Methods of treating cancer and enhancing efficacy of T cell redirection therapeutic agents

Abstract

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

Description

[0001] This application is a divisional application of the invention application with the application date of May 15, 2019, the Chinese national application number of 201980038160.6, and the invention title of "Methods for Treating Cancer and Enhancing the Efficacy of T-Cell Redirecting Therapeutic Agents". Technical Field

[0002] The present invention discloses methods for treating cancer and enhancing the efficacy of T-cell redirecting therapeutic agents. Background Art

[0003] T cells redirected to kill are a desired mode of action in many therapeutic areas. Generally speaking, T-cell redirecting molecules are engineered to have at least two antigen-binding sites, one of which binds to a surface antigen on a target cell and the other of which binds to a T-cell surface antigen. Among the T-cell surface antigens, the human CD3ε subunit of the TCR protein complex has been the primary target for redirecting T-cell killing. In both preclinical and clinical studies, various bispecific antibody formats have shown to mediate T-cell redirection (May C et al., Biochem Pharmacol, Vol. 84: pp. 1105-1112, 2012; Frankel S R and Baeuerle P A, Curr Opin Chem Biol, Vol. 17, No. 3: pp. 385-392, 2013).

[0004] Tumors evade immune recognition by creating an immunosuppressive tumor microenvironment (TME). In the TME, under conditions of persistent antigen and inflammation, T cells become exhausted or dysfunctional and gradually lose their effector functions and proliferative capacity. The engagement of therapeutics that mediate T-cell redirected killing with functionally impaired and available numbers of T cells can compromise the anti-tumor efficacy of the therapeutics. Therefore, there is a need to enhance T-cell function to achieve the optimal efficacy of therapeutics that mediate T-cell redirected killing. Summary of the Invention

[0005] The present disclosure provides a method for 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.

[0006] The present disclosure also provides a method for killing tumor cells of 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.

[0007] The present disclosure provides a method for enhancing the efficacy of a T-cell redirecting therapeutic agent in a subject having cancer, comprising administering to the subject an anti-CD38 antibody.

[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 and an anti-CD38 antibody to treat the cancer.

[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 has been treated with an anti-CD38 antibody prior to administration of the BCMA×CD3 bispecific antibody.

[0010] 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 recurrent or refractory to treatment with a prior anti-cancer therapeutic agent.

[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 and an anti-CD38 antibody to treat the multiple myeloma.

[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 has been treated with an anti-CD38 antibody prior to administration of the BCMA×CD3 bispecific antibody.

[0013] 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 recurrent or refractory to treatment with a prior multiple myeloma therapeutic agent.

[0014] 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 VH of SEQ ID NO:29 and VL of SEQ ID NO:30, the CD3 binding domain comprises VH of SEQ ID NO:39 and VL of SEQ ID NO:40, and the anti-CD38 antibody comprises VH of SEQ ID NO:4 and VL of SEQ ID NO:5.

[0015] The present disclosure also provides a method for treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a T cell redirecting therapeutic agent that binds to GPRC5D and an anti-CD38 antibody to treat the cancer.

[0016] The present disclosure also provides a method for 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 recurrent or refractory to treatment with a prior anti-cancer therapeutic agent.

[0017] The present disclosure also relates to 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, 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, LCDR2 of SEQ ID NO:10 and LCDR3 of SEQ ID NO:11.

[0018] The present disclosure also provides a method for treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a T cell redirecting therapeutic agent that binds to CD19 and an anti-CD38 antibody to treat the cancer.

[0019] The present disclosure also provides a method for enhancing the efficacy of a T cell redirecting therapeutic agent that binds to CD19 in a subject with cancer, comprising administering an anti-CD38 antibody to the subject prior to administering the T cell redirecting therapeutic agent that binds to CD19.

[0020] 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.

[0021] The present invention also provides a kit comprising the pharmaceutical composition of the present disclosure. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 Shows the lysis of the multiple myeloma (MM) cell line RPMI8226 mediated by JNJ-957. Peripheral blood mononuclear cells (PB MNC) from healthy donors were used as effector cells.

[0023] Figure 2 Shows the lysis of the multiple myeloma (MM) cell line UM9 mediated by JNJ-957. Peripheral blood mononuclear cells (PB MNC) from healthy donors were used as effector cells.

[0024] Figure 3 Shows the lysis of the multiple myeloma (MM) cell line U226 mediated by JNJ-957. Peripheral blood mononuclear cells (PB MNC) from healthy donors were used as effector cells.

[0025] Figure 4 Shows the lysis of the multiple myeloma (MM) cell line MM1 mediated by JNJ-957. Peripheral blood mononuclear cells (PB MNC) from healthy donors were used as effector cells.

[0026] Figure 5 Shows that in a representative example of RPMI 8226 cells incubated with PB MNC from healthy donors (n = 2), JNJ-957-mediated MM cell lysis was accompanied by CD4 + T cell activation and degranulation, as determined by increased surface expression of CD25 (activation).

[0027] Figure 6 Shows that in a representative example of RPMI 8226 cells incubated with PB MNC from healthy donors (n = 2), JNJ-957-mediated MM cell lysis was accompanied by CD4 + T cell activation and degranulation, as determined by increased surface expression of CD107a (degranulation).

[0028] Figure 7Shows that in representative examples of RPMI 8226 cells incubated with healthy donor PB MNC (n = 2), JNJ-957-mediated MM cell lysis was accompanied by CD4 + T cell activation and degranulation, as determined by the proportion of CD25 and CD107a double-positive CD4+ T cells.

[0029] Figure 8 Shows that in representative examples of RPMI 8226 cells incubated with healthy donor PB MNC (n = 2), JNJ-957-mediated MM cell lysis was accompanied by CD8 + T cell activation and degranulation, as determined by increased surface expression of CD25 (activation).

[0030] Figure 9 Shows that in representative examples of RPMI 8226 cells incubated with healthy donor PB MNC (n = 2), JNJ-957-mediated MM cell lysis was accompanied by CD8 + T cell activation and degranulation, as determined by increased surface expression of CD107a (degranulation).

[0031] Figure 10 Shows that in representative examples of RPMI 8226 cells incubated with healthy donor PB MNC (n = 2), JNJ-957-mediated MM cell lysis was accompanied by CD8 + T cell activation and degranulation, as determined by an increase in the proportion of CD25 and CD107a double-positive CD4+ T cells.

[0032] Figure 11 Shows 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. Multiple myeloma cells from daratumumab-refractory RRMM patients were resistant to daratumumab-mediated lysis ****P<0.0001

[0033] Figure 12 Shows the dose-response of JNJ-957-mediated lysis of plasma cells, T cells, and NK cells in fully autologous bone marrow (BM) MNC obtained from newly diagnosed multiple myeloma patients (NDMM, n = 8). 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] Figure 13Shows 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 multiple myeloma (MM) patients refractory to lenalidomide treatment (n = 15). 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.

[0035] Figure 14 Shows 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 refractory to treatment with lenalidomide and daratumumab (n = 11). 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.

[0036] Figure 15 Shows JNJ-957-mediated MM cell lysis accompanied by activation of CD4 + T cells (as evaluated by increased CD25 surface expression) in BM samples from patients with NDMM, RRMM not previously treated with daratumumab (RRMM), and daratumumab-refractory RRMM (RRMM daraR). 3930: isotype control; BC3B4: BCMA × blank bispecific antibody; 7008: blank × CD3 bispecific antibody.

[0037] Figure 16 Shows JNJ-957-mediated MM cell lysis accompanied by degranulation of CD4 + T cells (as evaluated by increased CD107a surface expression) in BM samples from patients with NDMM, RRMM not previously treated with daratumumab (RRMM), and daratumumab-refractory RRMM (RRMM daraR). 3930: isotype control; BC3B4: BCMA × blank bispecific antibody; 7008: blank × CD3 bispecific antibody.

[0038] Figure 17 Shows double-positive CD25 + CD107a + cells as CD4 in BM samples from patients with NDMM, RRMM not previously treated with daratumumab (RRMM), and daratumumab-refractory RRMM (RRMM daraR) treated with JNJ-957 at the specified concentration +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.

[0039] Figure 18 Shown is JNJ-957-mediated MM cell lysis accompanied by activation of CD8 + T cells (as assessed by increased CD25 surface expression) in BM samples from patients with NDMM, RRMM not previously treated with daratumumab (RRMM), and daratumumab-refractory RRMM (RRMM daraR). 3930: Isotype control; BC3B4: BCMA × blank bispecific antibody; 7008: Blank × CD3 bispecific antibody.

[0040] Figure 19 Shown is JNJ-957-mediated MM cell lysis accompanied by activation of CD8 + T cells (as assessed by increased CD107a surface expression) in BM samples from patients with NDMM, RRMM not previously treated with daratumumab (RRMM), and daratumumab-refractory RRMM (RRMM daraR). 3930: Isotype control; BC3B4: BCMA × blank bispecific antibody; 7008: Blank × CD3 bispecific antibody.

[0041] Figure 20 Shown are double positive CD25 + CD107a + cells as a percentage of CD8 + T cells in BM samples from patients with NDMM, RRMM not previously treated with daratumumab (RRMM), and daratumumab-refractory RRMM (RRMM daraR) treated with JNJ-957 at the indicated concentrations. 3930: Isotype control; BC3B4: BCMA × blank bispecific antibody; 7008: Blank × CD3 bispecific antibody. Double positive: CD25 and CD107a double positive CD8 + T cells.

[0042] Figure 21 Shown are the levels of BCMA expression (mean MFI ± SEM) on MM cells in subjects with NDMM, RRMM not previously treated with daratumumab, and daratumumab-refractory RRMM. The Mann-Whitney U test was used to calculate the P values between the specified groups; *P < 0.05; ns: not significant.

[0043] Figure 22Shows the PD-L1 expression levels (mean MFI ± SEM) on MM cells in NDMM, RRMM subjects naïve to daratumumab, and daratumumab-refractory RRMM subjects. Mann-Whitney U test was used to calculate the P values between the specified groups; *P<0.05; ns: not significant.

[0044] Figure 23 Shows the baseline percentages of Tregs in BM MNCs from NDMM, RRMM subjects naïve to daratumumab, and daratumumab-refractory RRMM. **p<0.01; ns: not significant.

[0045] Figure 24 Shows the baseline percentages of activated T cells (evaluated as HLA-DR positive) in BM MNCs from NDMM, RRMM subjects naïve to daratumumab, and daratumumab-refractory RRMM. **p<0.01; ns: not significant.

[0046] Figure 25 Shows the baseline percentages of various T cell subsets in BM MNCs from NDMM, RRMM subjects naïve to daratumumab, and daratumumab-refractory RRMM. *p<0.05; **p<0.01; Ns: not significant. TEMRA: CD45RA + CCR7-T cells; EM: effector memory; CM: central memory; N: naïve T cells.

[0047] Figure 26 Shows the lysis of multiple myeloma cells from NDMM patients mediated by JNJ-957 by autologous BM MNCs. Samples were dichotomized according to the frequency of Tregs at baseline (low ≤50%, high >50%). ns: not significant.

[0048] Figure 27 Shows the lysis of multiple myeloma cells from RRMM patients naïve to daratumumab mediated by JNJ-957 by autologous BM MNCs. Samples were dichotomized according to the frequency of Tregs at baseline (low ≤50%, high >50%). *p<0.05; **p<0.01; ns: not significant.

[0049] Figure 28 Shows the lysis of multiple myeloma cells from daratumumab-refractory RRMM patients mediated by JNJ-957 by autologous BM MNCs. Samples were dichotomized according to the frequency of Tregs at baseline (low ≤50%, high >50%). *p<0.05; ns: not significant.

[0050] Figure 29Shows the lysis of MM cells in BM samples from patients with NDMM (n = 9), RRMM not previously treated with daratumumab (n = 18), and daratumumab-refractory RRMM (n = 13) mediated by JNJ-957 after 48 hours of incubation. Data are shown as mean ± SEM, and the P-value was calculated using the Student's t-test. **P < 0.01

[0051] Figure 30 Shows that the lysis of MM cells in bone marrow (BM) samples obtained from patients with relapsed / refractory multiple myeloma (RRMM) (n = 8) mediated by JNJ-957 was enhanced in samples from the same patients who had received daratumumab ("exposed to Dara") when compared to samples from patients before the start of daratumumab treatment ("naïve to Dara treatment"). Data are shown as mean ± SEM; the P-value was calculated using the paired t-test. ns: not significant; *P < 0.05, **P < 0.01.

[0052] Figure 31 Shows the percentage of Tregs in sequential BM aspirates from RRMM patients before the start of daratumumab (before dara treatment) and at the development of daratumumab-refractory disease (exposed to dara). ns: not significant.

[0053] Figure 32 Shows the percentage of CD4 + in sequential BM aspirates from RRMM patients before the start of daratumumab (before dara treatment) and at the development of daratumumab-refractory disease (exposed to dara). ns: not significant.

[0054] Figure 33 Shows the percentage of CD8 + T cells in sequential BM aspirates from RRMM patients before the start of daratumumab (before dara treatment) and at the development of daratumumab-refractory disease (exposed to dara).

[0055] Figure 34 Shows that the lysis of RPMI8226 multiple myeloma cells using patient-derived PB MNCs as effector cells mediated by JNJ-957 was 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 ("naïve PBMNCs to dara treatment") (n = 5). Data are shown as mean ± SEM; the P-value was calculated using the paired t-test. ns: not significant; *P < 0.05.

[0056] Figure 35Shows the percentages of Tregs in PB-MNC samples from RRMM patients who have not received daratumumab treatment (before dara treatment) and daratumumab-refractory (during dara treatment).

[0057] Figure 36 Shows the percentages of CD4 + T cells in PB-MNC samples from RRMM patients who have not received daratumumab treatment (before dara treatment) and daratumumab-refractory (during dara treatment). ns: Not significant.

[0058] Figure 37 Shows the percentages of CD8 + T cells in PB-MNC samples from RRMM patients who have not received daratumumab treatment (before dara treatment) and daratumumab-refractory (during dara treatment). ns: Not significant.

[0059] Figure 38 Shows that the addition of daratumumab enhanced 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 JNJ-957 and daratumumab on the observed (Obs) MM cells were compared with the expected (Exp) lysis levels, where these lysis levels were calculated assuming the combined effect was achieved through an additive effect as shown in the method. Black bars show the group mean ± SEM. Paired Student's t-test was used to calculate the P value. ns: Not significant.

[0060] Figure 39 Shows that the addition of daratumumab enhanced JNJ-957-mediated MM cell lysis. BM MNCs from RRMM (n = 17) patients who had 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 JNJ-957 and daratumumab on the observed (Obs) MM cells were compared with the expected (Exp) lysis levels, where these lysis levels were calculated assuming the combined effect was achieved through an additive effect as shown in the method. Black bars show the group mean ± SEM. Paired Student's t-test was used to calculate the P value. ns: Not significant.

[0061] Figure 40It shows that the addition of daratumumab enhanced the lysis of MM cells mediated by JNJ-957. BM MNCs from daratumumab-refractory RRMM (n = 14) 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 JNJ-957 and daratumumab on the observed (O) MM cells were compared with the expected (E) lysis levels, where these lysis levels were calculated under the assumption that the combined effect was achieved through an additive effect as shown in the method. The black bars show the group means ± SEM. The paired Student's t-test was used to calculate the P-value. JNJ-957 is referred to as JNJ-7957 in the figure. Dara: Daratumumab. ns: Not significant.

[0062] Figure 41 It shows the lysis of Raji cell line mediated by blinatumomab using consecutive PB samples from 11 RRMM patients as effector cells (E:T was 10:1), 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, and then a blinatumomab-based cytotoxicity assay was performed. The data are presented as mean ± SEM and the experiments were performed in duplicate. Nonlinear regression analysis was used to calculate the statistical significance (P-value) between the indicated groups.

[0063] Figure 42 It shows the dose-response of the lysis of plasma cells, T cells, and NK cells in BM-MNC cells obtained from six patients with primary plasma cell leukemia (pPCL) mediated by JNJ-957. As shown, the percentage of lysis 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.

[0064] Figure 43Shows the lysis of MM cell lines (E:T was 10:1) mediated by anti-GPRC5D×CD3 antibodies using consecutive PB samples from 11 RRMM patients as effector cells, which were obtained directly before the start of daratumumab treatment (bottom line) and during daratumumab treatment (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, and then a blinatumomab-based cytotoxicity assay was performed. Data are represented as mean ± SEM and experiments were performed in duplicate.

[0065] Figure 44 Shows that the addition of daratumumab is an additive for MM cell lysis mediated by anti-GPRC5D×CD3 bispecific antibody (JNJ-7564). BM MNCs from RRMM patients (n = 17) who had not received daratumumab treatment were treated with anti-GPRC5D×CD3 bispecific antibody (0.00128 μg / mL to 0.8 μg / mL) alone or in combination with 0.1 μg / mL of daratumumab for 48 hours. The lysis levels of anti-GPRC5D×CD3 bispecific antibody and daratumumab on the observed (O) MM cells were compared with the expected (E) lysis levels, where these lysis levels were calculated assuming that the combined effect was achieved through an additive effect as shown in the method. Black bars show group mean ± SEM. Paired Student's t-test was used to calculate the P value. ns: not significant. Dara: daratumumab. Detailed Description

[0066] The methods disclosed in the present invention can be more easily understood by referring to the accompanying drawings that form a part of this disclosure and the following detailed description. It should be understood that the methods disclosed in the present invention are not limited to the specific methods described and / or shown herein, and 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.

[0067] As used herein, the singular forms "a", "an", and "the" include plural forms.

[0068] Various terms related to aspects of the specification are used throughout the specification and claims. Unless otherwise indicated, such terms are given their ordinary meaning in the art. Other specifically defined terms should be understood in a manner consistent with the definitions provided herein.

[0069] As used herein, "about" when used in reference to a numerical range, critical value, or specific value means within an acceptable error range of the specific value as determined by a person 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 measuring system. In the context of measurements, results, or embodiments, unless otherwise expressly stated in the Examples or elsewhere in the specification, "about" means within one standard deviation or up to 5%, whichever is greater, according to the conventions of the art.

[0070] "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, tetra-specific antibodies, etc.), dimeric, tetrameric, or multimeric antibodies, single-chain antibodies, domain antibodies, and any other modified configuration of an immunoglobulin molecule that contains an antigen-binding site with the desired specificity. "Full-length antibody" includes two heavy chains (HC) and two light chains (LC) interconnected by disulfide bonds, as well as their multimers (e.g., IgM). Each heavy chain consists of a heavy-chain variable region (VH) and a heavy-chain constant region (composed of the 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 (CDR), interspersed with framework regions (FR). Each VH and VL contains three CDRs and four FR segments, and are arranged in the following order from the amino-terminus to the carboxy-terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. Immunoglobulins can be designated as five major classes based on the amino acid sequence of the heavy-chain constant domain, namely IgA, IgD, IgE, IgG, and IgM. IgA and IgG are further subclassified into isotypes IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. Based on the amino acid sequence of their constant domains, the antibody light chains of any vertebrate species can be designated as one of two distinct types, namely κ and λ.

[0071] "Antigen-binding fragment" or "antigen-binding domain" refers to the antigen-binding portion of an immunoglobulin molecule. Antigen-binding fragments can 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 mimicking the CDRs of antibodies such as the FR3-CDR3-FR4 portion, HCDR1, HCDR2, and / or HCDR3 and LCDR1, LCDR2, and / or LCDR3. VH and VL domains can be linked together via a synthetic linker to form various types of single-chain antibody designs, where in the case where the VH and VL domains are expressed by separate single-chain antibody constructs, the VH / VL domains can pair intra- or intermolecularly to form a monovalent antigen-binding site, such as a single-chain Fv (scFv) or a bivalent antibody; for example, as described in International Patent Publications WO1998 / 44001, WO1988 / 01649, WO1994 / 13804, and WO1992 / 01047.

[0072] "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 contains the amino acid sequence of SEQ ID NO:2.

[0073] SEQ ID NO:2

[0074] MLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPLTCQRYCNASVTNSVKGTNAILWTCLGLSLIISLAVFVLMFLLRKINSEPLKDEFKNTGSGLLGMANIDLEKSRTGDEIILPRGLEYTVEECTCEDCIKSKPKVDSDHCFPLPAMEEGATILVTTKTNDYCKSLPAALSATEIEKSISAR

[0075] "Bispecific" refers to an antibody that specifically binds two different antigens or two different epitopes within the same antigen. Bispecific antibodies may have cross-reactivity to other related antigens, e.g., cross-reactivity to the same antigen from other species (homologs) such as human or monkey, e.g., cynomolgus macaque (Macaca cynomolgus) (cynomolgus, cyno), chimpanzee (Pan troglodytes), or may bind epitopes shared between two or more antigens.

[0076] "Cancer" refers to a wide variety of diseases characterized by the uncontrolled growth of abnormal cells in the body. Uncontrolled cell division and growth lead to the formation of malignant tumors that invade adjacent tissues and can also metastasize to distant parts of the body through the lymphatic system or bloodstream. "Cancer" or "cancer tissue" may include tumors.

[0077] "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.

[0078] CD123 (SEQ ID NO:57)

[0079] MVLLWLTLLLIALPCLLQTKEDPNPPITNLRMKAKAQQLTWDLNRNVTDIECVKDADYSMPAVNNSYCQFGAISLCEVTNYTVRVANPPFSTWILFPENSGKPWAGAENLTCWIHDVDFLSCSWAVGPGAPADVQYDLYLNVANRRQQYECLHYKTDAQGTRIGCRFDDISRLSSGSQSSHILVRGRSAAFGIPCTDKFVVFSQIEILTPPNMTAKCNKTHSFMHWKMRSHFNRKFRYELQIQKRMQPVITEQVRDRTSFQLLNPGTYTVQIRARERVYEFLSAWSTPQRFECDQEEGANTRAWRTSLLIALGTLLALVCVFVICRRYLVMQRLFPRIPHMKDPIGDSFQNDKLVVWEAGKAGLEECLVTEVQVVQKT

[0080] "CD19" refers to 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.

[0081] CD19 (SEQ ID NO:58)

[0082] MPPPRLLFFLLFLTPMEVRPEEPLVVKVEEGDNAVLQCLKGTSDGPTQQLTWSRESPLKPFLKLSLGLPGLGIHMRPLAIWLFIFNVSQQMGGFYLCQPGPPSEKAWQPGWTVNVEGSGELFRWNVSDLGGLGCGLKNRSSEGPSSPSGKLMSPKLYVWAKDRPEIWEGEPPCLPPRDSLNQSLSQDLTMAPGSTLWLSCGVPPDSVSRGPLSWTHVHPKGPKSLLSLELKDDRPARDMWVMETGLLLPRATAQDAGKYYCHRGNLTMSFHLEITARPVLWHWLLRTGGWKVSAVTLAYLIFCLCSLVGILHLQRALVLRRKRKRMTDPTRRFFKVTPPPGSGPQNQYGNVLSLPTPTSGLGRAQRWAAGLGGTAPSYGNPSSDVQADGALGSRSPPGVGPEEEEGEGYEEPDSEEDSEFYENDSNLGQDQLSQDGSGYENPEDEPLGPEDEDSFSNAESYENEDEELTQPVARTMDFLSPHGSAWDPSREATSLGSQSYEDMRGILYAAPQLRSIRGQPGPNHEEDADSYENMDNPDGPDPAWGGGGRMGTWSTR

[0083] "CD3" refers to a human antigen that is expressed on T cells as part of the multi - molecular T - cell receptor (TCR) complex and consists of a homodimer or heterodimer formed by the association of two or four receptor chains: CD3ε, CD3δ, CD3ζ, and CD3γ. Human CD3ε contains the amino acid sequence of SEQ ID NO:3. SEQ ID NO:22 shows the extracellular domain of CD3ε.

[0084] SEQ ID NO:3

[0085] MQSGTHWRVLGLCLLSVGVWGQDGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENCMEMDVMSVATIVIVDICITGGLLLLVYYWSKNRKAKAKPVTRGAGAGGRQRGQNKERPPPVPNPDYEPIRKGQRDLYSGLNQRRI

[0086] SEQ ID NO:22

[0087] DGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENCMEMD

[0088] "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.

[0089] CD33 (SEQ ID NO:97)

[0090] MPLLLLLPLLWAGALAMDPNFWLQVQESVTVQEGLCVLVPCTFFHPIPYYDKNSPVHGYWFREGAIISRDSPVATNKLDQEVQEETQGRFRLLGDPSRNNCSLSIVDARRRDNGSYFFRMERGSTKYSYKSPQLSVHVTDLTHRPKILIPGTLEPGHSKNLTCSVSWACEQGTPPIFSWLSAAPTSLGPRTTHSSVLIITPRPQDHGTNLTCQVKFAGAGVTTERTIQLNVTYVPQNPTTGIFPGDGSGKQETRAGVVHGAIGGAGVTALLALCLCLIFFIVKTHRRKAARTAVGRNDTHPTTGSASPKHQKKSKLHGPTETSSCSGAAPTVEMDEELHYASLNFHGMNPSKDTSTEYSEVRTQ

[0091] "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, which has amino acid residues 1-21 representing the cytoplasmic domain, amino acid residues 22-42 representing the transmembrane domain, and residues 43-300 representing the extracellular domain.

[0092] SEQ ID NO:1

[0093] MANCEFSPVSGDKPCCRLSRRAQLCLGVSILVLILVVVLAVVVPRWRQQWSGPGTTKRFPETVLARCVKYTEIHPEMRHVDCQSVWDAFKGAFISKHPCNITEEDYQPLMKLGTQTVPCNKILLWSRIKDLAHQFTQVQRDMFTLEDTLLGYLADDLTWCGEFNTSKINYQSCPDWRKDCSNNPVSVFWKTVSRRFAEAACDVVHVMLNGSRSKIFDKNSTFGSVEVHNLQPEKVQTLEAWVIHGGREDSRDLCQDPTIKELESIISKRNIQFSCKNIYRPDKFLQCVKNPEDSSCTSEI

[0094] "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 can also be any of the other antibody isotypes as described herein.

[0095] "Chimeric antigen receptor" or "CAR" refers to an engineered T cell receptor that transplants a ligand or antigen specificity 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 immunoreceptor. A CAR comprises an extracellular domain capable of binding to an antigen, a transmembrane domain, and at least one intracellular domain. The intracellular domain of a CAR comprises a polypeptide of a domain known to be used to transmit 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 capable of functioning to link the extracellular domain and the signaling domain. The chimeric antigen receptor may optionally comprise a hinge domain that serves as a linker between the extracellular domain and the transmembrane domain.

[0096] "Combination" means administering two or more therapeutic agents together as a mixture, simultaneously as a single agent, or sequentially as a single agent in any order to a subject.

[0097] "Complementary determining region" (CDR) is the region of an antibody that binds 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 numbering 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). Programs such as abYsis from 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).

[0098] The term "comprising" is intended to include examples covered by the terms "consisting essentially of" and "consisting of"; similarly, the term "consisting essentially of" is intended to include examples covered by the term "consisting of". Unless the context clearly requires otherwise, throughout the specification and claims, the words "comprising", "including", etc. shall be understood to have an inclusive meaning, rather than an exclusive or exhaustive meaning; that is, the meaning of "including but not limited to".

[0099] "enhanced" or "enhancing"Refers to an enhancement of one or more functions of a test molecule when compared to a control molecule, or an enhancement of the combined functions of a test molecule when compared to one or more control molecules. Exemplary functions that can be measured are tumor cell killing, T cell activation, relative or absolute T cell numbers, Fc-mediated effector functions (such as ADCC, CDC, and / or ADCP), or binding to Fcγ receptors (FcγR) or FcRn. "Enhanced" can be an enhancement of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% or greater, or an enhancement that is statistically significant.

[0100] "Fcγ receptor" (FcγR) refers to the well-known FcγRI, FcγRIIa, FcγRIIb, or FcγRIII. Activating FcγRs include FcγRI, FcγRIIa, and FcγRIII.

[0101] "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.

[0102] GPRC5D (SEQ ID NO:98)

[0103] MYKDCIESTGDYFLLCDAEGPWGIILESLAILGIVVTILLLLAFLFLMRKIQDCSQWNVLPTQLLFLLSVLGLFGLAFAFIIELNQQTAPVRYFLFGVLFALCFSCLLAHASNLVKLVRGCVSFSWTTILCIAIGCSLLQIIIATEYVTLIMTRGMMFVNMTPCQLNVDFVVLLVYVLFLMALTFFVSKATFCGPCENWKQHGRLIFITVLFSIIIWVVWISMLLRGNPQFQRQPQWDDPVVCIALVTNAW VFLLLYIVPELCILYRSCRQECPLQGNACPVTAYQHSFQVENQELSRARDSDGAEEDVALTSYGTPIQPQTVDPTQECFIPQAKLSPQQDAGGV

[0104] "Human antibody" refers to an antibody that is optimized to have minimal immune response when administered to a human subject. The variable regions of a human antibody are derived from human immunoglobulin sequences. If a human antibody contains a constant region or a portion of a constant region, the constant region is also derived from human immunoglobulin sequences. If the variable regions of a human antibody are derived from a system using human germline immunoglobulin or rearranged immunoglobulin genes, the human antibody contains a heavy chain variable region and a light chain variable region that are "derived from" human origin sequences. Such exemplary systems are human immunoglobulin gene libraries displayed on phage, and transgenic non-human animals, such as mice or rats carrying human immunoglobulin loci. Due to differences between the systems used to obtain human antibodies and human immunoglobulin loci, the introduction of somatic mutations, and the intentional introduction of substitutions into the framework or CDRs, "human antibodies" typically contain amino acid differences when compared to immunoglobulins expressed in humans. Generally, the amino acid sequence of a "human antibody" has at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence encoded by a human germline immunoglobulin gene or a rearranged immunoglobulin gene. In some cases, a "human antibody" may contain a consensus framework sequence derived from the analysis of human framework sequences (e.g., as described in Knappik et al., (2000) J Mol Biol, Vol. 296: pp. 57-86); or a synthetic HCDR3 incorporated into a human immunoglobulin gene library displayed on phage (e.g., as described in Shi et al., (2010) J Mol Biol, Vol. 397: pp. 385-396 and International Patent Publication WO2009 / 085462). Antibodies in which at least one CDR is derived from a non-human species are not included in the definition of "human antibody".

[0105] "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 human immunoglobulin sequences. A humanized antibody may contain substitutions in the framework such that the framework may not be an exact copy of an expressed human immunoglobulin or human immunoglobulin germline gene sequence.

[0106] "Isolated" refers to a homogeneous population of molecules (such as synthetic polynucleotides or proteins, such as antibodies) that have been substantially separated from and / or purified out of other components in the system (such as a recombinant cell) in which the molecule was produced, as well as proteins that have been subjected to at least one purification or isolation step. "Isolated antibody" refers to an antibody that is substantially free of other cellular materials and / or chemicals, and encompasses antibodies isolated to a higher 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.

[0107] "Monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibody molecules, i.e., each antibody comprising the population is identical, except for possible well-known modifications 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 typically bind to one epitope. Bispecific monoclonal antibodies bind to two different epitopes. Monoclonal antibodies can have heterogeneous glycosylation within the antibody population. Monoclonal antibodies can be monospecific or multispecific, such as bispecific, monovalent, bivalent or multivalent.

[0108] "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.

[0109] "Non-fixed combination" refers to independent pharmaceutical compositions in which a T cell redirecting therapeutic agent and an anti-CD38 antibody are administered simultaneously, in parallel or sequentially as independent entities without a specific time interval limitation, where such administration provides effective levels of both compounds in a subject.

[0110] "Multispecific" refers to an antibody that specifically binds to at least two different antigens or at least two different epitopes within the same antigen. Multispecific antibodies can bind, for example, two, three, four or five different antigens or different epitopes within the same antigen.

[0111] "Pharmaceutical composition" refers to a composition comprising an active ingredient and a pharmaceutically acceptable carrier.

[0112] "Pharmaceutically acceptable carrier" or "excipient" refers to the components in a pharmaceutical composition other than the active ingredient, which are non-toxic to the subject.

[0113] The "Philadelphia chromosome" or "Ph" refers to the well-known chromosomal translocation between chromosomes 9 and 22, resulting in the oncogenic BCR-ABL gene fusion with constitutively active tyrosine kinase activity. The translocation causes a portion of the BCR gene from chromosome 22q11 to fuse with a portion of the ABL gene from chromosome 9q34 and is designated as 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. The "Philadelphia chromosome" refers to all BCR-ABL fusion proteins formed as a result of the (9;22)(q34;q11) translocation.

[0114] "PSMA" refers to the 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.

[0115] PSMA (SEQ ID NO:99)

[0116] MWNLLHETDSAVATARRPRWLCAGALVLAGGFFLLGFLFGWFIKSSNEATNITPKHNMKAFLDELKAENIKKFLYNFTQIPHLAGTEQNFQLAKQIQSQWKEFGLDSVELAHYDVLLSYPNKTHPNYISIINEDGNEIFNTSLFEPPPPGYENVSDIVPPFSAFSPQGMPEGDLVYVNYARTEDFFKLERDMKINCSGKIVIARYGKVFRGNKVKNAQLAGAKGVILYSDPADYFAPGVKSYPDGWNLPGGGVQRGNILNLNGAGDPLTPGYPANEYAYRRGIAEAVGLPSIPVHPIGYYDAQKLLEKMGGSAPPDSSWRGSLKVPYNVGPGFTGNFSTQKVKMHIHSTNEVTRIYNVIGTLRGAVEPDRYVILGGHRDSWVFGGIDPQSGAAVVHEIVRSFGTLKKEGWRPRRTILFASWDAEEFGLLGSTEWAEENSRLLQERGVAYINADSSIEGNYTLRVDCTPLMYSLVHNLTKELKSPDEGFEGKSLYESWTKKSPSPEFSGMPRISKLGSGNDFEVFFQRLGIASGRARYTKNWETNKFSGYPLYHSVYETYELVEKFYDPMFKYHLTVAQVRGGMVFELANSIVLPFDCRDYAVVLRKYADKIYSISMKHPQEMKTYSVSFDSLFSAVKNFTEIASKFSERLQDFDKSNPIVLRMMNDQLMFLERAFIDPLGLPDRPFYRHVIYAPSSHNKYAGESFPGIYDALFDIESKVDPSKAWGEVKRQIYVAAFTVQAAAETLSEVA

[0117] "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 recombinant DNA, antibodies, or proteins.

[0118] "Reduced" or "reduction" means that one or more functions of a test molecule are reduced when compared to a control molecule, or that the combined function of a test molecule is reduced when compared to one or more control molecules. Exemplary functions that can be measured are tumor cell killing, T cell activation, relative or absolute T cell numbers, Fc-mediated effector functions (such as ADCC, CDC, and / or ADCP), or binding to Fcγ receptors (FcγR) or FcRn. "Reduced" can be a reduction of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% or greater, or a reduction that is statistically significant.

[0119] "rHuPh20" refers to recombinant human hyaluronidase having the amino acid sequence of SEQ ID NO: 105, which is the recombinant hyaluronidase described in International Patent Publication WO2004 / 078140 ( recombinant).

[0120] rHuPH20 (SEQ ID NO:105)

[0121] MGVLKFKHIFFRSFVKSSGVSQIVFTFLLIPCCLTLNFRAPPVIPNVPFLWAWNAPSEFCLGKFDEPLDMSLFSFIGSPRINATGQGVTIFYVDRLGYYPYIDSITGVTVNGGIPQKISLQDHLDKAKKDITFYMPVDNLGMAVIDWEEWRPTWARNWKPKDVYKNRSIELVQQQNVQLSLTEATEKAKQEFEKAGKDFLVETIKLGKLLRPNHLWGYYLFPDCYNHHYKKPGYNGSCFNVEIKRNDDLSWLWNESTALYPSIYLNTQQSPVAATLYVRNRVREAIRVSKIPDAKSPLPVFAYTRIVFTDQVLKFLSQDELVYTFGETVALGASGIVIWGTLSIMRSMKSCLLLDNYMETILNPYIINVTLAAKMCSQVLCQEQGVCIRKNWNSSDYLHLNPDNFAIQLEKGGKFTVRGKPTLEDLEQFSEKFYCSCYSTLSCKEKADVKDTDAVDVCIADGVCIDAFLKPPMETEEPQIFYNASPSTLSATMFIVSILFLIISSVASL

[0122] "Refractory" means cancer that is not amenable to surgical intervention and is initially unresponsive to treatment.

[0123] "Recurrent" refers to cancer that responds to treatment but then recurs.

[0124] "Subject" includes any human or non-human animal. "Non-human animal" includes all vertebrates, such as 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" may be used interchangeably.

[0125] "T cell redirecting therapeutic agent" refers to a molecule that comprises two or more binding regions, wherein one of the binding regions specifically binds a cell surface antigen (such as a tumor associated antigen) on a target cell or tissue, and wherein a second binding region of the molecule specifically binds a T cell antigen (such as CD3). This dual / multiple target binding ability recruits T cells to the target cell or tissue, thereby eradicating the target cell or tissue.

[0126] "TMEFF2" refers to a human transmembrane protein having 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.

[0127] TMEFF2 (SEQ ID NO:101)

[0128] MVLWESPRQCSSWTLCEGFCWLLLLPVMLLIVARPVKLAAFPTSLSDCQTPTGWNCSGYDDRENDLFLCDTNTCKFDGECLRIGDTVTCVCQFKCNNDYVPVCGSNGESYQNECYLRQAACKQQSEILVVSEGSCATDAGSGSGDGVHEGSGETSQKETSTCDICQFGAECDEDAEDVWCVCNIDCSQTNFNPLCASDGKSYDNACQIKEASCQKQEKIEVMSLGRCQDNTTTTTKSEDGHYARTDYAENANKLEESAREHHIPCPEHYNGFCMHGKCEHSINMQEPSCRCDAGYTGQHCEKKDYSVLYVVPGPVRFQYVLIAAVIGTIQIAVICVVVLCITRKCPRSNRIHRQKQNTGHYSSDNTTRASTRLI

[0129] "Therapeutically effective amount" means an amount that is effective, at the required dosage and for the required period of time, to achieve the desired therapeutic result. A therapeutically effective amount may vary according to factors such as the individual's disease state, age, sex, and weight, as well as 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, improvement of the patient's health.

[0130] "Treatment" refers to both therapeutic treatment and prophylactic or defensive measures, wherein the object is to prevent or slow down (alleviate) an undesired physiological change or disorder. Beneficial or desired clinical outcomes include alleviation of symptoms, diminishment of the extent of the disease, stabilization (i.e., not worsening) of the disease state, delay or slowing of disease progression, improvement or palliation of the disease state, and remission (whether partial or complete), whether detectable or undetectable. "Treatment" may also mean prolongation of survival as compared to expected survival if the subject were not receiving treatment. Individuals in need of treatment include those already suffering from a disorder or condition as well as those prone to developing a disorder or condition or those in whom prevention of a disorder or condition is desired.

[0131] "Tumor cell" or "cancer cell" refers to cancerous, precancerous or transformed cells in vivo, in vitro or in tissue culture, which have undergone phenotypic changes, either spontaneously or induced. These changes do not necessarily involve the uptake of new genetic material. However, transformation can occur by infection with transforming viruses and by the incorporation of new genomic nucleic acids, the uptake of exogenous nucleic acids, or it can occur spontaneously or after exposure to carcinogens, resulting in endogenous gene mutations. Examples of transformation / cancer are morphological changes, cell immortality, abnormal growth control, focus formation, proliferation, malignancy, adjustment of tumor-specific marker levels, invasion, tumor growth in vitro, in vivo and ex vivo in a suitable animal host (such as nude mice, etc.).

[0132] Unless otherwise expressly stated, throughout the specification, amino acid residues in the antibody constant regions are numbered according to the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991). Antibody constant chain numbering can be found, for example, on the ImMunoGeneTics website, in the IMGT Web resources of the IMGT Scientific Chart.

[0133] Substitutions in the CH3 region are represented as the modified position in the first CH3 domain of the first heavy chain / the modified position in the second CH3 domain of the second heavy chain. For example, F405L / K409R refers to the F405L mutation in the first CH3 region and the K09R mutation in the second CH3 region. L351Y_F405A_Y407V / T394W refers to the L351Y, F40FA, and Y407V mutations in the first CH3 region and the T394W mutation in the second CH3 region. D399FHKRQ / K409AGRH refers to the 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.

[0134] Conventional single-letter and three-letter amino acid codes are used herein, as shown in Table 1.

[0135] Table 1 .

[0136] Amino acid Three-letter code One-letter code Alanine Ala A Arginine Arg R Asparagine Asn N Aspartic acid Asp D Cysteine Cys C Glutamic acid 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

[0137] Combination of an anti-CD38 antibody and a T cell redirection therapeutic agent and uses thereof

[0138] The present invention is at least in part based on the discovery that the therapeutic agent JNJ-957 or the GPRC5D×CD3 antibody and the anti-CD38 antibody (daratumumab), each of which does not antagonize each other in terms of competing for binding to MM cells or acting on the mechanism or target of MM cells and mediating the killing of multiple myeloma cells when target engagement occurs on the same cell, and thus is suitable for use in combination therapy. The present invention is also at least in part based on the discovery that (daratumumab) enhances the killing of multiple myeloma cells obtained from heavily pre-treated relapsed / refractory multiple myeloma subjects mediated by JNJ-957. The present invention is also at least in part based on the discovery that (daratumumab) enhances the killing of tumor cells other than multiple myeloma cells by a T cell redirecting therapeutic agent targeting non-multiple myeloma tumor cells. Therefore, the combination of an anti-CD38 antibody and a T cell redirecting therapeutic agent and / or pre-treatment of a subject with an anti-CD38 antibody before administration of the T cell redirecting therapeutic agent can enhance the anti-tumor efficacy of monotherapy. Also, given that cancer is generally a heterogeneous disease, parts 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.

[0139] CD38 is a multifunctional protein that functions in receptor-mediated adhesion and signaling, as well as calcium mobilization mediated by its extracellular enzymatic 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 + levels via its NAD glycohydrolase activity, which involves modulating the regulatory T cell compartment (Adriouch et al., Microbes infect, Vol. 14: pp. 1284-1292, 2012; Chiarugi et al., NatureReviews, Vol. 12: pp. 741-752, 2012). In addition to signaling via Ca 2+ , CD38 signaling also occurs via interaction with antigen-receptor complexes or other types of receptor complexes (such as MHC molecules) on T cells and B cells, such that CD38 is involved not only in several cellular responses but also in the switch and secretion of IgG1. Anti-CD38 antibodies (daratumumab) have been identified herein to enhance the anti-tumor effect of T cell redirecting therapeutic agents. Without being bound by any particular theory, it is hypothesized (daratumumab) promotes the engagement of T cells with T cell redirecting therapeutic agents via its immunomodulatory activity in human subjects (i.e., reducing the numbers of immunosuppressive Tregs, MDSCs, and Bregs, increasing the numbers of CD8 + T cells as well as the ratio of CD8 + to Tregs, promoting the formation of CD8 + central memory cells and increasing T cell clonality) or even may result in an enhanced immune response in a subject.

[0140] 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 cancer.

[0141] The present disclosure also provides a method of killing tumor cells of a subject, comprising administering to the subject an anti-CD38 antibody and a T cell redirecting therapeutic agent that binds an antigen on the tumor cells for a time sufficient to kill the tumor cells.

[0142] The present disclosure also provides a method of enhancing the efficacy of a T cell redirecting therapeutic agent in a subject having cancer, comprising administering an anti-CD38 antibody to the subject.

[0143] In some embodiments, an anti-CD38 antibody is administered before administering a T cell redirecting therapeutic agent.

[0144] The T cell redirecting therapeutic agent 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 longer before administering the anti-CD38 antibody.

[0145] In some embodiments, the T cell redirecting therapeutic agent binds to an antigen on a tumor cell.

[0146] 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 (CSPG4, melanoma-associated chondroitin sulfate proteoglycan), epidermal growth factor receptor (EGFR), Her2, Her3, IGFR, IL3R, fibroblast activation protein (FAP), CDCP1, Derlin1, tenascin, frizzled protein 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.

[0147] In some embodiments, the T cell redirecting therapeutic agent binds to BCMA, GPRC5D, CD33, CD123, CD19, PSMA, TMEFF2, CD20, CD22, CD25, CD52, ROR1, HM1.24, CD38 or SLAMF7.

[0148] In some embodiments, the T cell redirecting therapeutic agent binds to CD3ε (CD3ε).

[0149] In some embodiments, the T cell redirecting therapeutic agent binds to CD3.

[0150] In some embodiments, the T cell redirecting therapeutic agent binds to CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, BTNL8, PD-1, CD195 or NKG2C. These antigens are more specific for CD8 + T cells as compared to CD3 (see, for example, International Patent Publication WO2018 / 187215).

[0151] In some embodiments, the T cell redirecting therapeutic agent comprises a CD3 binding domain comprising:

[0152] 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;

[0153] Heavy chain variable region (VH) of SEQ ID NO:39 and light chain variable region (VL) of SEQ ID NO:40;

[0154]

[0155] HCDR1 of SEQ ID NO:74, HCDR2 of SEQ ID NO:75, HCDR3 of SEQ ID NO:76, LCDR1 of SEQ IDNO:77, LCDR2 of SEQ ID NO:78 and LCDR3 of SEQ ID NO:79;

[0156] VH of SEQ ID NO:80 and VL of SEQ ID NO:81;

[0157] HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of the CD3 binding domain of SEQ ID NO:53; or

[0158] VH and VL of the CD3 binding domain of SEQ ID NO:53.

[0159] In some embodiments, the T cell redirecting therapeutic agent binds to BCMA. ​

[0160] In some embodiments, the T cell redirecting therapeutic agent comprises

[0161] a BCMA binding domain and a CD3 binding domain, the BCMA binding domain comprising the HCDR1 of SEQ ID NO:23, the HCDR2 of SEQ ID NO:24, the

[0162] HCDR3 of SEQ ID NO:25, the LCDR1 of SEQ ID NO:26, the LCDR2 of SEQ ID NO:27, and the LCDR3 of SEQ ID NO:28, and the CD3 binding domain comprising the

[0163] 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

[0164] 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.

[0165] In some embodiments, the T cell redirecting therapeutic agent that binds BCMA 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.

[0166] In some embodiments, T cell redirecting therapeutic agents that bind BCMA include ACTR cancer therapies from Seattle Genetics, AFM-26, ALLO-715, anti-BCMA allogeneic CAR-T cell therapies from CRISPR Therapeutics, anti-BCMA CAR-T therapies from Sorrento Therapeutics, anti-CD19 / BCMA CAR-T cell therapies from Hrain Biotechnology, BCMA CAR-T therapies from Chineo Med (Beijing), BCMA TAC-T cell therapies from Triumvira Immunologics, BCMA-CAR T cell therapies from Shanghai Unicar-Therapy Biomed, BCMA / CD3 antibodies from Regeneron, CAR-NK cell therapies from NantKwest, CC-93629, CMD-505, CTX-4419, CYAD-211, HDP-101, HPN-217, P-BCMA-ALLO1, TNB-383B, bb-2121, AUTO-2, BCMA chimeric antigen receptor therapies from Pregene, BCMA-CAR T cells from Shanghai Bioray Laboratory, BCMA-CAR-T cells from CARsgen Therapeutics, CAR-T / TCR-T cell immunotherapies from Shenzhen BinDeBio, ET-140, P-BCMA-101, REGN-5458, AMG-701, anti-BCMA CAR-T cell therapies from Cellular Biomedicine Group, bb-21217, BI-836909, CC-93269, Descartes-08, IM-21, JNJ-64007957, MEDI-2228 or PF-06863135.

[0167] In some embodiments, the T cell redirecting therapeutic agent comprises any one of the BCMA binding domains as described in International Patent Publication WO2017 / 031104.

[0168] In some embodiments, the T cell redirecting therapeutic agent binds GPRC5D.

[0169] In some embodiments, the T cell redirecting therapeutic agent comprises

[0170] GPRC5D binding domain and 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:

[0171] 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 SEQ ID NO:

[0172] 33 of HCDR1, 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

[0173] The GPRC5D binding domain comprises VH of SEQ ID NO:49 and VL of SEQ ID NO:50, and the CD3 binding domain comprises VH of SEQ ID NO:39 and VL of SEQ ID NO:40.

[0174] In some embodiments, the T cell redirecting therapeutic agent 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.

[0175] In some embodiments, the T cell redirecting therapeutic agent comprises a GPRC5D antibody of Eureka Therapeutics.

[0176] In some embodiments, the T cell redirecting therapeutic agent comprises any one of the GPRC5D binding domains described in International Patent Publication WO2018 / 0037651.

[0177] In some embodiments, the T cell redirecting therapeutic agent binds CD33.

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

[0179] A CD33-binding domain and a CD3-binding domain, the CD33-binding domain comprising 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 comprising 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

[0180] The CD33-binding domain comprises VH of SEQ ID NO:90 and VL of SEQ ID NO:91, and the CD3-binding domain comprises VH of SEQ ID NO:80 and VL of SEQ ID NO:81.

[0181] In some embodiments, the T cell redirecting therapeutic agent that binds CD33 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.

[0182] In some embodiments, the T cell redirecting therapeutic agent that binds CD33 includes the CAR-T / TCR-T cell immunotherapy of Shenzhen BinDeBio, AMG-330, AMV-564, JNJ-67571244, ICG-144, AMG-673, the CD33 CAR-T therapy INXN3004 of Ziopharm, huCD33-BsAb, VOR-33, HMBD-004A, GEM-333, TGB-3550 or CD33.taNK.

[0183] In some embodiments, the T cell redirecting therapeutic agent binds CD123.

[0184] In some embodiments, the T cell redirecting therapeutic agent comprises

[0185] A CD123-binding domain and a CD3-binding domain, wherein the CD123-binding domain comprises HCDR1 of SEQ ID NO:94, HCDR2 of SEQ ID NO:95, HCDR3 of SEQ ID NO:96, LCDR1 of SEQ ID NO:9, LCDR2 of SEQ ID NO:10, and LCDR3 of SEQ ID NO:59, 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; and / or

[0186] The CD123-binding domain comprises VH of SEQ ID NO:100 and VL of SEQ ID NO:61, and the CD3-binding domain comprises VH of SEQ ID NO:39 and VL of SEQ ID NO:40.

[0187] In some embodiments, the CD123-binding T cell redirecting therapeutic agent 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.

[0188] In some embodiments, the CD123-binding T cell redirecting therapeutic agent includes the acute myeloid leukemia therapy of TheraVectys, APVO-437, the anti-CD123 CAR-T cell therapy of Nanjing Legend Biotech, APVO-436, the CD123 CAR-T cell therapy of Hebei Senlang Biotechnology, fostamatinib, IM-23, JNJ-63709178, MB-102 of Mustang Bio, UCART-123, XmAb-14045, or the CD3-CD123 bispecific T cell engager of Sanofi.

[0189] In some embodiments, the T cell redirecting therapeutic agent comprises any of the CD123-binding domains described in International Patent Publication WO2016 / 036937.

[0190] In some embodiments, the T cell redirecting therapeutic agent binds to CD19.

[0191] In some embodiments, the T cell redirecting therapeutic agent comprises

[0192] 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

[0193] The amino acid sequence of SEQ ID NO:53.

[0194] In some embodiments, CD19-binding T cell redirecting therapeutic agents include axicabtagene ciloleucel, blinatumomab, tisagenlecleucel-t, AMG-562, AUTO-1 CAR-T CD19 of Cellular Biomedicine Group, CD19 chimeric antigen receptor T cell therapy of Ziopharm, CD19-CAR-T cell therapy of ioceltech Therapeutics, CD19-CAR-T cell therapy of Marino Biotechnology, CD19-CAR-T2 cell therapy of Guangdong Zhaotai InVivo, CD19 / 4-1BBL armored CAR T cell therapy of Juno Therapeutics, CSG-CD19, DI-B4, ET-190, GC-007F, GC-022, human CD19 T cell therapy of HRAIN Biotechnology, humanized anti-CD19 control CAR (3rd generation) of Kite Pharma, ICAR-19 CAR-T cells of Immune Cell Therapy, ICTCAR-003, iPD1 CD19 eCAR T cells of Marino Biotechnology, JWCAR029, PTG-01, PZ01, Senl_1904A, Senl_1904B, UCART-19, UWC-19, AUTO-3, BinD-19, CAR-T cell therapy of Shanghai Unicar-Therapy Biomed, CAR-T / TCR-T cell immunotherapy of Shenzhen BinDeBio, CD-19 CAR-T cell therapy of Miltenyi Biotec, CD19 CAR-T cells of Miltenyi Biotec, CD19-CART cell therapy of ShanghaiUnicar-Therapy Biomed, CD19-CAR T cell therapy of Takara Bio, CD19-CART of Shanghai Bioray Laboratory, CD19-targeted chimeric antigen receptor T cells of Sinobioway, CD19 / CD20 CAR-T cell therapy of Shanghai Longyao Biotechnology, 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, the 3rd generation CD19-CART cells + mbIL15 of Eden BioCell, A-329, ALLO-501, autologous homologous T cells redirected by anti-CD19 anti-CD20 bispecific CAR of Beijing Doing Biomedical Co, anti-CD19 CAR NK cell therapy of Allife Medical Science, anti-CD19 / BCMA CAR-T cell therapy of Hrain Biotechnology, ATA-2431, ATA-3219 of Celularity, AVA-008, CD19 CAR-T cell therapy, the 3rd generation CD19 chimeric antigen receptor T cell therapy of Ziopharm, CD19 dBiTE of Inovio, CD19 TCR cell therapy of Bellicum, CD19-ATAC of Wilex, CD19 / 20 CAR-T therapy of Chineo Med (Beijing), CD19 / CD22 dual-targeted therapy of Eureka Therapeutics, chimeric antigen receptor T cell (CAR-T) therapy of Helix BioPharma, CMD-502, CTX-110, CYAD-04, CYAD-221, ET-019002, FT-596, FT-819, γ-δ CAR-T therapy of TC Biopharm, ICTCAR-014, iDD-002, KITE-037, NI-2201, RB-1916, Senl_002, TAC01-CD19, TC-110, TC-310, TCB-003 or TI-7007.

[0195] In some embodiments, the T cell redirecting therapeutic agent binds to PSMA.

[0196] In some embodiments, the T cell redirecting therapeutic agent comprises

[0197] A PSMA-binding domain and a CD3-binding domain, wherein the PSMA-binding domain comprises 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 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 / or

[0198] The PSMA-binding domain comprises VH of SEQ ID NO:60 and VL of SEQ ID NO:61, and the CD3-binding domain comprises VH of SEQ ID NO:39 and VL of SEQ ID NO:40.

[0199] In some embodiments, the T cell-redirecting therapeutic agent that binds PSMA 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.

[0200] In some embodiments, the T cell-redirecting therapeutic agent binds TMEFF2.

[0201] In some embodiments, the T cell-redirecting therapeutic agent comprises

[0202] A TMEFF2-binding domain and a CD3-binding domain, wherein the TMEFF2-binding domain comprises

[0203] HCDR1 of SEQ ID NO:64, HCDR2 of SEQ ID NO:65, HCDR3 of SEQ ID NO:66, LCDR1 of SEQ ID NO:67, LCDR2 of SEQ ID NO:68, and LCDR3 of SEQ ID NO:69, 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

[0204] 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

[0205] NO:81.

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

[0207] In some embodiments, the T cell redirecting therapeutic agent binds CD20.

[0208] In some embodiments, the T cell redirecting therapeutic agent binds CD22.

[0209] In some embodiments, the T cell redirecting therapeutic agent binds CD25.

[0210] In some embodiments, the T cell redirecting therapeutic agent binds CD52.

[0211] In some embodiments, the T cell redirecting therapeutic agent binds ROR1.

[0212] In some embodiments, the T cell redirecting therapeutic agent binds HM1.24.

[0213] In some embodiments, the T cell redirecting therapeutic agent binds SLAMF7.

[0214] In some embodiments, the T cell redirecting therapeutic agent is a multispecific antibody, a chimeric antigen receptor (CAR), or a T cell comprising a CAR.

[0215] In some embodiments, the T cell redirecting therapeutic agent is a CAR.

[0216] In some embodiments, the T cell redirecting therapeutic agent is a T cell expressing a CAR.

[0217] In some embodiments, the T cell redirecting therapeutic agent is a multispecific antibody.

[0218] In some embodiments, the multispecific antibody is of the IgG1, IgG2, IgG3, or IgG4 isotype.

[0219] In some embodiments, the multispecific antibody is of the IgG1 isotype.

[0220] In some embodiments, the multispecific antibody is of the IgG2 isotype.

[0221] In some embodiments, the multispecific antibody is of the IgG3 isotype.

[0222] In some embodiments, the multispecific antibody is of the IgG4 isotype.

[0223] The multispecific antibody can be any allotype. It is expected that the allotype has no effect on the properties of the multispecific antibody, such as binding function or Fc-mediated effector function. The immunogenicity of therapeutic antibodies is associated with an increased risk of infusion reactions and a reduced duration of therapeutic response (Baert et al., (2003) N Engl J Med 348:602-08). The extent to which a therapeutic antibody induces an immune response in a host can be determined in part by the allotype of the antibody (Stickler et al., (2011) Genes and Immunity 12:213-21). Antibody allotypes are associated with amino acid sequence variations at specific positions in the constant region sequence of the antibody. Table 2 shows selected IgG1, IgG2, and IgG4 allotypes.

[0224] Table 2 .

[0225]

[0226] In some embodiments, the multispecific antibody comprises one or more Fc substitutions that reduce the binding of the multispecific antibody to Fc gamma receptors (FcγR). Substitutions that reduce the binding of the multispecific antibody to FcγR reduce the Fc effector functions of the multispecific antibody such as ADCC, ADCP, and / or CDC. 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.

[0227] 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 / P331A / D365E / L358M on IgG1, 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, wherein the residues are numbered according to the EU index.

[0228] In some embodiments, the one or more Fc substitutions are F234A / L235A on IgG4.

[0229] In some embodiments, the one or more Fc substitutions are L234A / L235A on IgG1.

[0230] In some embodiments, the one or more Fc substitutions are V234A / G237A / P238S / H268A / V309L / A330S / P331S on IgG2.

[0231] In some embodiments, the one or more Fc substitutions are F234A / L235A on IgG4.

[0232] In some embodiments, the one or more Fc substitutions are S228P / F234A / L235A on IgG4.

[0233] In some embodiments, the one or more Fc substitutions are N297A on all Ig isotypes.

[0234] In some embodiments, the one or more Fc substitutions are V234A / G237A on IgG2.

[0235] In some embodiments, the one or more Fc substitutions are K214T / E233P / L234V / L235A / G236 - deletion / A327G / P331A / D365E / L358M on IgG1.

[0236] In some embodiments, the one or more Fc substitutions are H268Q / V309L / A330S / P331S on IgG2.

[0237] 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.

[0238] In some embodiments, the one or more Fc substitutions are L234A / L235A / G237A / P238S / H268A / A330S / P331S on IgG1.

[0239] 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.

[0240] In some embodiments, the multispecific antibody further comprises an S228P substitution.

[0241] 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.

[0242] In some embodiments, the one or more asymmetric permutations 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.

[0243] In some embodiments, the one or more asymmetric permutations are F450L / K409R.

[0244] In some embodiments, the one or more asymmetric permutations are wild type / F409L_R409K.

[0245] In some embodiments, the one or more asymmetric permutations are T366Y / F405A.

[0246] In some embodiments, the one or more asymmetric permutations are T366W / F405W.

[0247] In some embodiments, the one or more asymmetric permutations are F405W / Y407A.

[0248] In some embodiments, the one or more asymmetric permutations are T394W / Y407T.

[0249] In some embodiments, the one or more asymmetric permutations are T394S / Y407A.

[0250] In some embodiments, the one or more asymmetric permutations are T366W / T394S.

[0251] In some embodiments, the one or more asymmetric permutations are F405W / T394S.

[0252] In some embodiments, the one or more asymmetric permutations are T366W / T366S_L368A_Y407V.

[0253] In some embodiments, the one or more asymmetric permutations are L351Y_F405A_Y407V / T394W.

[0254] In some embodiments, the one or more asymmetric permutations are T366I_K392M_T394W / F405A_Y407V.

[0255] In some embodiments, the one or more asymmetric permutations are T366L_K392M_T394W / F405A_Y407V.

[0256] In some embodiments, the one or more asymmetric permutations are L351Y_Y407A / T366A_K409F.

[0257] In some embodiments, the one or more asymmetric permutations are L351Y_Y407A / T366V_K409F.

[0258] In some embodiments, the one or more asymmetric permutations are Y407A / T366A_K409F.

[0259] In some embodiments, the one or more asymmetric permutations are T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W.

[0260] In some embodiments, the cancer is a hematologic malignancy or a solid tumor.

[0261] In some embodiments, the hematologic malignancy is multiple myeloma, smoldering multiple myeloma, monoclonal gammopathy of undetermined significance (MGUS), acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Waldenström macroglobulinemia, plasma cell leukemia, light chain amyloidosis (AL), precursor B-cell lymphoblastic leukemia, precursor B-cell lymphoblastic leukemia, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic lymphocytic leukemia (CLL), B-cell malignancy, 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.

[0262] In some embodiments, the hematologic malignancy is multiple myeloma.

[0263] In some embodiments, the multiple myeloma is newly diagnosed multiple myeloma.

[0264] In some embodiments, the multiple myeloma is relapsed or refractory multiple myeloma.

[0265] In some embodiments, the multiple myeloma is high-risk multiple myeloma. Subjects known to have high-risk multiple myeloma have early relapse and poor prognosis and outcomes. A subject may be classified as having high-risk multiple myeloma if the subject has one or more of the following cytogenetic abnormalities: 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.

[0266] In some embodiments, a subject with high-risk multiple myeloma has one or more chromosomal abnormalities, the one or more chromosomal abnormalities including: 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.

[0267] Various qualitative and / or quantitative methods can be used to determine the relapsed or refractory nature of the disease. Symptoms that may be relevant are, for example: a decline or stabilization in 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 in the body from one site to other organs, tissues or cells.

[0268] 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 the dysregulation of these genes. t(4;14)(p16;q32) involves the translocation of fibroblast growth factor receptor 3 (FGFR3) and multiple myeloma SET domain-containing protein (MMSET) (also known as WHSC1 / NSD2), and t(14;16)(q32;q23) involves the translocation of the MAF transcription factor C-MAF. Deletion of 17p (del17p) involves the loss of the p53 locus.

[0269] In some embodiments, multiple myeloma is recurrent or refractory to treatment with an anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotuzumab, ixazomib, melphalan, or thalidomide, or any combination thereof.

[0270] In some embodiments, multiple myeloma is recurrent or refractory to treatment with an anti-CD38 antibody. In some embodiments, multiple myeloma is recurrent or refractory to treatment with lenalidomide. In some embodiments, multiple myeloma is recurrent or refractory to treatment with bortezomib. In some embodiments, multiple myeloma is recurrent or refractory to treatment with pomalidomide. In some embodiments, multiple myeloma is recurrent or refractory to treatment with carfilzomib. In some embodiments, multiple myeloma is recurrent or refractory to treatment with elotuzumab. In some embodiments, multiple myeloma is recurrent or refractory to treatment with ixazomib. In some embodiments, multiple myeloma is recurrent or refractory to treatment with melphalan. In some embodiments, multiple myeloma is recurrent or refractory to treatment with thalidomide.

[0271] In some embodiments, the hematologic malignancy is AML.

[0272] In some embodiments, AML is AML with at least one genetic abnormality, AML with multilineage dysplasia, therapy-related AML, undifferentiated AML, AML with minimal maturation, AML with maturation, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroid leukemia, acute megakaryoblastic leukemia, acute basophilic leukemia, acute panmyelosis with fibrosis, or myeloid sarcoma.

[0273] In some embodiments, the AML is an AML having at least one genetic abnormality. In some embodiments, the AML is an AML having multilineage dysplasia. In some embodiments, the AML is therapy-related AML. In some embodiments, the AML is undifferentiated AML. In some embodiments, the AML is an AML having minimal maturation. In some embodiments, the AML is an AML having maturation. In some embodiments, the AML is acute myelomonocytic leukemia. In some embodiments, the AML is acute monocytic leukemia. In some embodiments, the AML is acute erythroid leukemia. In some embodiments, the AML is acute megakaryoblastic leukemia. In some embodiments, the AML is acute basophilic leukemia. In some embodiments, the AML is acute panmyelosis with fibrosis. In some embodiments, the AML is myeloid sarcoma.

[0274] 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), nucleophosmin (NPM1), isocitrate dehydrogenase 1 (IDH1), isocitrate dehydrogenase 2 (IDH2), DNA (cytosine-5)-methyltransferase 3 (DNMT3A), CCAAT / enhancer-binding protein α (CEBPA), U2 small nuclear RNA auxiliary factor 1 (U2AF1), zeste enhancer 2 polycomb repressive complex 2 subunit (EZH2), structural maintenance of chromosomes 1A (SMC1A) or structural maintenance of chromosomes 3 (SMC3).

[0275] 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 nucleophosmin (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 α (CEBPA). In some embodiments, the at least one genetic abnormality is a mutation of U2 small nuclear RNA auxiliary factor 1 (U2AF1). In some embodiments, the at least one genetic abnormality is a mutation of zeste enhancer 2 polycomb repressive complex 2 subunit (EZH2). In some embodiments, the at least one genetic abnormality is a mutation of structural maintenance of chromosomes 1A (SMC1A). In some embodiments, the at least one genetic abnormality is a mutation of structural maintenance of chromosomes 3 (SMC3).

[0276] In some embodiments, the at least one genetic abnormality is the translocation t(8;21)(q22;q22), the inversion inv(16)(p13;q22), the translocation t(16;16)(p13;q22), the translocation t(15;17)(q22;q12), the mutation FLT3-ITD in IDH1, the mutation R132H or R100Q / R104V / F108L / R119Q / I130V or the mutation R140Q or R172 in IDH2.

[0277] In some embodiments, the at least one genetic abnormality is the translocation t(8;21)(q22;q22). In some embodiments, the at least one genetic abnormality is the inversion inv(16)(p13;q22). In some embodiments, the at least one genetic abnormality is the translocation t(16;16)(p13;q22). In some embodiments, the at least one genetic abnormality is the translocation t(15;17)(q22;q12). In some embodiments, the at least one genetic abnormality is the mutation FLT3-ITD. In some embodiments, the at least one genetic abnormality is the mutation R132H in IDH1. In some embodiments, the at least one genetic abnormality is the mutation R100Q / R104V / F108L / R119Q / I130V in IDH1. In some embodiments, the at least one genetic abnormality is the mutation R140Q in IDH2. In some embodiments, the at least one genetic abnormality is the mutation R172 in IDH2.

[0278] In some embodiments, the hematologic malignancy is ALL.

[0279] In some embodiments, ALL is B-cell lineage ALL, T-cell lineage ALL, adult ALL, or pediatric ALL.

[0280] 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.

[0281] In some embodiments, a subject with ALL has the Philadelphia chromosome or exhibits resistance to treatment with a BCR-ABL kinase inhibitor or has acquired resistance to such treatment.

[0282] In some embodiments, a subject with ALL has the Philadelphia chromosome. In some embodiments, a subject with ALL exhibits resistance to treatment with a BCR-ABL kinase inhibitor or has acquired resistance to such treatment.

[0283] The Ph chromosome is present in approximately 20% of adults with ALL and a small fraction of children with ALL and is associated with a poor prognosis. At relapse, Ph+ positive ALL patients may be treated with tyrosine kinase inhibitor (TKI) regimens and thus may become resistant to TKIs. Accordingly, an anti-CD38 antibody can be administered to a subject who has become resistant to a selective or partially selective BCR-ABL inhibitor. Exemplary BCR-ABL inhibitors are, for example, imatinib, dasatinib, nilotinib, bosutinib, ponatinib, bafetinib, seratinib, tozasertib, or darusertib.

[0284] 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.

[0285] In some embodiments, a subject with ALL has a 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 chromosomal rearrangement.

[0286] Chromosomal rearrangements can be identified using well-known methods such as fluorescence in situ hybridization, chromosomal karyotyping, pulsed field gel electrophoresis, or sequencing.

[0287] In some embodiments, the hematologic malignancy is smoldering multiple myeloma.

[0288] In some embodiments, the hematologic malignancy is MGUS.

[0289] In some embodiments, the hematologic malignancy is ALL.

[0290] In some embodiments, the hematologic malignancy is DLBLC.

[0291] In some embodiments, the hematologic malignancy is BL.

[0292] In some embodiments, the hematologic malignancy is FL.

[0293] In some embodiments, the hematologic malignancy is MCL.

[0294] In some embodiments, the hematologic malignancy is Waldenström macroglobulinemia.

[0295] In some embodiments, the hematologic malignancy is plasma cell leukemia.

[0296] In some embodiments, the hematologic malignancy is AL.

[0297] In some embodiments, the hematologic malignancy is precursor B-cell lymphoblastic leukemia.

[0298] In some embodiments, the hematologic malignancy is precursor B-cell lymphoblastic leukemia.

[0299] In some embodiments, the hematologic malignancy is myelodysplastic syndrome (MDS).

[0300] In some embodiments, the hematologic malignancy is CLL.

[0301] In some embodiments, the hematologic malignancy is a B-cell malignancy.

[0302] In some embodiments, the hematologic malignancy is CML.

[0303] In some embodiments, the hematologic malignancy is HCL.

[0304] In some embodiments, the hematologic malignancy is blastic plasmacytoid dendritic cell neoplasm.

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

[0306] In some embodiments, the hematologic malignancy is non-Hodgkin lymphoma.

[0307] In some embodiments, the hematologic malignancy is MZL.

[0308] In some embodiments, the hematologic malignancy is MALT.

[0309] In some embodiments, the hematologic malignancy is plasma cell leukemia.

[0310] In some embodiments, the hematologic malignancy is ALCL.

[0311] In some embodiments, the hematologic malignancy is leukemia.

[0312] In some embodiments, the hematologic malignancy is lymphoma.

[0313] 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 advanced solid tumor.

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

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

[0316] In some embodiments, the solid tumor is non-small cell lung cancer (NSCLC).

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

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

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

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

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

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

[0323] In some embodiments, the solid tumor is pancreatic cancer.

[0324] In some embodiments, the solid tumor is melanoma.

[0325] In some embodiments, the solid tumor is esophageal cancer.

[0326] In some embodiments, the solid tumor is gastric cancer.

[0327] In some embodiments, the solid tumor is stomach cancer.

[0328] In some embodiments, the solid tumor is kidney cancer.

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

[0330] In some embodiments, the solid tumor is hepatocellular carcinoma.

[0331] In some embodiments, the solid tumor is renal cell carcinoma.

[0332] In some embodiments, the solid tumor is urothelial carcinoma.

[0333] In some embodiments, the solid tumor is head and neck cancer.

[0334] In some embodiments, the solid tumor is glioma.

[0335] In some embodiments, the solid tumor is glioblastoma.

[0336] In some embodiments, the solid tumor is colorectal cancer.

[0337] In some embodiments, the solid tumor is thyroid cancer.

[0338] In some embodiments, the solid tumor is epithelial cancer.

[0339] In some embodiments, the solid tumor is adenocarcinoma.

[0340] In some embodiments, the solid tumor is an advanced solid tumor.

[0341] 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.

[0342] 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.

[0343] 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.

[0344] In some embodiments, the anti-CD38 antibody comprises VH of SEQ ID NO:4 and VL of SEQ ID NO:5.

[0345] In some embodiments, the anti-CD38 antibody is of the IgG1 isotype.

[0346] In some embodiments, the anti-CD38 antibody comprises HC of SEQ ID NO:12 and LC of SEQ ID NO:13.

[0347] Other anti-CD38 antibodies for use in the methods of the present invention can be known antibodies, such as mAb003 comprising VH and VL sequences that are SEQ ID NO:14 and 15, respectively, and described in U.S. Patent 7,829,673. The VH and VL of mAb003 can be expressed as IgG1 / κ; mAb024 comprising VH and VL sequences that are SEQ ID NO:16 and 17, respectively, and described in U.S. Patent 7,829,673. The VH and VL of mAb024 can be expressed as IgG1 / κ; MOR-202 (MOR-03087) comprising VH and VL sequences that are SEQ ID NO:18 and 19, respectively, and described in U.S. Patent No. 8,088,896. The VH and VL of MOR-202 can be expressed as IgG1 / κ; or isatuximab; comprising VH and VL sequences that are SEQ ID NO:20 and 21, respectively, described in U.S. Patent 8,153,765. The VH and VL of isatuximab can be expressed as IgG1 / κ.

[0348] SEQ ID NO:4 (Daratumumab VH)

[0349] EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQAPGKGLEWVSAISGSGGGTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCAKDKILWFGEPVFDYWGQGTLVTVSS

[0350] SEQ ID NO:5 (Daratumumab VL)

[0351] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPTFGQGTKVEIK

[0352] SEQ ID NO:6 (Daratumumab HCDR1)

[0353] SFAMS

[0354] SEQ ID NO:7 (Daratumumab HCDR2)

[0355] AISGSGGGTYYADSVKG

[0356] SEQ ID NO:8 (Daratumumab HCDR3)

[0357] DKILWFGEPVFDY

[0358] SEQ ID NO:9 (Daratumumab LCDR1)

[0359] RASQSVSSYLA

[0360] SEQ ID NO:10 (Daratumumab LCDR2)

[0361] DASNRAT

[0362] SEQ ID NO:11 (Daratumumab LCDR3)

[0363] QQRSNWPPTF

[0364] SEQ ID NO:12 (Daratumumab HC)

[0365] EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQAPGKGLEWVSAISGSGGGTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCAKDKILWFGEPVFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0366] SEQ ID NO:13 (Daratumumab LC)

[0367] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWK VDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0368] SEQ ID NO:14

[0369] QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAFSWVRQAPGQGLEWMGRVIPFLGIANSAQKFQGRVTITADKSTSTAYMDLSSLRSEDTAVYYCARDDIAALGPFDYWGQGTLVTVSSAS

[0370] SEQ ID NO:15

[0371] DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQKPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPRTFGQGTKVEIK

[0372] SEQ ID NO:16

[0373] EVQLVQSGAEVKKPGESLKISCKGSGYSFSNYWIGWVRQMPGKGLEWMGIIYPHDSDARYSPSFQGQVTFSADKSISTAYLQWSSLKASDTAMYYCARHVGWGSRYWYFDLWGRGTLVTVSS

[0374] SEQ ID NO:17

[0375] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPGLLIYDASNRASGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK

[0376] SEQ ID NO:18

[0377] QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMNWVRQAPGKGLEWVSGISGDPSNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDLPLVYTGFAYWGQGTLVTVSS

[0378] SEQ ID NO:19

[0379] DIELTQPPSVSVAPGQTARISCSGDNLRHYYVYWYQQKPGQAPVLVIYGDSKRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQTYTGGASLVFGGGTKLTVLGQ

[0380] SEQ ID NO 20 :

[0381] QVQLVQSGAEVAKPGTSVKLSCKASGYTFTDYWMQWVKQRPGQGLEWIGTIYPGDGDTGYAQKFQGKATLTADKSSKTVYMHLSSLASEDSAVYYCARGDYYGSNSLDYWGQGTSVTVSS

[0382] SEQ ID NO:21 :

[0383] DIVMTQSHLSMSTSLGDPVSITCKASQDVSTVVAWYQQKPGQSPRRLIYSASYRYIGVPDRFTGSGAGTDFTFTISSVQAEDLAVYYCQQHYSPPYTFGGGTKLEIK

[0384] In some embodiments, the anti-CD38 antibody comprises:

[0385] VH of SEQ ID NO:14 and VL of SEQ ID NO:15;

[0386] VH of SEQ ID NO:16 and VL of SEQ ID NO:17;

[0387] VH of SEQ ID NO:18 and VL of SEQ ID NO:19; or

[0388] VH of SEQ ID NO:20 and VL of SEQ ID NO:21.

[0389] In some embodiments, the anti-CD38 antibody is of IgG1 isotype.

[0390] In some embodiments, 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.

[0391] In some embodiments, the T cell redirecting therapeutic agent is a BCMA×CD3 bispecific antibody.

[0392] In some embodiments, the T cell redirecting therapeutic agent is a GPRC5D×CD3 bispecific antibody.

[0393] In some embodiments, the T cell redirecting therapeutic agent is a CD33×CD3 bispecific antibody,

[0394] In some embodiments, the T cell redirecting therapeutic agent is a CD19×CD3 bispecific antibody.

[0395] In some embodiments, the T cell redirecting therapeutic agent is a CD123×CD3 bispecific antibody.

[0396] In some embodiments, the T cell redirecting therapeutic agent is a PSMA×CD3 bispecific antibody.

[0397] In some embodiments, the T cell redirecting therapeutic agent is a TMEFF2×CD3 bispecific antibody.

[0398] In some embodiments, the method further comprises administering to the subject one or more anti-cancer therapies.

[0399] 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.

[0400] In some embodiments, the one or more anti-cancer therapies are autologous stem cell transplantation (ASCT). In some embodiments, the one or more anti-cancer therapies are radiation. In some embodiments, the one or more anti-cancer therapies are surgery. In some embodiments, the one or more anti-cancer therapies are chemotherapeutic agents. In some embodiments, the one or more anti-cancer therapies are immunomodulators. In some embodiments, the one or more anti-cancer therapies are targeted cancer therapies.

[0401] In some embodiments, the one or more anti-cancer therapies are selected from lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, elotuzumab, ixazomib, melphalan, dexamethasone, vincristine, cyclophosphamide, daunorubicin, prednisone, rituximab, imatinib, dasatinib, nilotinib, bosutinib, ponatinib, bafetinib, seretinib, tozasertib 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.

[0402] In some embodiments, the anti-CD38 antibody is administered at a dose between about 8 mg / kg and about 16 mg / kg.

[0403] In some embodiments, the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising the anti-CD38 antibody at a concentration between about 20 mg / mL and about 120 mg / mL in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mannitol, and about 0.04% w / v polysorbate-20 (PS-20); the pH is about 5.5.

[0404] 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.

[0405] 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.

[0406] In some embodiments, the CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising

[0407] histidine between about 5 mM and about 15 mM;

[0408] sorbitol between about 100 mM and about 300 mM;

[0409] PS-20 between about 0.01% w / v and about 0.04% w / v; and

[0410] methionine between about 1 mg / mL and about 2 mg / mL, at a pH of about 5.5 to 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 1,800 mg of the anti-CD38 antibody;

[0413] about 30,000 U of rHuPH20;

[0414] about 10 mM of histidine;

[0415] about 300 mM of sorbitol;

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

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

[0418] In some embodiments, the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising

[0419] about 120 mg / mL of anti-CD38 antibody;

[0420] about 2,000 U / mL of rHuPH20;

[0421] about 10 mM of histidine;

[0422] about 300 mM of sorbitol;

[0423] about 0.04% (w / v) of PS-20; and

[0424] about 1 mg / mL of methionine, at a pH of about 5.6.

[0425] Combination of an anti-CD38 antibody and a BCMA×CD3 bispecific antibody

[0426] 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 cancer.

[0427] 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 cancer, wherein the subject has been treated with an anti-CD38 antibody prior to administration of the BCMA×CD3 bispecific antibody.

[0428] 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 cancer, wherein the subject is recurrent or refractory to treatment with a prior anti-cancer therapeutic agent.

[0429] T cell redirecting therapeutic agents such as BCMA×CD3 bispecific antibodies (such as JNJ-957) redirect T cells to BCMA-positive tumor cells (such as multiple myeloma cells), then perforin / granzyme is released or the FASL / FAS pathway is activated, and ultimately results in the death of BCMA-positive tumor cells. Thus, the efficacy of T cell redirecting therapeutic agents such as BCMA×CD3 bispecific antibodies can be affected by the availability and activity of the recruited T cells, as well as by the potentially regulated expression of tumor-associated antigens such as BCMA on the tumor cells.

[0430] In some embodiments, the cancer is a BCMA-expressing cancer.

[0431] B cell maturation antigen (BCMA) is a member of the tumor necrosis factor receptor family that binds to the cell membrane and is involved in the differentiation of B cells into plasma cells. The expression of BCMA is restricted to the B cell lineage, where BCMA is mainly expressed in the interfollicular region of the germinal center and 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).

[0432] In some embodiments, the cancer is a hematological malignancy.

[0433] 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 lymphoma, follicular lymphoma, mantle cell lymphoma, Waldenström macroglobulinemia, plasma cell leukemia, light chain amyloidosis, or non-Hodgkin lymphoma. A cancer diagnosis will be made by an experienced physician.

[0434] In some embodiments, the subject is recurrent or refractory to treatment with an anti-CD38 antibody or lenalidomide or a combination thereof.

[0435] In some embodiments, the subject is recurrent or refractory to treatment with an anti-CD38 antibody. In some embodiments, the subject is recurrent or refractory to treatment with lenalidomide.

[0436] In some embodiments, the subject is recurrent or refractory to treatment with a prior anti-cancer therapeutic agent (such as a therapeutic agent used to treat multiple myeloma or other hematological malignancies).

[0437] In some embodiments, the subject is recurrent or refractory to treatment with (thalidomide), (lenalidomide), (pomalidomide), (bortezomib), NINLARO (ixazomib), (carfilzomib), (panobinostat), (pamidronic acid), (zoledronic acid), (daratumumab), elotozumab, and melphalan.

[0438] In some embodiments, the subject is recurrent to treatment with (daratumumab).

[0439] 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.

[0440] In some embodiments, the BCMA×CD3 bispecific antibody is chimeric, humanized, or human.

[0441] In some embodiments, the BCMA×CD3 bispecific antibody is of the IgG1, IgG2, IgG3, or IgG4 isotype.

[0442] In some embodiments, the BCMA×CD3 bispecific antibody is of the IgG4 isotype.

[0443] In some embodiments, 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.

[0444] In some embodiments, the BCMA-binding domain comprises VH of SEQ ID NO:29 and VL of SEQ ID NO:30, and the CD3-binding domain comprises VH of SEQ ID NO:39 and VL of SEQ ID NO:40.

[0445] In some embodiments, the BCMA×CD3 bispecific antibody is of the IgG4 isotype and comprises phenylalanine at position 405 and arginine at position 409 in the first heavy chain (HC1) and leucine at position 405 and lysine at position 409 in the second heavy chain (HC2), wherein the residues are numbered according to the EU index.

[0446] In some embodiments, the BCMA×CD3 bispecific antibody further comprises proline at position 228, alanine at position 234, and alanine at position 235 in both HC1 and HC2.

[0447] 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.

[0448] In some embodiments, the BCMA×CD3 bispecific antibody is BI 836909, PF-06863135, AMG-701, or CC-93269.

[0449] 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.

[0450] In some embodiments, the anti-CD38 antibody comprises VH of SEQ ID NO:4 and VL of SEQ ID NO:5.

[0451] In some embodiments, the anti-CD38 antibody comprises a heavy chain (HC) of SEQ ID NO:12 and a light chain (LC) of SEQ ID NO:13.

[0452] In some embodiments, the anti-CD38 antibody is (daratumumab).

[0453] In some embodiments, the anti-CD38 antibody comprises:

[0454] VH of SEQ ID NO:14 and VL of SEQ ID NO:15;

[0455] VH of SEQ ID NO:16 and VL of SEQ ID NO:17;

[0456] VH of SEQ ID NO:18 and VL of SEQ ID NO:19; or

[0457] VH of SEQ ID NO:20 and VL of SEQ ID NO:21.

[0458] In some embodiments, the anti-CD38 antibody is chimeric, humanized, or human.

[0459] In some embodiments, the anti-CD38 antibody is of the IgG1, IgG2, IgG3, or IgG4 isotype.

[0460] In some embodiments, the anti-CD38 antibody is of the IgG1 isotype.

[0461] In some embodiments, the anti-CD38 antibody is administered at a dose between about 8 mg / kg and about 16 mg / kg.

[0462] In some embodiments, the BCMA×CD3 bispecific antibody and the anti-CD38 antibody are administered by intravenous injection.

[0463] In some embodiments, the BCMA×CD3 bispecific antibody is administered by intravenous injection and the anti-CD38 antibody is administered by subcutaneous injection.

[0464] In some embodiments, the BCMA×CD3 bispecific antibody and the anti-CD38 antibody are administered by subcutaneous injection.

[0465] In some embodiments, the method further comprises administering to the subject one or more anti-cancer therapies.

[0466] In some embodiments, the one or more anti-cancer therapies are selected from autologous hematopoietic stem cell transplantation (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulators, and targeted cancer therapies.

[0467] In some embodiments, the one or more anti-cancer therapies are selected from lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, elotuzumab, ixazomib, melphalan, prednisone, or dexamethasone or any combination thereof.

[0468] In some embodiments, the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising the anti-CD38 antibody at a concentration between about 20 mg / mL and about 120 mg / mL in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mannitol, and about 0.04% w / v polysorbate-20 (PS-20); the pH is about 5.5.

[0469] 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.

[0470] 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.

[0471] In some embodiments, the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising

[0472] Histidine between about 5 mM and about 15 mM;

[0473] Sorbitol between about 100 mM and about 300 mM;

[0474] PS-20 between about 0.01% w / v and about 0.04% w / v; and

[0475] Methionine between about 1 mg / mL and about 2 mg / mL, at a pH of about 5.5 to 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 1,800 mg of the anti-CD38 antibody;

[0478] About 30,000 U of rHuPH20;

[0479] About 10 mM of histidine;

[0480] About 300 mM of sorbitol;

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

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

[0483] In some embodiments, the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising

[0484] About 120 mg / mL of the anti-CD38 antibody;

[0485] About 2,000 U / mL of rHuPH20;

[0486] About 10 mM of histidine;

[0487] About 300 mM of sorbitol;

[0488] About 0.04% (w / v) of PS-20; and

[0489] About 1 mg / mL of methionine, at a pH of about 5.6.

[0490] 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.

[0491] 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.

[0492] The BCMA×CD3 bispecific antibody and / or the anti-CD38 antibody can be repeatedly administered 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 longer. The treatment process can also be repeated, as in chronic administration. The repeated administration can be at the same dose or different doses. For example, the BCMA×CD3 bispecific antibody and the anti-CD38 antibody can be administered by intravenous infusion at 8 mg / kg or at 16 mg / kg at weekly intervals for 8 weeks, then at 8 mg / kg or at 16 mg / kg every two weeks for another 16 weeks, and then at 8 mg / kg or at 16 mg / kg every four weeks.

[0493] 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 at least one day among the 1st day, 2nd day, 3rd day, 4th day, 5th day, 6th day, 7th day, 8th day, 9th day, 10th day, 11th day, 12th day, 13th day, 14th day, 15th day, 16th day, 17th day, 18th day, 19th day, 20th day, 21st day, 22nd day, 23rd day, 24th day, 25th day, 26th day, 27th day, 28th day, 29th day, 30th day, 31st day, 32nd day, 33rd day, 34th day, 35th day, 36th day, 37th day, 38th day, 39th day or 40th day after the start of treatment, or alternatively, in at least one week among the 1st week, 2nd week, 3rd week, 4th week, 5th week, 6th week, 7th week, 8th week, 9th week, 10th week, 11th week, 12th week, 13th week, 14th week, 15th week, 16th week, 17th week, 18th week, 19th week or 20th week, or any combination thereof, in a single dose or in divided doses once every 24 hours, 12 hours, 8 hours, 6 hours, 4 hours or 2 hours, 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, 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, 26 mg / kg, 27 mg / kg, 28 mg / kg, 29 mg / kg, 30 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg or 100 mg / kg per day).

[0494] The BCMA×CD3 bispecific antibody and the anti-CD38 antibody can also be administered prophylactically in order to reduce the risk of developing cancer (such as multiple myeloma), delay the onset of events in cancer progression and / or reduce the risk of recurrence after cancer remission.

[0495] In some embodiments, after administering an anti-CD38 antibody to a subject, a BCMA×CD3 bispecific 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 longer after administering the anti-CD38 antibody. In some embodiments, the subject to whom the BCMA×CD3 antibody is administered is resistant and / or refractory to treatment with the anti-CD38 antibody.

[0496] The present invention 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.

[0497] In some embodiments, the pharmaceutical composition comprises a BCMA×CD3 bispecific antibody and an anti-CD38 antibody, 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, 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.

[0498] In some embodiments, the pharmaceutical composition is a non-fixed combination.

[0499] In some embodiments, the pharmaceutical composition comprises from 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); the pH is about 5.5.

[0500] The BCMA×CD3 bispecific antibody can be formulated into a pharmaceutical composition comprising from about 20 mg / mL to about 120 mg / mL of the antibody, acetic acid, histidine, sodium chloride, mannitol and / or polysorbate-20.

[0501] In some embodiments, the pharmaceutical composition comprises about 1,800 mg of an anti-CD38 antibody and about 30,000 U of rHuPH20.

[0502] In some embodiments, the pharmaceutical composition comprises an anti-CD38 antibody at about 120 mg / mL and rHuPH20 at about 2,000 U / mL.

[0503] In some embodiments, the pharmaceutical composition further comprises one or more excipients.

[0504] In some embodiments, the one or more excipients are histidine, methionine, sorbitol, or polysorbate-20 (PS-20), or any combination thereof.

[0505] In some embodiments, the pharmaceutical composition comprises

[0506] an anti-CD38 antibody formulated in histidine between about 5 mM and about 15 mM at between about 100 mg / mL and about 120 mg / mL;

[0507] sorbitol between about 100 mM and about 300 mM;

[0508] PS-20 between about 0.01% w / v and about 0.04% w / v; and

[0509] methionine between about 1 mg / mL and about 2 mg / mL, at a pH of about 5.5 to 5.6.

[0510] In some embodiments, the pharmaceutical composition comprises about 10 mM of histidine.

[0511] In some embodiments, the pharmaceutical composition comprises about 300 mM of sorbitol.

[0512] In some embodiments, the pharmaceutical composition comprises about 0.04% (w / v) of PS-20.

[0513] In some embodiments, the pharmaceutical composition comprises about 1 mg / mL of methionine.

[0514] In some embodiments, the pharmaceutical composition comprises

[0515] about 1,800 mg of anti-CD38 antibody;

[0516] about 30,000 U of rHuPH20;

[0517] about 10 mM of histidine;

[0518] about 300 mM of sorbitol;

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

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

[0521] In some embodiments, the pharmaceutical composition comprises

[0522] an anti-CD38 antibody at about 120 mg / mL;

[0523] rHuPH20 at about 2,000 U / mL;

[0524] histidine at about 10 mM;

[0525] sorbitol at about 300 mM;

[0526] PS-20 at about 0.04% (w / v); and

[0527] methionine at about 1 mg / mL, at a pH of about 5.6.

[0528] The present disclosure also provides a kit comprising the pharmaceutical composition, the pharmaceutical composition comprising a BCMA×CD3 bispecific antibody and an anti-CD38 antibody.

[0529] Treatment of a recurrent or refractory subject with a BCMA×CD3 bispecific antibody

[0530] 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 cancer, wherein the subject is recurrent or refractory to treatment with a prior anti-cancer therapeutic agent.

[0531] In some embodiments, 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.

[0532] In some embodiments, the BCMA binding domain comprises VH of SEQ ID NO:29 and VL of SEQ ID NO:30, and the CD3 binding domain comprises VH of SEQ ID NO:39 and VL of SEQ ID NO:40.

[0533] In some embodiments, the BCMA×CD3 bispecific antibody is of the 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.

[0534] In some embodiments, the BCMA×CD3 bispecific antibody further comprises proline at position 228, alanine at position 234, and alanine at position 235 in both HC1 and HC2.

[0535] 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.

[0536] In some embodiments, the cancer is a hematological malignancy.

[0537] In some embodiments, the hematological malignancy is multiple myeloma.

[0538] In some embodiments, the multiple myeloma is high-risk multiple myeloma.

[0539] In some embodiments, a subject with high-risk multiple myeloma has one or more chromosomal abnormalities, including:

[0540] t(4;14)(p16;q32);

[0541] t(14;16)(q32;q23);

[0542] del17p;

[0543] 1qAmp;

[0544] t(4;14)(p16;q32) and t(14;16)(q32;q23);

[0545] t(4;14)(p16;q32) and del17p;

[0546] t(14;16)(q32;q23) and del17p; or

[0547] t(4;14)(p16;q32), t(14;16)(q32;q23), and del17p or any combination thereof.

[0548] In some embodiments, the subject is recurrent or refractory to treatment with an anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotuzumab, ixazomib, melphalan, or thalidomide, or any combination thereof.

[0549] In some embodiments, the subject is recurrent or refractory to treatment with lenalidomide. In some embodiments, the subject is recurrent or refractory to treatment with bortezomib. In some embodiments, the subject is recurrent or refractory to treatment with pomalidomide. In some embodiments, the subject is recurrent or refractory to treatment with carfilzomib. In some embodiments, the subject is recurrent or refractory to treatment with elotuzumab. In some embodiments, the subject is recurrent or refractory to treatment with ixazomib. In some embodiments, the subject is recurrent or refractory to treatment with melphalan. In some embodiments, the subject is recurrent or refractory to treatment with thalidomide.

[0550] In some embodiments, the subject is recurrent to treatment with an anti-CD38 antibody.

[0551] 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.

[0552] In some embodiments, the anti-CD38 antibody comprises VH of SEQ ID NO:4 and VL of SEQ ID NO:5.

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

[0554] In some embodiments, the anti-CD38 antibody comprises HC of SEQ ID NO:12 and LC of SEQ ID NO:13.

[0555] In some embodiments, the anti-CD38 antibody comprises:

[0556] VH of SEQ ID NO:14 and VL of SEQ ID NO:15;

[0557] VH of SEQ ID NO:16 and VL of SEQ ID NO:17;

[0558] VH of SEQ ID NO:18 and VL of SEQ ID NO:19; or

[0559] VH of SEQ ID NO:20 and VL of SEQ ID NO:21.

[0560] In some embodiments, the anti-CD38 antibody is of the IgG1 isotype.

[0561] In some embodiments, the subject is human.

[0562] In some embodiments, the method further comprises administering to the subject one or more anti-cancer therapies.

[0563] In some embodiments, the one or more anti-cancer therapies are selected from autologous hematopoietic stem cell transplantation (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulators, and targeted cancer therapies.

[0564] In some embodiments, the one or more anti-cancer therapies are selected from lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, elotuzumab, ixazomib, melphalan, prednisone, or dexamethasone, or any combination thereof.

[0565] Combination therapy with a T cell redirecting agent that binds GPRC5D and an anti-CD38 antibody

[0566] 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 agent that binds GPRC5D and an anti-CD38 antibody to treat cancer.

[0567] In some embodiments, the anti-CD38 antibody is administered to the subject prior to administering the T cell redirecting agent that binds GPRC5D.

[0568] In some embodiments, the subject is recurrent or refractory to treatment with a prior anti-cancer agent.

[0569] In some embodiments, the cancer is a GPRC5D-expressing cancer.

[0570] In some embodiments, the GPRC5D-expressing cancer is a hematologic malignancy or a solid tumor.

[0571] In some embodiments, the hematologic malignancy is leukemia, lymphoma, or multiple myeloma.

[0572] In some embodiments, the hematologic malignancy is leukemia. In some embodiments, the hematologic malignancy is lymphoma. In some embodiments, the hematologic malignancy is multiple myeloma.

[0573] In some embodiments, 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.

[0574] GPRC5D has been reported to be expressed in these tumors, see for example International Patent Publication WO2018 / 147245.

[0575] In some embodiments, the subject is relapsed or refractory to treatment with an anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotuzumab, ixazomib, melphalan, or thalidomide, or any combination thereof.

[0576] 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 elotuzumab. 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.

[0577] In some embodiments, the multiple myeloma is newly diagnosed multiple myeloma.

[0578] In some embodiments, the multiple myeloma is relapsed or refractory multiple myeloma.

[0579] In some embodiments, the multiple myeloma is high-risk multiple myeloma.

[0580] In some embodiments, a subject with high-risk multiple myeloma has one or more chromosomal abnormalities, including:

[0581] t(4;14)(p16;q32);

[0582] t(14;16)(q32;q23);

[0583] del17p;

[0584] 1qAmp;

[0585] t(4;14)(p16;q32) and t(14;16)(q32;q23);

[0586] t(4;14)(p16;q32) and del17p;

[0587] t(14;16)(q32;q23) and del17p; or

[0588] t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p or any combination thereof.

[0589] In some embodiments, the T cell redirecting therapeutic agent binds to CD3, CD3ε (CD3ε), CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, BTNL8, PD-1, CD195 or NKG2C.

[0590] In some embodiments, the T cell redirecting therapeutic agent 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, 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.

[0591] In some embodiments, the GPRC5D binding domain comprises VH of SEQ ID NO:49 and VL of SEQ ID NO:50, and the CD3 binding domain comprises VH of SEQ ID NO:39 and VL of SEQ ID NO:40.

[0592] In some embodiments, the T cell redirecting therapeutic agent that binds to GPRC5C is a multispecific antibody, a CAR or a T cell expressing a CAR.

[0593] In some embodiments, the multispecific antibody is of the IgG1, IgG2, IgG3 or IgG4 isotype.

[0594] In some embodiments, the multispecific antibody is of the IgG1 isotype. In some embodiments, the multispecific antibody is of the IgG2 isotype. In some embodiments, the multispecific antibody is of the IgG3 isotype. In some embodiments, the multispecific antibody is of the IgG4 isotype.

[0595] In some embodiments, the multispecific antibody comprises one or more Fc substitutions that reduce the binding of the multispecific antibody to Fc gamma receptors (FcγR).

[0596] 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 / P331A / D365E / L358M on IgG1, 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, wherein the residues are numbered according to the EU index.

[0597] In some embodiments, the multispecific antibody further comprises an S228P substitution.

[0598] 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.

[0599] In some embodiments, one or more asymmetric permutations 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.

[0600] 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.

[0601] 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.

[0602] In some embodiments, the anti-CD38 antibody comprises VH of SEQ ID NO:4 and VL of SEQ ID NO:5.

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

[0604] In some embodiments, the anti-CD38 antibody comprises HC of SEQ ID NO:12 and LC of SEQ ID NO:13.

[0605] In some embodiments, the anti-CD38 antibody comprises:

[0606] VH of SEQ ID NO:14 and VL of SEQ ID NO:15;

[0607] VH of SEQ ID NO:16 and VL of SEQ ID NO:17;

[0608] VH of SEQ ID NO:18 and VL of SEQ ID NO:19; or

[0609] VH of SEQ ID NO:20 and VL of SEQ ID NO:21.

[0610] In some embodiments, the anti-CD38 antibody is of the IgG1 isotype.

[0611] In some embodiments, the anti-CD38 antibody is administered at a dose between about 8 mg / kg and about 16 mg / kg.

[0612] In some embodiments, the T cell redirecting therapeutic agent that binds GPRC5D and the anti-CD38 antibody are administered by intravenous injection.

[0613] In some embodiments, the T cell redirecting therapeutic agent that binds GPRC5D is administered by intravenous injection and the anti-CD38 antibody is administered by subcutaneous injection.

[0614] In some embodiments, the T cell redirecting therapeutic agent that binds GPRC5D and the anti-CD38 antibody are administered by subcutaneous injection.

[0615] In some embodiments, the subject is a human.

[0616] In some embodiments, the T cell redirecting therapeutic agent that binds GPRC5D is a GPRC5D×CD3 bispecific antibody.

[0617] In some embodiments, the method further comprises administering to the subject one or more anti-cancer therapies.

[0618] In some embodiments, the one or more anti-cancer therapies are selected from autologous hematopoietic stem cell transplantation (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulators, and targeted cancer therapies.

[0619] In some embodiments, the one or more anti-cancer therapies are selected from lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, elotuzumab, ixazomib, melphalan, dexamethasone, or prednisone.

[0620] In some embodiments, the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising an anti-CD38 antibody between about 20 mg / mL and about 120 mg / mL in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mannitol, and about 0.04% w / v polysorbate-20 (PS-20); the pH is about 5.5.

[0621] 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.

[0622] 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.

[0623] In some embodiments, the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising

[0624] from about 100 mg / mL to about 120 mg / mL of the anti-CD38 antibody;

[0625] from about 5 mM to about 15 mM of histidine;

[0626] from about 100 mM to about 300 mM of sorbitol;

[0627] from about 0.01% w / v to about 0.04% w / v of PS-20; and

[0628] from about 1 mg / mL to about 2 mg / mL of methionine, at a pH of about 5.5 to 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 1,800 mg of the anti-CD38 antibody;

[0631] about 30,000 U of rHuPH20;

[0632] about 10 mM of histidine;

[0633] about 300 mM of sorbitol;

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

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

[0636] In some embodiments, the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition comprising

[0637] about 120 mg / mL of the anti-CD38 antibody;

[0638] rHuPH20 at about 2,000 U / mL;

[0639] histidine at about 10 mM;

[0640] sorbitol at about 300 mM;

[0641] PS-20 at about 0.04% (w / v); and

[0642] methionine at about 1 mg / mL, at a pH of about 5.6.

[0643] The present disclosure also relates to 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, 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, LCDR2 of SEQ ID NO:10 and LCDR3 of SEQ ID NO:11.

[0644] In some embodiments, the GPRC5D binding domain comprises VH of SEQ ID NO:49 and VL of SEQ ID NO:50, the CD3 binding domain comprises VH of SEQ ID NO:39 and VL of SEQ ID NO:40, and the anti-CD38 antibody comprises VH of SEQ ID NO:4 and VL of SEQ ID NO:5.

[0645] 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.

[0646] In some embodiments, the drug combination is a non-fixed combination.

[0647] In some embodiments, the drug combination comprises an anti-CD38 antibody at about 20 mg / mL to about 120 mg / mL in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mannitol, and about 0.04% w / v polysorbate-20 (PS-20); the pH is about 5.5.

[0648] In some embodiments, the drug combination comprises about 1,800 mg of an anti-CD38 antibody and about 30,000 U of rHuPH20.

[0649] In some embodiments, the drug combination comprises an anti-CD38 antibody at about 120 mg / mL and rHuPH20 at about 2,000 U / mL.

[0650] In some embodiments, the drug combination further comprises one or more excipients.

[0651] In some embodiments, the one or more excipients are histidine, methionine, sorbitol, or polysorbate-20 (PS-20) or any combination thereof.

[0652] In some embodiments, the pharmaceutical composition comprises

[0653] an anti-CD38 antibody between about 100 mg / mL and about 120 mg / mL;

[0654] histidine between about 5 mM and about 15 mM;

[0655] sorbitol between about 100 mM and about 300 mM;

[0656] PS-20 between about 0.01% w / v and about 0.04% w / v; and

[0657] methionine between about 1 mg / mL and about 2 mg / mL, with a pH of about 5.5 to 5.6.

[0658] In some embodiments, the drug combination comprises about 10 mM of histidine.

[0659] In some embodiments, the drug combination comprises about 300 mM of sorbitol.

[0660] In some embodiments, the drug combination comprises about 0.04% (w / v) of PS-20.

[0661] In some embodiments, the drug combination comprises about 1 mg / mL of methionine.

[0662] In some embodiments, the drug combination comprises

[0663] about 1,800 mg of an anti-CD38 antibody;

[0664] about 30,000 U of rHuPH20;

[0665] about 10 mM of histidine;

[0666] about 300 mM of sorbitol;

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

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

[0669] In some embodiments, the drug combination comprises

[0670] about 120 mg / mL of an anti-CD38 antibody;

[0671] about 2,000 U / mL of rHuPH20;

[0672] about 10 mM of histidine;

[0673] about 300 mM of sorbitol;

[0674] about 0.04% (w / v) of PS-20; and

[0675] about 1 mg / mL of methionine, at a pH of about 5.6.

[0676] The present disclosure also provides a drug combination comprising a T cell redirecting therapeutic agent that binds GPRC5D and an anti-CD38 antibody.

[0677] Treatment of a recurrent or refractory subject with a GPRC5D×CD3 bispecific antibody

[0678] 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 cancer, wherein the subject is recurrent or refractory to treatment with a prior anti-cancer therapeutic agent.

[0679] In some embodiments, 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, 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.

[0680] In some embodiments, the GPRC5D binding domain comprises VH of SEQ ID NO:49 and VL of SEQ ID NO:50, and the CD3 binding domain comprises VH of SEQ ID NO:39 and VL of SEQ ID NO:40.

[0681] In some embodiments, the GPRC5D×CD3 bispecific antibody is of the 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.

[0682] In some embodiments, the GPRC5D×CD3 bispecific antibody further comprises proline at position 228, alanine at position 234, and alanine at position 235 in both HC1 and HC2.

[0683] 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.

[0684] In some embodiments, the cancer is a hematological malignancy or a solid tumor.

[0685] In some embodiments, 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.

[0686] In some embodiments, the multiple myeloma is high-risk multiple myeloma.

[0687] In some embodiments, a subject with high-risk multiple myeloma has one or more chromosomal abnormalities, including:

[0688] t(4;14)(p16;q32);

[0689] t(14;16)(q32;q23);

[0690] del17p;

[0691] 1qAmp;

[0692] t(4;14)(p16;q32) and t(14;16)(q32;q23);

[0693] t(4;14)(p16;q32) and del17p;

[0694] t(14;16)(q32;q23) and del17p; or

[0695] t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p or any combination thereof.

[0696] In some embodiments, the subject is refractory or relapsed to treatment with an anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotuzumab, ixazomib, melphalan or thalidomide or any combination thereof.

[0697] In some embodiments, the subject is relapsed or refractory to treatment with an anti-CD38 antibody.

[0698] 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.

[0699] In some embodiments, the anti-CD38 antibody comprises VH of SEQ ID NO:4 and VL of SEQ ID NO:5.

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

[0701] In some embodiments, the anti-CD38 antibody comprises HC of SEQ ID NO:12 and LC of SEQ ID NO:13.

[0702] In some embodiments, the anti-CD38 antibody comprises:

[0703] VH of SEQ ID NO:14 and VL of SEQ ID NO:15;

[0704] VH of SEQ ID NO:16 and VL of SEQ ID NO:17;

[0705] VH of SEQ ID NO:18 and VL of SEQ ID NO:19; or

[0706] VH of SEQ ID NO:20 and VL of SEQ ID NO:21.

[0707] In some embodiments, the anti-CD38 antibody is of the IgG1 isotype.

[0708] In some embodiments, the subject is a human.

[0709] In some embodiments, the method further comprises administering to the subject one or more anti-cancer therapies.

[0710] In some embodiments, the one or more anti-cancer therapies are selected from autologous hematopoietic stem cell transplantation (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulators, and targeted cancer therapies.

[0711] In some embodiments, the one or more anti-cancer therapies are selected from lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, elotuzumab, ixazomib, melphalan, dexamethasone, vincristine, cyclophosphamide, daunorubicin, prednisone, rituximab, imatinib, dasatinib, nilotinib, bosutinib, ponatinib, bafetinib, seratinib, tozasertib 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.

[0712] Combination therapy with a T cell redirection therapeutic agent that binds CD19 and an anti-CD38 antibody

[0713] 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 agent and an anti-CD38 antibody to treat cancer.

[0714] In some embodiments, the subject has been treated with the anti-CD38 antibody prior to administration of the CD19-binding T cell redirecting therapeutic agent.

[0715] The present disclosure also provides a method of enhancing the efficacy of a CD19-binding T cell redirecting therapeutic agent in a subject having cancer, comprising administering an anti-CD38 antibody to the subject prior to administering the CD19-binding T cell redirecting therapeutic agent.

[0716] In some embodiments, the subject is recurrent or refractory to treatment with a prior anti-cancer therapeutic agent.

[0717] In some embodiments, the cancer is a hematological malignancy or a solid tumor.

[0718] In some embodiments, 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, Waldenström macroglobulinemia or T cell lymphoma.

[0719] 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 amenable to treatment with a CD19-binding T cell redirecting therapeutic agent.

[0720] In some embodiments, the T cell redirecting therapeutic agent binds CD3ε (CD3ε), CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, BTNL8, PD-1, CD195 or NKG2C.

[0721] In some embodiments, the CD19-binding T cell redirecting therapeutic agent comprises a CD19-binding domain of any of the following: 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.

[0722] In some embodiments, the CD19-binding T cell redirecting therapeutic agent 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.

[0723] In some embodiments, the CD19-binding T cell redirecting therapeutic agent is a bispecific antibody, a CAR or a CAR-expressing T cell.

[0724] 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.

[0725] In some embodiments, the anti-CD38 antibody comprises VH of SEQ ID NO:4 and VL of SEQ ID NO:5.

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

[0727] In some embodiments, the anti-CD38 antibody comprises HC of SEQ ID NO:12 and LC of SEQ ID NO:13.

[0728] In some embodiments, the anti-CD38 antibody comprises:

[0729] VH of SEQ ID NO:14 and VL of SEQ ID NO:15;

[0730] VH of SEQ ID NO:16 and VL of SEQ ID NO:17;

[0731] VH of SEQ ID NO:18 and VL of SEQ ID NO:19; or

[0732] VH of SEQ ID NO:20 and VL of SEQ ID NO:21.

[0733] In some embodiments, the anti-CD38 antibody is of the IgG1 isotype.

[0734] In some embodiments, the anti-CD38 antibody is administered at a dose between about 8 mg / kg and about 16 mg / kg.

[0735] In some embodiments, the CD19-binding T cell redirecting therapeutic agent and the anti-CD38 antibody are administered by intravenous injection.

[0736] In some embodiments, the CD19-binding T cell redirecting therapeutic agent is administered by intravenous injection and the anti-CD38 antibody is administered by subcutaneous injection.

[0737] In some embodiments, the CD19-binding T cell redirecting therapeutic agent and the anti-CD38 antibody are administered by subcutaneous injection.

[0738] In some embodiments, the subject is a human.

[0739] In some embodiments, the CD19-binding T cell redirecting therapeutic agent is a CD19×CD3 bispecific antibody.

[0740] In some embodiments, the method further comprises administering to the subject one or more anti-cancer therapies.

[0741] In some embodiments, the one or more anti-cancer therapies are selected from autologous hematopoietic stem cell transplantation (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulators, and targeted cancer therapies.

[0742] The present disclosure also provides a pharmaceutical 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.

[0743] In some embodiments, the anti-CD38 antibody comprises VH of SEQ ID NO:4 and VL of SEQ ID NO:5.

[0744] In some embodiments, the anti-CD38 antibody comprises the HC of SEQ ID NO:12 and the LC of SEQ ID NO:13.

[0745] In some embodiments, the drug combination is a non-fixed combination.

[0746] In some embodiments, the drug combination comprises from 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); the pH is about 5.5.

[0747] In some embodiments, the drug combination comprises about 1,800 mg of an anti-CD38 antibody and about 30,000 U of rHuPH20.

[0748] In some embodiments, the drug combination comprises about 120 mg / mL of an anti-CD38 antibody and about 2,000 U / mL of rHuPH20.

[0749] In some embodiments, the drug combination further comprises one or more excipients.

[0750] In some embodiments, the one or more excipients are histidine, methionine, sorbitol, or polysorbate-20 (PS-20) or any combination thereof.

[0751] In some embodiments, the drug combination comprises

[0752] an anti-CD38 antibody between about 100 mg / mL and about 120 mg / mL;

[0753] histidine between about 5 mM and about 15 mM;

[0754] sorbitol between about 100 mM and about 300 mM;

[0755] PS-20 between about 0.01% w / v and about 0.04% w / v; and

[0756] methionine between about 1 mg / mL and about 2 mg / mL, with a pH of about 5.5 to 5.6.

[0757] In some embodiments, the drug combination comprises

[0758] about 10 mM of histidine.

[0759] In some embodiments, the drug combination comprises about 300 mM of sorbitol.

[0760] In some embodiments, the drug combination comprises about 0.04% (w / v) of PS-20.

[0761] In some embodiments, the drug combination comprises about 1 mg / mL of methionine.

[0762] In some embodiments, the drug combination comprises

[0763] about 1,800 mg of an anti-CD38 antibody;

[0764] about 30,000 U of rHuPH20;

[0765] about 10 mM of histidine;

[0766] about 300 mM of sorbitol;

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

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

[0769] In some embodiments, the drug combination comprises

[0770] about 120 mg / mL of an anti-CD38 antibody;

[0771] about 2,000 U / mL of rHuPH20;

[0772] about 10 mM of histidine;

[0773] about 300 mM of sorbitol;

[0774] about 0.04% (w / v) of PS-20; and

[0775] about 1 mg / mL of methionine, at a pH of about 5.6.

[0776] In some embodiments, the drug combination comprises 35 mcg 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.

[0777] In some embodiments, blinatumomab is reconstituted with 3 mL of preservative-free sterile water for injection (USP).

[0778] The present disclosure provides a kit comprising a drug combination, which drug combination comprises 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.

[0779] T cell redirection therapeutic agent

[0780] Multispecific antibody

[0781] T cell redirecting therapeutic agents can be multi-specific molecules, such as bispecific antibodies. Various multi-specific and / or bispecific formats include the formats described herein and recombinant IgG-like dual-targeting molecules, where each side of the molecule contains Fab fragments or portions of Fab fragments of at least two different antibodies; IgG fusion molecules, where a full-length IgG antibody is fused to an additional Fab fragment or portion of a Fab fragment; Fc fusion molecules, where a single-chain Fv molecule or a stabilized diabody antibody is fused to a heavy chain constant domain, Fc region, or a portion thereof; Fab fusion molecules, where different Fab fragments are fused together; ScFv- and diabody-based heavy chain antibodies (e.g., domain antibodies, nanobodies), where 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 multi-specific antibodies generated by arm exchange. Exemplary multi-specific and / or bispecific forms include dual-targeting molecules, including dual-targeting (DT)-Ig (GSK / Domantis), diabody (Genentech) and mAb2 (F-Star), dual variable domain (DVD)-Ig (Abbott), Ts2Ab (MedImmune / AZ) and BsAb (Zymogenetics), HERCULES (Biogen Idec) and TvAb (Roche), ScFv / Fc fusions (Academic Institution), SCORPION (Emergent BioSolutions / Trubion, Zymogenetics / BMS) and dual affinity retargeting technology (Fc-DART) (MacroGenics), F(ab)2 (Medarex / AMGEN), bispecific 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 antibodies (AIT, ReceptorLogics), human serum albumin ScFv fusions (Merrimack) and COMBODY (Epigen Biotech), dual-targeting nanobodies (Ablynx), dual-targeting heavy chain only domain antibodies.Multiple forms of bispecific antibodies have been described, such as those described 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.

[0782] Method for generating the antibodies in the methods of the present invention

[0783] Antibodies that bind specifically to antigens for use in the methods of the present invention can also be selected de novo from, for example, phage display libraries, where the phages 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: pp. 57-86, 2000; Krebs et al., J Immunol Meth 254:67-84, 2001; Vaughan et al., Nature Biotechnology, Vol. 14, pp. 309-314, 1996; Sheets et al., PITAS (USA), Vol. 95: pp. 6157-6162, 1998; Hoogenboom and Winter, J Mol Biol, Vol. 227 p. 381, 1991; Marks et al., JMol Biol, Vol. 222: p. 581, 1991). Phage display libraries expressing antibody heavy chain variable regions and light chain variable regions as fusion proteins with the phage pIX coat protein are 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 a desired antigen such as BCMA, CD3, CD38, CD123, CD19, CD33, PSMA, or the extracellular domain of TMEFF2 can be screened from the antibody library, and the obtained positive clones can be further characterized, Fab isolated from the clone lysates, and then cloned into full-length antibodies. Such phage display methods for isolating human antibodies are well 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.

[0784] T-cell redirected bispecific antibodies can be produced in vitro in a cell-free environment by the following process: According to the method described in International Patent Publication WO2011 / 131746, asymmetric mutations are introduced into the CH3 regions of two monospecific homodimeric antibodies, and a bispecific heterodimeric antibody is formed from the 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 the cysteines in the hinge region; thus, bispecific antibodies are produced by Fab arm exchange. The incubation conditions can most desirably 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 reducing agents selected from 2-mercaptoethylamine, dithiothreitol, and tris(2-carboxyethyl)phosphine. For example, the following conditions can be used: incubation for at least 90 minutes at a temperature of at least 20 °C, at a pH of 5 - 8 such as pH 7.0 or pH 7.4, in the presence of at least 25 mM 2-MEA or at least 0.5 mM dithiothreitol.

[0785] Exemplary CH3 mutations for the first heavy chain and the second heavy chain of bispecific antibodies are K409R and / or F405L.

[0786] Additional CH3 mutations that can be used include techniques such as mutations (Genmab), Knob-in-Hole mutations (Genentech), electrostatic matching mutations (Amgen, NovoNordisk, Oncomed), chain exchange engineered domain body (SEEDbody) (EMD Serono), and other asymmetric mutations (e.g., Zymeworks).

[0787] mutations (Genmab) are disclosed in, for example, US9150663 and US2014 / 0303356, and include 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.

[0788] The Knob-in-hole mutation is disclosed, for example, in WO1996 / 027011 and involves mutations at the interface of the CH3 region, where 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 a preferential interaction between the first and second CH3 regions. Exemplary CH3 region mutations that form the knob and hole are T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S, and T366W / T366S_L368A_Y407V.

[0789] The formation of the heavy chain heterodimer can be facilitated by using electrostatic interactions, by replacing the positively charged residues on the first CH3 region and the negatively charged residues on the second CH3 region, as described in US2010 / 0015133, US2009 / 0182127, US2010 / 028637, or US2011 / 0123532.

[0790] Other asymmetric mutations that can be used to facilitate 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.

[0791] The SEEDbody mutation involves replacing selected IgG residues with IgA residues to facilitate heavy chain heterodimerization, as described in US20070287170.

[0792] Other exemplary mutations that can be used are R409D_K370E / D399K_E357K, S354C_T366W / Y349C_T366S_L368A_Y407V, Y349C_T366W / S354C_T366S_L368A_Y407V, 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 as described in WO2007 / 147901, WO 2011 / 143545, WO2013157954, WO2013096291 and US2018 / 0118849.

[0793] Additional bispecific or multispecific constructs useful as T cell redirecting therapeutic agents include bispecific variable domain immunoglobulins (DVDs) (International Patent Publication WO2009 / 134776; a DVD is a full-length antibody 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), constructs comprising various dimerization domains to link two antibody arms with different specificities (such as leucine zippers or collagen dimerization domains (International Patent Publication WO2012 / 022811, U.S. Patent 5,932,448; U.S. Patent 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), tandem diabody (Genentech), cross-linked Mab (Karmanos Cancer Center), mAb2 (F-Star) and CovX-body (CovX / Pfizer), IgG-like bispecific antibodies (InnClone / Eli Lilly), Ts2Ab (MedImmune / AZ) and BsAb (Zymogenetics), HERCULES (Biogen Idec) and TvAb (Roche), ScFv / Fc fusions (Academic Institution), SCORPION (Emergent BioSolutions / Trubion, Zymogenetics / BMS), dual affinity retargeting technology (Fc-DART) (MacroGenics) and bis(ScFv)2-Fab (National Engineering Research Center for Antibody Drugs Co., Ltd., Shanghai), dual action or Bis-Fab (Genentech), Dock-and-Lock (DNL) (ImmunoMedics), bivalent bispecific (Biotecnol) and Fab-Fv (UCB-Celltech). ScFv- and 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, ReceptorLogics), human serum albumin ScFv fusions (Merrimack) and COMBODY (Epigen Biotech), dual targeting nanobodies (Ablynx), dual targeting heavy chain domain antibodies only.

[0794] Fc engineering of antibodies

[0795] T-cell redirecting therapeutic agents such as bispecific or multispecific antibodies or the Fc region of an anti-CD38 antibody can comprise at least one substitution in the Fc region that reduces the binding of the T-cell redirecting therapeutic agent to activated Fc gamma receptors (FcγR) and / or reduces Fc effector functions such as C1q binding, complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), or phagocytosis (ADCP).

[0796] Fc positions that can be substituted to reduce Fc binding to activated FcγR and subsequently reduce effector functions are substitution 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 / P331A / D365E / L358M on IgG1, 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.

[0797] The Fc substitution that can be used to reduce CDC is the K322A substitution.

[0798] The well-known S228P substitution can also be made in IgG4 antibodies to enhance IgG4 stability.

[0799] Exemplary wild-type IgG1 comprises the amino acid sequence of SEQ ID NO:103.

[0800] SEQ ID NO:103 :

[0801] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0802] Exemplary wild-type IgG4 contains the amino acid sequence of SEQ ID NO: 104.

[0803] SEQ ID NO:104 :

[0804] ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0805] "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 having lytic activity (such as natural killer cells (NK), monocytes, macrophages, and neutrophils) via Fcγ receptors (FcγR) expressed on the effector cells. For example, NK cells express FcγRIIIa, while monocytes express FcγRI, FcγRII, and FcγRIIIa. The ADCC activity of an antibody can be evaluated 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 released from the lysed cells (such as a radioactive substrate, a fluorescent dye, or a native intracellular protein). In an exemplary assay, target cells can be used at a ratio of 1 target cell to 4 effector cells. The target cells are pre-labeled with BATDA and combined with the effector cells and the test antibody. The samples are incubated for 2 hours, and cell lysis is measured by measuring the BATDA released into the supernatant. The data are normalized against the maximum cytotoxicity using 0.67% Triton X-100 (Sigma Aldrich) and the minimum control measured by the spontaneous release of BATDA from the target cells in the absence of any antibody.

[0806] "Antibody-dependent cellular phagocytosis" ("ADCP") refers to the mechanism of eliminating antibody-coated target cells through internalization by phagocytic cells (such as macrophages or dendritic cells). ADCP can be evaluated by using macrophages derived from monocytes 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 antibody of the present invention. After incubation, the cells can be separated using cell dissociation solution (accutase). Macrophages can be identified using anti-CD11b antibodies and anti-CD14 antibodies conjugated to a fluorescent label, and the percentage of phagocytosis can be determined based on the GFP fluorescence % in the + CD14 + macrophages.

[0807] "Complement-dependent cytotoxicity" (CDC) refers to the mechanism of inducing cell death, in which the Fc effector domain of a target-binding antibody binds and activates the complement component C1q, which in turn activates the complement cascade, leading to the death of the target cell. Activation of the complement can also result in the deposition of complement components on the surface of the target cell, and these complement components promote CDC by binding to complement receptors on leukocytes (e.g., CR3). The CDC of cells can be measured, for example, by inoculating Daudi cells at 1×10 5 cells / well (50 μL / well) into RPMI-B (RPMI supplemented with 1% BSA), adding 50 μL of the test antibody at a final concentration between 0 μg / mL and 100 μg / mL to the wells, incubating the reaction at room temperature for 15 minutes, adding 11 μL of pooled human serum to the wells, and incubating the reaction at 37 °C for 45 minutes. The percentage of propidium iodide-stained cells can be detected as the percentage of lysed cells (%) using standard methods in a FACS assay.

[0808] The binding of an antibody to FcγR or FcRn can be evaluated on cells engineered to express each receptor using flow cytometry. In an exemplary binding assay, 2×10 5 cells / well are inoculated into a 96-well plate and blocked in BSA staining buffer (BD Biosciences, San Jose, USA) at 4 °C for 30 minutes. The cells are incubated with the test antibody on ice at 4 °C for 1.5 hours. After washing twice with BSA staining buffer, the cells are incubated with an R-PE-labeled anti-human IgG secondary antibody (Jackson Immunoresearch Laboratories) at 4 °C for 45 minutes. The cells are washed twice in staining buffer and then resuspended in 150 μL of staining buffer containing a 1:200 dilution of DRAQ7 live / dead stain (Cell Signaling Technology, Danvers, USA). The PE and DRAQ7 signals of the stained cells are detected using a Miltenyi MACSQuant flow cytometer (Miltenyi Biotec, Auburn, USA) in channels B2 and B4, respectively. Live cells are gated based on DRAQ7 exclusion, and the geometric mean fluorescence signal of at least 10,000 live events collected is determined. Analysis is performed using FlowJo software (Tree Star). The data are plotted as the logarithm of the antibody concentration versus the mean fluorescence signal. Perform a non-linear regression analysis 。

[0809] Chimeric antigen receptor (CAR)

[0810] Chimeric antigen receptors (CARs) are genetically engineered receptors. These engineered receptors can be readily inserted into and expressed by immune cells, including T cells, according to techniques known in the art. For a CAR, a single receptor can be programmed to recognize a specific antigen, and when bound to that antigen, activate the immune cell to attack and destroy cells carrying the antigen. When these antigens are present on tumor cells, immune cells expressing the CAR can target and kill the tumor cells.

[0811] A CAR typically comprises an extracellular domain that binds an antigen (e.g., prostate-specific antigen), an optional linker, a transmembrane domain, and a cytoplasmic domain that contains a co-stimulatory domain and / or a signaling domain.

[0812] The extracellular domain of a CAR can contain any polypeptide that binds the desired antigen (e.g., prostate-specific antigen). The extracellular domain can include a scFv, a portion of an antibody, or an alternative scaffold. A CAR can also be engineered to bind two or more desired antigens, which can be arranged in tandem and separated by a linker sequence. For example, one or more domain antibodies, scFvs, shark VHH antibodies, or other VH-only antibody fragments can be organized one after the other via a linker to provide bispecificity or multispecificity to the CAR.

[0813] The transmembrane domain of the CAR can be derived from the transmembrane domain of CD8, the α, β or ζ chains of the 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 (CD11a, CD18), ICOS (CD278), 4-1BB (CD137), 4-1BBL, GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), CD160, CD19, IL2Rβ, IL2Rγ, IL7Rα, ITGA1, VLA1, CD49a, ITGA4, VLA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, TNFR2, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), SLAMF6 (NTB-A, Lyl08), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, PAG / Cbp, NKp44, NKp30, NKp46, NKG2D and / or NKG2C.

[0814] The intracellular co-stimulatory domain of the CAR can be derived from the intracellular domain of one or more co-stimulatory molecules. Co-stimulatory molecules are well-known cell surface molecules other than antigen receptors or Fc receptors that provide the second signal required for the effective activation and function of T lymphocytes upon antigen binding. Exemplary co-stimulatory domains that can be used for the CAR are the intracellular domains of 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.

[0815] The intracellular signaling domain of the CAR can be derived from the signaling domains of, for example, ΟO3ζ, CD3ε, CD22, CD79a, CD66d, or CD39. The "intracellular signaling domain" refers to the part of the CAR polypeptide that participates in transducing the information of the effective CAR binding to the target antigen into the interior of the immune effector cell to trigger effector cell functions, such as activation, cytokine production, proliferation, and cytotoxic activity, including the release of cytotoxic factors to the target cells bound by the CAR, or other cellular responses triggered after the antigen binds to the extracellular CAR domain.

[0816] The optional linker of the CAR located between the extracellular domain and the transmembrane domain can be a polypeptide with a length of about 2 to 100 amino acids. The linker can include flexible residues (such as glycine and serine) or be composed of flexible residues, such that adjacent protein domains can 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 can be cleavable or non-cleavable. Examples of cleavable linkers include 2A linkers (such as T2A), 2A-like linkers, or their functional equivalents and combinations thereof. The linker can also be derived from the hinge region or a part of the hinge region of any immunoglobulin.

[0817] Exemplary CARs that can be used are, for example, CARs that contain an extracellular domain that binds to the prostate neoantigen of the present invention, a CD8 transmembrane domain, and a CD3ζ signaling domain. Other exemplary CARs contain an extracellular domain that binds to the prostate neoantigen of the present invention, a CD8 or CD28 transmembrane domain, a CD28, 41BB, or OX40 co-stimulatory domain, and a CD3ζ signaling domain.

[0818] The CAR is generated by standard molecular biology techniques. The extracellular domain that binds to the desired antigen can be derived from an antibody or an antigen-binding fragment thereof produced using the techniques described herein.

[0819] Although 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.

[0820] Other embodiments of the present invention

[0821] Certain other embodiments of the present invention are set forth below according to the disclosures elsewhere herein. The features of the embodiments of the present invention set forth above as related to the invention disclosed herein also relate to each of these other numbered embodiments.

[0822] Embodiment 1. An anti-CD38 antibody for use in combination with a T cell redirecting therapeutic agent in the treatment of a subject having cancer.

[0823] Embodiment 2. An anti-CD38 antibody for enhancing the efficacy of a T cell redirecting therapeutic agent in a subject with cancer.

[0824] 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 with cancer.

[0825] Embodiment 4. Use of an anti-CD38 antibody in combination with a T cell redirecting therapeutic agent, characterized in that it is for the preparation of a combination that can be used to treat a subject with cancer in a patient in need thereof.

[0826] Embodiment 5. The anti-CD38 antibody used according to any one of Embodiments 1 to 4, wherein the anti-CD38 antibody is administered before the administration of the T cell redirecting therapeutic agent.

[0827] Embodiment 6. The anti-CD38 antibody used according to any one of Embodiments 1 to 5, wherein the T cell redirecting therapeutic agent binds to BCMA, GPRC5D, CD33, CD123, CD19, PSMA, TMEFF2 or CD20.

[0828] Embodiment 7. The anti-CD38 antibody used according to any one of Embodiments 1 to 6, 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.

[0829] Embodiment 8. The anti-CD38 antibody used according to any one of Embodiments 1 to 7, wherein the T cell redirecting therapeutic agent comprises a CD3 binding domain, and the CD3 binding domain comprises

[0830] 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;

[0831] Heavy chain variable region (VH) of SEQ ID NO:39 and light chain variable region (VL) of SEQ ID NO:40;

[0832] variable region (VL);

[0833] 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;

[0834] VH of SEQ ID NO:80 and VL of SEQ ID NO:81;

[0835] HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of the CD3-binding domain of SEQ ID NO:53; or

[0836] VH and VL of the CD3-binding domain of SEQ ID NO:53.

[0837] Embodiment 9. The anti-CD38 antibody used according to any one of Embodiments 1 to 8, wherein the T cell redirection therapeutic agent comprises

[0838] 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

[0839] The BCMA-binding domain comprises VH of SEQ ID NO:29 and VL of SEQ ID NO:30, and the CD3-binding domain comprises VH of SEQ ID NO:39 and VL of SEQ ID NO:40.

[0840] Embodiment 10. The anti-CD38 antibody used according to any one of Embodiments 1 to 9, wherein the T cell redirection 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.

[0841] Embodiment 11. The anti-CD38 antibody used according to any one of Embodiments 1 to 10, wherein the T cell redirecting therapeutic agent comprises

[0842] 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

[0843] the GPRC5D binding domain comprises VH of SEQ ID NO:49 and VL of SEQ ID NO:50, and the CD3 binding domain comprises VH of SEQ ID NO:39 and VL of SEQ ID NO:40.

[0844] Embodiment 12. The anti-CD38 antibody used according to any one of Embodiments 111, wherein the T cell redirecting therapeutic agent 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.

[0845] Embodiment 13. The anti-CD38 antibody used according to any one of Embodiments 1 to 12, wherein the T cell redirecting therapeutic agent comprises

[0846] a CD33 binding domain and a CD3 binding domain, the CD33 binding domain comprising 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 comprising 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

[0847] The CD33 binding domain comprises VH of SEQ ID NO:90 and VL of SEQ ID NO:91, and the CD3 binding domain comprises VH of SEQ ID NO:80 and VL of SEQ ID NO:81.

[0848] Embodiment 14. The anti-CD38 antibody used according to any one of Embodiments 1 to 13, wherein the T cell redirecting therapeutic agent 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.

[0849] Embodiment 15. The anti-CD38 antibody used according to any one of Embodiments 1 to 14, wherein the T cell redirecting therapeutic agent comprises

[0850] a CD123 binding domain and a CD3 binding domain, the CD123 binding domain comprising HCDR1 of SEQ ID NO:94, HCDR2 of SEQ ID NO:95, HCDR3 of SEQ ID NO:96, 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

[0851] the CD123 binding domain comprises VH of SEQ ID NO:100 and VL of SEQ ID NO:61, and the CD3 binding domain comprises VH of SEQ ID NO:39 and VL of SEQ ID NO:40.

[0852] Embodiment 16. The anti-CD38 antibody used according to any one of Embodiments 1 to 15, wherein the T cell redirecting therapeutic agent 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.

[0853] Embodiment 17. The anti-CD38 antibody used according to any one of Embodiments 1 to 16, wherein the T cell redirecting therapeutic agent comprises

[0854] 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

[0855] The amino acid sequence of SEQ ID NO:53.

[0856] Embodiment 18. The anti-CD38 antibody used according to any one of Embodiments 1 to 17, wherein the T cell redirecting therapeutic agent comprises

[0857] A PSMA binding domain and a CD3 binding domain, wherein the PSMA binding domain comprises 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 comprises HCDR1 of SEQ ID NO:33, HCDR2 of SEQID 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

[0858] The PSMA binding domain comprises VH of SEQ ID NO:60 and VL of SEQ ID NO:61, and the CD3 binding domain comprises VH of SEQ ID NO:39 and VL of SEQ ID NO:40.

[0859] Embodiment 19. The anti-CD38 antibody used according to any one of Embodiments 1 to 18, wherein the T cell redirecting therapeutic agent comprises HC1 of SEQ ID NO:62, LC1 of SEQ ID NO:63, HC2 of SEQ ID NO:41 and LC2 of SEQID NO:42.

[0860] Embodiment 20. The anti-CD38 antibody used according to any one of Embodiments 1 to 19, wherein the T cell redirecting therapeutic agent comprises

[0861] The TMEFF2 binding domain and the CD3 binding domain, wherein the TMEFF2 binding domain comprises HCDR1 of SEQ ID NO: 64, HCDR2 of SEQ ID NO: 65, HCDR3 of SEQ ID NO: 66, LCDR1 of SEQ ID NO: 67, LCDR2 of SEQ ID NO: 68 and LCDR3 of SEQ ID NO: 69, 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

[0862] The TMEFF2 binding domain comprises VH of SEQ ID NO: 70 and VL of SEQ ID NO: 71, and the CD3 binding domain comprises VH of SEQ ID NO: 80 and VL of SEQ ID NO: 81.

[0863] Embodiment 21. The anti-CD38 antibody used according to any one of Embodiments 1 to 20, wherein the T cell redirection therapeutic agent 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.

[0864] Embodiment 22. The anti-CD38 antibody used according to any one of Embodiments 1 to 21, wherein the T cell redirection therapeutic agent is a multispecific antibody, a chimeric antigen receptor (CAR) or a T cell comprising the CAR.

[0865] Embodiment 23. The anti-CD38 antibody used according to Embodiment 22, wherein the multispecific antibody is an IgG1, IgG2, IgG3 or IgG4 isotype.

[0866] Embodiment 24. The anti-CD38 antibody used according to Embodiment 22 or 23, wherein the multispecific antibody comprises one or more Fc substitutions that reduce the binding of the multispecific antibody to the Fc gamma receptor (FcγR).

[0867] Embodiment 25. The anti-CD38 antibody used according to any one of Embodiments 22 to 24, wherein one or more of the 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 / P331A / D365E / L358M on IgG1, 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, wherein the residues are numbered according to the EU index.

[0868] Embodiment 26. The anti-CD38 antibody used according to Embodiment 25, wherein the multispecific antibody further comprises an S228P substitution.

[0869] Embodiment 27. The anti-CD38 antibody used 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.

[0870] Embodiment 28. The anti-CD38 antibody used according to any one of Embodiment 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_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.

[0871] Embodiment 29. The anti-CD38 antibody used according to any one of Embodiments 1 to 28, wherein the subject has newly diagnosed cancer.

[0872] Embodiment 30. The anti-CD38 antibody used according to any one of Embodiments 1 to 29, wherein the subject is recurrent or refractory to a previous anti-cancer therapy.

[0873] Embodiment 31. The anti-CD38 antibody used according to any one of Embodiments 1 to 30, wherein the cancer is a hematological malignancy or a solid tumor.

[0874] Embodiment 32. The anti-CD38 antibody used 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 lymphoma (BL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Waldenström macroglobulinemia, plasma cell leukemia, light chain amyloidosis (AL), precursor B-cell lymphoblastic leukemia, precursor B-cell lymphoblastic leukemia, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic lymphocytic leukemia (CLL), B-cell malignancy, 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.

[0875] Embodiment 33. The anti-CD38 antibody used according to any one of Embodiments 1 to 32, wherein the multiple myeloma is newly diagnosed multiple myeloma.

[0876] Embodiment 34. The anti-CD38 antibody used according to any one of Embodiments 1 to 32, wherein the multiple myeloma is relapsed or refractory multiple myeloma.

[0877] Embodiment 35. The anti-CD38 antibody used according to any one of Embodiments 1 to 34, wherein the multiple myeloma is high-risk multiple myeloma.

[0878] Embodiment 36. The anti-CD38 antibody used according to Embodiment 35, wherein the subject with the high-risk multiple myeloma has one or more chromosomal abnormalities, and the one or more chromosomal abnormalities include:

[0879] t(4;14)(p16;q32);

[0880] t(14;16)(q32;q23);

[0881] del17p;

[0882] 1qAmp;

[0883] t(4;14)(p16;q32) and t(14;16)(q32;q23);

[0884] t(4;14)(p16;q32) and del17p;

[0885] t(14;16)(q32;q23) and del17p; or

[0886] t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p or any combination thereof.

[0887] Embodiment 37. The anti-CD38 antibody used according to any one of Embodiments 1 to 36, wherein the multiple myeloma is recurrent or refractory to treatment with the anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotuzumab, ixazomib, melphalan or thalidomide or any combination thereof.

[0888] Embodiment 38. The anti-CD38 antibody used 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, gastric carcinoma, kidney cancer, colon cancer, bladder cancer, cervical tumor, melanoma, hepatocellular carcinoma, renal cell carcinoma, urothelial carcinoma, head and neck cancer, glioma or glioblastoma.

[0889] Embodiment 39. The anti-CD38 antibody used 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.

[0890] Embodiment 40. The anti-CD38 antibody used according to Embodiment 32, wherein the AML is AML with at least one genetic abnormality, AML with multilineage dysplasia, treatment-related AML, undifferentiated AML, AML with minimal maturation, AML with maturation, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, acute megakaryoblastic leukemia, acute basophilic leukemia, acute panmyelosis with fibrosis or myeloid sarcoma.

[0891] Embodiment 41. The anti-CD38 antibody used according to Embodiment 40, wherein the at least one genetic abnormality is a translocation between chromosome 8 and 21, a translocation or inversion in chromosome 16, a translocation between chromosome 15 and 17, an alteration in chromosome 11, or a mutation in fms-related tyrosine kinase 3 (FLT3), nucleophosmin (NPM1), isocitrate dehydrogenase 1 (IDH1), isocitrate dehydrogenase 2 (IDH2), DNA (cytosine-5)-methyltransferase 3 (DNMT3A), CCAAT / enhancer-binding protein α (CEBPA), U2 small nuclear RNA auxiliary 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).

[0892] Embodiment 42. The anti-CD38 antibody used 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.

[0893] Embodiment 43. The anti-CD38 antibody used according to Embodiment 32, wherein the ALL is B-cell lineage ALL, T-cell lineage ALL, adult ALL or pediatric ALL.

[0894] Embodiment 44. The anti-CD38 antibody used according to Embodiment 43, wherein the subject with ALL has the Philadelphia chromosome or shows resistance to treatment with a BCR-ABL kinase inhibitor or has acquired resistance to such treatment.

[0895] Embodiment 45. The anti-CD38 antibody used 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.

[0896] Embodiment 46. The anti-CD38 antibody used according to any one of Embodiments 1 to 45, wherein the anti-CD38 antibody comprises VH of SEQ ID NO:4 and VL of SEQ ID NO:5.

[0897] Embodiment 47. The anti-CD38 antibody used according to any one of Embodiments 1 to 46, wherein the anti-CD38 antibody is of the IgG1 isotype.

[0898] Embodiment 48. The anti-CD38 antibody used according to any one of Embodiments 1 to 47, wherein the anti-CD38 antibody comprises an HC of SEQ ID NO:12 and an LC of SEQ ID NO:13.

[0899] Embodiment 49. The anti-CD38 antibody used according to any one of Embodiments 1 to 44, wherein the anti-CD38 antibody comprises

[0900] a VH of SEQ ID NO:14 and a VL of SEQ ID NO:15;

[0901] a VH of SEQ ID NO:16 and a VL of SEQ ID NO:17;

[0902] a VH of SEQ ID NO:18 and a VL of SEQ ID NO:19; or

[0903] a VH of SEQ ID NO:20 and a VL of SEQ ID NO:21.

[0904] Embodiment 50. The anti-CD38 antibody used according to Embodiment 49, wherein the anti-CD38 antibody is of the IgG1 isotype.

[0905] Embodiment 51. The anti-CD38 antibody used according to any one of Embodiments 1 to 50, wherein the T cell redirection 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.

[0906] Embodiment 52. The anti-CD38 antibody used according to any one of Embodiments 1 to 51, further comprising administering to the subject one or more anti-cancer therapies.

[0907] Embodiment 53. The anti-CD38 antibody used according to any one of Embodiments 1 to 52, wherein the one or more anti-cancer therapies are selected from autologous hematopoietic stem cell transplantation (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulators and targeted cancer therapies.

[0908] Embodiment 54. The anti-CD38 antibody used 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, elotuzumab, ixazomib, melphalan, dexamethasone, vincristine, cyclophosphamide, daunorubicinol, prednisone, rituximab, imatinib, dasatinib, nilotinib, bosutinib, ponatinib, bafetinib, seretinib, tozasertib or darasertib, 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.

[0909] Embodiment 55. The anti-CD38 antibody used according to any one of Embodiments 1 to 54, wherein the anti-CD38 antibody is administered at a dose between about 8 mg / kg and about 16 mg / kg.

[0910] Embodiment 56. The anti-CD38 antibody used 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, the pharmaceutical composition comprising the anti-CD38 antibody between about 20 mg / mL and about 120 mg / mL in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mannitol and about 0.04% w / v polysorbate-20 (PS-20); the pH is about 5.5.

[0911] Embodiment 57. The anti-CD38 antibody used 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, the pharmaceutical composition comprising about 1,800 mg of the anti-CD38 antibody and about 30,000 U of rHuPH20.

[0912] Embodiment 58. The anti-CD38 antibody used according to Embodiment 57, wherein the anti-CD38 antibody is administered or provided for administration in the form of a pharmaceutical composition, the pharmaceutical composition comprising about 120 mg / mL of the anti-CD38 antibody and about 2,000 U / mL of rHuPH20.

[0913] Embodiment 59. The anti-CD38 antibody used 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, the pharmaceutical composition comprising

[0914] histidine between about 5 mM and about 15 mM;

[0915] Sorbitol between about 100 mM and about 300 mM;

[0916] PS-20 between about 0.01% w / v and about 0.04% w / v; and

[0917] Methionine between about 1 mg / mL and about 2 mg / mL, at a pH of about 5.5 to 5.6.

[0918] Embodiment 60. The anti-CD38 antibody used 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, the pharmaceutical composition comprising

[0919] About 1,800 mg of the anti-CD38 antibody;

[0920] About 30,000 U of rHuPH20;

[0921] About 10 mM of histidine;

[0922] About 300 mM of sorbitol;

[0923] About 0.04% (w / v) of PS-20; and

[0924] About 1 mg / mL of methionine, at a pH of about 5.6.

[0925] Embodiment 61. The anti-CD38 antibody used 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, the pharmaceutical composition comprising

[0926] About 120 mg / mL of the anti-CD38 antibody;

[0927] About 2,000 U / mL of rHuPH20;

[0928] About 10 mM of histidine;

[0929] About 300 mM of sorbitol;

[0930] About 0.04% (w / v) of PS-20; and

[0931] About 1 mg / mL of methionine, at a pH of about 5.6.

[0932] Embodiment 62. A BCMA×CD3 bispecific antibody for use in combination with an anti-CD38 antibody to treat a subject with cancer.

[0933] Embodiment 63. The BCMA×CD3 bispecific antibody used according to Embodiment 62, wherein the subject has been treated with an anti-CD38 antibody before administration of the BCMA×CD3 bispecific antibody.

[0934] Embodiment 64. The BCMA×CD3 bispecific antibody used 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 comprises 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.

[0935] Embodiment 65. The BCMA×CD3 bispecific antibody used according to any one of Embodiments 62 to 64, wherein the BCMA-binding domain comprises VH of SEQ ID NO:29 and VL of SEQ ID NO:30, and the CD3-binding domain comprises VH of SEQ ID NO:39 and VL of SEQ ID NO:40.

[0936] Embodiment 66. The BCMA×CD3 bispecific antibody used according to any one of Embodiments 62 to 65, wherein the BCMA×CD3 bispecific antibody is of the 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.

[0937] Embodiment 67. The BCMA×CD3 bispecific antibody used according to any one of Embodiments 62 to 66, wherein the BCMA×CD3 bispecific antibody further comprises proline at position 228, alanine at position 234, and alanine at position 235 in both HC1 and HC2.

[0938] Embodiment 68. The BCMA×CD3 antibody used 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.

[0939] Embodiment 69. The BCMA×CD3 bispecific antibody used according to any one of Embodiments 62 to 68, wherein the cancer is a BCMA-expressing cancer.

[0940] Embodiment 70. The BCMA×CD3 bispecific antibody used according to any one of Embodiments 62 to 69, wherein the cancer is a hematologic malignancy.

[0941] Embodiment 71. The BCMA×CD3 bispecific antibody used according to any one of Embodiments 62 to 70, wherein the subject is recurrent or refractory to treatment with the anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotuzumab, ixazomib, melphalan, or thalidomide, or any combination thereof.

[0942] Embodiment 72. The BCMA×CD3 bispecific antibody used according to any one of Embodiments 62 to 71, wherein the subject is recurrent or refractory to treatment with the anti-CD38 antibody.

[0943] Embodiment 73. The BCMA×CD3 bispecific antibody used according to any one of Embodiments 62 to 72, wherein the hematologic malignancy is multiple myeloma, myeloma, DLBLC, CLL, Waldenström macroglobulinemia, or non-Hodgkin lymphoma.

[0944] Embodiment 74. The BCMA×CD3 bispecific antibody used according to Embodiment 73, wherein the multiple myeloma is newly diagnosed multiple myeloma.

[0945] Embodiment 75. The BCMA×CD3 bispecific antibody used according to Embodiment 74, wherein the multiple myeloma is recurrent or refractory multiple myeloma.

[0946] Embodiment 76. The BCMA×CD3 bispecific antibody used according to Embodiment 74, wherein the multiple myeloma is high-risk multiple myeloma.

[0947] Embodiment 77. The BCMA×CD3 bispecific antibody used according to Embodiment 76, wherein the subject with the high-risk multiple myeloma has one or more chromosomal abnormalities, and the one or more chromosomal abnormalities include:

[0948] t(4;14)(p16;q32);

[0949] t(14;16)(q32;q23);

[0950] del17p;

[0951] 1qAmp;

[0952] t(4;14)(p16;q32) and t(14;16)(q32;q23);

[0953] t(4;14)(p16;q32) and del17p;

[0954] t(14;16)(q32;q23) and del17p; or

[0955] t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p or any combination thereof.

[0956] Embodiment 78. The BCMA×CD3 bispecific antibody used 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.

[0957] Embodiment 79. The BCMA×CD3 bispecific antibody used according to any one of Embodiments 62 to 78, wherein the anti-CD38 antibody comprises VH of SEQ ID NO:4 and VL of SEQ ID NO:5.

[0958] Embodiment 80. The BCMA×CD3 bispecific antibody used according to any one of Embodiments 62 to 79, wherein the anti-CD38 antibody is of IgG1 isotype.

[0959] Embodiment 81. The BCMA×CD3 bispecific antibody used according to any one of Embodiments 62 to 80, wherein the anti-CD38 antibody comprises HC of SEQ ID NO:12 and LC of SEQ ID NO:13.

[0960] Embodiment 82. The BCMA×CD3 bispecific antibody used according to any one of Embodiments 62 to 77, wherein the anti-CD38 antibody comprises

[0961] VH of SEQ ID NO:14 and VL of SEQ ID NO:15;

[0962] VH of SEQ ID NO:16 and VL of SEQ ID NO:17;

[0963] VH of SEQ ID NO:18 and VL of SEQ ID NO:19; or

[0964] VH of SEQ ID NO:20 and VL of SEQ ID NO:21.

[0965] Embodiment 83. The BCMA×CD3 bispecific antibody used according to Embodiment 82, wherein the anti-CD38 antibody is of IgG1 isotype.

[0966] Embodiment 84. The BCMA×CD3 bispecific antibody used according to any one of Embodiments 62 to 83, wherein the anti-CD38 antibody is administered at a dose between about 8 mg / kg and about 16 mg / kg.

[0967] Embodiment 85. The BCMA×CD3 bispecific antibody used 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.

[0968] Embodiment 86. The BCMA×CD3 bispecific antibody used 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.

[0969] Embodiment 87. The BCMA×CD3 bispecific antibody used according to any one of Embodiments 62 to 86, wherein the subject is a human.

[0970] Embodiment 88. The BCMA×CD3 bispecific antibody used according to any one of Embodiments 62 to 87, further comprising administering to the subject one or more anti-cancer therapies.

[0971] Embodiment 89. The BCMA×CD3 bispecific antibody used according to Embodiment 88, wherein the one or more anti-cancer therapies are selected from autologous hematopoietic stem cell transplantation (ASCT), radiotherapy, surgery, chemotherapeutic agents, immunomodulators, and targeted cancer therapies.

[0972] Embodiment 90. The BCMA×CD3 bispecific antibody used 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, elotuzumab, ixazomib, melphalan, prednisone or dexamethasone or any combination thereof.

[0973] Embodiment 91. The BCMA×CD3 bispecific antibody used 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 the anti-CD38 antibody at a concentration of between about 20 mg / mL and about 120 mg / mL in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mannitol and about 0.04% w / v polysorbate-20 (PS-20); the pH is about 5.5.

[0974] Embodiment 92. The BCMA×CD3 bispecific antibody used 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.

[0975] Embodiment 93. The BCMA×CD3 bispecific antibody used 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.

[0976] Embodiment 94. The BCMA×CD3 bispecific antibody used 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

[0977] histidine between about 5 mM and about 15 mM;

[0978] sorbitol between about 100 mM and about 300 mM;

[0979] PS-20 between about 0.01% w / v and about 0.04% w / v; and

[0980] methionine between about 1 mg / mL and about 2 mg / mL, with a pH of about 5.5 to 5.6.

[0981] Embodiment 95. The BCMA×CD3 bispecific antibody used 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, the pharmaceutical composition comprising

[0982] about 1,800 mg of the anti-CD38 antibody;

[0983] about 30,000 U of rHuPH20;

[0984] about 10 mM of histidine;

[0985] about 300 mM of sorbitol;

[0986] about 0.04% (w / v) of PS-20; and

[0987] about 1 mg / mL of methionine, with a pH of about 5.6.

[0988] Embodiment 96. The BCMA×CD3 bispecific antibody used 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, the pharmaceutical composition comprising

[0989] about 120 mg / mL of the anti-CD38 antibody;

[0990] about 2,000 U / mL of rHuPH20;

[0991] about 10 mM of histidine;

[0992] about 300 mM of sorbitol;

[0993] about 0.04% (w / v) of PS-20; and

[0994] about 1 mg / mL of methionine, with a pH of about 5.6.

[0995] Embodiment 97. A BCMA×CD3 bispecific antibody for treating a subject with cancer, wherein the subject is recurrent or refractory to treatment with a previous anti-cancer therapeutic agent.

[0996] Embodiment 98. The BCMA×CD3 bispecific antibody used according to Embodiment 97, wherein the BCMA×CD3 bispecific antibody comprises a BCMA binding domain and a CD3 binding domain, the BCMA binding domain comprises 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.

[0997] Embodiment 99. The BCMA×CD3 bispecific antibody used according to Embodiment 97 or 98, wherein the BCMA binding domain comprises VH of SEQ ID NO:29 and VL of SEQ ID NO:30, and the CD3 binding domain comprises VH of SEQ ID NO:39 and VL of SEQ ID NO:40.

[0998] Embodiment 100. The BCMA×CD3 bispecific antibody used 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.

[0999] Embodiment 101. The BCMA×CD3 bispecific antibody used according to Embodiment 100, wherein the BCMA×CD3 bispecific antibody further comprises proline at position 228, alanine at position 234 and alanine at position 235 in both HC1 and HC2.

[1000] Embodiment 102. The BCMA×CD3 antibody used 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.

[1001] Embodiment 103. The BCMA×CD3 bispecific antibody used according to any one of Embodiments 97 to 102, wherein the cancer is a hematological malignancy.

[1002] Embodiment 104. The BCMA×CD3 bispecific antibody used according to Embodiment 103, wherein the hematological malignancy is high-risk multiple myeloma.

[1003] Embodiment 105. The BCMA×CD3 bispecific antibody used according to Embodiment 104, wherein the multiple myeloma is high-risk multiple myeloma.

[1004] Embodiment 106. The BCMA×CD3 bispecific antibody used according to Embodiment 105, wherein the subject with the high-risk multiple myeloma has one or more chromosomal abnormalities, and the one or more chromosomal abnormalities include:

[1005] t(4;14)(p16;q32);

[1006] t(14;16)(q32;q23);

[1007] del17p;

[1008] 1qAmp;

[1009] t(4;14)(p16;q32) and t(14;16)(q32;q23);

[1010] t(4;14)(p16;q32) and del17p;

[1011] t(14;16)(q32;q23) and del17p; or

[1012] t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p or any combination thereof.

[1013] Embodiment 107. The BCMA×CD3 bispecific antibody used 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, elotuzumab, ixazomib, melphalan or thalidomide or any combination thereof.

[1014] Embodiment 108. The BCMA×CD3 bispecific antibody used according to any one of Embodiments 97 to 107, wherein the subject is relapsed to treatment with the anti-CD38 antibody.

[1015] Embodiment 109. The BCMA×CD3 bispecific antibody used 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.

[1016] Embodiment 110. The BCMA×CD3 bispecific antibody used according to any one of Embodiments 97 to 109, wherein the anti-CD38 antibody comprises VH of SEQ ID NO:4 and VL of SEQ ID NO:5.

[1017] Embodiment 111. The BCMA×CD3 bispecific antibody used according to any one of Embodiments 97 to 110, wherein the anti-CD38 antibody is of IgG1 isotype.

[1018] Embodiment 112. The BCMA×CD3 bispecific antibody used according to any one of Embodiments 97 to 111, wherein the anti-CD38 antibody comprises HC of SEQ ID NO:12 and LC of SEQ ID NO:13.

[1019] Embodiment 113. The BCMA×CD3 bispecific antibody used according to any one of Embodiments 97 to 108, wherein the anti-CD38 antibody comprises

[1020] VH of SEQ ID NO:14 and VL of SEQ ID NO:15;

[1021] VH of SEQ ID NO:16 and VL of SEQ ID NO:17;

[1022] VH of SEQ ID NO:18 and VL of SEQ ID NO:19; or

[1023] VH of SEQ ID NO:20 and VL of SEQ ID NO:21.

[1024] Embodiment 114. The BCMA×CD3 bispecific antibody used according to Embodiment 113, wherein the anti-CD38 antibody is of IgG1 isotype.

[1025] Embodiment 115. The BCMA×CD3 bispecific antibody used according to any one of Embodiments 97 to 114, wherein the subject is a human.

[1026] Embodiment 116. The BCMA×CD3 bispecific antibody used according to any one of Embodiments 97 to 115 further comprises administering to the subject one or more anti-cancer therapies.

[1027] Embodiment 117. The BCMA×CD3 bispecific antibody used according to Embodiment 116, wherein the one or more anti-cancer therapies are selected from autologous hematopoietic stem cell transplantation (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulators, and targeted cancer therapies.

[1028] Embodiment 118. The BCMA×CD3 bispecific antibody used according to Embodiment 116, wherein the one or more anti-cancer therapies are selected from lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, elotuzumab, ixazomib, melphalan, prednisone, or dexamethasone, or any combination thereof.

[1029] Embodiment 119. 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 the VH of SEQ ID NO:29 and the VL of SEQ ID NO:30, the CD3-binding domain comprising the VH of SEQ ID NO:39 and the VL of SEQ ID NO:40, and the anti-CD38 antibody comprising the VH of SEQ ID NO:4 and the VL of SEQ ID NO:5.

[1030] Embodiment 120. The 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.

[1031] Embodiment 121. The pharmaceutical composition according to Embodiment 119 or 120, wherein the pharmaceutical composition is a non-fixed combination.

[1032] Embodiment 122. The pharmaceutical composition according to Embodiment 121, comprising from 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); the pH is about 5.5.

[1033] Embodiment 123. The pharmaceutical composition according to Embodiment 121 comprises about 1,800 mg of the anti-CD38 antibody and about 30,000 U of rHuPH20.

[1034] Embodiment 124. The pharmaceutical composition according to Embodiment 123 comprises about 120 mg / mL of the anti-CD38 antibody and about 2,000 U / mL of rHuPH20.

[1035] Embodiment 125. The pharmaceutical composition according to Embodiment 124 further comprises one or more excipients.

[1036] Embodiment 126. The pharmaceutical composition according to Embodiment 125, wherein the one or more excipients are histidine, methionine, sorbitol or polysorbate-20 (PS-20) or any combination thereof.

[1037] Embodiment 127. The pharmaceutical composition according to Embodiment 126, wherein the pharmaceutical composition comprises

[1038] the anti-CD38 antibody between about 100 mg / mL and about 120 mg / mL;

[1039] histidine between about 5 mM and about 15 mM;

[1040] sorbitol between about 100 mM and about 300 mM;

[1041] PS-20 between about 0.01% w / v and about 0.04% w / v; and

[1042] methionine between about 1 mg / mL and about 2 mg / mL, with a pH of about 5.5 to 5.6.

[1043] Embodiment 128. The pharmaceutical composition according to Embodiment 127 comprises about 10 mM of histidine.

[1044] Embodiment 129. The pharmaceutical composition according to Embodiment 127 or 128 comprises about 300 mM of sorbitol.

[1045] Embodiment 130. The pharmaceutical composition according to any one of Embodiments 127 to 129 comprises about 0.04% (w / v) of PS-20.

[1046] Embodiment 131. The pharmaceutical composition according to any one of Embodiments 127 to 130 comprises about 1 mg / mL of methionine.

[1047] Embodiment 132. The pharmaceutical composition according to any one of embodiments 127 to 131, comprising

[1048] about 1,800 mg of the anti-CD38 antibody;

[1049] about 30,000 U of rHuPH20;

[1050] about 10 mM of histidine;

[1051] about 300 mM of sorbitol;

[1052] about 0.04% (w / v) of PS-20; and

[1053] about 1 mg / mL of methionine, with a pH of about 5.6.

[1054] Embodiment 133. The pharmaceutical composition according to any one of embodiments 127 to 132, comprising

[1055] about 120 mg / mL of the anti-CD38 antibody;

[1056] about 2,000 U / mL of rHuPH20;

[1057] about 10 mM of histidine;

[1058] about 300 mM of sorbitol;

[1059] about 0.04% (w / v) of PS-20; and

[1060] about 1 mg / mL of methionine, with a pH of about 5.6.

[1061] Embodiment 134. A kit, comprising the pharmaceutical composition according to any one of embodiments 119 to 133.

[1062] Embodiment 135. A T cell redirecting therapeutic agent that binds to GPRC5D for combined treatment with an anti-CD38 antibody of a subject suffering from cancer.

[1063] Embodiment 136. The T cell redirecting therapeutic agent that binds to GPRC5D used according to embodiment 135, wherein the anti-CD38 antibody is administered to the subject before the T cell redirecting therapeutic agent that binds to GPRC5D is administered.

[1064] Embodiment 137. The T cell redirecting therapeutic agent that binds to GPRC5D used according to embodiment 135 or 136, wherein the subject is recurrent or refractory to treatment with a prior anti-cancer therapeutic agent.

[1065] Embodiment 138. The anti-GPRC5D T cell redirection therapeutic agent used according to any one of Embodiments 135 to 137, wherein the cancer is a GPRC5D-expressing cancer.

[1066] Embodiment 139. The anti-GPRC5D T cell redirection therapeutic agent used according to any one of Embodiments 135 to 138, wherein the GPRC5D-expressing cancer is a hematological malignancy or a solid tumor.

[1067] Embodiment 140. The anti-GPRC5D T cell redirection therapeutic agent used according to Embodiment 139, wherein the hematological malignancy is leukemia, lymphoma or multiple myeloma.

[1068] Embodiment 141. The anti-GPRC5D T cell redirection 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.

[1069] Embodiment 142. The anti-GPRC5D T cell redirection therapeutic agent used according to any one of Embodiments 135 to 141, wherein the subject is recurrent or refractory to treatment with the anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotuzumab, ixazomib, melphalan or thalidomide or any combination thereof.

[1070] Embodiment 143. The anti-GPRC5D T cell redirection therapeutic agent used according to any one of Embodiments 135 to 142, wherein the subject is recurrent or refractory to treatment with the anti-CD38 antibody.

[1071] Embodiment 144. The anti-GPRC5D T cell redirection therapeutic agent used according to any one of Embodiments 140 to 143, wherein the multiple myeloma is newly diagnosed multiple myeloma.

[1072] Embodiment 145. The anti-GPRC5D T cell redirection therapeutic agent used according to any one of Embodiments 140 to 143, wherein the multiple myeloma is recurrent or refractory multiple myeloma.

[1073] Embodiment 146. The anti-GPRC5D T cell redirection therapeutic agent used according to any one of Embodiments 140 to 145, wherein the multiple myeloma is high-risk multiple myeloma.

[1074] Embodiment 147. The GPRC5D-binding T cell redirection therapeutic agent used according to Embodiment 146, wherein the subject with the high-risk multiple myeloma has one or more chromosomal abnormalities, and the one or more chromosomal abnormalities include:

[1075] t(4;14)(p16;q32);

[1076] t(14;16)(q32;q23);

[1077] del17p;

[1078] 1qAmp;

[1079] t(4;14)(p16;q32) and t(14;16)(q32;q23);

[1080] t(4;14)(p16;q32) and del17p;

[1081] t(14;16)(q32;q23) and del17p; or

[1082] t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p or any combination thereof.

[1083] Embodiment 148. The GPRC5D-binding T cell redirection therapeutic agent used according to any one of Embodiments 135 to 147, wherein the T cell redirection therapeutic agent binds to CD3, CD3ε (CD3ε), CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, BTNL8, PD-1, CD195 or NKG2C.

[1084] Embodiment 149. The GPRC5D-binding T cell redirecting therapeutic agent used 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 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, 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.

[1085] Embodiment 150. The GPRC5D-binding T cell redirecting therapeutic agent used according to any one of Embodiments 135 to 149, wherein the GPRC5D-binding domain comprises VH of SEQ ID NO:49 and VL of SEQ ID NO:50, and the CD3-binding domain comprises VH of SEQ ID NO:39 and VL of SEQ ID NO:40.

[1086] Embodiment 151. The GPRC5D-binding T cell redirecting therapeutic agent used according to any one of Embodiments 135 to 150, wherein the GPRC5C-binding T cell redirecting therapeutic agent is a multispecific antibody, a CAR, or a T cell expressing the CAR.

[1087] Embodiment 152. The GPRC5D-binding T cell redirecting therapeutic agent used according to Embodiment 151, wherein the multispecific antibody is of the IgG1, IgG2, IgG3, or IgG4 isotype.

[1088] Embodiment 153. The GPRC5D-binding T cell redirecting therapeutic agent used according to any one of Embodiments 151 to 152, wherein the multispecific antibody comprises one or more Fc substitutions that reduce the binding of the multispecific antibody to the Fc gamma receptor (FcγR).

[1089] Embodiment 154. The GPRC5D-binding T cell redirection therapeutic agent used 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 / G236-deletion / A327G / P331A / D365E / L358M on IgG1, 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, wherein the residues are numbered according to the EU index.

[1090] Embodiment 155. The GPRC5D-binding T cell redirection therapeutic agent used according to Embodiment 154, wherein the multispecific antibody further comprises an S228P substitution.

[1091] Embodiment 156. The GPRC5D-binding T cell redirection therapeutic agent used 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.

[1092] Embodiment 157. The GPRC5D-binding T cell redirecting therapeutic agent used according to any one of Embodiment 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.

[1093] 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.

[1094] Embodiment 159. The GPRC5D-binding T cell redirecting therapeutic agent used 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.

[1095] Embodiment 160. The GPRC5D-binding T cell redirecting therapeutic agent used according to any one of Embodiments 135 to 159, wherein the anti-CD38 antibody comprises VH of SEQ ID NO:4 and VL of SEQ ID NO:5.

[1096] Embodiment 161. The GPRC5D-binding T cell redirecting therapeutic agent used according to any one of Embodiments 135 to 160, wherein the anti-CD38 antibody is of IgG1 isotype.

[1097] Embodiment 162. The anti-GPRC5D T cell redirecting therapeutic agent used 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.

[1098] Embodiment 163. The anti-GPRC5D T cell redirecting therapeutic agent used according to any one of Embodiments 135 to 158, wherein the anti-CD38 antibody comprises

[1099] VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15;

[1100] VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17;

[1101] VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19; or

[1102] VH of SEQ ID NO: 20 and VL of SEQ ID NO: 21.

[1103] Embodiment 164. The anti-GPRC5D T cell redirecting therapeutic agent used according to Embodiment 163, wherein the anti-CD38 antibody is of IgG1 isotype.

[1104] Embodiment 165. The anti-GPRC5D T cell redirecting therapeutic agent used according to any one of Embodiments 135 to 164, wherein the anti-CD38 antibody is administered at a dose between about 8 mg / kg and about 16 mg / kg.

[1105] Embodiment 166. The anti-GPRC5D T cell redirecting therapeutic agent used according to any one of Embodiments 135 to 165, wherein the anti-GPRC5D T cell redirecting therapeutic agent and the anti-CD38 antibody are administered by intravenous injection.

[1106] Embodiment 167. The anti-GPRC5D T cell redirecting therapeutic agent used according to any one of Embodiments 135 to 165, wherein the anti-GPRC5D T cell redirecting therapeutic agent is administered by intravenous injection, and the anti-CD38 antibody is administered by subcutaneous injection.

[1107] Embodiment 168. The anti-GPRC5D T cell redirecting therapeutic agent used according to any one of Embodiments 135 to 167, wherein the subject is a human.

[1108] Embodiment 169. The GPRC5D-binding T cell redirecting therapeutic agent used according to any one of Embodiments 135 to 168, wherein the GPRC5D-binding T cell redirecting therapeutic agent is a GPRC5D×CD3 bispecific antibody.

[1109] Embodiment 170. The GPRC5D-binding T cell redirecting therapeutic agent used according to any one of Embodiments 135 to 170, further comprising administering to the subject one or more anti-cancer therapies.

[1110] 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 hematopoietic stem cell transplantation (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulators, and targeted cancer therapies.

[1111] 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, elotuzumab, ixazomib, melphalan, dexamethasone, or prednisone.

[1112] Embodiment 173. The GPRC5D-binding T cell redirecting therapeutic agent used 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, the pharmaceutical composition comprising the anti-CD38 antibody at a concentration between about 20 mg / mL and about 120 mg / mL in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mannitol, and about 0.04% w / v polysorbate-20 (PS-20); the pH is about 5.5.

[1113] Embodiment 174. The GPRC5D-binding T cell redirecting therapeutic agent used 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, the pharmaceutical composition comprising about 1,800 mg of the anti-CD38 antibody and about 30,000 U of rHuPH20.

[1114] 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, the pharmaceutical composition comprising about 120 mg / mL of the anti-CD38 antibody and about 2,000 U / mL of rHuPH20.

[1115] Embodiment 176. The GPRC5D-binding T cell redirecting therapeutic agent used 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

[1116] the anti-CD38 antibody between about 100 mg / mL and about 120 mg / mL;

[1117] histidine between about 5 mM and about 15 mM;

[1118] sorbitol between about 100 mM and about 300 mM;

[1119] PS-20 between about 0.01% w / v and about 0.04% w / v; and

[1120] methionine between about 1 mg / mL and about 2 mg / mL, at a pH of about 5.5 to 5.6.

[1121] Embodiment 177. The GPRC5D-binding T cell redirecting therapeutic agent used 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, the pharmaceutical composition comprising

[1122] about 1,800 mg of the anti-CD38 antibody;

[1123] about 30,000 U of rHuPH20;

[1124] about 10 mM of histidine;

[1125] about 300 mM of sorbitol;

[1126] about 0.04% (w / v) of PS-20; and

[1127] about 1 mg / mL of methionine, at a pH of about 5.6.

[1128] Embodiment 178. The GPRC5D-binding T cell redirecting therapeutic agent used 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, the pharmaceutical composition comprising

[1129] about 120 mg / mL of the anti-CD38 antibody;

[1130] about 2,000 U / mL of rHuPH20;

[1131] about 10 mM of histidine;

[1132] Sorbitol at about 300 mM;

[1133] PS-20 at about 0.04% (w / v); and

[1134] Methionine at about 1 mg / mL, pH about 5.6.

[1135] Embodiment 179. A GPRC5D×CD3 bispecific antibody for treating a subject with cancer, wherein the subject is recurrent or refractory to treatment with a prior anti-cancer therapeutic agent.

[1136] Embodiment 180. The GPRC5D×CD3 bispecific antibody used according to Embodiment 179, 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, 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.

[1137] Embodiment 181. The GPRC5D×CD3 bispecific antibody used according to Embodiment 179 or 180, wherein the GPRC5D binding domain comprises VH of SEQ ID NO:49 and VL of SEQ ID NO:50, and the CD3 binding domain comprises VH of SEQ ID NO:39 and VL of SEQ ID NO:40.

[1138] Embodiment 182. The GPRC5D×CD3 bispecific antibody used according to any one of Embodiments 179 to 181, wherein the GPRC5D×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, where the residues are numbered according to the EU index.

[1139] Embodiment 183. The GPRC5D×CD3 bispecific antibody used according to Embodiment 182, wherein the GPRC5D×CD3 bispecific antibody further comprises proline at position 228, alanine at position 234, and alanine at position 235 in both HC1 and HC2.

[1140] Embodiment 184. The GPRC5D×CD3 bispecific antibody used 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.

[1141] Embodiment 185. The GPRC5D×CD3 bispecific antibody used according to any one of Embodiments 179 to 184, wherein the cancer is a hematological malignancy or a solid tumor.

[1142] Embodiment 186. The GPRC5D×CD3 bispecific antibody used 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.

[1143] Embodiment 187. The GPRC5D×CD3 bispecific antibody used according to Embodiment 186, wherein the multiple myeloma is high-risk multiple myeloma.

[1144] Embodiment 188. The GPRC5D×CD3 bispecific antibody used according to Embodiment 187, wherein the subject with the high-risk multiple myeloma has one or more chromosomal abnormalities, and the one or more chromosomal abnormalities include:

[1145] t(4;14)(p16;q32);

[1146] t(14;16)(q32;q23);

[1147] del17p;

[1148] 1qAmp;

[1149] t(4;14)(p16;q32) and t(14;16)(q32;q23);

[1150] t(4;14)(p16;q32) and del17p;

[1151] t(14;16)(q32;q23) and del17p; or

[1152] t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p or any combination thereof.

[1153] Embodiment 189. The GPRC5D×CD3 bispecific antibody used 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, elotuzumab, ixazomib, melphalan or thalidomide or any combination thereof.

[1154] Embodiment 190. The GPRC5D×CD3 bispecific antibody used according to any one of Embodiments 179 to 189, wherein the subject is relapsed or refractory to treatment with the anti-CD38 antibody.

[1155] Embodiment 191. The GPRC5D×CD3 bispecific antibody used 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.

[1156] Embodiment 192. The GPRC5D×CD3 bispecific antibody used according to any one of Embodiments 179 to 191, wherein the anti-CD38 antibody comprises VH of SEQ ID NO:4 and VL of SEQ ID NO:5.

[1157] Embodiment 193. The GPRC5D×CD3 bispecific antibody used according to any one of Embodiments 179 to 192, wherein the anti-CD38 antibody is of IgG1 isotype.

[1158] Embodiment 194. The GPRC5D×CD3 bispecific antibody used according to any one of Embodiments 179 to 193, wherein the anti-CD38 antibody comprises HC of SEQ ID NO:12 and LC of SEQ ID NO:13.

[1159] Embodiment 195. The GPRC5D×CD3 bispecific antibody used according to any one of Embodiments 179 to 190, wherein the anti-CD38 antibody comprises

[1160] VH of SEQ ID NO:14 and VL of SEQ ID NO:15;

[1161] VH of SEQ ID NO:16 and VL of SEQ ID NO:17;

[1162] VH of SEQ ID NO:18 and VL of SEQ ID NO:19; or

[1163] VH of SEQ ID NO:20 and VL of SEQ ID NO:21.

[1164] Embodiment 196. The GPRC5D×CD3 bispecific antibody used according to Embodiment 195, wherein the anti-CD38 antibody is of IgG1 isotype.

[1165] Embodiment 197. The GPRC5D×CD3 bispecific antibody used according to any one of Embodiments 179 to 196, wherein the subject is a human.

[1166] Embodiment 198. The GPRC5D×CD3 bispecific antibody used according to any one of Embodiments 179 to 197, further comprising administering to the subject one or more anti-cancer therapies.

[1167] Embodiment 199. The GPRC5D×CD3 bispecific antibody used according to Embodiment 198, wherein the one or more anti-cancer therapies are selected from autologous hematopoietic stem cell transplantation (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulators, and targeted cancer therapies.

[1168] Embodiment 200. The GPRC5D×CD3 bispecific antibody used according to Embodiment 198, wherein the one or more anti-cancer therapies are selected from lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, elotuzumab, ixazomib, melphalan, dexamethasone, vincristine, cyclophosphamide, daunorubicin, prednisone, rituximab, imatinib, dasatinib, nilotinib, bosutinib, ponatinib, bafetinib, seretinib, tozasertib or darusentan, cytarabine, daunomycin, 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.

[1169] Embodiment 201. 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, LCDR2 of SEQ ID NO:10 and LCDR3 of SEQ ID NO:11.

[1170] Embodiment 202. The drug combination according to Embodiment 201, wherein the GPRC5D-binding domain comprises VH of SEQ ID NO:49 and VL of SEQ ID NO:50, and the CD3-binding domain comprises VH of SEQ ID NO:39 and VL of SEQ ID NO:40, and the anti-CD38 antibody comprises VH of SEQ ID NO:4 and VL of SEQ ID NO:5.

[1171] Embodiment 203. The 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.

[1172] Embodiment 204. The drug combination according to any one of Embodiments 201 to 203, wherein the drug combination is a non-fixed combination.

[1173] Embodiment 205. The pharmaceutical combination according to Embodiment 204, comprising from 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); the pH is about 5.5.

[1174] 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.

[1175] Embodiment 207. The pharmaceutical composition according to Embodiment 206, comprising about 120 mg / mL of the anti-CD38 antibody and about 2,000 U / mL of rHuPH20.

[1176] Embodiment 208. The pharmaceutical combination according to Embodiment 207, further comprising one or more excipients.

[1177] 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.

[1178] Embodiment 210. The pharmaceutical combination according to Embodiment 209, wherein the pharmaceutical composition comprises

[1179] the anti-CD38 antibody between about 100 mg / mL and about 120 mg / mL;

[1180] histidine between about 5 mM and about 15 mM;

[1181] sorbitol between about 100 mM and about 300 mM;

[1182] PS-20 between about 0.01% w / v and about 0.04% w / v; and

[1183] methionine between about 1 mg / mL and about 2 mg / mL, with a pH of about 5.5 to 5.6.

[1184] Embodiment 211. The pharmaceutical combination according to Embodiment 209 or 210, comprising about 10 mM of histidine.

[1185] Embodiment 212. The pharmaceutical combination according to any one of Embodiments 209 to 211, comprising about 300 mM of sorbitol.

[1186] Embodiment 213. The pharmaceutical combination according to any one of Embodiments 209 to 212 comprises about 0.04% (w / v) of PS-20.

[1187] Embodiment 214. The pharmaceutical combination according to any one of Embodiments 209 to 213 comprises about 1 mg / mL of methionine.

[1188] Embodiment 215. The pharmaceutical combination according to any one of Embodiments 209 to 214 comprises

[1189] about 1,800 mg of the anti-CD38 antibody;

[1190] about 30,000 U of rHuPH20;

[1191] about 10 mM of histidine;

[1192] about 300 mM of sorbitol;

[1193] about 0.04% (w / v) of PS-20; and

[1194] about 1 mg / mL of methionine, with a pH of about 5.6.

[1195] Embodiment 216. The pharmaceutical combination according to any one of Embodiments 209 to 215 comprises

[1196] about 120 mg / mL of the anti-CD38 antibody;

[1197] about 2,000 U / mL of rHuPH20;

[1198] about 10 mM of histidine;

[1199] about 300 mM of sorbitol;

[1200] about 0.04% (w / v) of PS-20; and

[1201] about 1 mg / mL of methionine, with a pH of about 5.6.

[1202] Embodiment 217. A kit comprising the pharmaceutical combination according to any one of Embodiments 201 to 215.

[1203] Embodiment 218. A T cell redirection therapeutic agent that binds to CD19 for use in combination with an anti-CD38 antibody in the treatment of a subject with cancer.

[1204] Embodiment 219. An anti-CD38 antibody for enhancing the efficacy of a CD19-binding T cell redirecting therapeutic agent in a subject with cancer, wherein the subject has been treated with the anti-CD38 antibody prior to administration of the CD19-binding T cell redirecting therapeutic agent.

[1205] Embodiment 220. The T cell redirecting therapeutic agent or the anti-CD38 antibody used according to Embodiment 218 or 219, wherein the subject is recurrent or refractory to treatment with a prior anti-cancer therapeutic agent.

[1206] Embodiment 221. The T cell redirecting therapeutic agent or the anti-CD38 antibody used according to any one of Embodiments 218 to 221, wherein the cancer is a hematological malignancy or a solid tumor.

[1207] 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, Waldenström macroglobulinemia or T cell lymphoma.

[1208] 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.

[1209] Embodiment 224. The T cell redirecting therapeutic agent or the anti-CD38 antibody used 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.

[1210] Embodiment 225. The T cell redirecting therapeutic agent or the anti-CD38 antibody used according to any one of embodiments 218 to 224, wherein the CD19-binding T cell redirecting therapeutic agent comprises a CD19-binding domain of any of the following: 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.

[1211] Embodiment 226. The T cell redirecting therapeutic agent or the anti-CD38 antibody used according to any one of embodiments 218 to 225, wherein the CD19-binding T cell redirecting therapeutic agent 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.

[1212] Embodiment 227. The T cell redirecting therapeutic agent or the anti-CD38 antibody used according to any one of embodiments 218 to 226, wherein the CD19-binding T cell redirecting therapeutic agent is a multispecific antibody, a CAR, or a T cell expressing the CAR.

[1213] Embodiment 228. The T cell redirecting therapeutic agent or the anti-CD38 antibody used 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.

[1214] Embodiment 229. The T cell redirecting therapeutic agent or the anti-CD38 antibody used according to any one of embodiments 218 to 228, wherein the anti-CD38 antibody comprises VH of SEQ ID NO:4 and VL of SEQ ID NO:5.

[1215] Embodiment 230. The T cell redirecting therapeutic agent or the anti-CD38 antibody used according to any one of embodiments 218 to 229, wherein the anti-CD38 antibody is of IgG1 isotype.

[1216] Embodiment 231. The T cell redirecting therapeutic agent or the anti-CD38 antibody used according to any one of embodiments 218 to 230, wherein the anti-CD38 antibody comprises HC of SEQ ID NO:12 and LC of SEQ ID NO:13.

[1217] Embodiment 232. The T cell redirecting therapeutic agent or the anti-CD38 antibody used according to any one of embodiments 218 to 227, wherein the anti-CD38 antibody comprises

[1218] VH of SEQ ID NO:14 and VL of SEQ ID NO:15;

[1219] VH of SEQ ID NO:16 and VL of SEQ ID NO:17;

[1220] VH of SEQ ID NO:18 and VL of SEQ ID NO:19; or

[1221] VH of SEQ ID NO:20 and VL of SEQ ID NO:21.

[1222] Embodiment 233. The T cell redirecting therapeutic agent or the anti-CD38 antibody used according to embodiment 232, wherein the anti-CD38 antibody is of IgG1 isotype.

[1223] Embodiment 234. The T cell redirecting therapeutic agent or the anti-CD38 antibody used according to any one of Embodiments 218 to 233, wherein the anti-CD38 antibody is administered at a dose between about 8 mg / kg and about 16 mg / kg.

[1224] Embodiment 235. The T cell redirecting therapeutic agent or the anti-CD38 antibody used according to any one of Embodiments 218 to 234, wherein the CD19-binding T cell redirecting therapeutic agent and the anti-CD38 antibody are administered by intravenous injection.

[1225] Embodiment 236. The T cell redirecting therapeutic agent or the anti-CD38 antibody used according to any one of Embodiments 218 to 234, wherein the CD19-binding T cell redirecting therapeutic agent is administered by intravenous injection, and the anti-CD38 antibody is administered by subcutaneous injection.

[1226] Embodiment 237. The T cell redirecting therapeutic agent or the anti-CD38 antibody used according to any one of Embodiments 218 to 236, wherein the subject is a human.

[1227] Embodiment 238. The T cell redirecting therapeutic agent or the anti-CD38 antibody used according to any one of Embodiments 218 to 237, wherein the CD19-binding T cell redirecting therapeutic agent is a CD19×CD3 bispecific antibody.

[1228] Embodiment 239. The T cell redirecting therapeutic agent or the anti-CD38 antibody used according to any one of Embodiments 218 to 238, further comprising administering to the subject one or more anti-cancer therapies.

[1229] 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 hematopoietic stem cell transplantation (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulators, and targeted cancer therapies.

[1230] Embodiment 241. A pharmaceutical 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.

[1231] Embodiment 242. The drug combination according to Embodiment 241, wherein the anti-CD38 antibody comprises VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5.

[1232] Embodiment 243. The drug combination according to Embodiment 241 or 242, wherein the anti-CD38 antibody comprises HC of SEQ ID NO: 12 and LC of SEQ ID NO: 13.

[1233] Embodiment 244. The drug combination according to any one of Embodiments 241 to 243, wherein the drug combination is a non-fixed combination.

[1234] Embodiment 245. The drug combination according to any one of Embodiments 241 to 244, comprising the anti-CD38 antibody at about 20 mg / mL to about 120 mg / mL in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mannitol and about 0.04% w / v polysorbate-20 (PS-20); the pH is about 5.5.

[1235] Embodiment 246. The drug 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.

[1236] Embodiment 247. The drug combination according to Embodiment 246, comprising the anti-CD38 antibody at about 120 mg / mL and rHuPH20 at about 2,000 U / mL.

[1237] Embodiment 248. The drug combination according to Embodiment 246 or 257, further comprising one or more excipients.

[1238] Embodiment 249. The drug 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.

[1239] Embodiment 250. The drug combination according to any one of Embodiments 246 to 249, wherein the drug combination comprises

[1240] the anti-CD38 antibody between about 100 mg / mL and about 120 mg / mL;

[1241] histidine between about 5 mM and about 15 mM;

[1242] sorbitol between about 100 mM and about 300 mM;

[1243] PS-20 between about 0.01% w / v and about 0.04% w / v; and

[1244] methionine between about 1 mg / mL and about 2 mg / mL, at a pH of about 5.5 to 5.6.

[1245] Embodiment 251. The pharmaceutical combination according to any one of Embodiments 246 to 250, comprising about 10 mM of histidine.

[1246] Embodiment 252. The pharmaceutical combination according to any one of Embodiments 246 to 251, comprising about 300 mM of sorbitol.

[1247] Embodiment 253. The pharmaceutical combination according to any one of Embodiments 246 to 252, comprising about 0.04% (w / v) of PS-20.

[1248] Embodiment 254. The pharmaceutical combination according to any one of Embodiments 246 to 253, comprising about 1 mg / mL of methionine.

[1249] Embodiment 255. The pharmaceutical combination according to any one of Embodiments 246 to 254, comprising

[1250] about 1,800 mg of the anti-CD38 antibody;

[1251] about 30,000 U of rHuPH20;

[1252] about 10 mM of histidine;

[1253] about 300 mM of sorbitol;

[1254] about 0.04% (w / v) of PS-20; and

[1255] about 1 mg / mL of methionine, at a pH of about 5.6.

[1256] Embodiment 256. The pharmaceutical composition according to any one of Embodiments 246 to 255, comprising

[1257] about 120 mg / mL of the anti-CD38 antibody;

[1258] about 2,000 U / mL of rHuPH20;

[1259] about 10 mM of histidine;

[1260] about 300 mM of sorbitol;

[1261] about 0.04% (w / v) of PS-20; and

[1262] Methionine at approximately 1 mg / mL, pH of approximately 5.6.

[1263] Embodiment 257. A kit comprising the pharmaceutical composition according to any one of Embodiments 241 to 256.

[1264] Examples

[1265] The following examples are provided to further describe some of the embodiments disclosed herein. These examples are intended to illustrate and not limit the disclosed embodiments of the invention.

[1266] General materials and methods

[1267] Antibodies and reagents

[1268] The anti-BCMA / anti-CD3 antibody JNJ-957 (described in WO2017031104A1) and daratumumab were prepared by Janssen Pharmaceuticals. CNTO7008 (CD3×blank), BC3B4 (BCMA×blank), and 3930 (IgG isotype control) (all prepared by Janssen Pharmaceuticals) were used as control antibodies. JNJ-957 is also known as JNJ-7957.

[1269] JNJ-957 comprises a BCMA-binding arm BCMB69 and a CD3-binding arm CD3B219, the amino acid sequences of which are shown in Tables 3 and 4, respectively.

[1270] Table 3 :

[1271]

[1272] Table 4 .

[1273]

[1274] Bone marrow and peripheral blood mononuclear cells

[1275] Peripheral blood mononuclear cells (PBMCs) from healthy donors and MM patients and bone marrow mononuclear cells (BM-MNCs) from MM patient BM aspirates were isolated by Ficoll-Hypaque density gradient centrifugation.

[1276] Cell lines and cultures

[1277] Cultivate the luciferase (LUC)-transduced multiple myeloma cell lines UM9, RPMI8226, U266, and MM1.S, as well as the untransduced multiple myeloma cell lines NCI-H929 and RPMI8226 in RPMI 1640 (Invitrogen) supplemented with 10% fetal bovine serum (FBS; Lonza) and antibiotics (100 units / mL penicillin, 100 μg / ml streptomycin; both from Life Technologies).

[1278] Flow cytometry analysis of bone marrow and blood samples from MM patients

[1279] Identify and localize MM cells in BM, and analyze the expression levels of cell surface markers by staining 1.0×10 6 cells / mL with HuMax-003 (CD38) FITC (this antibody binds to an epitope different from the epitope 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). Identify BM or PB immune cell subsets, and analyze the expression levels of cell surface markers by staining 1.0×10 6 cells / mL 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). Analyze all BM samples within 24 hours from the time of sample collection.

[1280] 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 to verify the optical path and fluidics flow. This process achieved controlled and standardized results and allowed for the determination of long-term drift and incidental variations within the flow cytometer. No variations that could affect these results were observed. Spectral overlap was determined using compensation beads, and compensation was calculated automatically using Diva software. Flow cytometry data were analyzed using FACSDiva software.

[1281] Flow cytometry-based ex vivo lysis assay in BM-MNC

[1282] BM-MNCs from MM patients containing tumor cells and autologous effector cells were used for the lysis assay. Sample viability at incubation was over 98%, as evaluated by using 7-AAD (Becton Dickinson). For the lysis assay, BM-MNCs were incubated in RPMI + 10% fetal bovine serum with control antibody or JNJ-957 (0.0064 μg / mL to 4.0 μg / mL) and / or daratumumab (10 μg / mL) in a 96-well U-bottom plate for 48 hours. 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, viable MM cells were counted by single-platform flow cytometry analysis of CD138 + cells in the presence of Flow-Count Fluorospheres (Beckman Coulter) and LIVE / DEAD Fixable Dead Cell Stain Near-IR reactive dye (Invitrogen) 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 - (in the presence of JNJ-957, viable CD138 +Absolute number of cells / viable CD138 in untreated wells + Absolute number of cells) × 100%.

[1283] The activation and degranulation of JNJ-957-induced CD4 + and CD8 + T cells were analyzed by flow cytometry for cell surface expression of CD25 and CD107a, respectively.

[1284] Flow cytometry-based lysis assay in MM cell lines using PB MNC as effector cells .

[1285] The BCMA-positive MM cell line was co-cultured with PB MNCs from healthy donors or MM patients at an effector-to-target ratio of 9:1 in the presence of control antibody or JNJ-957 (0.00256 μg / mL to 4.0 μg / mL) in 96-well U-bottom plates for 48 hours. The viability of MM cells was determined by flow cytometry as described above.

[1286] Bioluminescence imaging (BLI)-based lysis assay using LUC-transduced MM cell lines

[1287] Transduced MM cell lines were cultured for 16 hours in the presence or absence of pooled BM stromal cells (BMSCs) obtained from newly diagnosed MM patients (n = 12), then incubated with effector cells (freshly isolated PBMCs from healthy donors) at an effector-to-target ratio of 9:1, and then JNJ-957 (0.00256 μg / mL to 4.0 μg / mL) or control antibody was serially diluted in 96-well flat-bottom plates (Greiner-Bio-One) for 48 hours. After adding the substrate luciferin (150 μg / mL; Promega) for 10 minutes, the viability of LUC + -MM cells was determined by BLI. The lysis of MM cells was determined using the following formula: Lysis % = 1 - (average BLI signal in the presence of effector cells and JNJ-957 / average BLI signal in untreated wells in the presence of effector cells) × 100%.

[1288] To evaluate the effect of in vivo pretreatment of PB MNCs with daratumumab monotherapy on the efficacy of JNJ-957, the 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 the best response to daratumumab monotherapy (effector-to-target ratio 9:1). BLI measurements were performed as described previously.

[1289] Cytogenetic analysis

[1290] Cytogenetic abnormalities in purified MM cells were evaluated by fluorescence in situ hybridization (FISH) and single nucleotide polymorphism (SNP) arrays. High-risk disease was defined by the presence of del(17p), del(1p), ampl(1q), t(4;14), or t(14;16). 2 The presence was defined as

[1291] Soluble BCMA assay

[1292] Soluble BCMA (sBCMA) was measured in cell culture supernatants using the MSD GOLD TM 96-well Small Spot Streptavidin SECTOR plate (Meso Scale Diagnostics) according to the manufacturer's recommended protocol.

[1293] Granzyme B assay

[1294] 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.

[1295] Multiplex cytokine assay

[1296] 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 the V-Plex Proinflammatory Panel 1 Human Kit (Meso Scale Diagnostics) according to the manufacturer's protocol.

[1297] Statistical analysis

[1298] In cases where the data did not follow a normal distribution, a two-tailed (paired) Student's t-test or Mann-Whitney U test or Wilcoxon paired signed-rank test was used to compare variables. The association between variables was described using the Spearman rank correlation coefficient. A P-value of less than 0.05 was considered significant. For the combination therapy of JNJ-957 and daratumumab, the expected lysis value was calculated using the following formula to test the null hypothesis of 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 described. If the observed value was significantly higher than the expected value (P < 0.05), the null hypothesis of "additive effect" was rejected.

[1299] Lysis of multiple myeloma cell lines mediated by anti-BCMA / anti-CD3 antibody JNJ-957 in Example 1 + accompanied by With T cell activation and degranulation

[1300] In the concentration range of JNJ-957 (0.00128 μg / mL to 4.0 μg / mL), healthy donor (HD) peripheral blood mononuclear cells were used as effector cells to evaluate the effect of JNJ-957 on mediating the lysis of RPMI8226 ( Figure 1 ), UM9 ( Figure 2 ), U226 ( Figure 3 ), and MM1.S ( Figure 4 ) multiple myeloma cell lines. JNJ-957 mediated the lysis of all tested cell lines in a dose-dependent manner and achieved almost 100% maximum efficacy at an antibody concentration of approximately 0.1 μg / ml, depending on the Figure 1 , Figure 2 , Figure 3 , and Figure 4 cell lines as seen in

[1301] 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 effect 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 against the MM cell lines RPMI-8226, UM9, and U266 (data not shown). Although at lower concentrations (P < 0.0001), BMSCs in MM1.S cells moderately inhibited JNJ-957-mediated MM cell lysis, this effect could be completely eliminated by increasing the dose of JNJ-7957.

[1302] T cell activation was evaluated in the RPMI 8226 cell line. Treatment with JNJ-957 led to the activation and degranulation of both CD4 + and CD8 + T cells in a dose-dependent manner, as confirmed by the increased cell surface expression of CD25 and CD107a or by the proportion of double-positive CD25 and CD107a cells, respectively. Figure 5 The increased percentage of JNJ-957-mediated CD25+CD4 T cells is shown. Figure 6 The increased percentage of JNJ-957-mediated CD107a+CD4 T cells is shown. Figure 7 The increased percentage of JNJ-957-mediated double-positive CD25+CD107+CD4 T cells is shown. Figure 8 The increased percentage of JNJ-957-mediated CD25+CD8 T cells is shown. Figure 9Shows an increase in the percentage of JNJ-957-mediated CD107a+ CD8 T cells. Figure 10 Shows an increase in the percentage of JNJ-957-mediated double-positive CD25+ CD107+ CD8 T cells.

[1303] Example 2 Daratumumab improves the efficacy of T cell redirected antibodies

[1304] Patients

[1305] The expression level of BCMA, the composition of immune cell subsets, and the ex vivo efficacy of JNJ-957 were evaluated in 55 BM aspirates obtained from 11 newly diagnosed MM patients, 21 relapsed / refractory MM patients naïve to daratumumab, and 17 relapsed / refractory MM patients refractory to daratumumab (relapsed / refractory daratumumab patients participated in phase 1 and 2 studies of daratumumab combined with 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 at the time of progressive disease before the initiation of daratumumab monotherapy and during daratumumab treatment. In the same study, we obtained results from serial peripheral blood samples of 10 patients before the initiation of daratumumab monotherapy and at the time of maximum response to daratumumab.

[1306] In the DARA / ATRA study (NCT02751255), patients with MM required systemic therapy and had relapsed from ≥2 lines of prior recurrent or refractory treatment. Patients were ≥18 years of age, had a life expectancy ≥3 months, a WHO performance status ≤2, and measurable disease.

[1307] During the first phase of the study, daratumumab was administered according to a recommended dose and schedule (16 mg / kg once weekly for 8 weeks, then once every 2 weeks for 16 weeks, and once every 4 weeks until PD). The protocol was approved by the study site ethics committee or institutional review board and was developed in accordance with the principles of the Declaration of Helsinki, International Conference on Harmonization, and Good Clinical Practice guidelines. All patients provided written informed consent.

[1308] Baseline characteristics of patients participating in phase 1 and 2 studies NCT02751255 are shown in Tables 5 and 6. RRMM patients had received a mean of 5 (range 1 to 9) prior therapies, and RRMM dara R patients had received a mean of 6 (range 3 to 12) prior therapies. Table 7 shows an updated summary of the baseline characteristics of patients participating in phase 1 and 2 studies.

[1309] Table 5.

[1310]

[1311] Table 6 .

[1312]

[1313] Table 7 .

[1314]

[1315]

[1316] *High-risk diseases are defined by the presence of del(17p), del(1p), ampl(1q), t(4;14), or t(14;16).

[1317] **According to the International Myeloma Working Group Uniform Response Criteria, refractory disease is defined as progressive disease during treatment, no response (< PR), or progressive disease within 60 days of discontinuation of treatment.

[1318] #BM aspirates were obtained immediately when progressive disease developed during daratumumab monotherapy (n = 15), and 2 BM samples were obtained at 22 months and 48 months after progression during daratumumab monotherapy, after 3 and 5 other treatments, respectively.

[1319] §In addition, 1 of 19 patients was lenalidomide-intolerant;

[1320] In addition, 4 of 17 patients were bortezomib-intolerant;

[1321] In addition, 3 of 16 patients were bortezomib-intolerant;

[1322] 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

[1323] Results

[1324] Daratumumab mediates efficient lysis of MM cells from newly diagnosed (NDMM) and relapsed / refractory patients not previously treated with daratumumab, while cells from daratumumab-refractory RRMM patients are resistant to lysis( Figure 11 ).

[1325] In samples from newly diagnosed (ND) MM patients (n = 8), the mean lysis rate of JNJ-957 on MM cells at 4.0 μg / mL was 79% (range: 66% to 92%; Figure 12 ). Samples from lenalidomide (LEN)-refractory patients (n = 15; mean lysis rate at 4.0 μg / mL: 69%; range: 24% to 98%; Figure 13 ) also achieved similar MM lysis, but with greater variability. These patient samples were also bortezomib-refractory patients (mean lysis rate of 73%), pomalidomide (82)%, and carfilzomib (9%). JNJ-957 was also effective in samples from daratumumab (DARA)-refractory MM patients (n = 11; mean lysis rate at 4.0 μg / mL: 83%; range: 52% to 99%; Figure 14 ). In none of the tested samples were NK- and T-cell frequencies affected.

[1326] When compared with JNJ-957, CD3×isotype control antibody and BCMA×isotype control antibody showed significantly lower activity in different patient samples, indicating the need for crosslinking of MM cells and effector T cells and the absence of direct effects of BCMA blockade.

[1327] Lysis of primary MM cells mediated by JNJ-957 was associated with a dose-dependent increase in the percentage of activated CD4 + and CD8 + T cells, as evaluated by the expression of the CD25 activation antigen. JNJ-957 treatment also resulted in CD4 + and CD8 + T-cell degranulation, as determined by the cell surface expression of CD107a. There were no differences in the degree of T-cell activation and degranulation among NDMM, RRMM patients not previously treated with daratumumab, and daratumumab-refractory RRMM patients. Figure 15 Shows the percentage increase in JNJ-957-mediated CD25+CD4 T cells. Figure 16 Shows the percentage increase in JNJ-957-mediated CD107a+CD4 T cells. Figure 17 Shows the percentage increase in JNJ-957-mediated double-positive CD25+CD107+CD4 T cells. Figure 18Shows an increase in the percentage of CD25+CD8 T cells mediated by JNJ-957. Figure 19 Shows an increase in the percentage of CD107a+CD8 T cells mediated by JNJ-957. Figure 20 Shows an increase in the percentage of double-positive CD25+CD107+CD8 T cells mediated by JNJ-957.

[1328] The levels of granzyme B and various cytokines in JNJ-957-treated BM-MNC supernatants from RRMM patients who had not received daratumumab treatment and daratumumab-refractory patients were also evaluated. JNJ-957-mediated T cell activation led to 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).

[1329] In all BM samples, the efficacy of JNJ-957 in mediating MM cell killing was neither associated with tumor characteristics (BCMA or PD-L1 expression, presence of standard or high-risk cytogenetic abnormalities) nor with patient characteristics (such as effector:target ratio, composition of the T cell system, or PD-1 / HLA-DR expression on T cells). However, when analyzing patient categories separately, the expression levels of BCMA ( Figure 21 ) and PD-L1 ( Figure 22 ) were significantly higher in RRMM patients compared to NDMM patients, regardless of daratumumab exposure. Although the number of patients was small, the activity of JNJ-957 was negatively correlated with the PD-L1 expression level in RRMM patients who had not received daratumumab treatment (p = 0.045).

[1330] The composition of immune cells in BM aspirates from NDMM, RRMM patients who had not received daratumumab treatment, and daratumumab RRMM samples was evaluated to gain insight into the differential effects of JNJ-957 in samples obtained from three patient subgroups. In the combined patient group, a high T cell frequency (p = 0.034) and a high E:T ratio (p = 0.029) were associated with enhanced JNJ-7957-mediated lysis of MM cells. Other immune parameters (number of T cells, Tregs, PD-1 + T cells, HLA-DR + T cells, or naive T cells) did not affect JNJ-7957-mediated lysis of MM cells.

[1331] In subgroup analysis, when compared to NDMM patients, the Tregs ( Figure 23 ) and activated T cells (defined by the expression of HLA-DR) ( Figure 24) had a significantly higher frequency and a lower frequency of naive T cells. Additionally, patient samples refractory to daratumumab contained significantly more TEMRA T cells than samples from patients who had not received daratumumab treatment ( Figure 25 ). However, in this subgroup analysis, the frequencies of activated, naive, central memory (CM), effector memory (EM), or TEMRA T cells were not associated with the response to JNJ-7957. A high baseline percentage of Tregs showed a negative impact on JNJ-957-mediated MM cell lysis in patient samples with RRMM, which could be overcome with the optimal dose. Lysis of JNJ-597-mediated NDMM mediated by autologous effector cells and dichotomized according to the baseline percentage of Tregs ( Figure 26 ), RRMM not treated with daratumumab ( Figure 27 ), and RRMM refractory to daratumumab ( Figure 28 ) patient samples were evaluated. The 50th percentile was used to classify samples as "low" or "high" based on Treg content: NDMM: low: ≤7.34%, high: >7.34%. RRMM not treated with daratumumab: low ≤15.57%, high >15.57%. RRMM refractory to daratumumab: low ≤11.24%, high >11.24%. Higher Treg concentrations inhibited MM cell lysis in JNJ-957-mediated samples of RRMM not treated with daratumumab and RRMM refractory to daratumumab. The Treg effect was abrogated at higher JNJ-957 concentrations.

[1332] The proportion of PD-1 + T cells and the E:T ratio were similar in the three patient groups. Only in patients with NDMM, a low frequency of T cells (P = 0.010) and a high frequency of PD-1 + T cells (P = 0.048) impaired JNJ-957-mediated lysis of MM cells (data not shown).

[1333] The effect of daratumumab treatment on the efficacy of JNJ-957 was evaluated by assessing JNJ-957-mediated lysis in BM samples from patients with NDMM (n = 9), RRMM not treated with daratumumab (n = 18), and RRMM 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. Figure 29 The percentage of lysis in the patient population is shown. Data are shown as mean ± SEM, and the P value was calculated using the Student's t test.

[1334] Due to the recently discovered immune-stimulatory effect of DARA, which may contribute to the improvement of tumor reduction, serial BM aspirates (n = 5) from MM patients were analyzed before and after DARA treatment. Here, we observed that compared to the samples before the start of DARA, BCMA expression was comparable in the samples obtained after disease progression during DARA, but there was an improvement in the lysis of MM cells by JNJ-957 (average lysis rate at 4.0 μg / mL: 93% vs. 74%; Figure 30 ). Among these BM aspirates, the percentage of Treg ( Figure 31 ) and CD4 + cells ( Figure 32 ) was slightly reduced, while the percentage of CD8+ cells ( Figure 33 ) increased in the samples from patients who had not received daratumumab treatment compared to those from patients exposed to daratumumab. In this study, the samples were obtained from patients with a median duration of daratumumab monotherapy of 3 (1 to 7) months. In a subsequent study of samples from 8 RRMM patients, the percentages of CD38 + Treg and Breg were significantly reduced in the samples from dara-refractory patients compared to those from patients who had not received daratumumab treatment (data not shown).

[1335] The lysis of the RPMI 8226 multiple myeloma cell line mediated by JNJ-957 was tested using serial PB MNC samples from RRMM patients before and during daratumumab treatment as effector cells. During daratumumab treatment, PB MNC 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 months to 14 months). Figure 34 Enhanced JNJ-957-mediated lysis of RPMI 8226 was shown using PB MNC from patients exposed to dara. Among PB-MNC samples, the percentage of Treg ( Figure 35 ) and CD4+ cells ( Figure 36 ) was slightly reduced, while the percentage of CD8+ cells ( Figure 37 ) increased in the samples from patients who had not received daratumumab treatment compared to those from patients exposed to daratumumab. In this study, the samples were obtained from patients with a median duration of daratumumab treatment of 3 (1 to 7) months.

[1336] The efficacy of the combination of JNJ-957 and daratumumab was also tested in killing MM cells obtained from patients with NDMM or RRMM who had not received dara treatment. Figure 38Shows the percentage of lysis of BM MNCs from newly diagnosed MM (NDMM) patients (n = 8) treated with JNJ-957 alone (0.032 μg / mL to 0.8 μg / mL) or in combination with 10 μg / mL of daratumumab for 48 hours. The lysis levels of JNJ-957 and daratumumab on the observed (obs) MM cells were compared with the expected (exp) lysis levels, where these lysis levels were calculated assuming that the combined effect was achieved through an additive effect as shown in the method. Black bars show the group mean ± SEM. Paired Student's t-test was used to calculate the P-value. Figure 39 Shows the percentage of lysis of BMMNCs in patients with RRNN who have not received dara treatment. Figure 40 Shows the percentage of lysis of BM MNCs in patients with RRMM refractory to daratumumab.

[1337] Therefore, the study shows that JNJ-957 is effective in samples of newly diagnosed and heavily pretreated MM patients. A high percentage of regulatory T cells negatively impacts the efficacy of JNJ-957 at low doses, however this negative impact is overcome by increasing the dose of JNJ-957. Pretreatment with daratumumab in vivo enhances the anti-MM cell efficacy of JNJ-957.

[1338] The combination of JNJ-957 and daratumumab shows additive efficacy ex vivo; furthermore, in vivo pretreatment with daratumumab enhances the ex vivo efficacy of BCMA×CD3.

[1339] Example 3 Daratumumab treatment enhances the ex vivo efficacy of blinatumomab

[1340] To evaluate whether daratumumab treatment is also beneficial for other T cell redirection therapies, paired daratumumab-naive and daratumumab-exposed PB-MNCs from 11 MM patients were used to treat CD19 with blinatumomab (FDA-approved CD19×CD3 BiTE for the treatment of acute lymphoblastic leukemia) + Raji cells. Similar to the observations made with JNJ-957, when compared with daratumumab-naive PB-MNCs, the activity of blinatumomab was significantly enhanced by co-incubation with daratumumab-exposed PB-MNCs (P < 0.0001; Figure 41 ). Blinatumomab contains the amino acid sequence of SEQ ID NO:53.

[1341] SEQ ID NO:53

[1342] DIQLTQSPASLAVSLGQRATISCKASQSVDYDGDSYLNWYQQIPGQPPKLLIYDASNLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAATYHCQQSTEDPWTFGGGTKLEIKGGGGSGGGGSGGGGSQVQLQQSGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIWPGDGDTNYNGKFKGKATLTADESSSTAYMQLSSLASEDSAVYFCARRETTTVGRYYYAMDYWGQGTTVTVSSGGGGSDIKLQQSGAELARPGASVKMSCKTSGYTFTRYTMHWVKQRPGQGLEWIGYINPSRGYTNYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYCLDYWGQGTTLTVSSVEGGSGGSGGSGGSGGVDDIQLTQSPAIMSASPGEKVTMTCRASSSVSYMNWYQQKSGTSPKRWIYDTSKVASGVPYRFSGSGSGTSYSLTISSMEAEDAATYYCQQWSSNPLTFGAGTKLELKHHHHHH

[1343] Example 4 JNJ-957 effectively kills primary pPCL cells

[1344] The ex vivo activity of JNJ-957 was evaluated in BM samples from 6 patients with newly diagnosed pPCL, which was characterized by positive clinical behavior. Tumor cell lysis in these pPCL samples mediated by JNJ-957 was similar to that observed in NDMM and RRMM samples not treated with daratumumab, but lower than that observed in samples from daratumumab-refractory RRMM patients (p = 0.0014)( Figure 42 ). Although the median E:T ratio in pPCL samples decreased by approximately 8-fold, when compared with NDMM, CD4 + (P = 0.0040) and CD8 + T cells (P < 0.0001) were both more activated, and the degree of CD8 + T cell degranulation (P = 0.0141) was better. CD4 + T cell degranulation was similar to that observed in NDMM.

[1345] 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 hours, after which viable CD138 + tumor cells, as well as T cells and NK cells, were counted. Data are presented as mean percent lysis of cells ± SEM. All experiments were performed in duplicate.

[1346] Example 5 Combination of GPRC5D×CD3 bispecific antibody and daratumumab

[1347] To further evaluate whether daratumumab treatment is also beneficial for other T cell redirection therapies, paired daratumumab-naïve and daratumumab-exposed PB-MNCs from 11 MM patients were used to treat RPMI MM cells with a GPRC5D×CD3 bispecific antibody (samples were obtained from the same patients as described in the above Examples). As a control, antibodies in which the CD3 or GPRC5D-binding VH / VL domains were replaced with blank domains that bind an irrelevant antigen (gp120) were used (control mAb 3930 blank×blank, control mAb 7008: blank×CD3, control mAb GPRC5D×blank). The antibodies were tested at concentrations from 0.00064 to 4.0 μg / ml. The GPRC5D×CD3 bispecific antibody mediated MM cell lysis in both daratumumab-naïve and daratumumab-refractory samples with similar potency ( Figure 43 ).

[1348] The efficacy of the combination of the GPRC5D×CD3 bispecific antibody and daratumumab was also tested in killing MM cells obtained from patients with NDMM or RRMM who had not received dara treatment. Figure 44 The percentage of BM MNC lysis of primary MM cells mediated by the GPRC5D×CD3 bispecific antibody (0.0128 μg / mL to 0.8 μg / mL) alone or in combination with 0.1 μg / mL of daratumumab is shown for 48 hours. The lysis levels of the GPRC5D×CD3 bispecific antibody and daratumumab on the observed (O) MM cells were compared with the expected (E) lysis levels, where these lysis levels were calculated assuming the combined effect was achieved by an additive effect as shown in the method. Black bars show group means ± SEM. Paired Student's t-tests were used to calculate P values. Co-incubation with daratumumab enhanced the MM cell lysis by the GPRC5D×CD3 bispecific antibody in an additive manner.

[1349] 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.

[1350] The GPRC5D×CD3 bispecific antibody used in the experiment is described in WO20180037651A1 and comprises the following sequences:

[1351] A GPRC5D-binding domain and a CD3-binding domain, the GPRC5D-binding domain comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:43, 44, 45, 446, 47, and 48 respectively, and the CD3-binding domain comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:33, 34, 35, 36, 37, and 38 respectively;

[1352] The GPRC5D-binding domain comprises VH of SEQ ID NO:49 and VL of SEQ ID NO:50, and the CD3-binding domain comprises VH of SEQ ID NO:39 and VL of SEQ ID NO:40; and

[1353] 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.

[1354] The anti-GPRC5D×CD3 bispecific antibody is of IgG4 isotype.

[1355] HC1 contains S228P, F234A, and L235A substitutions.

[1356] HC2 contains S228P, F234A, L235A, F405L, and R409K substitutions.

[1357] Table 8 .

[1358]

[1359]

[1360] Example 6 Combination of T cell redirected therapy and anti-CD38 antibody

[1361] The effect of combining additional T cell redirection therapy with an anti-CD38 antibody was evaluated as described in Examples 1 to 5. The additive or synergistic effect of this combination on mediating the killing of tumor cells targeted by T cell redirection therapy (i.e., tumor cells expressing the antigen bound by T cell redirection therapy) was tested. As described in the Examples, the effect of pre-treatment with an anti-CD38 antibody on the efficacy of T cell redirection therapy was evaluated.

[1362] The T cell redirection therapies tested in combination with the anti-CD38 antibody included PSMA×CD3, TMEFF2×CD3, CD123×CD3, and CD33×CD3 bispecific antibodies.

[1363] An exemplary PSMA×CD3 bispecific antibody is PS3B27, which comprises a PSMA binding domain PSMB127 and a CD3 binding domain CD3B219. Table 9 shows the amino acid sequence of PS3B27. The amino acid sequence of CD3B219 is shown in Table 4.

[1364] The exemplary PSMA×CD3 bispecific antibody used in the experiments comprised the following sequences:

[1365] A PSMA binding domain and a CD3 binding domain, the PSMA binding domain comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:54, 55, 56, 9, 10, and 59 respectively, and the CD3 binding domain comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:33, 34, 35, 36, 37, and 38 respectively;

[1366] The PSMA binding domain comprises VH of SEQ ID NO:60 and VL of SEQ ID NO:61, and the CD3 binding domain comprises VH of SEQ ID NO:39 and VL of SEQ ID NO:40; and

[1367] 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.

[1368] The anti-PSMA×CD3 bispecific antibody is of the IgG4 isotype.

[1369] HC1 comprises S228P, F234A, and L235A substitutions.

[1370] HC2 contains S228P, F234A, L235A, F405L and R409K substitutions.

[1371] Table 9 .

[1372]

[1373]

[1374] An exemplary TMEFF2×CD3 bispecific antibody is TMCB150, which contains 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.

[1375] The exemplary TMEFF2×CD3 bispecific antibody used in the experiment is TMCB150 and contains the following sequences:

[1376] A TMEFF2 binding domain and a CD3 binding domain, the TMEFF2 binding domain contains HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NO:64, 65, 66, 67, 68 and 69 respectively, and the CD3 binding domain contains HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NO:74, 75, 76, 77, 78 and 79 respectively;

[1377] The TMEFF2 binding domain contains VH of SEQ ID NO:70 and VL of SEQ ID NO:71, and the CD3 binding domain contains VH of SEQ ID NO:80 and VL of SEQ ID NO:81; and

[1378] The first heavy chain (HC1) of SEQ ID NO:72, the first light chain (LC1) of SEQ ID NO:73, the second heavy chain (HC2) of SEQ ID NO:82 and the second light chain (LC2) of SEQ ID NO:83.

[1379] The anti-TMEFF2×CD3 bispecific antibody is of IgG4 isotype.

[1380] HC1 contains S228P, F234A and L235A substitutions.

[1381] HC2 contains S228P, F234A, L235A, F405L and R409K substitutions.

[1382] Table 10 .

[1383]

[1384] Table 11 .

[1385]

[1386] An exemplary CD33×CD3 bispecific antibody is C3CB189, which comprises a CD33 binding arm C33B904 and a CD3 binding arm CD3B376. Table 12 shows the amino acid sequence of C33B904. The amino acid sequence of CD3B376 is shown in Table 11.

[1387] The exemplary CD33×CD3 bispecific antibody used in the experiment is C3CB189 and comprises the following sequences:

[1388] A CD33 binding domain and a CD3 binding domain, wherein the CD33 binding domain comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NO:84, 85, 86, 87, 88 and 89 respectively, and the CD3 binding domain comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NO:74, 75, 76, 77, 78 and 79 respectively;

[1389] The CD33 binding domain comprises VH of SEQ ID NO:90 and VL of SEQ ID NO:91, and the CD3 binding domain comprises VH of SEQ ID NO:80 and VL of SEQ ID NO:81; and

[1390] The first heavy chain (HC1) of SEQ ID NO:92, the first light chain (LC1) of SEQ ID NO:93, the second heavy chain (HC2) of SEQ ID NO:82 and the second light chain (LC2) of SEQ ID NO:83.

[1391] The anti-CD33×CD3 bispecific antibody is of IgG4 isotype.

[1392] HC1 contains S228P, F234A and L235A substitutions.

[1393] HC2 contains S228P, F234A, L235A, F405L and R409K substitutions.

[1394] Table 12 .

[1395]

[1396]

[1397] An exemplary CD123×CD3 bispecific antibody is 8747, which comprises 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.

[1398] The exemplary CD123×CD3 bispecific antibody used in the experiment is 8747 and comprises the following sequences:

[1399] A CD123-binding domain and a CD3-binding domain, the CD123-binding domain comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NO:94, 95, 96, 9, 10 and 59 respectively, and the CD3-binding domain comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of SEQ ID NO:33, 34, 35, 36, 37 and 38 respectively;

[1400] The CD123-binding domain comprises VH of SEQ ID NO:100 and VL of SEQ ID NO:61, and the CD3-binding domain comprises VH of SEQ ID NO:39 and VL of SEQ ID NO:40; and

[1401] The first heavy chain (HC1) of SEQ ID NO:102, the first light chain (LC1) of SEQ ID NO:63, the second heavy chain (HC2) of SEQ ID NO:41 and the second light chain (LC2) of SEQ ID NO:42.

[1402] The anti-CD123×CD3 bispecific antibody is of IgG4 isotype.

[1403] HC1 contains S228P, F234A and L235A substitutions.

[1404] HC2 contains S228P, F234A, L235A, F405L and R409K substitutions.

[1405] Table 13 .

[1406]

[1407] To evaluate the effect of pretreatment with anti-CD38 antibody on the efficacy of tumor killing by T cell redirected therapeutics, tumor cells were isolated from subjects having an antigen (such as CD123, CD33, PSMA, TMEFF2, etc.) to which the T cell redirected therapeutic binds or using established tumor cell lines. As described in the examples, the killing of tumor cells was evaluated ex vivo by co-incubating the tumor cells with PB-MNC obtained from subjects exposed to anti-CD38 antibody or subjects not treated with anti-CD38 antibody, and the percentage of tumor cell lysis in each group was evaluated. In separate examples, the T cell redirected therapeutic and anti-CD38 antibody were incubated with target cells and effector cells together or alone, and tumor cell killing mediated by the combination therapeutic relative to the individual therapeutics was evaluated.

[1408] 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 antibody on CD123×CD3 bispecific antibody-mediated tumor cell killing.

[1409] 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 evaluate the effect of anti-CD38 antibody on CD33×CD3 bispecific antibody-mediated tumor cell killing.

[1410] TMEFF2-positive tumor cells (such as LnCP cells) were used as target cells to evaluate the effect of anti-CD38 antibody on TMEFF2×CD3 bispecific antibody-mediated tumor cell killing.

[1411] TMEFF2-positive tumor cells (such as LnCP cells) were used as target cells to evaluate the effect of anti-CD38 antibody on PSMA×CD3 bispecific antibody-mediated tumor cell killing.

[1412] PBMC or BM-MNC isolated from subjects who had received anti-CD38 antibody or subjects not treated with anti-CD38 antibody were used as effector cells.

[1413] Those skilled in the art will recognize that many changes and modifications can be made to the preferred embodiments of the invention, and such changes and modifications can be made without departing from the essence of the invention. Accordingly, the appended claims are intended to cover all such equivalent variations that fall within the true spirit and scope of the invention.

[1414] The disclosure of each patent, patent application, and patent publication cited or described in this document is hereby incorporated by reference in its entirety.

Claims

1. Use of an anti-CD38 antibody and a T cell redirecting therapeutic agent in the preparation of a medicament for treating cancer in a subject.

2. Use of an anti-CD38 antibody in the preparation of a medicament for enhancing the efficacy of a T cell redirecting therapeutic agent in a subject with cancer.

3. The use according to claim 1 or 2, wherein the anti-CD38 antibody is administered before the T cell redirecting therapeutic agent.

4. The use according to claim 1 or 2, wherein the T cell redirecting therapeutic agent binds to GPRC5D, BCMA, CD33, CD123, CD19, PSMA, TMEFF2 or CD20.

5. The use according to claim 1 or 2, 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.

6. The use according to claim 5, wherein the T cell redirecting therapeutic agent comprises a CD3 binding domain, and the CD3 binding domain comprises a) 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; b) heavy chain variable region (VH) of SEQ ID NO:39 and light chain variable region (VL) of SEQ ID NO:40; c) 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; d) VH of SEQ ID NO:80 and VL of SEQ ID NO:81; e) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 of the CD3 binding domain of SEQ ID NO:53; or f) VH and VL of the CD3 binding domain of SEQ ID NO:

53.

7. The use according to claim 5, wherein the T cell redirecting therapeutic agent comprises a) A GPRC5D-binding domain and a CD3-binding domain, wherein 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, 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; and / or b) A GPRC5D-binding domain and a CD3-binding domain, wherein the GPRC5D-binding domain comprises VH of SEQ ID NO:49 and VL of SEQ ID NO:50, and the CD3-binding domain comprises VH of SEQ ID NO:39 and VL of SEQ ID NO:

40.

8. The use according to claim 7, wherein the T cell redirection therapeutic agent 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.

9. The use according to claim 5, wherein the T cell redirection therapeutic agent comprises a) A BCMA-binding domain and a CD3-binding domain, wherein the BCMA-binding domain comprises 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; and / or b) A BCMA-binding domain and a CD3-binding domain, wherein the BCMA-binding domain comprises VH of SEQ ID NO:29 and VL of SEQ ID NO:30, and the CD3-binding domain comprises VH of SEQ ID NO:39 and VL of SEQ ID NO:

40.

10. The use according to claim 9, 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.

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