell redirecting therapeutic for use according to any one of Embodiments 135 to 138, wherein the GPRC5D-expressing cancer is a hematological malignancy or a solid tumor.

[1058] Embodiment 140. The GPRC5D-binding T cell redirecting therapeutic for use according to Embodiment 139, wherein the hematological malignancy is leukemia, lymphoma or multiple myeloma.

[1059] Embodiment 141. The GPRC5D-binding T cell redirecting therapeutic agent used according to Embodiment 139, wherein the solid tumor is ovarian cancer, lung cancer, gastric cancer, prostate cancer, kidney cancer, liver cancer, pancreatic cancer, colon cancer, esophageal cancer, bladder cancer, cervical tumor or malignant melanoma.

[1060] Embodiment 142. The GPRC5D-binding T cell redirecting therapeutic for use according to any one of Embodiments 135 to 141, wherein the subject is relapsed or refractory to treatment with the anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotozumab, ixazomib, melphalan or thalidomide or any combination thereof.

[1061] Embodiment 143. The GPRC5D-binding T cell redirecting therapeutic for use according to any one of Embodiments 135 to 142, wherein the subject is relapsed or refractory to treatment with the anti-CD38 antibody.

[1062] Embodiment 144. The GPRC5D-binding T cell redirecting therapeutic for use according to any one of Embodiments 140 to 143, wherein the multiple myeloma is newly diagnosed multiple myeloma.

[1063] Embodiment 145. The GPRC5D-binding T cell redirecting therapeutic for use according to any one of Embodiments 140 to 143, wherein the multiple myeloma is relapsed or refractory multiple myeloma.

[1064] Embodiment 146. The GPRC5D-binding T cell redirecting therapeutic for use according to any one of Embodiments 140 to 145, wherein the multiple myeloma is high-risk multiple myeloma.

[1065] Embodiment 147. The GPRC5D-binding T cell redirecting therapeutic for use according to Embodiment 146, wherein the subject with the high-risk multiple myeloma has one or more chromosomal abnormalities, the one or more chromosomal abnormalities comprising:

[1066] t(4;14)(p16;q32);

[1067] t(14;16)(q32;q23);

[1068] del17p;

[1069] 1qAmp;

[1070] t(4;14)(p16;q32) and t(14;16)(q32;q23);

[1071] t(4;14)(p16;q32) and del17p;

[1072] t(14;16)(q32;q23) and del17p; or

[1073] t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p or any combination thereof.

[1074] Embodiment 148. The T cell redirecting therapeutic agent that binds to GPRC5D for use according to any one of Embodiments 135 to 147, wherein the T cell redirecting therapeutic agent binds to CD3, CD3ε (CD3ε), CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, BTNL8, PD-1, CD195 or NKG2C.

[1075] Embodiment 149. The GPRC5D-binding T cell redirecting therapeutic agent for use according to any one of Embodiments 135 to 148, wherein the T cell redirecting therapeutic agent comprises a GPRC5D binding domain and a CD3 binding domain, the GPRC5D binding domain comprising HCDR1 of SEQ ID NO:43, HCDR2 of SEQ ID NO:44, HCDR3 of SEQ ID NO:45, LCDR1 of SEQ ID NO:46, LCDR2 of SEQ ID NO:47, and LCDR3 of SEQ ID NO:48, and the CD3 binding domain comprises HCDR1 of SEQ ID NO:33, HCDR2 of SEQ ID NO:34, HCDR3 of SEQ ID NO:35, LCDR1 of SEQ ID NO:36, LCDR2 of SEQ ID NO:37, and LCDR3 of SEQ ID NO:38.

[1076] Embodiment 150. The GPRC5D-binding T cell redirecting therapeutic agent for use according to any one of Embodiments 135 to 149, wherein the GPRC5D binding domain comprises the VH of SEQ ID NO:49 and the VL of SEQ ID NO:50, and the CD3 binding domain comprises the VH of SEQ ID NO:39 and the VL of SEQ ID NO:40.

[1077] Embodiment 151. The GPRC5D-binding T cell redirection therapeutic agent used according to any one of Embodiments 135 to 150, wherein the GPRC5C-binding T cell redirection therapeutic agent is a multispecific antibody, a CAR, or a T cell expressing the CAR.

[1078] Embodiment 152. The GPRC5D-binding T cell redirecting therapeutic for use according to Embodiment 151, wherein the multispecific antibody is of IgG1, IgG2, IgG3 or IgG4 isotype.

[1079] Embodiment 153. The GPRC5D-binding T cell redirecting therapeutic for use according to any one of Embodiments 151 to 152, wherein the multispecific antibody comprises one or more Fc substitutions that reduce binding of the multispecific antibody to an Fcγ receptor (FcγR).

[1080] Embodiment 154. The GPRC5D-binding T cell redirecting therapeutic for use according to any one of Embodiments 151 to 153, wherein the one or more Fc substitutions are selected from F234A / L235A on IgG4, L234A / L235A on IgG1, V234A / G237A / P238S / H268A / V309L / A330S / P331S on IgG2, F234A / L235A on IgG4, S228P / F234A / L235A on IgG4, N297A on all Ig isotypes, V234A / G237A on IgG2, K214T / E233P / L234V / L235A on IgG1. 5A / G236-deletion / A327G / P331A / D365E / L358M on IgG2, H268Q / V309L / A330S / P331S on IgG2, S267E / L328F on IgG1, L234F / L235E / D265A on IgG1, L234A / L235A / G237A / P238S / H268A / A330S / P331S on IgG1, S228P / F234A / L235A / G237A / P238S on IgG4, and S228P / F234A / L235A / G236-deletion / G237A / P238S on IgG4, where the residues are numbered according to the EU index.

[1081] Embodiment 155. The GPRC5D-binding T cell redirecting therapeutic agent for use according to Embodiment 154, wherein the multispecific antibody further comprises an S228P substitution.

[1082] Embodiment 156. The GPRC5D-binding T cell redirecting therapeutic agent for use according to any one of Embodiments 151 to 155, wherein the multispecific antibody comprises one or more asymmetric substitutions in the first CH3 domain or in the second CH3 domain or in both the first CH3 domain and the second CH3 domain.

[1083] Embodiment 157. The T cell redirecting therapeutic agent that binds to GPRC5D for use according to any one of Embodiments 156, wherein the one or more asymmetric substitutions are selected from F450L / K409R, wild type / F409L_R409K, T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S and T366W / T366S_L368A_Y407V, L351Y_F405A_Y407V / T394W, T366I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F and T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W.

[1084] Embodiment 158. The GPRC5D-binding T cell redirecting therapeutic agent used according to any one of Embodiments 151 to 157, wherein the multispecific antibody comprises HC1 of SEQ ID NO:51, LC1 of SEQ ID NO:52, HC2 of SEQ ID NO:41, and LC2 of SEQ ID NO:42.

[1085] Embodiment 159. The GPRC5D-binding T cell redirecting therapeutic agent for use according to any one of Embodiments 135 to 158, wherein the anti-CD38 antibody comprises HCDR1 of SEQ ID NO:6, HCDR2 of SEQ ID NO:7, HCDR3 of SEQ ID NO:8, LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10, and LCDR3 of SEQ ID NO:11.

[1086] Embodiment 160. The GPRC5D-binding T cell redirecting therapeutic for use according to any one of Embodiments 135 to 159, wherein the anti-CD38 antibody comprises the VH of SEQ ID NO:4 and the VL of SEQ ID NO:5.

[1087] Embodiment 161. The GPRC5D-binding T cell redirecting therapeutic for use according to any one of Embodiments 135 to 160, wherein the anti-CD38 antibody is of the IgG1 isotype.

[1088] Embodiment 162. The GPRC5D-binding T cell redirecting therapeutic for use according to any one of Embodiments 135 to 161, wherein the anti-CD38 antibody comprises the HC of SEQ ID NO:12 and the LC of SEQ ID NO:13.

[1089] Embodiment 163. The T cell redirecting therapeutic agent that binds to GPRC5D for use according to any one of Embodiments 135 to 158, wherein the anti-CD38 antibody comprises

[1090] VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15;

[1091] VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17;

[1092] VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19; or

[1093] VH of SEQ ID NO:20 and VL of SEQ ID NO:21.

[1094] Embodiment 164. The GPRC5D-binding T cell redirecting therapeutic for use according to Embodiment 163, wherein the anti-CD38 antibody is of the IgG1 isotype.

[1095] Embodiment 165. The GPRC5D-binding T cell redirecting therapeutic for use according to any one of Embodiments 135 to 164, wherein the anti-CD38 antibody is administered at a dose of between about 8 mg / kg to about 16 mg / kg.

[1096] Embodiment 166. The GPRC5D-binding T cell redirecting therapeutic for use according to any one of Embodiments 135 to 165, wherein the GPRC5D-binding T cell redirecting therapeutic and the anti-CD38 antibody are administered by intravenous injection.

[1097] Embodiment 167. The GPRC5D-binding T cell redirecting therapeutic for use according to any one of Embodiments 135 to 165, wherein the GPRC5D-binding T cell redirecting therapeutic is administered by intravenous injection and the anti-CD38 antibody is administered by subcutaneous injection.

[1098] Embodiment 168. The GPRC5D-binding T cell redirecting therapeutic for use according to any one of Embodiments 135 to 167, wherein the subject is a human.

[1099] Embodiment 169. The GPRC5D-binding T cell redirecting therapeutic agent for use according to any one of Embodiments 135 to 168, wherein the GPRC5D-binding T cell redirecting therapeutic agent is a GPRC5D×CD3 bispecific antibody.

[1100] Embodiment 170. The GPRC5D-binding T cell redirecting therapeutic for use according to any one of Embodiments 135 to 170 further comprises administering one or more anti-cancer therapies to the subject.

[1101] Embodiment 171. The GPRC5D-binding T cell redirecting therapeutic agent used according to Embodiment 170, wherein the one or more anti-cancer therapies are selected from autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulators and targeted cancer therapies.

[1102] Embodiment 172. The GPRC5D-binding T cell redirecting therapeutic agent used according to Embodiment 170, wherein the one or more anti-cancer therapies are selected from lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, elotozumab, ixazomib, melphalan, dexamethasone or prednisone.

[1103] Embodiment 173. The GPRC5D-binding T cell redirecting therapeutic agent for use according to any one of Embodiments 135 to 172, wherein the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising between about 20 mg / mL and about 120 mg / mL of the anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mannitol and about 0.04% w / v polysorbate-20 (PS-20); pH is about 5.5.

[1104] Embodiment 174. The GPRC5D-binding T cell redirecting therapeutic agent for use according to any one of Embodiments 135 to 172, wherein the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising about 1,800 mg of the anti-CD38 antibody and about 30,000 U of rHuPH20.

[1105] Embodiment 175. The GPRC5D-binding T cell redirecting therapeutic agent used according to Embodiment 174, wherein the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising about 120 mg / mL of the anti-CD38 antibody and about 2,000 U / mL of rHuPH20.

[1106] Embodiment 176. The T cell redirecting therapeutic agent that binds to GPRC5D for use according to Embodiment 174 or 175, wherein the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition, the pharmaceutical composition comprising

[1107] between about 100 mg / mL to about 120 mg / mL of said anti-CD38 antibody;

[1108] between about 5 mM to about 15 mM histidine;

[1109] between about 100 mM and about 300 mM sorbitol;

[1110] Between about 0.01% w / v to about 0.04% w / v PS-20; and

[1111] Between about 1 mg / mL to about 2 mg / mL methionine, pH about 5.5 to 5.6.

[1112] Embodiment 177. The T cell redirecting therapeutic agent that binds to GPRC5D for use according to any one of Embodiments 174 to 176, wherein the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising

[1113] about 1,800 mg of the anti-CD38 antibody;

[1114] About 30,000U of rHuPH20;

[1115] About 10 mM histidine;

[1116] About 300 mM sorbitol;

[1117] About 0.04% (w / v) PS-20; and

[1118] About 1 mg / mL of methionine, pH about 5.6.

[1119] Embodiment 178. The T cell redirecting therapeutic agent that binds to GPRC5D for use according to any one of Embodiments 174 to 177, wherein the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising

[1120] about 120 mg / mL of the anti-CD38 antibody;

[1121] About 2,000 U / mL of rHuPH20;

[1122] About 10 mM histidine;

[1123] About 300 mM sorbitol;

[1124] About 0.04% (w / v) PS-20; and

[1125] About 1 mg / mL of methionine, pH about 5.6.

[1126] Embodiment 179. A GPRC5D×CD3 bispecific antibody for use in treating a subject having cancer, wherein the subject is relapsed or refractory to treatment with a prior anti-cancer therapeutic.

[1127] Embodiment 180. The GPRC5D×CD3 bispecific antibody for use according to Embodiment 179, wherein the GPRC5D×CD3 bispecific antibody comprises a GPRC5D binding domain and a CD3 binding domain, the GPRC5D binding domain comprising HCDR1 of SEQ ID NO:43, HCDR2 of SEQ ID NO:44, HCDR3 of SEQ ID NO:45, LCDR1 of SEQ ID NO:46, LCDR2 of SEQ ID NO:47, and LCDR3 of SEQ ID NO:48, and the CD3 binding domain comprises HCDR1 of SEQ ID NO:33, HCDR2 of SEQ ID NO:34, HCDR3 of SEQ ID NO:35, LCDR1 of SEQ ID NO:36, LCDR2 of SEQ ID NO:37, and LCDR3 of SEQ ID NO:38.

[1128] Embodiment 181. The GPRC5D×CD3 bispecific antibody for use according to Embodiment 179 or 180, wherein the GPRC5D binding domain comprises the VH of SEQ ID NO:49 and the VL of SEQ ID NO:50, and the CD3 binding domain comprises the VH of SEQ ID NO:39 and the VL of SEQ ID NO:40.

[1129] Embodiment 182. The GPRC5D×CD3 bispecific antibody for use according to any one of Embodiments 179 to 181, wherein the GPRC5D×CD3 bispecific antibody is of the IgG4 isotype and comprises a phenylalanine at position 405 and an arginine at position 409 in HC1 and a leucine at position 405 and a lysine at position 409 in HC2, wherein the residues are numbered according to the EU index.

[1130] Embodiment 183. The GPRC5D×CD3 bispecific antibody for use according to Embodiment 182, wherein the GPRC5D×CD3 bispecific antibody further comprises a proline at position 228, an alanine at position 234, and an alanine at position 235 in both HC1 and HC2.

[1131] Embodiment 184. The GPRC5D×CD3 bispecific antibody for use according to any one of Embodiments 179 to 183, wherein the GPRC5D×CD3 bispecific antibody comprises HC1 of SEQ ID NO:51, LC1 of SEQ ID NO:52, HC2 of SEQ ID NO:41 and LC2 of SEQ ID NO:42.

[1132] Embodiment 185. The GPRC5D×CD3 bispecific antibody for use according to any one of Embodiments 179 to 184, wherein the cancer is a hematological malignancy or a solid tumor.

[1133] Embodiment 186. The GPRC5D×CD3 bispecific antibody for use according to Embodiment 185, wherein the cancer is multiple myeloma, lymphoma, melanoma, breast cancer, endometrial cancer, ovarian cancer, lung cancer, gastric cancer, prostate cancer, kidney cancer, liver cancer, pancreatic cancer, colon cancer, esophageal cancer, bladder cancer or cervical tumor.

[1134] Embodiment 187. The GPRC5D×CD3 bispecific antibody for use according to Embodiment 186, wherein the multiple myeloma is high-risk multiple myeloma.

[1135] Embodiment 188. The GPRC5D×CD3 bispecific antibody for use according to Embodiment 187, wherein the subject suffering from the high-risk multiple myeloma has one or more chromosomal abnormalities, the one or more chromosomal abnormalities comprising:

[1136] t(4;14)(p16;q32);

[1137] t(14;16)(q32;q23);

[1138] del17p;

[1139] 1qAmp;

[1140] t(4;14)(p16;q32) and t(14;16)(q32;q23);

[1141] t(4;14)(p16;q32) and del17p;

[1142] t(14;16)(q32;q23) and del17p; or

[1143] t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p or any combination thereof.

[1144] Embodiment 189. The GPRC5D×CD3 bispecific antibody for use according to any one of Embodiments 179 to 188, wherein the subject is refractory or relapsed to treatment with the anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotozumab, ixazomib, melphalan or thalidomide or any combination thereof.

[1145] Embodiment 190. The GPRC5D×CD3 bispecific antibody for use according to any one of Embodiments 179 to 189, wherein the subject is relapsed or refractory to treatment with the anti-CD38 antibody.

[1146] Embodiment 191. The GPRC5D×CD3 bispecific antibody for use according to any one of Embodiments 179 to 190, wherein the anti-CD38 antibody comprises HCDR1 of SEQ ID NO:6, HCDR2 of SEQ ID NO:7, HCDR3 of SEQ ID NO:8, LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10 and LCDR3 of SEQ ID NO:11.

[1147] Embodiment 192. The GPRC5D×CD3 bispecific antibody for use according to any one of Embodiments 179 to 191, wherein the anti-CD38 antibody comprises the VH of SEQ ID NO:4 and the VL of SEQ ID NO:5.

[1148] Embodiment 193. The GPRC5D×CD3 bispecific antibody for use according to any one of Embodiments 179 to 192, wherein the anti-CD38 antibody is of the IgG1 isotype.

[1149] Embodiment 194. The GPRC5D×CD3 bispecific antibody for use according to any one of Embodiments 179 to 193, wherein the anti-CD38 antibody comprises the HC of SEQ ID NO:12 and the LC of SEQ ID NO:13.

[1150] Embodiment 195. The GPRC5D×CD3 bispecific antibody for use according to any one of Embodiments 179 to 190, wherein the anti-CD38 antibody comprises

[1151] VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15;

[1152] VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17;

[1153] VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19; or

[1154] VH of SEQ ID NO:20 and VL of SEQ ID NO:21.

[1155] Embodiment 196. The GPRC5D×CD3 bispecific antibody for use according to Embodiment 195, wherein the anti-CD38 antibody is of IgG1 isotype.

[1156] Embodiment 197. The GPRC5D×CD3 bispecific antibody for use according to any one of Embodiments 179 to 196, wherein the subject is a human.

[1157] Embodiment 198. The GPRC5D×CD3 bispecific antibody for use according to any one of Embodiments 179 to 197, further comprising administering one or more anti-cancer therapies to the subject.

[1158] Embodiment 199. The GPRC5D×CD3 bispecific antibody for use according to Embodiment 198, wherein the one or more anti-cancer therapies are selected from autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulators and targeted cancer therapies.

[1159] Embodiment 200. The GPRC5D×CD3 bispecific antibody for use according to Embodiment 198, wherein the one or more anti-cancer therapies are selected from lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, elotozumab, ixazomib, melphalan, dexamethasone, vincristine, cyclophosphamide, hydroxydaunorubicin, prednisone, rituximab, imatinib, dasatinib, nilotinib, bosutinib, ponatinib, bafitinib, sacatinib, tauzerti or darusertib, cytarabine, daunorubicin, idarubicin, mitoxantrone, hydroxyurea, decitabine, cladribine, fludarabine, topotecan, etoposide 6-thioguanine, corticosteroids, methotrexate, 6-mercaptopurine, azacitidine, arsenic trioxide and all-trans retinoic acid or any combination thereof.

[1160] Embodiment 201. A pharmaceutical combination comprising a GPRC5D×CD3 bispecific antibody and an anti-CD38 antibody, wherein the GPRC5D×CD3 bispecific antibody comprises a GPRC5D binding domain and a CD3 binding domain, wherein the GPRC5D binding domain comprises the HCDR1 of SEQ ID NO:43, the HCDR2 of SEQ ID NO:44, the HCDR3 of SEQ ID NO:45, the LCDR1 of SEQ ID NO:46, the LCDR2 of SEQ ID NO:47, and the LCDR3 of SEQ ID NO:48, wherein the CD3 binding domain comprises the HCDR1 of SEQ ID NO:33, the HCDR2 of SEQ ID NO:34, the HCDR3 of SEQ ID NO:35, the LCDR1 of SEQ ID NO:36, the LCDR2 of SEQ ID NO:37, and the LCDR3 of SEQ ID NO:38, and wherein the anti-CD38 antibody comprises the HCDR1 of SEQ ID NO:6, the HCDR2 of SEQ ID NO:7, the HCDR3 of SEQ ID NO:8, the LCDR1 of SEQ ID NO:9, the LCDR2 of SEQ ID NO:10 LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10 and LCDR3 of SEQ ID NO:11.

[1161] Embodiment 202. A drug combination according to Embodiment 201, wherein the GPRC5D binding domain comprises the VH of SEQ ID NO:49 and the VL of SEQ ID NO:50, and the CD3 binding domain comprises the VH of SEQ ID NO:39 and the VL of SEQ ID NO:40, and the anti-CD38 antibody comprises the VH of SEQ ID NO:4 and the VL of SEQ ID NO:5.

[1162] Embodiment 203. A drug combination according to Embodiment 201 or 202, wherein the GPRC5D×CD3 bispecific antibody comprises HC1 of SEQ ID NO:51, LC1 of SEQ ID NO:52, HC2 of SEQ ID NO:41 and LC2 of SEQ ID NO:42, and the anti-CD38 antibody comprises HC of SEQ ID NO:12 and LC of SEQ ID NO:13.

[1163] Embodiment 204. The drug combination according to any one of Embodiments 201 to 203, which is a non-fixed combination.

[1164] Embodiment 205. The pharmaceutical combination according to embodiment 204, comprising about 20 mg / mL to about 120 mg / mL of the anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mannitol and about 0.04% w / v polysorbate-20 (PS-20); pH is about 5.5.

[1165] Embodiment 206. The pharmaceutical combination according to Embodiment 204, comprising about 1,800 mg of the anti-CD38 antibody and about 30,000 U of rHuPH20.

[1166] Embodiment 207. The pharmaceutical composition of Embodiment 206, comprising about 120 mg / mL of the anti-CD38 antibody and about 2,000 U / mL of rHuPH20.

[1167] Embodiment 208. The pharmaceutical combination according to embodiment 207, further comprising one or more excipients.

[1168] Embodiment 209. The pharmaceutical combination according to embodiment 208, wherein the one or more excipients are histidine, methionine, sorbitol or polysorbate-20 (PS-20) or any combination thereof.

[1169] Embodiment 210. The pharmaceutical combination according to embodiment 209, wherein the pharmaceutical composition comprises

[1170] between about 100 mg / mL to about 120 mg / mL of said anti-CD38 antibody;

[1171] between about 5 mM to about 15 mM histidine;

[1172] between about 100 mM and about 300 mM sorbitol;

[1173] Between about 0.01% w / v to about 0.04% w / v PS-20; and

[1174] Between about 1 mg / mL to about 2 mg / mL methionine, pH about 5.5 to 5.6.

[1175] Embodiment 211. The pharmaceutical combination according to embodiment 209 or 210, comprising about 10 mM histidine.

[1176] Embodiment 212. The pharmaceutical combination according to any one of Embodiments 209 to 211, comprising about 300 mM sorbitol.

[1177] Embodiment 213. The pharmaceutical combination according to any one of Embodiments 209 to 212, comprising about 0.04% (w / v) PS-20.

[1178] Embodiment 214. The pharmaceutical combination according to any one of Embodiments 209 to 213, comprising about 1 mg / mL of methionine.

[1179] Embodiment 215. A pharmaceutical combination according to any one of Embodiments 209 to 214, comprising

[1180] about 1,800 mg of the anti-CD38 antibody;

[1181] About 30,000U of rHuPH20;

[1182] About 10 mM histidine;

[1183] About 300 mM sorbitol;

[1184] About 0.04% (w / v) PS-20; and

[1185] About 1 mg / mL of methionine, pH about 5.6.

[1186] Embodiment 216. A pharmaceutical combination according to any one of Embodiments 209 to 215, comprising

[1187] about 120 mg / mL of the anti-CD38 antibody;

[1188] About 2,000 U / mL of rHuPH20;

[1189] About 10 mM histidine;

[1190] About 300 mM sorbitol;

[1191] About 0.04% (w / v) PS-20; and

[1192] About 1 mg / mL of methionine, pH about 5.6.

[1193] Embodiment 217. A kit comprising the pharmaceutical combination according to any one of embodiments 201 to 215.

[1194] Embodiment 218. A T cell redirecting therapeutic that binds CD19 for use in combination with an anti-CD38 antibody to treat a subject having cancer.

[1195] Embodiment 219. An anti-CD38 antibody for enhancing the efficacy of a CD19-binding T cell redirecting therapeutic in a subject having cancer, wherein the subject has been treated with the anti-CD38 antibody prior to administration of the CD19-binding T cell redirecting therapeutic.

[1196] Embodiment 220. The T cell redirecting therapeutic or the anti-CD38 antibody for use according to Embodiment 218 or 219, wherein the subject is relapsed or refractory to treatment with a previous anti-cancer therapeutic.

[1197] Embodiment 221. The T cell redirecting therapeutic or the anti-CD38 antibody for use according to any one of Embodiments 218 to 221, wherein the cancer is a hematological malignancy or a solid tumor.

[1198] Embodiment 222. The T cell redirecting therapeutic agent or the anti-CD38 antibody used according to Embodiment 221, wherein the hematological malignancy is lymphoma, B cell malignancy, Hodgkin lymphoma, non-Hodgkin lymphoma, DLBLC, FL, MCL, marginal zone B cell lymphoma (MZL), mucosa-associated lymphoid tissue lymphoma (MALT), CLL, ALL, AML, Waldenstrom's macroglobulinemia or T cell lymphoma.

[1199] Embodiment 223. The T cell redirecting therapeutic agent or the anti-CD38 antibody used according to Embodiment 221, wherein the solid tumor is lung cancer, liver cancer, cervical cancer, colon cancer, breast cancer, ovarian cancer, pancreatic cancer, melanoma, glioblastoma, prostate cancer, esophageal cancer or gastric cancer.

[1200] Embodiment 224. The T cell redirecting therapeutic agent or the anti-CD38 antibody for use according to any one of Embodiments 218 to 223, wherein the T cell redirecting therapeutic agent binds to CD3ε (CD3ε), CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, BTNL8, PD-1, CD195 or NKG2C.

[1201] Embodiment 225. The T cell redirecting therapeutic agent or the anti-CD38 antibody for use according to any one of Embodiments 218 to 224, wherein the T cell redirecting therapeutic agent that binds to CD19 comprises the CD19 binding domain of: blinatumomab, axicabtagene ciloleucel, tisagenlecleucel-t, inebilizumab, lisocabtagene maraleucel, XmAb-5574, CIK-CAR.CD19, ICTCAR-011, IM-19, JCAR-014, loncastuximab tesirine, MB-CART2019.1, OXS-1550, PBCAR-0191, PCAR-019, PCAR-119, Senl-001, TI-1007, XmAb-5 871, PTG-01, PZ01, Senl_1904A, Senl_1904B, UCART-19, CSG-CD19, DI-B4, ET-190, GC-007F or GC-022.

[1202] Embodiment 226. The T cell redirecting therapeutic agent or the anti-CD38 antibody for use according to any one of Embodiments 218 to 225, wherein the T cell redirecting therapeutic agent that binds to CD19 comprises: blinatumomab, axicabtagene ciloleucel, tisagenlecleucel-t, inebilizumab, lisocabtagenemaraleucel, XmAb-5574, CIK-CAR.CD19, ICTCAR-011, IM-19, JCAR-014, loncastuximabtesirine, MB-CART201 9.1, OXS-1550, PBCAR-0191, PCAR-019, PCAR-119, Senl-001, TI-1007, XmAb-5871, PTG-0 1. PZ01, Senl_1904A, Senl_1904B, UCART-19, CSG-CD19, DI-B4, ET-190, GC-007F or GC-022.

[1203] Embodiment 227. The T cell redirection therapeutic agent or the anti-CD38 antibody used according to any one of Embodiments 218 to 226, wherein the CD19-binding T cell redirection therapeutic agent is a multispecific antibody, a CAR, or a T cell expressing the CAR.

[1204] Embodiment 228. The T cell redirecting therapeutic agent or the anti-CD38 antibody for use according to any one of Embodiments 218 to 227, wherein the anti-CD38 antibody comprises HCDR1 of SEQ ID NO:6, HCDR2 of SEQ ID NO:7, HCDR3 of SEQ ID NO:8, LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10 and LCDR3 of SEQ ID NO:11.

[1205] Embodiment 229. The T cell redirecting therapeutic agent or the anti-CD38 antibody for use according to any one of Embodiments 218 to 228, wherein the anti-CD38 antibody comprises the VH of SEQ ID NO:4 and the VL of SEQ ID NO:5.

[1206] Embodiment 230. The T cell redirecting therapeutic or the anti-CD38 antibody for use according to any one of Embodiments 218 to 229, wherein the anti-CD38 antibody is of the IgG1 isotype.

[1207] Embodiment 231. The T cell redirecting therapeutic agent or the anti-CD38 antibody for use according to any one of Embodiments 218 to 230, wherein the anti-CD38 antibody comprises the HC of SEQ ID NO:12 and the LC of SEQ ID NO:13.

[1208] Embodiment 232. The T cell redirecting therapeutic agent or the anti-CD38 antibody for use according to any one of Embodiments 218 to 227, wherein the anti-CD38 antibody comprises

[1209] VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15;

[1210] VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17;

[1211] VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19; or

[1212] VH of SEQ ID NO:20 and VL of SEQ ID NO:21.

[1213] Embodiment 233. The T cell redirecting therapeutic agent or the anti-CD38 antibody for use according to Embodiment 232, wherein the anti-CD38 antibody is of IgG1 isotype.

[1214] Embodiment 234. The T cell redirecting therapeutic or the anti-CD38 antibody for use according to any one of Embodiments 218 to 233, wherein the anti-CD38 antibody is administered at a dose of between about 8 mg / kg to about 16 mg / kg.

[1215] Embodiment 235. The T cell redirecting therapeutic or the anti-CD38 antibody for use according to any one of Embodiments 218 to 234, wherein the CD19 binding T cell redirecting therapeutic and the anti-CD38 antibody are administered by intravenous injection.

[1216] Embodiment 236. The T cell redirecting therapeutic or the anti-CD38 antibody for use according to any one of Embodiments 218 to 234, wherein the CD19-binding T cell redirecting therapeutic is administered by intravenous injection and the anti-CD38 antibody is administered by subcutaneous injection.

[1217] Embodiment 237. The T cell redirecting therapeutic or the anti-CD38 antibody for use according to any one of Embodiments 218 to 236, wherein the subject is a human.

[1218] Embodiment 238. The T cell redirecting therapeutic or the anti-CD38 antibody for use according to any one of Embodiments 218 to 237, wherein the CD19-binding T cell redirecting therapeutic is a CD19×CD3 bispecific antibody.

[1219] Embodiment 239. The T cell redirecting therapeutic agent or the anti-CD38 antibody for use according to any one of Embodiments 218 to 238 further comprises administering one or more anti-cancer therapies to the subject.

[1220] Embodiment 240. The T cell redirecting therapeutic agent or the anti-CD38 antibody used according to Embodiment 238, wherein the one or more anti-cancer therapies are selected from autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulators and targeted cancer therapies.

[1221] Embodiment 241. A drug combination comprising a CD19×CD3 bispecific antibody and an anti-CD38 antibody, wherein the CD19×CD3 bispecific antibody comprises blinatumomab of SEQ ID NO:53, and the anti-CD38 antibody comprises HCDR1 of SEQ ID NO:6, HCDR2 of SEQ ID NO:7, HCDR3 of SEQ ID NO:8, LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10, and LCDR3 of SEQ ID NO:11.

[1222] Embodiment 242. The drug combination according to Embodiment 241, wherein the anti-CD38 antibody comprises the VH of SEQ ID NO:4 and the VL of SEQ ID NO:5.

[1223] Embodiment 243. The drug combination according to Embodiment 241 or 242, wherein the anti-CD38 antibody comprises the HC of SEQ ID NO:12 and the LC of SEQ ID NO:13.

[1224] Embodiment 244. The drug combination according to any one of Embodiments 241 to 243, which is a non-fixed combination.

[1225] Embodiment 245. The pharmaceutical combination of any one of Embodiments 241 to 244, comprising about 20 mg / mL to about 120 mg / mL of said anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mannitol, and about 0.04% w / v polysorbate-20 (PS-20); pH is about 5.5.

[1226] Embodiment 246. The pharmaceutical combination according to any one of Embodiments 241 to 243, comprising about 1,800 mg of the anti-CD38 antibody and about 30,000 U of rHuPH20.

[1227] Embodiment 247. The pharmaceutical combination of Embodiment 246, comprising about 120 mg / mL of the anti-CD38 antibody and about 2,000 U / mL of rHuPH20.

[1228] Embodiment 248. The pharmaceutical combination according to embodiment 246 or 257, further comprising one or more excipients.

[1229] Embodiment 249. The pharmaceutical combination according to any one of embodiments 246 to 248, wherein the one or more excipients are histidine, methionine, sorbitol or polysorbate-20 (PS-20) or any combination thereof.

[1230] Embodiment 250. The drug combination according to any one of Embodiments 246 to 249, wherein the drug combination comprises

[1231] between about 100 mg / mL to about 120 mg / mL of said anti-CD38 antibody;

[1232] between about 5 mM to about 15 mM histidine;

[1233] between about 100 mM and about 300 mM sorbitol;

[1234] Between about 0.01% w / v to about 0.04% w / v PS-20; and

[1235] Between about 1 mg / mL to about 2 mg / mL methionine, pH about 5.5 to 5.6.

[1236] Embodiment 251. The pharmaceutical combination according to any one of Embodiments 246 to 250, comprising about 10 mM histidine.

[1237] Embodiment 252. The pharmaceutical combination according to any one of Embodiments 246 to 251, comprising about 300 mM sorbitol.

[1238] Embodiment 253. The pharmaceutical combination according to any one of Embodiments 246 to 252, comprising about 0.04% (w / v) PS-20.

[1239] Embodiment 254. The pharmaceutical combination according to any one of embodiments 246 to 253, comprising about 1 mg / mL of methionine.

[1240] Embodiment 255. A pharmaceutical combination according to any one of Embodiments 246 to 254, comprising

[1241] about 1,800 mg of the anti-CD38 antibody;

[1242] About 30,000U of rHuPH20;

[1243] About 10 mM histidine;

[1244] About 300 mM sorbitol;

[1245] About 0.04% (w / v) PS-20; and

[1246] About 1 mg / mL of methionine, pH about 5.6.

[1247] Embodiment 256. A pharmaceutical composition according to any one of Embodiments 246 to 255, comprising

[1248] about 120 mg / mL of the anti-CD38 antibody;

[1249] About 2,000 U / mL of rHuPH20;

[1250] About 10 mM histidine;

[1251] About 300 mM sorbitol;

[1252] About 0.04% (w / v) PS-20; and

[1253] About 1 mg / mL of methionine, pH about 5.6.

[1254] Embodiment 257. A kit comprising a pharmaceutical composition according to any one of Embodiments 241 to 256.

[1255] Example

[1256] The following examples are provided to further describe some of the embodiments disclosed herein. These examples are intended to illustrate, but not to limit, the embodiments disclosed herein.

[1257] General Materials and Methods

[1258] Antibodies and reagents

[1259] The anti-BCMA / anti-CD3 antibody JNJ-957 (described in WO2017031104A1) and daratumumab are made by Janssen Pharmaceuticals. CNTO7008 (CD3×blank), BC3B4 (BCMA×blank), and 3930 (IgG isotype control) (all made by Janssen Pharmaceuticals) were used as control antibodies. JNJ-957 is also known as JNJ-7957.

[1260] JNJ-957 comprises a BCMA binding arm BCMB69 and a CD3 binding arm CD3B219, whose amino acid sequences are shown in Tables 3 and 4, respectively.

[1261] Table 3 :

[1262]

[1263] Table 4 .

[1264]

[1265] Bone marrow and peripheral blood mononuclear cells

[1266] Peripheral blood mononuclear cells (PBMCs) from healthy donors and MM patients and bone marrow mononuclear cells (BM-MNCs) from BM aspirates of MM patients were isolated by Ficoll-Hypaque density gradient centrifugation.

[1267] Cell lines and cultures

[1268] Luciferase (LUC)-transduced multiple myeloma cell lines UM9, RPMI8226, U266 and MM1.S and non-transduced multiple myeloma cell lines NCI-H929 and RPMI8226 were cultured in RPMI 1640 (Invitrogen) supplemented with 10% fetal bovine serum (FBS; Lonza) and antibiotics (100 units / mL penicillin, 100 μg / ml streptomycin; both obtained from Life Technologies).

[1269] Flow cytometric analysis of bone marrow and blood samples from MM patients

[1270] MM cells localized to the BM were identified and stained with HuMax-003 (CD38) FITC (this antibody binds to an epitope different from that bound by daratumumab, Janssen Pharmaceuticals), CD138 PE, CD56 PC7, CD45 Krome Orange (all from Beckman Coulter), CD269 (BCMA) APC (Biolegend), CD274 (PD-L1) BV421, and CD19 APC-H7 (all from Becton Dickinson) at 1.0 × 10 6 Cell surface marker expression levels were analyzed at 1.0 × 10 cells / mL. BM or PB immune cell subsets were identified and stained with CD45 Krome Orange, CD56 PC7 (all from Beckman Coulter), CD14 APC-H7, CD19 APC-H7, CD3 V450, CD4 APC-H7 or PE, CD8 FITC, CD45-RA APC, CD127 PE.Cy7, CD62L PE, CD274 (PD-1) BV421, CD16 APC, HLA-DR APC-H7 (all from Becton Dickinson), and CD25 PE (Dako) at 1.0 × 10 6 The expression levels of cell surface markers were analyzed by RT-PCR with 10% cytotoxicity (100 ng / mL) and 4% cytotoxicity (100 ng / mL) of BM samples. All BM samples were analyzed within 24 hours from the time of sample collection.

[1271] Flow cytometry was performed using a 7-laser LSRFORTESSA (Becton Dickinson). Fluorescently labeled beads (CS&T beads, Becton Dickinson) were used daily to monitor the performance of the flow cytometer and verify the optical path and stream flow. This process achieved controlled standardized results and allowed the determination of long-term drift and incidental changes within the flow cytometer. No changes were observed that could affect these results. Compensation beads were used to determine spectral overlap, and compensation was automatically calculated using Diva software. Flow cytometry data were analyzed using FACS Diva software.

[1272] Flow cytometry-based ex vivo lysis assay in BM-MNCs

[1273] BM-MNCs derived from MM patients, containing tumor cells as well as autologous effector cells, were used for lysis assays. The sample viability at incubation was over 98%, as assessed by using 7-AAD (Becton Dickinson). For lysis assays, BM-MNCs were incubated in RPMI+10% fetal bovine serum with control antibodies or JNJ-957 (0.0064 μg / mL to 4.0 μg / mL) and / or daratumumab (10 μg / mL) for 48 hours in 96-well U-bottom plates. Primary CD138 in BM-MNCs + The viability of MM cells was determined by flow cytometry as previously described (van der Veers et al., Haematologica, 2011; Vol. 96, No. 2: pp. 284-290; van der Veer MS et al., Blood Cancer J, 2011; Vol. 1, No. 10: p. e41; Nijhof IS et al., Leukemia, 2015; Vol. 29, No. 10: pp. 2039-2049; Nijhof IS et al., Blood, 2016; Vol. 128, No. 7: pp. 959-970). In both assays, CD138 was detected in the presence of Flow-Count Fluorospheres (Beckman Coulter) and LIVE / DEAD Fixable Dead Cell Stain Near-IR reactive dye (Invitrogen). + Single-platform flow cytometric analysis of cells was performed to count the viable MM cells to determine the absolute number of live MM cells. The percentage of lysis induced by JNJ-957 was then calculated using the following formula: Lysed MM cells % = 1-(viable CD138 in the presence of JNJ-957) +Absolute number of cells / surviving CD138 in untreated wells + absolute number of cells)×100%.

[1274] JNJ-957-induced CD4 + and CD8 + T cell activation and degranulation.

[1275] Flow cytometry-based lysis assay in MM cell lines with PB MNCs as effector cells .

[1276] BCMA-positive MM cell lines were co-cultured with PB MNCs from healthy donors or MM patients at an effector to target ratio of 9:1 in 96-well U-bottom plates in the presence of control antibodies or JNJ-957 (0.00256 μg / mL to 4.0 μg / mL) for 48 hours. The viability of MM cells was determined by flow cytometry as described above.

[1277] Bioluminescence imaging (BLI)-based lysis assay using LUC-transduced MM cell lines

[1278] LUC-transduced MM cell lines were cultured for 16 h in the presence or absence of pooled BM stromal cells (BMSCs) obtained from newly diagnosed MM patients (n = 12) and then incubated with effector cells (freshly isolated PBMCs from healthy donors) at an effector to target ratio of 9:1, followed by serial dilutions of JNJ-957 (0.00256 μg / mL to 4.0 μg / mL) or control antibodies in 96-well flat-bottom plates (Greiner-Bio-One) for 48 h. LUC was determined by BLI 10 min after addition of the substrate luciferin (150 μg / mL; Promega) + - Survival of MM cells Lysis of MM cells was determined using the following formula: % lysis = 1 - (mean BLI signal in the presence of effector cells and JNJ-957 / mean BLI signal in untreated wells in the presence of effector cells) x 100%.

[1279] To evaluate the effect of in vivo pretreatment of PB MNCs with daratumumab monotherapy on the efficacy of JNJ-957, LUC-transduced MM cell line 4 was also co-cultured with PB MNCs obtained from MM patients before the start of daratumumab monotherapy and at the time of optimal response to daratumumab monotherapy (effector to target ratio 9:1). BLI assays were performed as previously described.

[1280] Cytogenetic analysis

[1281] Purified MM cells were evaluated for cytogenetic abnormalities by fluorescence in situ hybridization (FISH) and single nucleotide polymorphism (SNP) arrays. High-risk disease was determined by del(17p), del(1p), ampl(1q), t(4;14), or t(14;16) 2 is defined by its existence.

[1282] Soluble BCMA assay

[1283] MSD GOLD was used according to the manufacturer's recommended procedures. TM Soluble BCMA (sBCMA) was measured in cell culture supernatants using a 96-well Small Spot Streptavidin SECTOR plate (Meso Scale Diagnostics).

[1284] Granzyme B assay

[1285] Granzyme B was measured in cell culture supernatants using the MSD R-Plex Granzyme B assay plate (Meso Scale Diagnostics) according to the manufacturer's protocol.

[1286] Multiplex cytokine assay

[1287] Cytokines [interferon-γ (IFN-γ), interleukin (IL)-2, IL-6, IL-8, IL-10, and tumor necrosis factor-α (TNF-α)] in cell culture supernatants were analyzed using V-Plex Proinflammatory Panel 1 Human Kit (Meso Scale Diagnostics) according to the manufacturer's protocol.

[1288] Statistical analysis

[1289] In cases where the data did not follow a normal distribution, comparisons between variables were performed using a two-tailed (paired) Student's t-test or the Mann-Whitney U test or the Wilcoxon paired signed-rank test. The association between variables was described using the Spearman rank correlation coefficient. P values ​​below 0.05 were considered significant. For the combination treatment of JNJ-957 and daratumumab, the expected lysis value was calculated using the following formula to test the null hypothesis that there was only an additive effect between JNJ-957 and daratumumab: Expected lysis % = (lysis % of JNJ-957 + lysis % of daratumumab) – (lysis % of JNJ-957 × lysis % of daratumumab), as previously 20、23、24 If the observed value is significantly higher than the expected value (P < 0.05), the null hypothesis of "additive effect" is rejected.

[1290] Example 1 Anti-BCMA / anti-CD3 antibody JNJ-957 mediated BCMA + Lysis of multiple myeloma cell lines With T cell activation and degranulation

[1291] The effects of JNJ-957 on RPMI8226-mediated PD-1 expression were evaluated using healthy donor (HD) peripheral blood mononuclear cells as effector cells over a range of JNJ-957 concentrations (0.00128 μg / mL to 4.0 μg / mL). Figure 1 )、UM9( Figure 2 )、U226( Figure 3 ) and MM1.S( Figure 4 ) multiple myeloma cell lines. JNJ-957 mediated lysis of all tested cell lines in a dose-dependent manner and achieved a maximal efficacy of almost 100% at an antibody concentration of approximately 0.1 μg / ml, depending on Figure 1 , Figure 2 , Figure 3 and Figure 4 Cell lines seen in .

[1292] It has been previously shown that BMSCs protect MM cells against various anti-MM agents (including daratumumab and MM reactive T cells). Therefore, the potential impact of BMSC-MM cell interaction on the efficacy of JNJ-957 was evaluated. The presence of BMSCs did not affect the activity of JNJ-957 on MM cell lines RPMI-8226, UM9 and U266 (data not shown). Although BMSCs in MM1.S cells moderately inhibited JNJ-957-mediated MM cell lysis at lower concentrations (P<0.0001), this effect can be completely eliminated by increasing the JNJ-7957 dose.

[1293] T cell activation was assessed in the RPMI 8226 cell line. Treatment with JNJ-957 resulted in CD4 + and CD8 + T cells were both activated and degranulated in a dose-dependent manner, as evidenced by increased cell surface expression of CD25 and CD107a or by the proportion of double-positive CD25 and CD107a cells, respectively. Figure 5 JNJ-957-mediated increase in the percentage of CD25+CD4 T cells is shown. Figure 6 JNJ-957-mediated increase in the percentage of CD107a+CD4 T cells is shown. Figure 7 JNJ-957-mediated increase in the percentage of double-positive CD25+CD107+CD4 T cells is shown. Figure 8 JNJ-957-mediated increase in the percentage of CD25+CD8 T cells is shown. Fig. 9JNJ-957-mediated increase in the percentage of CD107a+CD8 T cells is shown. Fig.10 JNJ-957-mediated increase in the percentage of double-positive CD25+CD107+CD8 T cells is shown.

[1294] Example 2 Daratumumab improves the efficacy of T cell redirecting antibodies

[1295] patient

[1296] BCMA expression levels, composition of immune cell subsets, and ex vivo efficacy of JNJ-957 were evaluated in 55 BM aspirates obtained from 11 newly diagnosed MM patients, 21 daratumumab-naïve relapsed / refractory MM patients, and 17 daratumumab-refractory relapsed / refractory MM patients (daratumumab-relapsed / refractory patients participated in phase 1 and 2 studies of daratumumab plus all-trans retinoic acid (ATRA); clinical trial identifier NCT02751255) and primary plasma cell leukemia (pPCL; n = 6). Serial BM samples were obtained from 8 patients treated in the DARA / ATRA study just before the start of daratumumab monotherapy and at the time of progressive disease during daratumumab treatment. In the same study, we obtained serial peripheral blood samples from 10 patients just before the start of daratumumab monotherapy and at the time of maximal response to daratumumab.

[1297] In the DARA / ATRA study (NCT02751255), patients with MM who required systemic therapy and were relapsed or refractory to ≥2 lines of therapy were enrolled. Patients were ≥18 years of age, had a life expectancy of ≥3 months, a WHO performance status ≤2, and measurable disease.

[1298] During the first phase of this study, daratumumab was administered according to the recommended dose and schedule (16 mg / kg once a week for 8 weeks, then every 2 weeks for 16 weeks, and every 4 weeks until PD). The study site ethics committee or institutional review board approved the protocol, which was developed in accordance with the principles of the Declaration of Helsinki, the International Conference on Harmonization, and the Code of Clinical Practice Guidelines. All patients signed informed consent.

[1299] The baseline characteristics of patients enrolled in the Phase 1 and Phase 2 study NCT02751255 are shown in Tables 5 and 6. RRMM patients had received an average of 5 (range 1 to 9) prior therapies, and RRMM dara R patients had received an average of 6 (range 3 to 12) prior therapies. Table 7 shows an updated summary of the baseline characteristics of patients enrolled in the Phase 1 and Phase 2 studies.

[1300] Table 5.

[1301]

[1302] Table 6 .

[1303]

[1304] Table 7 .

[1305]

[1306]

[1307] *High-risk disease is defined by the presence of del(17p), del(1p), apl(1q), t(4;14), or t(14;16).

[1308] **According to the International Harmonized Response Criteria for Multiple Myeloma, refractory disease is defined as progressive disease during treatment, no response (less than PR), or progressive disease within 60 days of stopping treatment.

[1309] #BM aspirates were obtained immediately upon development of progressive disease during daratumumab monotherapy (n=15), and 2 BM samples were obtained 22 and 48 months after development of progressive disease during daratumumab monotherapy, after 3 and 5 additional treatment terms, respectively.

[1310] §In addition, 1 of the 19 patients was intolerant to lenalidomide;

[1311] In addition, 4 of the 17 patients were intolerant to bortezomib;

[1312] In addition, 3 of the 16 patients were intolerant to bortezomib;

[1313] Abbreviations: MM, multiple myeloma; NDMM, newly diagnosed MM; RRMM, relapsed / refractory MM; Dara, daratumumab; pPCL, primary plasma cell leukemia; n, number; IgG, immunoglobulin G; IgA, immunoglobulin A; FLC, free light chain; del, deletion; amp, amplification; t, translocation; PI, proteasome inhibitor; IMiD, immunomodulatory drug;

[1314] result

[1315] Daratumumab mediated efficient lysis of MM cells from newly diagnosed (NDMM) and relapsed / refractory daratumumab-naïve patients, whereas cells from RRMM daratumumab-refractory patients were resistant to lysis ( Fig.11 ).

[1316] In newly diagnosed (ND) MM patient samples (n=8), the average lysis rate of MM cells by JNJ-957 at 4.0 μg / mL was 79% (range: 66% to 92%; Fig.12 ). Patient samples refractory to lenalidomide (LEN) (n = 15; mean lysis rate at 4.0 μg / mL: 69%; range: 24% to 98%; Fig.13 ) also achieved similar MM lysis, but with greater variability, with these patient samples also being refractory to bortezomib (mean lysis rate, 73%), pomalidomide (82%), and carfilzomib (9%). JNJ-957 was also effective in samples from MM patients refractory to daratumumab (DARA) (n = 11; mean lysis rate at 4.0 μg / mL: 83%; range: 52% to 99%; Fig.14 ). NK- and T-cell frequencies were not affected in any of the samples tested.

[1317] When compared with JNJ-957, CD3×control antibody and BCMA×control antibody showed significantly lower activity in different patient samples, indicating the requirement for cross-linking of MM cells and effector T cells and the absence of a direct effect of BCMA blockade.

[1318] JNJ-957-mediated lysis of primary MM cells and activation of CD4 + and CD8 + JNJ-957 treatment also resulted in a dose-dependent increase in the percentage of T cells, as assessed by expression of the CD25 activation antigen. + and CD8 + T cell degranulation, as determined by cell surface expression of CD107a. There were no differences in the extent of T cell activation and degranulation between NDMM, daratumumab-naïve RRMM, and daratumumab-refractory RRMM patients. Fig.15 JNJ-957-mediated increase in the percentage of CD25+CD4 T cells is shown. Fig.16 JNJ-957-mediated increase in the percentage of CD107a+CD4 T cells is shown. Fig.17 JNJ-957-mediated increase in the percentage of double-positive CD25+CD107+CD4 T cells is shown. Fig.18JNJ-957-mediated increase in the percentage of CD25+CD8 T cells is shown. Fig.19 JNJ-957-mediated increase in the percentage of CD107a+CD8 T cells is shown. Fig. 20 JNJ-957-mediated increase in the percentage of double-positive CD25+CD107+CD8 T cells is shown.

[1319] Granzyme B and various cytokines levels in JNJ-957-treated BM-MNC supernatants from RRMM patients who did not receive daratumumab and were refractory to daratumumab were also evaluated. JNJ-957-mediated T cell activation resulted in a dose-dependent increase in the levels of granzyme B, IFN-γ, IL-2, IL-6, IL-8, IL-10, and TNF-α (data not shown).

[1320] Across all BM samples, the efficacy of JNJ-957 in mediating MM cell killing was not associated with either tumor characteristics (BCMA or PD-L1 expression, presence of standard or high-risk cytogenetic abnormalities) or patient characteristics (such as effector:target ratio, composition of the T-cell system, or PD-1 / HLA-DR expression on T cells). However, when patient categories were analyzed separately, BCMA ( Fig.21 ) and PD-L1( Fig. 22 ) expression levels were significantly higher in RRMM patients, regardless of daratumumab exposure. Although the number of patients was small, the activity of JNJ-957 was inversely correlated with PD-L1 expression levels in RRMM patients who had not received daratumumab treatment (p = 0.045).

[1321] The composition of immune cells in BM aspirate NDMM, daratumumab-naïve RRMM, and daratumumab-RRMM samples was evaluated to gain insight into the differential effects of JNJ-957 in samples obtained from the three patient subgroups. In the combined patient groups, high T cell frequencies (p=0.034) and high E:T ratios (p=0.029) were associated with enhanced JNJ-7957-mediated lysis of MM cells. Other immune parameters (T cells, Tregs, PD-1 + T cells, HLA-DR + The number of T cells or naive T cells) did not affect JNJ-7957-mediated lysis of MM cells.

[1322] In subgroup analysis, when compared with NDMM patients, RRMM patients had higher Treg ( Fig.23 ) and activated T cells (defined by expression of HLA-DR) ( Fig.24) and a lower frequency of naive T cells. In addition, samples from patients refractory to daratumumab contained significantly more TEMRA T cells than samples not previously treated with daratumumab ( Fig.25 ). However, in this subgroup analysis, the frequency of activated, naive, central memory (CM), effector memory (EM), or TEMRA T cells did not correlate with response to JNJ-7957. High baseline percentages of Tregs showed a negative effect on JNJ-957-mediated lysis of MM cells in RRMM patient samples, which could be overcome by optimal dosing. JNJ-597-mediated lysis of NDMM mediated by autologous effector cells was evaluated, dichotomized according to the baseline percentage of Tregs ( Fig.26 ), RRMM who have not received daratumumab treatment ( Fig. 27 ) and daratumumab-refractory RRMM ( Fig.28 ) patient samples. The 50th percentile was used to classify samples as “low” or “high” based on Treg content: NDMM: low: ≤7.34%, high: >7.34%. Daratumumab-naïve RRMM: low ≤15.57%, high >15.57%. Daratumumab-refractory RRMM: low ≤11.24%, high >11.24%. Higher Treg concentrations inhibited JNJ-957-mediated lysis of MM cells in daratumumab-naïve RRMM and daratumumab-refractory RRMM samples. The Treg effect was abolished at higher JNJ-957 concentrations.

[1323] PD-1 in the three patient groups + The proportion of T cells and E:T ratio were similar. Only in NDMM patients, low frequency of T cells (P = 0.010) and high frequency of PD-1 + T cells (P=0.048) impaired JNJ-957-mediated lysis of MM cells (data not shown).

[1324] The effect of daratumumab treatment on the efficacy of JNJ-957 was evaluated by assessing JNJ-957-mediated lysis in BM samples from NDMM (n=9), RRMM not treated with daratumumab (n=18), and RRMM patients refractory to daratumumab (n=13) after 48 hours of incubation. At relatively low concentrations of JNJ-957 (0.0064 μg / mL to 0.032 μg / mL), tumor cell lysis was significantly better in patients exposed to daratumumab compared to RRMM and NDMM patients not receiving daratumumab treatment. Fig.29 The percentage of lysis in the patient population is shown. Data are shown as mean ± SEM, and P values ​​were calculated using Student's t-test.

[1325] Since the recently discovered immunostimulatory effects of DARA may contribute to the improved tumor reduction, serial BM aspirates from MM patients were analyzed before and after DARA treatment (n=5). Here we observed comparable BCMA expression in samples obtained after disease progression during DARA compared with samples before DARA initiation, but improved MM cell lysis by JNJ-957 (mean lysis at 4.0 μg / mL: 93% vs. 74%; Fig.30 In these BM aspirates, Tregs ( Fig.31 ) and CD4 + cell( Fig.32 ) was slightly decreased, while the percentage of CD8+ cells ( Fig.33 ) percentage increase. In this study, samples were obtained from patients treated with daratumumab monotherapy for a median duration of 3 (1 to 7) months. In a subsequent study of samples from 8 RRMM patients, CD38 + The percentages of Treg and Breg were significantly reduced in daratumumab-refractory patient samples and in daratumumab-naive patient samples (data not shown).

[1326] JNJ-957-mediated lysis of the RPMI 8226 multiple myeloma cell line was tested as effector cells using serial PB MNC samples from RRMM patients before and during daratumumab treatment. During daratumumab treatment, PB MNCs exposed to daratumumab were obtained from patients with a good response (partial response, very good partial response, or complete response) and a median duration of daratumumab treatment of 11 months (range 7 to 14 months). Fig.34 Figure 2 shows enhancement of JNJ-957-mediated RPMI 8226 lysis using PB MNCs from patients exposed to daratumumab. In PB-MNC samples, Tregs ( Fig.35 ) and CD4+ cells ( Fig.36 ) was slightly decreased, while the percentage of CD8+ cells ( Fig.37 ) percentage increase. In this study, samples were obtained from patients treated with daratumumab for a median duration of 3 (1 to 7) months.

[1327] The combination of JNJ-957 and daratumumab was also tested for efficacy in killing MM cells obtained from NDMM or RRMM patients who had not received dara treatment. Fig.38The percentage of lysis of BM MNCs of newly diagnosed MM (NDMM) patients (n=8) treated with JNJ-957 (0.032 μg / mL to 0.8 μg / mL) alone or in combination with 10 μg / mL of daratumumab for 48 hours is shown. The observed (obs) lysis levels of MM cells by JNJ-957 and daratumumab were compared with the expected (exp) lysis levels, where these lysis levels were calculated under the assumption that the combined effect was achieved by an additive effect as shown in the methods. The black bars show the group mean ± SEM. P values ​​were calculated using paired Student's t-tests. Fig.39 The percentage of BMMNC lysis in RRNN dara-naive patients is shown. Fig.40 Shown are the percentages of lysis of BM MNCs in patients with RRMM refractory to daratumumab.

[1328] Thus, the study showed that JNJ-957 was effective in newly diagnosed and heavily pretreated MM patient samples. High percentages or regulatory T cells negatively affected JNJ-957 efficacy at low doses, which was however overcome by increasing the dose of JNJ-957. Pretreatment with daratumumab in vivo enhanced the efficacy of JNJ-957 against MM cells.

[1329] The combination of JNJ-957 and daratumumab showed additive efficacy ex vivo; furthermore, in vivo pretreatment with daratumumab enhanced the ex vivo efficacy of BCMA×CD3.

[1330] Example 3 Daratumumab treatment enhances the ex vivo efficacy of blinatumomab

[1331] To evaluate whether daratumumab treatment also benefits other T cell redirecting therapies, paired daratumumab-naïve and daratumumab-exposed PB-MNCs from 11 MM patients were treated with blinatumomab, an FDA-approved CD19 × CD3 BiTE for acute lymphoblastic leukemia. + Similar to the observations made with JNJ-957, the activity of blinatumomab was significantly enhanced by co-incubation with PB-MNCs exposed to daratumumab when compared with PB-MNCs that had not been treated with daratumumab (P < 0.0001; Fig.41 ). Blinatumomab comprises the amino acid sequence of SEQ ID NO:53.

[1332] SEQ ID NO:53

[1333] DIQLTQSPASLAVSLGQRATISCKASQSVDYDGDSYLNWYQQIPGQPPKLLIYDASNLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAATYHCQQSTEDPWTFGGGTKLEIKGGGGSGGGGSGGGGS QVQLQQSGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIWPGDGDTNYNGKFKGKATLTADESSSTAYMQLSSLASEDSAVYFCARRETTTVGRYYYAMDYWGQGTTVTVSSGG GGSDIKLQQSGAELARPGASVKMSCKTSGYTFTRYTMHWVKQRPGQGLEWIGYINPSRGYTNYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYCLDYWGQGTTLTVSSVEGG SGGSGGSGGSGGVDDIQLTQSPAIMSASPGEKVTMTCRASSSVSYMNWYQQKSGTSPKRWIYDTSKVASGVPYRFSGGSGSGTSYSLTISSMEAEDAATYYCQQWSSNPLTFGAGTKLELKHHHHHH

[1334] Example 4 JNJ-957 effectively kills primary pPCL cells

[1335] The ex vivo activity of JNJ-957, characterized by positive clinical behavior, was evaluated in BM samples from 6 patients with newly diagnosed pPCL. JNJ-957-mediated tumor cell lysis in these pPCL samples was similar to that observed in NDMM and RRMM samples that had not received daratumumab treatment, but was lower than that observed in samples from RRMM patients that were refractory to daratumumab (p=0.0014)( Fig.42 Although the median E:T ratio was approximately 8-fold lower in pPCL samples, CD4 + (P=0.0040) and CD8 + The activation degree of both T cells and CD8 + The degranulation degree of T cells was better (P=0.0141). + Degranulation of T cells was similar to that observed in NDMM.

[1336] BM-MNCs were obtained from 6 pPCL patients and incubated with JNJ-957 (0.0064 to 4.0 μg / mL) or control antibodies 3930, BC3B4, and 7008 (4.0 μg / mL) for 48 h, after which the survival of CD138 + Tumor cells as well as T cells and NK cells were counted. Data are presented as mean % lysis of cells ± SEM. All experiments were performed in duplicate.

[1337] Example 5 Combination of GPRC5D×CD3 bispecific antibody and daratumumab

[1338] To further evaluate whether daratumumab treatment is also beneficial for other T cell redirection therapies, RPMI MM cells were treated with GPRC5D×CD3 bispecific antibody using paired daratumumab-naive and daratumumab-exposed PB-MNCs from 11 MM patients (samples were obtained from the same patients as described in the Examples above). As controls, antibodies in which the CD3 or GPRC5D binding VH / VL domains were replaced by blank domains binding to an unrelated antigen (gp120) were used (control mAb 3930 blank×blank, control mAb 7008: blank×CD3, control mAb GPRC5D×blank). The antibodies were tested at concentrations of 0.00064 to 4.0 μg / ml. The GPRC5D×CD3 bispecific antibody mediated MM cell lysis in both daratumumab-naive and daratumumab-refractory samples with similar efficacy ( Fig.43 ).

[1339] The combination of GPRC5D×CD3 bispecific antibody and daratumumab was also tested for efficacy in killing MM cells obtained from NDMM or RRMM patients who had not received dara treatment. Fig.44 The percentage of BM MNC lysis of primary MM cells mediated by GPRC5D×CD3 bispecific antibodies (0.0128 μg / mL to 0.8 μg / mL) alone or in combination with 0.1 μg / mL of daratumumab for 48 hours is shown. The observed (O) lysis levels of MM cells by GPRC5D×CD3 bispecific antibodies and daratumumab were compared with the expected (E) lysis levels, where these lysis levels were calculated under the assumption that the combined effect was achieved by an additive effect as shown in the methods. The black bars show the group mean ± SEM. Paired Student's t-tests were used to calculate P values. Co-incubation with daratumumab enhanced MM cell lysis by GPRC5D×CD3 bispecific antibodies in an additive manner.

[1340] The GPRC5D×CD3 bispecific antibody comprises a GPRC5D binding arm GC5B596 and a CD3 binding arm CD3B219. The amino acid sequence of GC5B596 is shown in Table 8. The amino acid sequence of CD3B219 is shown in Table 4.

[1341] The GPRC5D×CD3 bispecific antibody used in the experiment is described in WO20180037651A1 and comprises the following sequence:

[1342] a GPRC5D binding domain and a CD3 binding domain, the GPRC5D binding domain comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 43, 44, 45, 446, 47 and 48, respectively, and the CD3 binding domain comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 33, 34, 35, 36, 37 and 38, respectively;

[1343] The GPRC5D binding domain comprises the VH of SEQ ID NO:49 and the VL of SEQ ID NO:50, and the CD3 binding domain comprises the VH of SEQ ID NO:39 and the VL of SEQ ID NO:40; and

[1344] A first heavy chain (HC1) of SEQ ID NO:51, a first light chain (LC1) of SEQ ID NO:52, a second heavy chain (HC2) of SEQ ID NO:41, and a second light chain (LC2) of SEQ ID NO:42.

[1345] The anti-GPRC5D×CD3 bispecific antibody is of IgG4 isotype.

[1346] HC1 contains S228P, F234A and L235A substitutions.

[1347] HC2 contains S228P, F234A, L235A, F405L and R409K substitutions.

[1348] Table 8 .

[1349]

[1350]

[1351] Example 6 Combination of T cell redirection therapy and anti-CD38 antibodies

[1352] The effect of combining an additional T cell redirection therapy with an anti-CD38 antibody was evaluated similarly as described in Examples 1 to 5. The combination was tested for additive or synergistic effects on mediating killing of tumor cells targeted by the T cell redirection therapy (i.e., tumor cells expressing an antigen bound by the T cell redirection therapy). As described in the Examples, the effect of pretreatment with an anti-CD38 antibody on the efficacy of the T cell redirection therapy was evaluated.

[1353] T cell redirecting therapies tested in combination with anti-CD38 antibodies include PSMA×CD3, TMEFF2×CD3, CD123×CD3, and CD33×CD3 bispecific antibodies.

[1354] An exemplary PSMA×CD3 bispecific antibody is PS3B27, comprising a PSMA binding domain PSMB127 and a CD3 binding domain CD3B219. The amino acid sequence of PS3B27 is shown in Table 9. The amino acid sequence of CD3B219 is shown in Table 4.

[1355] The exemplary PSMA×CD3 bispecific antibody used in the experiments comprises the following sequence:

[1356] a PSMA binding domain and a CD3 binding domain, the PSMA binding domain comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 54, 55, 56, 9, 10, and 59, respectively, and the CD3 binding domain comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 33, 34, 35, 36, 37, and 38, respectively;

[1357] The PSMA binding domain comprises the VH of SEQ ID NO:60 and the VL of SEQ ID NO:61, and the CD3 binding domain comprises the VH of SEQ ID NO:39 and the VL of SEQ ID NO:40; and

[1358] A first heavy chain (HC1) of SEQ ID NO:62, a first light chain (LC1) of SEQ ID NO:63, a second heavy chain (HC2) of SEQ ID NO:41, and a second light chain (LC2) of SEQ ID NO:42.

[1359] The anti-PSMA×CD3 bispecific antibody is of IgG4 isotype.

[1360] HC1 contains S228P, F234A and L235A substitutions.

[1361] HC2 contains S228P, F234A, L235A, F405L and R409K substitutions.

[1362] Table 9 .

[1363]

[1364]

[1365] An exemplary TMEFF2×CD3 bispecific antibody is TMCB150, comprising a TMEFF2 binding arm TMEB762 and a CD3 binding arm CD3B376. Table 10 shows the amino acid sequence of TMEB762. Table 11 shows the amino acid sequence of CD3B376.

[1366] An exemplary TMEFF2×CD3 bispecific antibody used in the experiments is TMCB150 and comprises the following sequence:

[1367] a TMEFF2 binding domain and a CD3 binding domain, the TMEFF2 binding domain comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 64, 65, 66, 67, 68 and 69, respectively, and the CD3 binding domain comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 74, 75, 76, 77, 78 and 79, respectively;

[1368] The TMEFF2 binding domain comprises the VH of SEQ ID NO:70 and the VL of SEQ ID NO:71, and the CD3 binding domain comprises the VH of SEQ ID NO:80 and the VL of SEQ ID NO:81; and

[1369] A first heavy chain (HC1) of SEQ ID NO:72, a first light chain (LC1) of SEQ ID NO:73, a second heavy chain (HC2) of SEQ ID NO:82, and a second light chain (LC2) of SEQ ID NO:83.

[1370] The anti-TMEFF2×CD3 bispecific antibody is of IgG4 isotype.

[1371] HC1 contains S228P, F234A and L235A substitutions.

[1372] HC2 contains S228P, F234A, L235A, F405L and R409K substitutions.

[1373] Table 10 .

[1374]

[1375] Table 11 .

[1376]

[1377] An exemplary CD33×CD3 bispecific antibody is C3CB189, comprising a CD33 binding arm C33B904 and a CD3 binding arm CD3B376. Table 12 shows the amino acid sequence of C33B904.

[1378] The amino acid sequence of CD3B376 is shown in Table 11.

[1379] An exemplary CD33×CD3 bispecific antibody used in the experiments is C3CB189 and comprises the following sequence:

[1380] a CD33 binding domain and a CD3 binding domain, the CD33 binding domain comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 84, 85, 86, 87, 88 and 89, respectively, and the CD3 binding domain comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 74, 75, 76, 77, 78 and 79, respectively;

[1381] The CD33 binding domain comprises the VH of SEQ ID NO:90 and the VL of SEQ ID NO:91, and the CD3 binding domain comprises the VH of SEQ ID NO:80 and the VL of SEQ ID NO:81; and

[1382] A first heavy chain (HC1) of SEQ ID NO:92, a first light chain (LC1) of SEQ ID NO:93, a second heavy chain (HC2) of SEQ ID NO:82, and a second light chain (LC2) of SEQ ID NO:83.

[1383] The anti-CD33×CD3 bispecific antibody is of IgG4 isotype.

[1384] HC1 contains S228P, F234A and L235A substitutions.

[1385] HC2 contains S228P, F234A, L235A, F405L and R409K substitutions.

[1386] Table 12 .

[1387]

[1388]

[1389] An exemplary CD123×CD3 bispecific antibody is 8747, comprising a CD123 binding arm I3RB218 and a CD3 binding arm CD3B219. 8747 is described in WO2016036937A1. Table 13 shows the amino acid sequence of I3RB218. Table 4 shows the amino acid sequence of CD3B219.

[1390] The exemplary CD123×CD3 bispecific antibody used in the experiments is 8747 and comprises the following sequence:

[1391] a CD123 binding domain and a CD3 binding domain, the CD123 binding domain comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 94, 95, 96, 9, 10, and 59, respectively, and the CD3 binding domain comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 33, 34, 35, 36, 37, and 38, respectively;

[1392] The CD123 binding domain comprises the VH of SEQ ID NO: 100 and the VL of SEQ ID NO: 61, and the CD3 binding domain comprises the VH of SEQ ID NO: 39 and the VL of SEQ ID NO: 40; and

[1393] A first heavy chain (HC1) of SEQ ID NO: 102, a first light chain (LC1) of SEQ ID NO: 63, a second heavy chain (HC2) of SEQ ID NO: 41, and a second light chain (LC2) of SEQ ID NO: 42.

[1394] The anti-CD123×CD3 bispecific antibody is of IgG4 isotype.

[1395] HC1 contains S228P, F234A and L235A substitutions.

[1396] HC2 contains S228P, F234A, L235A, F405L and R409K substitutions.

[1397] Table 13 .

[1398]

[1399] In order to evaluate the effect of pretreatment with anti-CD38 antibodies on the efficacy of killing tumors by T cell redirection therapeutic agents, tumor cells are isolated from subjects expressing antigens bound by T cell redirection therapeutic agents (such as CD123, CD33, PSMA, TMEFF2, etc.) or using established tumor cell lines. As described in the examples, the killing of tumor cells is evaluated in vitro by incubating tumor cells with PB-MNC obtained from subjects exposed to anti-CD38 antibodies or not treated with anti-CD38 antibodies, and the percentage of tumor cell lysis in each group is evaluated. In a separate embodiment, T cell redirection therapeutic agents and anti-CD38 antibodies are incubated together or alone with target cells and effector cells, and tumor cell killing mediated by the combined therapeutic agent relative to the individual therapeutic agent is evaluated.

[1400] CD123-positive tumor cells (such as AML tumors) or cell lines (such as AML cell lines KG1a, HL60 or MOLM13) were used as target cells to evaluate the effect of anti-CD38 antibodies on CD123×CD3 bispecific antibody-mediated tumor cell killing.

[1401] CD33-positive tumor cells (such as AML tumors) or cell lines (such as AML cell lines KG1a, HL60 or MOLM13) were used as target cells to assess the effect of anti-CD38 antibodies on CD33×CD3 bispecific antibody-mediated tumor cell killing.

[1402] TMEFF2-positive tumor cells (such as LnCP cells) were used as target cells to evaluate the effect of anti-CD38 antibodies on TMEFF2×CD3 bispecific antibody-mediated tumor cell killing.

[1403] TMEFF2-positive tumor cells (such as LnCP cells) were used as target cells to evaluate the effect of anti-CD38 antibodies on PSMA×CD3 bispecific antibody-mediated tumor cell killing.

[1404] PBMCs or BM-MNCs isolated from subjects who had received or had not received anti-CD38 antibody treatment were used as effector cells.

[1405] Those skilled in the art will appreciate that many changes and modifications may be made to the preferred embodiments of the present invention, and such changes and modifications may be made without departing from the spirit of the present invention. Therefore, the appended claims are intended to cover all such equivalent changes that fall within the true spirit and scope of the present invention.

[1406] The disclosures of each patent, patent application, and patent publication cited or described in this document are hereby incorporated by reference in their entirety.

Claims

1. Use of an anti-CD38 antibody and a T cell redirecting therapeutic agent for the preparation of a medicament for treating multiple myeloma in a subject, wherein the anti-CD38 antibody comprises a heavy chain (HC) of SEQ ID NO: 12 and a light chain (LC) of SEQ ID NO: 13; and wherein the T cell redirecting therapeutic agent comprises a first heavy chain (HC1) of SEQ ID NO:31, a first light chain (LC1) of SEQ ID NO:32, a second heavy chain (HC2) of SEQ ID NO:41, and a second light chain (LC2) of SEQ ID NO:

42.

2. The use according to claim 1, wherein the anti-CD38 antibody and the T cell redirecting therapeutic agent are formulated as separate compositions.

3. The use according to claim 1, wherein the anti-CD38 antibody is administered before the T cell redirecting therapeutic agent is administered.

4. The use according to any one of claims 1 to 3, wherein the multiple myeloma is newly diagnosed multiple myeloma.

5. The use according to any one of claims 1 to 3, wherein the multiple myeloma is relapsed or refractory multiple myeloma. The use according to claim 4 , wherein the multiple myeloma is high-risk multiple myeloma.

7. The use according to claim 5, wherein the multiple myeloma is high-risk multiple myeloma.

8. The use according to claim 6 or 7, wherein the subject suffering from the high-risk multiple myeloma has one or more chromosomal abnormalities, the chromosomal abnormalities comprising: a)t(4;14)(p16;q32); b)t(14; 16)(q32;q23); c)del17p; d) 1qAmp; e) t(4;14)(p16;q32) and t(14;16)(q32;q23); f) t(4;14)(p16;q32) and del17p; g) t(14;16)(q32;q23) and del17p; or h) t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p, or any combination thereof.

9. The use according to claim 5, wherein the multiple myeloma is relapsed or refractory to treatment with the anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotozumab, ixazomib, melphalan or thalidomide or any combination thereof.

10. The use of any one of claims 1-3, 6-7 or 9, further comprising administering one or more anti-cancer therapies to the subject.

11. The use according to claim 10, wherein the one or more anti-cancer therapies are selected from autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulators and targeted cancer therapies.

12. The use according to claim 11, wherein the one or more anticancer therapies are selected from lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, elotozumab, ixazomib, melphalan, dexamethasone, vincristine, cyclophosphamide, hydroxydaunorubicin, prednisone, rituximab, imatinib, dasatinib, nilotinib, bosutinib, ponatinib, bafitinib, sacatinib, tauzerti or darusertib, cytarabine, daunorubicin, idarubicin, mitoxantrone, hydroxyurea, decitabine, cladribine, fludarabine, topotecan, etoposide 6-thioguanine, corticosteroids, methotrexate, 6-mercaptopurine, azacitidine, arsenic trioxide and all-trans retinoic acid or any combination thereof.

13. The use according to any one of claims 1-3, 6-7, 9 or 11-12, wherein the anti-CD38 antibody is administered at a dose between 8 mg / kg and 16 mg / kg.

14. The use according to any one of claims 1-3, 6-7, 9 or 11-12, wherein the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising between 20 mg / mL and 120 mg / mL of the anti-CD38 antibody in 25 mM acetic acid, 60 mM sodium chloride, 140 mannitol and 0.04% w / v polysorbate-20; pH is 5.

5.

15. The use according to claim 13, wherein the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising a) between 5 mM and 15 mM histidine; b) between 100 mM and 300 mM sorbitol; c) between 0.01% w / v and 0.04% w / v polysorbate-20; and d) between 1 mg / mL and 2 mg / mL methionine, pH 5.5 to 5.

6.

16. The use according to any one of claims 1 to 3, wherein the multiple myeloma is BCMA-expressing multiple myeloma.

17. The use according to any one of claims 1-3, wherein the T cell redirecting therapeutic agent and the anti-CD38 antibody are administered by intravenous injection.

18. The use according to claim 13, wherein the T cell redirecting therapeutic agent and the anti-CD38 antibody are administered by intravenous injection.

19. The use according to any one of claims 1-3, wherein the T cell redirecting therapeutic agent is administered by intravenous injection and the anti-CD38 antibody is administered by subcutaneous injection.

20. The use according to any one of claims 1-3, wherein the subject is a human.

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