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

Abstract

To provide a method of treating cancers such as hematologic malignancy and multiple myeloma, which have shown relapse or refractory to treatment with prior anti-cancer therapeutics.SOLUTION: The present invention provides a method for administering a therapeutically effective amount of a BCMA×CD3 bispecific antibody to a subject. The BCMA×CD3 bispecific antibody is an IgG4 isotype and comprises phenylalanine at a position 405 and arginine at a position 409 in the HC1 and leucine at a position 405 and lysine at a position 409 in the HC2, wherein residue numbering is according to an EU Index.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Methods for treating cancer and for improving the efficacy of T cell redirecting therapeutics are disclosed. do. [Background technology]

[0002] Redirected killing of T cells is a desirable mode of action in many therapeutic areas. In this study, T cell redirecting molecules bind to surface antigens on target cells at one site and target antigens at the other site. The antibody is engineered to have at least two antigen-binding sites, each of which binds to a T cell surface antigen. Among the T cell surface antigens, the human CD3 epsilon subunit of the TCR protein complex These are the most targeted antibodies to redirect T cell killing. Antibody formats mediate T cell redirection in both preclinical and clinical studies has been shown (May C et al., Biochem Pharmacol, 8 4:1105-12,2012, Frankel S R&Baeuerle PA, Curr Opin Chem Biol,17(3):385-92,2013).

[0003] Tumors create an immunosuppressive tumor microenvironment (TME). In the TME, under conditions of persistent antigen and inflammation, T cells are depleted or become dysfunctional, progressively losing their effector functions and proliferative capacity. Loss of function of available T cells involved in therapeutic-mediated T cell redirection killing. The capacity and number of these molecules may impair the anti-tumor efficacy of the therapeutic agent. Summary of the Invention [Problem to be solved by the invention]

[0004] Therefore, for optimal efficacy of therapeutics that mediate T cell redirected killing, T cell There is a need to improve cell functionality. [Means for solving the problem]

[0005] The present disclosure provides a method of treating cancer in a subject, comprising administering to a subject a therapeutically effective amount of an anti-CD38 antibody. and administering a T cell redirecting therapeutic to a subject to treat cancer. do.

[0006] The present disclosure also provides a method of killing tumor cells in a subject, comprising administering to the subject an anti-CD38 antibody. The body and T cells bind to antigens on tumor cells long enough to kill the tumor cells. Also provided are methods that include administering a cell-redirecting therapeutic agent.

[0007] The present disclosure provides a method for improving the efficacy of T cell redirecting therapeutics in subjects with cancer. The present invention provides a method for treating a rheumatoid arthritis, the method comprising administering to a subject an anti-CD38 antibody.

[0008] The present disclosure also provides a method of treating cancer in a subject, comprising administering a therapeutically effective amount of BCMAx administering a CD3 bispecific antibody and an anti-CD38 antibody to a subject to treat cancer. A method is provided.

[0009] The present disclosure also provides a method of treating cancer in a subject, comprising administering a therapeutically effective amount of BCMAx administering a CD3 bispecific antibody to a subject to treat cancer, wherein the subject is Also provided are methods wherein the subject is treated with an anti-CD38 antibody prior to administration of the CD3 bispecific antibody.

[0010] The present disclosure also provides a method of treating cancer in a subject, comprising administering a therapeutically effective amount of BCMAx administering a CD3 bispecific antibody to a subject to treat cancer, wherein the subject has previously undergone anti-cancer therapy. Also provided are methods in which the cancer is relapsed or refractory to treatment with a therapeutic agent.

[0011] The present disclosure also provides a method of treating multiple myeloma in a subject, comprising administering a therapeutically effective amount of BCMA×CD3 bispecific antibody and anti-CD38 antibody were administered to subjects to treat multiple myeloma. Also provided are methods, including treating

[0012] The present disclosure also provides a method of treating multiple myeloma in a subject, comprising administering a therapeutically effective amount of administering a BCMAxCD3 bispecific antibody to a subject to treat multiple myeloma. and the subject has been treated with an anti-CD38 antibody prior to administration of the BCMAxCD3 bispecific antibody. , a method is also provided.

[0013] The present disclosure also provides a method of treating multiple myeloma in a subject, comprising administering a therapeutically effective amount of administering a BCMAxCD3 bispecific antibody to a subject to treat multiple myeloma. and wherein the subject is relapsed or refractory to prior treatment with a multiple myeloma therapeutic agent. provide.

[0014] The present disclosure also provides a BCMA-binding domain comprising a VH of SEQ ID NO: 29 and a VL of SEQ ID NO: 30. and a CD3 binding domain comprising a VH of SEQ ID NO: 39 and a VL of SEQ ID NO: 40. BCMAxCD3 bispecific antibody and anti-C antibody comprising VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5 Also provided are pharmaceutical compositions comprising the D38 antibody.

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

[0016] The present disclosure also provides a method of treating cancer in a subject, comprising administering a therapeutically effective amount of GPRC5 administering a DxCD3 bispecific antibody to a subject to treat cancer, wherein the subject has previously Also provided are methods for treating cancer that is relapsed or refractory to treatment with an anti-cancer therapeutic agent.

[0017] The present disclosure also provides HCDR1 of SEQ ID NO: 43, HCDR2 of SEQ ID NO: 44, HCDR3 of SEQ ID NO: 45 HCDR3 of SEQ ID NO: 46, LCDR1 of SEQ ID NO: 47, and LCDR2 of SEQ ID NO: 4 GPRC5D binding domain containing LCDR3 of SEQ ID NO: 8, and HCDR1 of SEQ ID NO: 33, HCDR2 of sequence number 34, HCDR3 of sequence number 35, LCDR1 of sequence number 36, a CD3 binding domain comprising LCDR2 of SEQ ID NO: 37 and LCDR3 of SEQ ID NO: 38 GPRC5D×CD3 bispecific antibody and HCDR1 of SEQ ID NO: 6, HCDR of SEQ ID NO: 7 R2, HCDR3 of SEQ ID NO: 8, LCDR1 of SEQ ID NO: 9, LCDR2 of SEQ ID NO: 10, and an anti-CD38 antibody comprising an LCDR3 of SEQ ID NO: 11. do.

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

[0019] The present disclosure also provides a method for redirecting T cells that bind to CD19 in a subject with cancer. a method for improving the efficacy of a T cell-redirecting therapeutic agent that binds to CD19, comprising administering the agent to a subject; Also provided are methods comprising administering an anti-CD38 antibody to the subject prior to administering the drug.

[0020] The present disclosure also provides a CD19xCD3 bispecific antibody, including blinatumomab of SEQ ID NO: 53. 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 Also provided are pharmaceutical combinations comprising an anti-CD38 antibody.

[0021] The present disclosure also provides kits comprising the pharmaceutical compositions of the present disclosure. [Brief explanation of the drawings]

[0022] [Figure 1] Figure 1 shows JNJ-957-mediated lysis of the multiple myeloma (MM) cell line RPMI8226. Peripheral blood mononuclear cells (PB MNC) from a healthy donor were used as effector cells. [Figure 2] Figure 1 shows JNJ-957-mediated lysis of the multiple myeloma (MM) cell line UM9. Peripheral blood mononuclear cells (PB MNC) from a healthy donor were used as effector cells. [Figure 3] Figure 1 shows JNJ-957-mediated lysis of the multiple myeloma (MM) cell line U226. Peripheral blood mononuclear cells (PB MNC) from a healthy donor were used as effector cells. [Figure 4] Figure 1 shows JNJ-957-mediated lysis of the multiple myeloma (MM) cell line MM1. Peripheral blood mononuclear cells (PB MNC) from a healthy donor were used as effector cells. [Figure 5]Representative examples (n=2) of RPMI8226 cells incubated with PB MNCs from healthy donors show that JNJ-957-mediated MM cell lysis is accompanied by CD4+ T cell activation and degranulation as determined by increased surface expression of CD25 (activation). [Figure 6] Representative examples (n=2) of RPMI8226 cells incubated with PB MNCs from healthy donors show that JNJ-957-mediated MM cell lysis is accompanied by CD4+ T cell activation and degranulation as determined by increased surface expression of CD107a (degranulation). [Figure 7] Representative examples (n=2) of RPMI8226 cells incubated with PB MNCs from healthy donors show that JNJ-957-mediated MM cell lysis is accompanied by CD4+ T cell activation and degranulation as determined by the percentage of CD25 and CD107a double-positive CD4+ T cells. [Figure 8] Representative examples (n=2) of RPMI8226 cells incubated with PB MNCs from healthy donors show that JNJ-957-mediated MM cell lysis is accompanied by CD8+ T cell activation and degranulation as determined by increased surface expression (activation) of CD25. [Figure 9] Representative examples (n=2) of RPMI8226 cells incubated with PB MNCs from healthy donors show that JNJ-957-mediated MM cell lysis is accompanied by CD8+ T cell activation and degranulation as determined by increased surface expression of CD107a (degranulation). [Figure 10] Representative examples (n=2) of RPMI8226 cells incubated with PB MNCs from healthy donors show that JNJ-957-mediated MM cell lysis is accompanied by CD8+ T cell activation and degranulation as determined by an increased percentage of CD25 and CD107a double-positive CD4+ T cells. [Figure 11]In vitro daratumumab-mediated lysis of MM cells from patients with newly diagnosed multiple myeloma (NDMM) and daratumumab-naive relapsed / refractory MM (RRMM). Multiple myeloma cells from patients with daratumumab-refractory RRMM were resistant to daratumumab-mediated lysis.*** *P<0.0001 [Figure 12] Dose-response analysis of JNJ-957-mediated lysis of plasma cells, T cells, and NK cells in fully autologous bone marrow (BM) MNCs obtained from newly diagnosed multiple myeloma patients (NDMM, n=8). Percent lysis was measured at various antibody concentrations (0.0064–4.0 μg / mL) as indicated. Circles (top line): plasma cells; squares (middle line): T cells; triangles (bottom line): NK cells. [Figure 13] Dose-response diagram of JNJ-957-mediated lysis of plasma, T cells, and NK cells in fully autologous bone marrow (BM) MNCs obtained from multiple myeloma (MM) patients (n=15) refractory to lenalidomide treatment. Percent lysis was measured at various antibody concentrations (0.0064-4.0 μg / mL) as indicated. Circles (top line): plasma cells; squares (middle line): T cells; triangles (bottom line): NK cells. [Figure 14] Dose-response diagram of JNJ-957-mediated lysis of plasma, T cells, and NK cells in fully autologous bone marrow (BM) MNCs obtained from MM patients (n=11) refractory to treatment with lenalidomide and daratumumab. Percent lysis was measured at various antibody concentrations (0.0064–4.0 μg / mL) as indicated. Circles (top line): plasma cells; squares (middle line): T cells; triangles (bottom line): NK cells. [Figure 15]JNJ-957-mediated MM cell lysis is accompanied by activation of CD4+ T cells (assessed by increased CD25 surface expression) in BM samples from patients with NDMM, daratumumab-naive RRMM (RRMM), and daratumumab-refractory RRMM (RRMM). 3930: isotype control, BC3B4: BCMA x null bispecific antibody, 7008: null x CD3 bispecific antibody. [Figure 16] JNJ-957-mediated MM cell lysis is accompanied by CD4+ T cell degranulation (as assessed by increased CD107a surface expression) in BM samples from NDMM, daratumumab-naive RRMM (RRMM), and daratumumab-refractory RRMM (RRMM-DaraR) patients. 3930: isotype control, BC3B4: BCMA x null bispecific antibody, 7008: null x CD3 bispecific antibody. [Figure 17] Double-positive CD25+CD107a+ cells as a percentage of CD4+ T cells in BM samples from NDMM, daratumumab-naive RRMM (RRMM), and daratumumab-refractory RRMM (RRMM-DaraR) patients treated with JNJ-957 at the indicated concentrations. 3930: isotype control, BC3B4: BCMA x null bispecific antibody, 7008: null x CD3 bispecific antibody. Double-positive: CD25 and CD107a double-positive CD4+ T cells. [Figure 18] Figure 1 shows that JNJ-957-mediated MM cell lysis is accompanied by activation of CD8+ T cells (as assessed by increased CD25 surface expression) in BM samples from NDMM, daratumumab-naive RRMM (RRMM), and daratumumab-refractory RRMM (RRMM-DaraR) patients. 3930: isotype control, BC3B4: BCMA x null bispecific antibody, 7008: null x CD3 bispecific antibody. [Figure 19]Figure 3 shows that JNJ-957-mediated MM cell lysis is accompanied by degranulation of CD8+ T cells (as assessed by increased CD107a surface expression) in BM samples from NDMM, daratumumab-naive RRMM (RRMM), and daratumumab-refractory RRMM (RRMM-DaraR) patients. 3930: isotype control, BC3B4: BCMA x null bispecific antibody, 7008: null x CD3 bispecific antibody. [Figure 20] Double-positive CD25+CD107a+ cells as a percentage of CD8+ T cells in BM samples from NDMM, daratumumab-naive RRMM (RRMM), and daratumumab-refractory RRMM (RRMM-DaraR) patients treated with JNJ-957 at the indicated concentrations. 3930: isotype control, BC3B4: BCMA x null bispecific antibody, 7008: null x CD3 bispecific antibody. Double-positive: CD25 and CD107a double-positive CD8+ T cells. [Figure 21] BCMA expression levels on MM cells (mean MFI ± SEM) in NDMM, daratumumab-naive RRMM, and daratumumab-refractory RRMM subjects are shown. P values ​​between the indicated groups were calculated using the Mann-Whitney U test. *P<0.05, ns: not significant. [Figure 22] PD-L1 expression levels on MM cells (mean MFI ± SEM) in NDMM, daratumumab-naive RRMM, and daratumumab-refractory RRMM subjects are shown. P values ​​between the indicated groups were calculated using the Mann-Whitney U test. *P<0.05, ns: not significant. [Figure 23] Baseline percentages of Tregs in BM MNCs from NDMM, daratumumab-naive RRMM, and daratumumab-refractory RRMM are shown. **p<0.01, ns: not significant. [Figure 24] Baseline percentages of activated T cells (as assessed by HLA-DR positivity) in BM MNC of NDMM, daratumumab-naive RRMM, and daratumumab-refractory RRMM are shown. **p<0.01, ns: not significant. [Figure 25]Baseline proportions of various T cell subsets in BM MNC from NDMM, daratumumab-naive RRMM, and daratumumab-refractory RRMM are shown. *p<0.05, **p<0.01, Ns: not significant. TEMRA: CD45RA+CCR7- T cells, EM: effector memory, CM: central memory, N: naive T cells. [Figure 26] Figure 1 shows JNJ-957-mediated lysis of multiple myeloma cells from NDMM patients mediated by autologous BM MNCs. Samples were dichotomized for baseline Treg frequency (low < 50th percentile, high > 50th percentile). Ns: not significant. [Figure 27] Figure 1 shows JNJ-957-mediated lysis of multiple myeloma cells from daratumumab-naive RRMM patients mediated by autologous BM MNCs. Samples were dichotomized by baseline Treg frequency (low ≤ 50th percentile, high > 50th percentile). *p<0.05, **p<0.01, Ns: not significant. [Figure 28] Figure 1 shows JNJ-957-mediated lysis of multiple myeloma cells from a patient with daratumumab-refractory RRMM mediated by autologous BM MNC. Samples were dichotomized by baseline Treg frequency (low ≦50th percentile, high >50th percentile). *p<0.05, ns: not significant. [Figure 29] Figure 1 shows JNJ-957-mediated lysis of MM cells from BM samples of patients with NDMM (n=9), daratumumab-naive RRMM (n=18), and daratumumab-refractory RRMM (n=13) after 48 hours of incubation. Data are presented as mean ± SEM, and P values ​​were calculated using Student's t-test. **P<0.01. [Figure 30]Figure 1 shows that JNJ-957-mediated lysis of MM cells in bone marrow (BM) samples obtained from patients with relapsed / refractory multiple myeloma (RRMM) (n=8) was increased in samples from patients who received daratumumab ("Dara-exposed") compared with samples from the same patients before the start of daratumumab treatment ("Dara-naive"). Data are presented as mean ± SEM. P values ​​were calculated using a paired t-test. ns: not significant. *P<0.05, **P<0.01. [Figure 31] Percentage of Tregs in sequential BM aspirates of RRMM patients before initiation of daratumumab (pre-Dara) and at the time of onset of daratumumab-refractory disease (Dara-exposed) are shown. ns: no significant difference. [Figure 32] Percentage of CD4+ cells in sequential BM aspirates of RRMM patients before initiation of daratumumab (pre-Dara) and at the time of onset of daratumumab-refractory disease (Dara-exposed) are shown. ns: no significant difference. [Figure 33] Percentage of CD8+ T cells in sequential BM aspirates of RRMM patients before initiation of daratumumab (pre-Dara) and at the time of onset of daratumumab-refractory disease (Dara-exposed) are shown. [Figure 34] Using patient-derived PB MNCs as effector cells, JNJ-957-mediated lysis of RPMI8226 multiple myeloma cells was augmented by PB MNCs from patients receiving daratumumab ("PBMNC dara-naive") compared with samples from the same patients before the start of daratumumab treatment ("PBMNC dara-naive") (n=5). Data are presented as mean ± SEM. P values ​​were calculated using a paired t-test. ns: not significant. *P<0.05. [Figure 35] The percentage of Tregs in PB-MNC samples from daratumumab-naive (pre-Dara) and daratumumab-refractory (daratumumab) RRMM patients is shown. [Figure 36] The percentage of CD4+ T cells in PB-MNC samples from daratumumab-naive (pre-Daratumumab) and daratumumab-refractory (daratumumab) RRMM patients is shown. ns: no significant difference. [Figure 37]The percentage of CD8+ T cells in PB-MNC samples from daratumumab-naive (pre-Daratumumab) and daratumumab-refractory (daratumumab) RRMM patients is shown. ns: no significant difference. [Figure 38] This figure 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 (0.032-0.8 μg / mL) alone or in combination with 10 μg / mL daratumumab for 48 hours. The observed (Obs) levels of MM cell lysis by JNJ-957 and daratumumab were compared with the expected (Exp) levels, calculated assuming a combinatorial effect achieved by additive effects as described in the methods. Black bars indicate group means ± SEM. P values ​​were calculated using a paired Student's t-test. ns: not significant. [Figure 39] This figure shows that the addition of daratumumab enhanced JNJ-957-mediated MM cell lysis. BM MNCs from daratumumab-naive RRMM (n=17) patients were treated with JNJ-957 (0.032-0.8 μg / mL) alone or in combination with 10 μg / mL daratumumab for 48 hours. Observed (Obs) lysis levels of MM cells by JNJ-957 and daratumumab were compared with expected (Exp) lysis levels, which were calculated assuming a combinatorial effect achieved by additive effects as described in the methods. Black bars indicate group means ± SEM. P values ​​were calculated using a paired Student's t-test. ns: not significant. [Figure 40]Figure 1 shows that the addition of daratumumab enhanced JNJ-957-mediated MM cell lysis. BM MNCs from daratumumab-refractory RRMM (n=14) patients were treated with JNJ-957 (0.032-0.8 μg / mL) alone or in combination with 10 μg / mL daratumumab for 48 hours. Observed (O) levels of MM cell lysis by JNJ-957 and daratumumab were compared to expected (E) levels, calculated assuming a combinatorial effect achieved by additive effects as described in Methods. Black bars represent group means ± SEM. P values ​​were calculated using a paired Student's t-test. JNJ-957 is referred to as JNJ-7957 in the figures. Dara: daratumumab. ns: not significant. [Figure 41] Figure 1 shows blinatumomab-mediated lysis of the Raji cell line using sequential PB samples from 11 RRMM patients as effector cells (10:1 E:T). These were obtained directly before the initiation of daratumumab treatment (black, bottom line) and during daratumumab treatment (gray, top line). The median duration of treatment was 7 months (range 2-14 months). After incubating Raji cells with blinatumomab (0.01-10 μg / mL) in the presence of these PB-MNCs for 48 hours, a blinatumomoab-based cytotoxicity assay was performed. Data represent the mean ± SEM, and experiments were performed in duplicate. Statistical significance (P values) between the indicated groups was calculated using nonlinear regression analysis. [Figure 42] Dose response of JNJ-957-mediated lysis of plasma, T cells, and NK cells from BM-MNC cells obtained from six patients with primary plasma leukemia (pPCL). Percent lysis was measured at various antibody concentrations (0.0064-4.0 μg / mL) as indicated. Top line: plasma cells; bottom line: overlapping lines for T cells and NK cells. JNJ-957 is referred to as JNJ-7957 in the figures. [Figure 43]Anti-GPRC5D × CD3 antibody-mediated lysis of MM cell lines is shown using sequential PB samples from 11 RRMM patients as effector cells (E:T ratio of 10:1), obtained directly before (bottom line) and during (top line) daratumumab treatment. The median duration of treatment was 7 months (range 2-14 months). After incubating Raji cells with blinatumomab (0.01-10 μg / mL) in the presence of these PB-MNCs for 48 hours, a blinatumomab-based cytotoxicity assay was performed. Data represent the mean ± SEM, and experiments were performed in duplicate. [Figure 44] This figure shows that the addition of daratumumab was additive to anti-GPRC5D x CD3 bispecific antibody (JNJ-7564)-mediated MM cell lysis. BM MNCs from daratumumab-naive RRMM patients (n=17) were treated for 48 hours with anti-GPRC5D x CD3 bispecific antibody (0.00128-0.8 μg / mL) alone or in combination with 0.1 μg / mL daratumumab. The observed (O) levels of MM cell lysis by anti-GPRC5D x CD3 bispecific antibody and daratumumab were compared to the expected (E) levels of lysis, calculated assuming a combinatorial effect achieved by additive effects as described in the methods. Black bars indicate group means ± SEM. P values ​​were calculated using a paired Student's t-test. ns: not significant. Dara: daratumumab. DETAILED DESCRIPTION OF THE INVENTION

[0023] The disclosed method is described in detail below in conjunction with the accompanying drawings, which form a part of this disclosure. The disclosed method can be more readily understood by reference to the detailed description. It is not intended to be limited to the specific methods described and / or illustrated herein, and the use of The terms used herein are for the purpose of describing particular embodiments by way of example only and are not intended to be limiting unless otherwise specified in the claims. It should be understood that the present invention is not intended to be limited to the methods of any of the patents cited herein. , published patent applications and publications are incorporated herein by reference as if in their entireties. It is incorporated in the same way as the

[0024] As used herein, the singular forms "a," "an," and "the" include plural forms. Let's say.

[0025] Throughout this specification and claims, various terms are used to refer to aspects of this specification. Unless otherwise specified, such terms shall be given their ordinary meaning in the art. Other specifically defined terms are provided herein. shall be construed in a manner consistent with the definition.

[0026] "About," when used in reference to a numerical range, cutoff, or specific value, is intended to be an indication of a range of values ​​that would be readily apparent to one of ordinary skill in the art. This means that the value is within the allowable error range for the particular value determined by the The magnitude of the error depends in part on how the value of is measured or determined, i.e., on the limitations of the measurement system. In the context of an assay, result, or embodiment, the invention may be differently described in the examples or elsewhere in the specification. Unless expressly stated, "about" means within one standard deviation or 5% according to the practice in the art. This means that the value is within the range of either the range of

[0027] "Antibody" is intended in a broad sense and includes murine, human, humanized, and chimeric monoclonal antibodies. monoclonal antibodies, antigen-binding fragments, bispecific, trispecific, tetraspecific, etc. Multispecific antibodies, dimeric, tetrameric or multimeric antibodies, single chain antibodies, antibody domains and any other modification of the immunoglobulin molecule to contain an antigen-binding site of the required specificity. "Full-length antibodies" include immunoglobulin molecules containing disulfide bond-bound structures. Two heavy chains (HC) and two light chains (LCH) are interconnected Each heavy chain consists of a heavy chain variable region (he LC), and a multimer thereof (e.g., IgM). heavy chain variable region (VH), and heavy chain constant region (domain CH1, hinge, Each light chain is composed of a light chain variable region (CH2, CH3). It consists of a light chain constant region (CL) and a variable region (VL). The VH and VL regions are interspersed with framework regions (FR). The hypervariable regions are called complementarity determining regions (CDRs). Each VH and VL can be further divided into regions, from the amino terminus to the carboxy terminus: Arranged in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4 Immunoglobulins are composed of three CDR and four FR segments, each of which is placed in a different position. Depending on the amino acid sequence of the chain constant domain, there are five major classes: IgA, IgD IgA and IgG can be assigned to the isotypes IgE, IgG, and IgM. These are further subdivided as IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. The antibody light chains of any vertebrate species are identified based on the amino acid sequence of their constant domains. , into one of two distinct types: kappa (κ) and lambda (λ) can be assigned.

[0028] An "antigen-binding fragment" or "antigen-binding domain" refers to a portion of an immunoglobulin molecule that binds to an antigen. An antigen-binding fragment refers to a portion of a polypeptide, such as a synthetic polypeptide, an enzymatically obtainable polypeptide, or a polypeptide that is a target of the invention. It may be a recombinant or genetically engineered polypeptide, and may comprise VH, VL, VH and VL, Fab, F(ab')2, Fd and Fv fragments, one VH domain or one VL domain Domain antibodies (dAbs) consisting of shark variable IgNAR domains , camelized VH domains, FR3-CDR3-FR4 regions, and other fragments that mimic the CDRs of antibodies. The minimum recognition unit, HCDR1, HCDR2, and / or HCDR VH and VL include LCDR1, LCDR2, and / or LCDR3. The domains are linked to each other via synthetic linkers to form various types of single-chain antibody designs. and where the VH and VL domains are expressed by separate single chain antibody constructs. In this case, VH / VL domains pair intramolecularly or intermolecularly to form a monovalent antigen-binding site, e.g., For example, it can form a single chain Fv (scFv) or a diabody. These are described, for example, in WO 1998 / 44001, WO 1988 / 01649, It is described in patent applications 1994 / 13804 and 1992 / 01047.

[0029] "BCMA" refers to CD269 or TNFRSF17 (UniProt Q02223) BCMA is a human B-cell maturation antigen (B-cell maturation antigen). The extracellular domain of BCMA is Q0222 3. Human BCMA comprises the amino acid sequence of SEQ ID NO:2.

[0030] SEQ ID NO: 2 MLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPLTCQR YCNASVTNSVKGTNAILWTCLGLSLIISLAVFVLMFLLRK INSEPLKDEFKNTGSGLLGMANIDLEKSRTGDEIILPRGL EYTVEECTCEDCIKSKPKVDSDHCFPLPAMEEGATILVTT KTNDYCKSLPAALSATEIEKSISAR

[0031] "Bispecific" refers to a molecule that is specific for two different antigens or two different epitopes on the same antigen. Bispecific antibodies refer to antibodies that bind to different antigens. Bispecific antibodies can bind to different antigens, e.g., human or monkey, For example, Macaca cynomolgus (cynomolgus monkey, cyno) or Pan cross-reactive with the same antigen in other species (homologues), such as troglodytes Alternatively, it may bind to an epitope shared between two or more different antigens.

[0032] "Cancer" refers to a wide range of diseases characterized by the uncontrolled growth of abnormal cells in the body. Uncontrolled cell division and growth can lead to malignant tumors that invade adjacent tissues. and may metastasize to distant parts of the body via the lymphatic system or bloodstream. "Cancerous tissue" may include tumors.

[0033] "CD123" refers to a human interleukin (IL-1) having the amino acid sequence shown in SEQ ID NO:57. It refers to the extracellular domain of the CD12 receptor subunit alpha (IR3RA). 3 spans residues 19-305 of SEQ ID NO:57.

[0034] CD123 (SEQ ID NO: 57) MVLLWLTLLLLIALPCLLQTKEDPNPPITNLRMKAKAQQL TWDLNRNVTDIECVKDADYSMPAVNNSYCQFGAISLCEVT NYTVRVANPPFSTWILFPENSGKPWAGAENLTCWIHDVDF LSCSWAVGPGAPADVQYDLYLNVANRRQQYECLHYKTDAQ GTRIGCRFDDISRLSSGSQSSHILVRGRSAAFGIPCTDKF VVFSQIEILTPPNMTAKKCNKTHSFMHWKMRSHFNRKFRYE LQIQKRMQPVITEQVRDRTSFQLLNPGTYTVQIRARERVY EFLSAWSTPQRFECDQEEGANTRAWRTSLLIALGTLLALV CVFVICRRYLVMQRLFPRIPHMKDPIGDSFQNDKLVVWEA GKAGLEECLVTEVQVVQKT

[0035] "CD19" refers to the human B lymphocyte antigen CD19 having the amino acid sequence of SEQ ID NO: 58. The extracellular domain of CD19 spans residues 20 to 291 of SEQ ID NO:58.

[0036] CD19 (SEQ ID NO: 58) MPPPRLFFLLFLTPMEVRPEEPLVVKVEEGDNAVLQCL KGTSDGPTQQLTWSRESPLKP FLKLSLGLPGLGIHMRPLAIWLFIFNVSQQMGGFYLCQP GPPSEKAWQPGWTVNVEGSGE LFRWNVSDLGGLGCGLKNRSSEGPSSPSGKLMSPKLYVW AKDRPEIWEGEPPCLPPRDSL NQSLSQDLTMAPGSTLWLSCGVPPDSVSRGPLSWTHVHP KGPKSLLSLELKDDRPARDMW VMETGLLLPRATAQDAGKYYCHRGNLTMSFHLEITARPV LWHWLLRTGGWKVSAVTLAYL IFCLCSLVGILHLQRALVLRRKRKRMTDPTRRFFKVTPP PGSGPQNQYGNVLSLPTPTSG LGRAQRWAAGLGGTAPSYGNPSSDVQADGALGSRSPPGV GPEEEEGEGYEEPDSEEDSEF YENDSNLGQDQLSQDGSGYENPEDEPLGPEDEDSFSNAE SYENEDEELTQPVARTMDFLS PHGSAWDPSREATSLGSQSYEDMRGILYAAPQLRSIRGQ PGPNHEEDADSYENMDNPDGP DPAWGGGGRMGTWSTR

[0037] CD3 is a part of the multi-molecular T cell receptor (TCR) complex It is expressed on T cells and has two or four receptor chains: CD3 epsilon, CD3 delta, and CD It consists of homodimers or heterodimers formed from the association of CD3 zeta and CD3 gamma. Refers to a human antigen. Human CD3 epsilon comprises the amino acid sequence of SEQ ID NO: 3. SEQ ID NO: 22 indicates the extracellular domain of CD3 epsilon.

[0038] SEQ ID NO: 3 MQSGTHWRVLGLCLLSVGVWGQDGNEEMGGITQTPYKVS ISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDE DHLSLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVC ENCMEMDVMSVATIVIVDICITGGLLLLVYYWSKNRKAKA KPVTRGAGAGGRQRGQNKERPPPVPNPDYEPIRKGQRDLY SGLNQRRI

[0039] SEQ ID NO: 22 DGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQH NDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPR GSKPEDANFYLYLRARVCENCMEMD

[0040] "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 to 259 of SEQ ID NO:97.

[0041] CD33 (SEQ ID NO: 97) MPLLLLLPLLWAGALAMDPNFWLQVQESVTVQEGLCVLV PCTFFHPIPYYDKNSPVHGYWFREGAIISRDSPVATNKLD QEVQEETQGRFRLLGDPSRNNCSLSIVDARRRDNGSYFFR MERGSTKYSYKSPQLSVHVTDLTHRPKILIPGTLEPGHSK NLTCSVSWACEQGTPPIFSWLSAAPTSLGPRTTHSSVLII TPRPQDHGTNLTCQVKFAGAGVTTERTIQLNVTYVPQNPT TGIFPGDGSGKQETRAGVVHGAIGGAGVTALLALCLCLIF FIVKTHRRKAARTAVGRNDTHPTTGSASPKHQKKSKLHGP TETSSCSGAAPTVEMDEELHYASLNFHGNMNPSKDTSTEYS EVRTQ

[0042] "CD38" refers to the human CD38 protein (UniProt accession number P28907) ( Synonyms: ADP-ribosyl cyclase 1, cADPr hydrolase 1, cyclic ADP-ribo Human CD38 has the amino acid sequence shown in SEQ ID NO: 1. In CD38, amino acid residues 1 to 21 represent the cytoplasmic domain, and amino acid residues 22 to Single pass, where 42 represents the transmembrane domain and residues 43–300 represent the extracellular domain. It is a type II transmembrane protein.

[0043] SEQ ID NO: 1 MANCEFSPVSGDKPCCRLSRRAQLCLGVSILVLILVVVL AVVVPRWRQQWSGPGTTKRFPETVLARCVKYTEIHPEMRH VDCQSVWDAFKGAFISKHPCNITEEDYQPLMKLGTQTVPC NKILLWSRIKDLAHQFTQVQRDMFTLEDTLLGYLADDLTW CGEFNTSKINYQSCPDWRKDCSNNPVSVFWKTVSRRFAEA ACDVVHVMLNGSRSKIFDKNSTFGSVEVHNLQPEKVQTLE AWVIHGGREDSRDLCQDPTIKELESIISKRNIQFSCKNIY RPDKFLQCVKNPEDSSCTSEI

[0044] "CH3 region" or "CH3 domain" refers to the CH3 region of an immunoglobulin. The CH3 region of an IgG1 antibody corresponds to amino acid residues 341 to 446. The CH3 region may also be of any of the other antibody isotypes described herein.

[0045] "Chimeric antigen receptors" or "CARs" are molecules that transfer ligand or antigen specificity onto T cells. engineered T cell receptors (e.g., naive T cells, central memory T cells, effector T cells) CAR also refers to an artificial T cell receptor (ARTR), a T cell receptor, ... CARs are also known as chimeric T cell receptors, chimeric immune receptors, or chimeric immune receptors. a cell capable of binding to the protease, a transmembrane domain, and at least one intracellular domain; The CAR intracellular domain activates or inhibits biological processes within the cell. Polypeptides known to function as domains that transmit signals that cause harm The transmembrane domain is known to span the cell membrane, and the extracellular domain and Any peptide or polypeptide that can function to bind a signaling domain. The chimeric antigen receptor may optionally contain a linker between the extracellular domain and the transmembrane domain. It may also contain a hinge domain that functions as a

[0046] "Combination" refers to two or more therapeutic agents, either together in a mixture or as a single agent. It means that the compounds are administered to a subject either concurrently or sequentially in any order as single agents.

[0047] A "complementarity determining region (CDR)" is the region of an antibody that binds to an antigen. bat(Wu et al. J Exp Med132:211-50,1970)(K abat et al., Sequences of Proteins of Imm unological interest,5th Ed.Public Health Service,National Institutes of Health,B ethesda, Md., 1991), Chothia (Chothia et al. J Mol Biol 196:901-17,1987), IMGT (Lefranc et al. Dev Comp Immunol 27:55-77, 2003), and AbM(Martin and Thornton J Bmol Biol263:8 It can be defined using various descriptions such as (00-15, 1996). The correspondence between the numbering of the variable regions and the numbering of the nucleotide sequences is depicted (e.g., Lefranc et al. l.Dev Comp Immunol27:55-77,2003;Honegger and Pluckthun, J Mol Biol309:657-70,2001 ;International ImMunoGeneTics (IMGT) database (Web source, see http: / / www_imgt_org) UCL Using available programs such as abYsis by Business PLC As used herein, "CDR", "HCDR1" and "CDR2" can be used to delineate CDRs. ", "HCDR2", "HCDR3", "LCDR1", "LCDR2", and "LCD Unless otherwise expressly stated herein, the term "R3" refers to the compound of the formula (I) of Kabat, C, supra. It contains CDRs defined by any of the methods of Hothia, IMGT, or AbM.

[0048] The term "comprising" is used interchangeably with the terms "consisting essentially of" and "consisting of." Similarly, the use of "consisting essentially of" is intended to include examples encompassed by the term. The term is intended to include examples encompassed by the term "consisting of." Unless otherwise required, the word "comprises" will be used throughout the specification and claims. "include," "comprising," and the like mean inclusive, as opposed to exclusive or exclusive. be interpreted in a general sense, i.e., "including but not limited to" It should be.

[0049] "Improve" or "improved" means the improvement of one or more of the activity of a test molecule compared to a control molecule. may show an improvement in two or more functions or a significant improvement in the function of the test molecule compared to one or more control molecules. This refers to the improvement of one or more functions of a combination of components. These include tumor cell killing, T cell activation, relative or absolute T cell numbers, and Fc-mediated effector activity. target function (e.g., ADCC, CDC, and / or ADCP), or Fcγ receptor ( "Improved" refers to binding to FcγR or FcRn by about 10%, 20%, 30%, or 40%. 0%, 40%, 50%, 60%, 70%, 80%, 90%, 100% or more The improvement can be a statistically significant improvement.

[0050] "Fc gamma receptors" (FcγR) are the well-known FcγRI, FcγRIIa, FcγR Activating FcγR refers to FcγRI, FcγRIIa, FcγRIIb, or FcγRIII. and FcγRIII.

[0051] "GPRC5D" is a human G protein having the amino acid sequence shown in SEQ ID NO:98. It refers to the binding receptor family C group 5 member D.

[0052] GPRC5D (SEQ ID NO: 98) MYKDCIESTGDYFLLCDAEGPWGIILESLAILGIVVTIL LLLAFLFLMRKIQDCSQWNVL PTQLLFLLSVLGLFGLAFAFIIELNQQTAPVRYFLFGVL FALCFSCLLAHASNLVKLVRG CVSFSWTTILCIAIGCSLLQIIIATEYVTLIMTRGMMFV NMTPCQLNVDFVVLLVYVLFL MALTFFVSKATFCGPCENWKQHGRLIFITVLFSIIIWVV WISMLLRGNPQFQRQPQWDDP VVCIALVTNAWVFLLLYIVPELCILYRSCRQECPLQGNA CPVTAYQHSFQVENQELSRAR DSDGAEEDVALTSYGTPIQPQTVDPTQECFIPQAKLSPQ QDAGGV

[0053] A "human antibody" is an antibody that is optimized to provoke a minimal immune response when administered to a human subject. Human antibodies refer to antibodies whose variable regions are derived from human immunoglobulin sequences. If the antibody contains a constant region or a portion of a constant region, the constant region may also be derived from a human immunoglobulin. Human antibodies are antibodies in which the variable regions of the human antibody are derived from human germline immunoglobulin or Sequences of human origin when obtained from systems using rearranged immunoglobulin genes are Exemplary of such systems include heavy and light chain variable regions derived from A human immunoglobulin gene library displayed on phage and a human immunoglobulin gene library This includes transgenic non-human animals such as mice or rats that carry the gene locus. , typically differences in the systems used to obtain human antibodies and human immunoglobulin loci , introduction of somatic mutations or substitutions into the framework or CDRs or both The deliberate introduction of amino acids results in amino acid differences when compared to human-expressed immunoglobulins. Typically, a "human antibody" is a human antibody derived from human germline immunoglobulins or rearranged or modified human antibodies. The amino acid sequence is compared to the amino acid sequence encoded by the immunoglobulin gene. Columns are at least approximately 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical. In some cases, a "human antibody" is a human antibody, e.g., K et al. (2000) J Mol Biol 296:57-86 a consensus framework sequence derived from analysis of human framework sequences, For example, Shi et al. (2010) J Mol Biol 397:385-9 6 and WO 2009 / 085462, The antibody may contain a synthetic HCDR3 engineered into an immunoglobulin gene library. Antibodies in which at least one CDR is derived from a non-human species are not included in the definition of a "human antibody." stomach.

[0054] A "humanized antibody" is an antibody in which at least one CDR is derived from a non-human species and at least one FDR is derived from a non-human species. Humanized antibodies refer to antibodies whose framework is derived from human immunoglobulin sequences. The framework can contain substitutions, so that the framework is or may not be an exact copy of a human immunoglobulin germline gene sequence.

[0055] "Isolated" means that the molecule is actually separated from other components of the system in which it is produced, such as a recombinant cell. A homogeneous population of molecules (e.g., synthetic polynucleotides) that have been qualitatively separated and / or purified. and a protein such as a peptide or antibody) that has been subjected to at least one purification or isolation step. An "isolated antibody" refers to a protein that is substantially free of other cellular material and / or chemicals. This means that the antibody has a higher purity, e.g., 80%, 81%, 82%, 83%, 84%, 8 5%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 9 Includes antibodies isolated to 5%, 96%, 97%, 98%, 99%, or 100% purity do.

[0056] A "monoclonal antibody" is a substantially homogeneous population of antibody molecules (i.e., The individual antibodies to be produced may be modified in a variety of ways, including known modifications such as removal of the C-terminal lysine from the antibody heavy chain. or amino acid isomerization or deamidation, methionine oxidation, or asparagine or glutamic acid oxidation. It refers to antibodies obtained from a human antibody that is identical to the human antibody except for post-translational modifications such as glutamate deamidation. Monoclonal antibodies typically bind to one antigenic epitope. A monoclonal antibody binds to two different antigenic epitopes. Monoclonal antibodies are monospecific and may have heterogeneous glycosylation within a population. or may be multispecific, such as bispecific, and may be monovalent, bivalent, or multivalent. That's fine.

[0057] A "mutation" is a change in a polypeptide or polynucleotide sequence compared to a reference sequence. A modification refers to an engineered or naturally occurring modification of one or more amino acids or polynucleotides. The amino acid sequence may be a substitution, insertion or deletion of a base.

[0058] "Non-fixed combination" refers to the individual pharmaceuticals of the T cell redirecting therapeutic agent and the anti-CD38 antibody. The compositions may be combined as separate entities simultaneously, concurrently, or sequentially without any specific intervening time limit. Such administration results in effective levels of the two compounds in the subject's body. to provide.

[0059] "Multispecific" refers to an antibody that specifically binds to at least two different antigens, or A multispecific antibody refers to an antibody that binds to at least two different epitopes within a single molecule. For example, two, three, four, or five different antigens, or different epitopes within the same antigen. It can bind to the peptide.

[0060] A "pharmaceutical composition" refers to a composition comprising an active ingredient and a pharmaceutically acceptable carrier.

[0061] A "pharmaceutically acceptable carrier" or "excipient" is any substance other than an active ingredient that is not toxic to a subject. refers to the ingredients in the pharmaceutical composition.

[0062] The "Philadelphia chromosome" or "Ph" is a constitutively active tyrosine kinase The well-known mutation between chromosomes 9 and 22 results in the oncogenic BCR-ABL gene fusion, which is This refers to a chromosomal translocation, in which part of the BCR gene on chromosome 22q11 is transferred to another chromosome. It is fused to a portion of the ABL gene on 9q34, which is defined as the International System of Human Cytogenetic Nomenclature (International ... Under the International System for Human Cytogenetic Nomenclature (ISCN), t(9;2 2) (q34;q11). Depending on the exact location of the fusion, the resulting fusion The molecular weight of the protein can range from 185 to 210 kDa. "Chromosomes" are all BCR-ABL chromosomes formed by the (9;22)(q34;q11) translocation. Refers to a fusion protein.

[0063] "PSMA" refers to human prostate-specific membrane antigen, which has the amino acid sequence of SEQ ID NO: 99 The extracellular domain spans residues 44 to 750 of SEQ ID NO:99.

[0064] PSMA (SEQ ID NO: 99) MWNLLHETDSAVATARRPRWLCAGALVLAGGFFLLGFLF GWFIKSSNEATNITPKHNMKAFLDELKAENIKKFLYNFTQ IPHLAGTEQNFQLAKQIQSQWKEFGLDSVELAHYDVLLSY PNKTHPNYISIINEDGNEIFNTSLFEPPPPGYENVSDIVP PFSAFSPQGMPEGDLVYVNYARTEDFFKLERDMKINCSGK IVIARYGKVFRGNKVKNAQLAGAKGVILYSDPADYFAPGV KSYPDGWNLPGGGVQRGNILNLNGAGDPLTPGYPANEYAY RRGIAEAVGLPSIPVHPIGYYDAQKLLEKMGGSAPPDSSW RGSLKVPYNVGPGFTGNFSTQKVKMHIHSTNEVTRIYNVI GTLRGAVEPDRYVILGGHRDSWVFGGIDPQSGAAVVHEIV RSFGTLKKEGWRPRRTILFASWDAEEFGLLGSTEWAEENS RLLQERGVAYINADSSIEGNYTLRVDCTPLMYSLVHNLTK ELKSPDEGFEGKSLYESWTKKSPSPEFSGMPRISKLGSGN DFEVFFQRLGIASGRARYTKNWETNKFSGYPLYHSVYETY ELVEKFYDPMFKYHLTVAQVRGGMVFELANSIVLPFDCRD YAVVLRKYADKIYSISMKHPQEMKTYSVSFDSLFSAVKNF TEIASKFSERLQDFDKSNPIVLRMMNDQLMFLERAFIDPL GLPDRPFYRHVIYAPSSHNKYAGESFPGIYDALFDIESKV DPSKAWGEVKRQIYVAAFTVQAAAETLSEVA

[0065] "Recombinant" refers to the joining of segments from different sources to form recombinant DNA, antibodies, or When producing a protein, it is prepared, expressed, produced, or isolated by recombinant means. Refers to DNA, antibodies, and other proteins.

[0066] "Reduce" or "reduced" refers to the reduction or increase in one or more of a test molecule compared to a control molecule. A reduction in two or more functions of a test molecule when compared to one or more control molecules. The term refers to a reduction in one or more of the following functions: , tumor cell killing, T cell activation, relative or absolute T cell numbers, Fc-mediated effectors -function (e.g., ADCC, CDC, and / or ADCP), or Fcγ receptor (F "Reduced" refers to binding to FcRn by about 10%, 20%, 30%, or , 40%, 50%, 60%, 70%, 80%, 90%, 100% or lower It can be a statistically significant decrease or improvement.

[0067] "rHuPh20" refers to the recombinant hyaluronan described in WO 2004 / 078140. Amino acid sequence of SEQ ID NO: 105, Ionidase (HYLENEX® Recombinant) It refers to a recombinant human hyalurodinase having the sequence

[0068] rHuPH20 (SEQ ID NO: 105) MGVLKFKHIFFRSFVKSSGVSQIVFTFLLIPCCLTLNFR APPVIPNVPFLWAWNAPSEFCLGKFDEPLDMSLFSFIGSP RINATGQGVTIFYVDRLGYYPYIDSITGVTVNGGIPQKIS LQDHLDKAKKDITFYMPVDNLGMAVIDWEEWRPTWARNWK PKDVYKNRSIELVQQQNVQLSLTEATEKAKQEFEKAGKDF LVETIKLGKLLRPNHLWGYYLFPDCYNHHYKKPGYNGSCF NVEIKRNDDLSWLWNESTALYPSIYLNTQQSPVAATLYVR NRVREAIRVSKIPDAKSPLPVFAYTRIVFTDQVLKFLSQD ELVYTFGETVALGASGIVIWGTLSIMRSMKSCLLLDNYME TILNPYIINVTLAAKMCSQVLCQEQGVCIRKNWNSSDYLH LNPDNFAIQLEKGGKFTVRGKPTLEDLEQFSEKFYCSCYS TLSCKEKADVKDTDAVDVCIADGVCIDAFLKPPMETEEPQ IFYNASPSTLSATMFIVSILFLIISSVASL

[0069] "Refractory" refers to disease that is not modifiable to surgical intervention and does not initially respond to therapy. It refers to a type of cancer.

[0070] "Recurrent" refers to cancer that responds to treatment but then recurs.

[0071] A "subject" includes any human or non-human animal. A "non-human animal" includes, for example, a non-human Mammals such as primates, sheep, dogs, cats, horses, cows, chickens, amphibians, and reptiles Except as otherwise stated, the term "patient" refers to all vertebrates, including mammals and non-mammals. The terms "subject" and "subject" are used interchangeably.

[0072] "T cell redirecting therapeutic" refers to a molecule that contains two or more binding domains. One of the binding domains binds to a cell surface antigen (such as a tumor-associated antigen) on a target cell or tissue. The second binding domain of the molecule specifically binds to a T cell antigen (such as CD3). This dual / multiple target binding ability allows T cells to be recruited to target cells or tissues, leads to the eradication of the organization.

[0073] "TMEFF2" contains EGF-like and two folate statin-like domains 2 (also known as Tomoregly). The amino acid sequence of the full-length human TMEFF2 is The extracellular domain of TMEFF2 is shown in SEQ ID NO: 101. The extracellular domain of TMEFF2 is shown in SEQ ID NO: 101. The total number is 374.

[0074] TMEFF2 (SEQ ID NO: 101) MVLWESPRQCSSWTLCEGFCWLLLLPVMLLIVARPKLA AFPTSLSDCQTPTGWNCSGYDDRENDLFLCDTNTCKFDGE CLRIGDTVTCVCQFKCNNDYVPVCGSNGESYQNECYLRQA ACKQQSEILVVSEGSCATDAGSGSGDGVHEGSGETSQKET STCDICQFGAECDEDAEDVWCVCNIDCSQTNFNPLCASDG KSYDNACQIKEASCQKQEKIEVMSLGRCQDNTTTTTKSED GHYARTDYAENANKLEESAREHHIPCPEHYNGFCMHKCE HSINMQEPSCRCDAGYTGQHCEKKDYSVLYVVPGPVRFQY VLIAAVIGTIQIAVICVVVLCITRKPRSNRIHRQKQNTG HYSSDNTTRASTRLI

[0075] A "therapeutically effective amount" is an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result. The therapeutically effective amount will depend on factors such as the individual's condition, age, sex, and weight, as well as the individual's The ability of a single therapeutic agent or combination of therapeutic agents to elicit a desired response in Exemplary indicators of an effective therapeutic agent or combination of therapeutic agents include: For example, improved patient health.

[0076] "Treating" or "treatment" refers to both therapeutic treatment and prophylactic or preventative measures. The purpose of the present invention is to prevent or delay (alleviate) undesirable physiological changes or disorders. A beneficial or desired clinical outcome may be detectable or undetectable. Whether it is a symptomatic relief, a reduction in the extent of the disease, or a stable (i.e., not worsening) state of the disease, the state of the disease, delay or slowing of disease progression, improvement or palliation of the disease state, and remission (even if partial) "Treatment" also refers to the treatment of a subject who is not receiving treatment. This can mean a longer survival compared to the survival expected for the original disease. Those who are taking the drug include those who already have a condition or disease and those who are prone to having a condition or disease. This includes those seeking to treat or prevent a condition or disease.

[0077] "Tumor cells" or "cancer cells" refer to cells that grow in the body, either in vivo, ex vivo, or in tissue culture. cancerous, precancerous, or transformed cells with spontaneous or induced phenotypic changes These changes do not necessarily involve the incorporation of new genetic material. Transformation involves infection with a transforming virus and the integration of new genomic nucleic acid, as well as the uptake of exogenous nucleic acid. It can also be caused by carcinogens, occur spontaneously, or after exposure to carcinogens. This may result in mutations in endogenous genes. Transformation / cancer can be caused by a variety of factors, including in vitro and in vivo. Morphological changes, cell immortalization, abnormal growth control, lesion formation in vivo and ex vivo Growth, proliferation, malignant lesions, regulation of tumor-specific marker levels, invasiveness, and preference for nude mice This is exemplified by the growth of tumors in a suitable animal host.

[0078] Throughout this specification, the numbering of amino acid residues in antibody constant regions is as defined herein. Unless otherwise explicitly stated, Kabat et al., Sequences of Proteins of Immunological Interest,5th E d.Public Health Service,National Institute tes of Health, Bethesda, MD. (1991) The numbering of antibody constant chains follows, for example, the ImMunoGeneTics Visit the IMGT Scientific Charts IMGT Web Resources website can be found.

[0079] The substitution in the CH3 region is at a modified position in the first CH3 domain of the first heavy chain. position(s) / modified position(s) in the second CH3 domain of the second heavy chain; For example, F405L / K409R is expressed as F40 in the first CH3 region. This refers to the 5L mutation and the K09R mutation in the second CH3 region. Y407V / T394W is a nucleotide sequence consisting of L351Y, F40FA, and Y in the first CH3 region. This refers to the 407V mutation and the T394W mutation in the second CH3 region. RQ / K409AGRH, D399 may be replaced by F, H, KR, or Q, and K4 This refers to a mutation in which 09 can be replaced by A, G, R, or H.

[0080] The conventional one-letter and three-letter amino acid codes shown in Table 1 are used herein.

[0081] [Table 1]

[0082] Combinations of anti-CD38 antibodies with T cell redirecting therapeutic agents and their uses The present invention provides a method for the production of multiple myeloma cells, each of which induces the killing of multiple myeloma cells upon target engagement on the cells. wound-mediated therapeutic agent JNJ-957 or GPRC5D x CD3 antibody and anti-CD38 antibody DARZALEX® (daratumumab) competes or inhibits binding to MM cells They do not antagonize each other in terms of their mechanism of action on MM cells or their reciprocal downregulation of targets, but The present invention is based, at least in part, on the discovery that the compounds of the present invention are suitable for use as combination therapies. Also, previous treatment with DARZALEX® (daratumumab) has been associated with many JNJ-95 multiple myeloma cells obtained from treated relapsed / refractory multiple myeloma subjects The present invention is based, at least in part, on the discovery that DAR 7-mediated killing is enhanced. ZALEX® (daratumumab) targets non-multiple myeloma tumor cells and inhibits T-cell proliferation. Cell-redirecting therapy increases killing of tumor cells other than multiple myeloma cells Therefore, anti-CD38 antibodies and T cell redirection therapy anti-CD38 antibody in combination with a T-cell redirecting therapy and / or prior to administration of a T-cell redirecting therapy Pretreatment of a subject with rituximab can improve the antitumor efficacy of the monotherapy. Given that cancers are typically heterogeneous, a subset of cancers may benefit from combination therapy to address the deeper aspects of the disease. It is possible to have sufficient expression of one target versus the other exclusively, aiding in rapid eradication.

[0083] CD38 has functions in receptor-mediated adhesion and signal transduction, as well as its exocytic functions. It mediates calcium mobilization through the activity of a cyclic ADP-ribose (cADPR) and CD38 is a multifunctional protein that catalyzes the formation of cytokines and ADPR. It mediates secretion and lymphocyte activation and proliferation (Funaro et al., J Im munol 145:2390-6,1990;Terhorst et al.,Ce ll 771-80,1981;Guse et al.,Nature 398:70 -3, 1999). CD38 also regulates the NAD glycohydrolase activity. Extracellular NAD implicated in the regulation of the sexual T cell compartment + Adjust the level (Adri ouch et al., Microbes infection14:1284-92,20 12;Chiarugi et al.,Nature Reviews 12:741 -52,2012). Ca 2+ In addition to signaling through , antigen receptor complexes on T and B cells or other types of receptor complexes (e.g., MHC molecules ) and thus CD38 mediates several cellular responses as well as It is also involved in the switching and secretion of IgG1 and IgG2. DARZALEX® (daratumumab) is a T-cell redirecting therapeutic agent for the treatment of cancer. It is identified as improving the effectiveness of the method. Although it is not our intention to do so, DARZALEX® (daratumumab) has not been shown to be effective in human subjects. Immunomodulatory activity in the immune system (i.e., reducing the number of immunosuppressive Tregs, MDSCs, and Bregs) and CD8 + T cell counts and CD8 + Increased the ratio of CD8 to Tregs + Central In the subject, this is achieved through the promotion of T cell proliferation and T cell clonality. Even if the T cells are not specifically targeted, they can still result in an improved immune response, thus potentially contributing to the development of T cell redirecting therapeutics. It can be hypothesized that this may facilitate cell engagement.

[0084] The present disclosure provides a method of treating cancer in a subject, comprising administering to a subject a therapeutically effective amount of an anti-CD38 antibody. and administering a T cell redirecting therapeutic to a subject to treat cancer. do.

[0085] The present disclosure also provides a method of killing tumor cells in a subject, comprising administering to the subject an anti-CD38 antibody. The body and T cells bind to antigens on tumor cells long enough to kill the tumor cells. Also provided are methods that include administering a cell-redirecting therapeutic agent.

[0086] The present disclosure also provides methods for improving the efficacy of T cell redirecting therapeutics in subjects with cancer. Also provided are methods for treating a patient with rheumatoid arthritis, the methods comprising administering to the subject an anti-CD38 antibody.

[0087] In some embodiments, the anti-CD38 antibody is administered prior to administration of the T cell redirecting therapy. It is given.

[0088] T cell redirecting therapy was administered before administration of anti-CD38 antibody, and on days 1, 2, 3, 4, and 5. Day, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, 2 months, 3 months , 4 months, 5 months, 6 months or more before the administration.

[0089] In some embodiments, the T cell redirecting therapeutic binds to an antigen on a tumor cell. .

[0090] In some embodiments, the antigen on the tumor cell is BCMA, GPRC5D, CD33, CD123, CD19, PSMA, TMEFF2, CD20, CD10, CD21, CD 22, CD25, CD30, CD34, CD37, CD44v6, CD45, CD52, CD133, ROR1, B7-H6, B7-H3, HM1.24, SLAMF7, Fms FLT-like tyrosine kinase 3 (FLT-3, CD135), chondroitin sulfate proteoglycans Chondroitin sulfate proteoglycan 4 (CSPG4, melanoma-associated chondroitin sulfate proteoglycan 4) Acid proteoglycan, epidermal growth factor receptor (EGFR) FR), Her2, Her3, IGFR, IL3R, fibroblast activation protein (fibr oblast activating protein (FAP), CDCP1, Derlin1, tenascin, f rizzled1-10, VEGFR2(KDR / FLK1), VEGFR3(FLT4 , CD309), PDGFR-alpha (CD140a), PDGFR-beta (CD1 40b), endoglucan, CLEC14, Tem1-8, or Tie2. Further exemplary antigens on the cells include A33, CAMPATH-1 (CDw52), oncofetal antigen (CEA), carbohydrase IX (MN / CA IX), de2-7, EGFRv III, EpCAM, Ep-CAM, folate binding protein, G250, c-Kit (CD 117), CSF1R (CD115), HLA-DR, IGFR, IL-2 receptor, IL 3R, MCSP (melanoma-associated cell surface chondroitin sulfate proteoglycan), Muc- 1. Prostate stem cell antigen (PSCA), prostate-specific antigen (PSA), hK2, TAG-7 2, or tumor cell neoantigens.

[0091] In some embodiments, the T cell redirecting therapeutic is a T cell targeting agent selected from the group consisting of BCMA, GPRC5D, C D33, CD123, CD19, PSMA, TMEFF2, CD20, CD22, CD2 5, binds to CD52, ROR1, HM1.24, CD38, or SLAMF7.

[0092] In some embodiments, the T cell redirecting therapeutic is a CD3 epsilon (CD3ε )

[0093] In some embodiments, the T cell redirecting therapeutic binds to CD3.

[0094] In some embodiments, the T cell redirecting therapeutic is a CD8, KI2L4, NKG 2E, NKG2D, NKG2F, BTNL3, CD186, BTNL8, PD-1, CD These antigens bind to CD8, 195, or NKG2C, when compared to CD3. + More specific to T cells (see, e.g., WO 2018 / 187215 sea ​​bream).

[0095] In some embodiments, the T cell redirecting therapeutic 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; A heavy chain variable region (VH) of SEQ ID NO: 39 and a light chain variable region (VL) of SEQ ID NO: 40; 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 , VH of SEQ ID NO: 80 and VL of SEQ ID NO: 81; HCDR1, HCDR2, HCDR3, LCDR of the CD3 binding domain of SEQ ID NO: 53 1, LCDR2, and LCDR3, or It comprises a CD3 binding domain comprising the VH and VL of the CD3 binding domain of SEQ ID NO: 53.

[0096] In some embodiments, the T cell redirecting therapeutic binds to BCMA.

[0097] In some embodiments, the T cell redirecting therapeutic 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 a BCMA binding domain comprising: an HCDR1 of SEQ ID NO: 33; an HCDR2 of SEQ ID NO: 34; R2, HCDR3 of SEQ ID NO: 35, LCDR1 of SEQ ID NO: 36, LCDR of SEQ ID NO: 37 2, and a CD3 binding domain comprising an LCDR3 of SEQ ID NO: 38, and / or A BCMA binding domain comprising a VH of SEQ ID NO: 29 and a VL of SEQ ID NO: 30, and the sequence It comprises a CD3 binding domain comprising a VH of sequence number 39 and a VL of sequence number 40.

[0098] In some embodiments, the T cell redirecting therapeutic that binds BCMA is The first heavy chain (HC1) of SEQ ID NO: 31, the first light chain (LC1) of SEQ ID NO: 32, the first light chain (LC2) of SEQ ID NO: 41 2 heavy chain (HC2), and a second light chain (LC2) of SEQ ID NO: 42.

[0099] In some embodiments, the T cell redirecting therapeutic that binds BCMA is Seat ACTR Cancer Therapies, AFM-26, ALLO-715, C by tle Genetics Anti-BCMA allogeneic CAR-T cell therapy by RISPR Therapeutics, So Anti-BCMA CAR-T therapy from Rrento Therapeutics, Hrai Anti-CD19 / BCMA CAR-T cell therapy by C Biotechnology BCMA CAR-T therapy by hineo Med (Beijing), Triumv BCMA TAC-T cell therapy by ira Immunologics, Shang BCMA-CAR T-cell therapy by Unicar-Therapy Biomed method, BCMA / CD3 antibody by Regeneron, CAR by NantKwest -NK cell therapy, CC-93629, CMD-505, CTX-4419, CYAD-2 11, HDP-101, HPN-217, P-BCMA-ALLO1, TNB-383B BCMA chimeric antigen receptor therapy with bb-2121, AUTO-2, and Pregene , BCMA-CAR T by Shanghai Bioray Laboratory cells, BCMA-CAR-T cells by CARsgen Therapeutics, S henzhen BinDeBio's CAR-T / TCR-T cell immunotherapy, ET- 140, P-BCMA-101, REGN-5458, AMG-701, Cellula r Anti-BCMA CAR-T cell therapy by Biomedicine Group, bb -21217, BI-836909, CC-93269, Descartes-08, I M-21, JNJ-64007957, MEDI-2228, or PF-0686313 Includes 5.

[0100] In some embodiments, the T cell redirecting therapeutic is a T cell redirecting therapeutic described in WO 2017 / 031 It comprises any one of the BCMA binding domains described in No. 104.

[0101] In some embodiments, the T cell redirecting therapeutic binds to GPRC5D.

[0102] In some embodiments, the T cell redirecting therapeutic 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 GPRC5D binding domain comprising HCDR1 of SEQ ID NO: 33, H of SEQ ID NO: 34 CDR2, HCDR3 of SEQ ID NO: 35, LCDR1 of SEQ ID NO: 36, LC of SEQ ID NO: 37 a CD3 binding domain comprising a DR2 and an LCDR3 of SEQ ID NO: 38, and / or a GPRC5D-binding domain comprising a VH of SEQ ID NO: 49 and a VL of SEQ ID NO: 50; and It comprises a CD3 binding domain comprising a VH of SEQ ID NO: 39 and a VL of SEQ ID NO: 40.

[0103] In some embodiments, the T cell redirecting therapeutic that binds to GPRC5D has the sequence HC1 of SEQ ID NO: 51, LC1 of SEQ ID NO: 52, HC2 of SEQ ID NO: 41, and LC3 of SEQ ID NO: 42 Includes LC2.

[0104] In some embodiments, the T cell redirecting therapeutic is Eureka Therapeutics. Includes GPRC5D antibodies from eutics.

[0105] In some embodiments, the T cell redirecting therapeutic is a compound disclosed in WO 2018 / 003 7651.

[0106] In some embodiments, the T cell redirecting therapeutic binds to CD33.

[0107] In some embodiments, the T cell redirecting therapeutic comprises HCDR1 of SEQ ID NO: 84, HCDR2 of SEQ ID NO: 85, HCDR3 of SEQ ID NO: 86, LCDR1 of SEQ ID NO: 87, a CD33 binding domain comprising an LCDR2 of sequence number 88 and an LCDR3 of sequence number 89; and HCDR1 of SEQ ID NO: 74, HCDR2 of SEQ ID NO: 75, HCDR of SEQ ID NO: 76 3. LCDR1 of SEQ ID NO: 77, LCDR2 of SEQ ID NO: 78, and LCDR of SEQ ID NO: 79 a CD3 binding domain comprising R3, and / or A CD33 binding domain comprising a VH of SEQ ID NO: 90 and a VL of SEQ ID NO: 91, and the sequence It comprises a CD3 binding domain comprising a VH of sequence number 80 and a VL of sequence number 81.

[0108] In some embodiments, the T cell redirecting therapeutic that binds CD33 is 92, LC1 of SEQ ID NO: 93, HC2 of SEQ ID NO: 82, and LC of SEQ ID NO: 83 Includes 2.

[0109] In some embodiments, the T cell redirecting therapeutic that binds CD33 is Shen AMG-33, CAR-T / TCR-T cell immunotherapy by zhen BinDeBio 0, AMV-564, JNJ-67571244, ICG-144, AMG-673, Z CD33 CAR-T therapy INXN3004, huCD33-Bs by iopharm Ab, VOR-33, HMBD-004A, GEM-333, TGB-3550, or C Includes D33.taNK.

[0110] In some embodiments, the T cell redirecting therapeutic binds to CD123.

[0111] In some embodiments, the T cell redirecting therapeutic 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 a CD123 binding domain comprising HCDR1 of SEQ ID NO: 33, HCDR of SEQ ID NO: 34, R2, HCDR3 of SEQ ID NO: 35, LCDR1 of SEQ ID NO: 36, LCDR of SEQ ID NO: 37 2, and a CD3 binding domain comprising an LCDR3 of SEQ ID NO: 38, and / or a CD123 binding domain comprising a VH of SEQ ID NO: 100 and a VL of SEQ ID NO: 61; and It comprises a CD3 binding domain comprising a VH of SEQ ID NO: 39 and a VL of SEQ ID NO: 40.

[0112] In some embodiments, the T cell redirecting therapeutic that binds CD123 is HC1 of SEQ ID NO: 102, LC1 of SEQ ID NO: 63, HC2 of SEQ ID NO: 41, and LC3 of SEQ ID NO: 42 Includes LC2.

[0113] In some embodiments, the T cell redirecting therapeutic that binds CD123 is raVectys Acute Myeloid Leukemia Therapy, APVO-437, Nanjing L APVO-43, an anti-CD123 CAR-T cell therapy from egend Biotech 6. CD123 CA by Hebei Senlang Biotechnology RT cell therapy, flotetuzumab, IM-23, JNJ-637091 78, MB-102, UCART-123, XmAb-1 by Mustang Bio 4045, or the CD3-CD123 bispecific T cell engager by Sanofi Includes.

[0114] In some embodiments, the T cell redirecting therapeutic is a T cell redirecting therapeutic described in WO 2016 / 036 It comprises any one of the CD123 binding domains described in US Pat. No. 937.

[0115] In some embodiments, the T cell redirecting therapeutic binds to CD19.

[0116] In some embodiments, the T cell redirecting therapeutic HCDR1, HCDR2, HCDR3, LCD of the CD19 binding domain of SEQ ID NO: 53 a CD19 binding domain comprising R1, LCDR2, and LCDR3, and the sequence of SEQ ID NO: 53 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 of the CD3 binding domain and a CD3 binding domain comprising LCDR3, and / or It comprises the amino acid sequence of SEQ ID NO:53.

[0117] In some embodiments, the T cell redirecting therapeutic that binds CD19 is axica Butagenciloleucel, blinatumomab, tisagenlecleucel-t, AMG-562 , AUTO-1 CAR by Cellular Biomedicine Group -T CD19, CD19 Chimeric Antigen Receptor T Cell Therapy by Ziopharm, ioc CD19-CAR-T cell therapy by Eltech Therapeutics, Mar CD19-CAR-T cell therapy by ino Biotechnology, Guang Dong Zhaotai InVivo's CD19-CAR-T2 cell therapy, Ju CD19 / 4-1BBL-armed CAR T cell therapy by No Therapeutics Law, CSG-CD19, DI-B4, ET-190, GC-007F, GC-022, H Human CD19 T cell therapy by RAIN Biotechnology, Kite P Humanized anti-CD19 regulatory CAR (3rd generation) by harma, Immune Cell ICAR-19 CAR-T cells, ICTCAR-003, and Mar Therapy iPD1 CD19 eCAR T cells by Ino Biotechnology, J WCAR029, PTG-01, PZ01, Senl_1904A, Senl_1904 B, UCART-19, UWC-19, AUTO-3, BinD-19, Shanghai i CAR-T cell therapy by Unicar-Therapy Biomed, Shen zhen BinDeBio's CAR-T / TCR-T cell immunotherapy, Milten CD-19 CAR-T cell therapy by yi Biotec, Shanghai Uni CD19 CAR-T cells by Car-Therapy Biomed, Takara CD19-CAR T cell therapy by Shanghai Bioray La CD19-CART by Boratory, CD19 targeting by Sinobioway Synthesized chimeric antigen receptor T cells, Shanghai Longyao Biotechnol CD19 / CD20 CAR-T cell therapy by ogy, CIK-CAR.CD19, I CTCAR-011, IM-19, JCAR-014, loncastuximab tesirine, M B-CART2019.1, OXS-1550, PBCAR-0191, PCAR-01 9, PCAR-119, Senl-001, TI-1007, XmAb-5871, rice Bilimumab, lisocabtagene maraleucel, XmAb- 5574, 3rd generation CD19-CART cells + mbIL by Eden BioCell 15, A-329, ALLO-501, Beijing Doing Biomedic Anti-CD19 anti-CD20 bispecific CAR redirected autologous T cells by al Co, Al anti-CD19 CAR NK cell therapy by life Medical Science; Anti-CD19 / BCMA CAR-T cells by Hrain Biotechnology Therapy, ATA-2431, ATA-3219.AVA-008.Celularity CD19 CAR-T cell therapy by Ziopharm, CD19 chimeric antigen receptor Third generation T cell therapy, CD19 dBiTE by Inovio, and Bellicum CD19 TCR cell therapy by Wilex, CD19-ATAC by Chineo M CD19 / 20 CAR-T therapy by ed(Beijing), Eureka The Helix BioPharma, a CD19 / CD22 dual-targeted therapy from rapeutics Chimeric antigen receptor T cell (CAR-T) therapy with RMA, CMD-502, and CTX-1 10, CYAD-04, CYAD-221, ET-019002, FT-596, FT- 819, Gamma-Delta CAR-T Therapy by TC Biopharm, ICTCAR- 014, iDD-002, KITE-037, NI-2201, RB-1916, Sen l_002, TAC01-CD19, TC-110, TC-310, TCB-003, or Includes the TI-7007.

[0118] In some embodiments, the T cell redirecting therapeutic binds to PSMA.

[0119] In some embodiments, the T cell redirecting therapeutic 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 A PSMA binding domain comprising: HCDR1 of SEQ ID NO: 33; HCDR2 of SEQ ID NO: 34; 2. HCDR3 of SEQ ID NO: 35, LCDR1 of SEQ ID NO: 36, LCDR2 of SEQ ID NO: 37 and a CD3 binding domain comprising an LCDR3 of SEQ ID NO: 38, and / or A PSMA binding domain comprising a VH of SEQ ID NO: 60 and a VL of SEQ ID NO: 61, and the sequence It comprises a CD3 binding domain comprising a VH of sequence number 39 and a VL of sequence number 40.

[0120] In some embodiments, the T cell redirecting therapeutic that binds PSMA is 62, LC1 of SEQ ID NO: 63, HC2 of SEQ ID NO: 41, and LC of SEQ ID NO: 42 Includes 2.

[0121] In some embodiments, the T cell redirecting therapeutic binds to TMEFF2.

[0122] In some embodiments, the T cell redirecting therapeutic 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 a TMEFF2-binding domain comprising HCDR1 of SEQ ID NO: 74, H of SEQ ID NO: 75, CDR2, HCDR3 of SEQ ID NO: 76, LCDR1 of SEQ ID NO: 77, LC a CD3 binding domain comprising an LCDR2 and an LCDR3 of SEQ ID NO: 79, and / or a TMEFF2-binding domain comprising a VH of SEQ ID NO: 70 and a VL of SEQ ID NO: 71; and It comprises a CD3 binding domain comprising a VH of SEQ ID NO: 80 and a VL of SEQ ID NO: 81.

[0123] In some embodiments, the T cell redirecting therapeutic that binds to TMEFF2 has the sequence HC1 of SEQ ID NO: 72, LC1 of SEQ ID NO: 73, HC2 of SEQ ID NO: 82, and LC3 of SEQ ID NO: 83 Includes LC2.

[0124] In some embodiments, the T cell redirecting therapeutic binds to CD20.

[0125] In some embodiments, the T cell redirecting therapeutic binds to CD22.

[0126] In some embodiments, the T cell redirecting therapeutic binds to CD25.

[0127] In some embodiments, the T cell redirecting therapeutic binds to CD52.

[0128] In some embodiments, the T cell redirecting therapeutic binds to ROR1.

[0129] In some embodiments, the T cell redirecting therapeutic binds to HM1.24.

[0130] In some embodiments, the T cell redirecting therapeutic binds to SLAMF7.

[0131] In some embodiments, the T cell redirecting therapeutic is a multispecific antibody, a chimeric antigen receptor, or a chimeric antigen receptor. receptor (CAR), or T cells containing a CAR.

[0132] In some embodiments, the T cell redirecting therapeutic is a CAR.

[0133] In some embodiments, the T cell redirecting therapeutic is a T cell expressing a CAR. do.

[0134] In some embodiments, the T cell redirecting therapeutic is a multispecific antibody.

[0135] In some embodiments, the multispecific antibody is an IgG1, IgG2, IgG3, or IgG1 antibody. It is the gG4 isotype.

[0136] In some embodiments, the antibody is of the IgG1 isotype.

[0137] In some embodiments, the antibody is of the IgG2 isotype.

[0138] In some embodiments, the antibody is of the IgG3 isotype.

[0139] In some embodiments, the antibody is of the IgG4 isotype.

[0140] Multispecific antibodies may be of any allotype. It is not expected to affect the properties of multispecific antibodies, such as Fc-mediated effector functions. Immunogenicity of therapeutic antibodies is associated with an increased risk of infusion reactions and a shorter duration of therapeutic response. (Baert et al., (2003) N Engl J Med 348: The extent to which a therapeutic antibody induces an immune response in the host depends on the allotype of the antibody. This can be partially determined by the size of the gap (Stickler et al., (2011) Ge nes and Immunity 12:213-21). Antibody allotypes are Table 2 shows the amino acid sequence of selected Ig G1, IgG2, and IgG4 allotypes are shown.

[0141] [Table 2]

[0142] In some embodiments, the multispecific antibody is a multispecific antibody Fcγ receptor (Fcγ The multispecific antibody comprises one or more Fc substitutions that reduce binding to FcγR. Substitutions that reduce binding to the multispecific antibody may also reduce ADCC, ADCP, and / or CDC of the multispecific antibody. which reduces Fc effector function. Specific substitutions are made in the wild-type IgG1 of SEQ ID NO: 103. Or, comparison can be made with wild-type IgG4 of SEQ ID NO: 104.

[0143] In some embodiments, the one or more Fc substitutions are F234A / L235A, L234A / L235A on IgG1, V234A / G237 on IgG2 A / P238S / H268A / V309L / A330S / P331S, F2 on IgG4 34A / L235A, S228P / F234A / L235A on IgG4, all IgA N297A on isotype, V234A / G237A on IgG2, K21 on IgG1 4T / E233P / L234V / L235A / G236 deletion / A327G / P331A / D365E / L358M, H268Q / V309L / A330S / P331 on IgG2 S, S267E / L328F on IgG1, L234F / L235E / D2 on IgG1 65A, L234A / L235A / G237A / P238S / H268A / on IgG1 A330S / P331S, S228P / F234A / L235A / G237 on IgG4 A / P238S and S228P / F234A / L235A / G236 deletion on IgG4 / G237A / P238S, and the residue numbering is according to the EU index. Follow the instructions.

[0144] In some embodiments, the one or more Fc substitutions are F234A / It is L235A.

[0145] In some embodiments, the one or more Fc substitutions are L234A / It is L235A.

[0146] In some embodiments, the one or more Fc substitutions are V234A / G237A / P238S / H268A / V309L / A330S / P331S.

[0147] In some embodiments, the one or more Fc substitutions are F234A / It is L235A.

[0148] In some embodiments, the one or more Fc substitutions are S228P / F234A / L235A.

[0149] In some embodiments, one or more Fc substitutions are present on all Ig isotypes. The aircraft is N297A.

[0150] In some embodiments, the one or more Fc substitutions are V234A / It is G237A.

[0151] In some embodiments, the one or more Fc substitutions are K214T / E233P / L234V / L235A / G236 deletion / A327G / P331A / D36 It is 5E / L358M.

[0152] In some embodiments, the one or more Fc substitutions are H268Q / V309L / A330S / P331S.

[0153] In some embodiments, the one or more Fc substitutions are S267E / In some embodiments, the one or more Fc substitutions are IgG1 The above are L234F / L235E / D265A.

[0154] In some embodiments, the one or more Fc substitutions are L234A / L235A / G237A / P238S / H268A / A330S / P331S.

[0155] In some embodiments, the one or more Fc substitutions are S228P / F234A / L235A / G237A / P238S and S228P / F23 on IgG4 4A / L235A / G236 deletion / G237A / P238S.

[0156] In some embodiments, the multispecific antibody further comprises a S228P substitution.

[0157] In some embodiments, the multispecific antibody comprises a first CH3 domain or a second CH3 domain. In the H3 domain, or in both the first CH3 domain and the second CH3 domain, one or contains two or more asymmetric substitutions.

[0158] In some embodiments, the one or more asymmetric substitutions are F450L / K409R , wild type / F409L_R409K, T366Y / F405A, T366W / F405W , F405W / Y407A, T394W / Y407T, T394S / Y407A, T36 6W / T394S, F405W / T394S and T366W / T366S_L368A_ Y407V, L351Y_F405A_Y407V / T394W, T366I_K392 M_T394W / F405A_Y407V, T366L_K392M_T394W / F4 05A_Y407V, L351Y_Y407A / T366A_K409F, L351Y_ Y407A / T366V_K409F, Y407A / T366A_K409F, and T 350V_L351Y_F405A_Y407V / T350V_T366L_K392L _T394W.

[0159] In some embodiments, the one or more asymmetric substitutions are F450L / K409R is.

[0160] In some embodiments, the one or more asymmetric substitutions are wild-type / F409L_R It is 409K.

[0161] In some embodiments, the one or more asymmetric substitutions are T366Y / F405A is.

[0162] In some embodiments, the one or more asymmetric substitutions are T366W / F405W is.

[0163] In some embodiments, the one or more asymmetric substitutions are F405W / Y407A is.

[0164] In some embodiments, the one or more asymmetric substitutions are T394W / Y407T is.

[0165] In some embodiments, the one or more asymmetric substitutions are T394S / Y407A is.

[0166] In some embodiments, the one or more asymmetric substitutions are T366W / T394S is.

[0167] In some embodiments, the one or more asymmetric substitutions are F405W / T394S is.

[0168] In some embodiments, the one or more asymmetric substitutions are T366W / T366S _L368A_Y407V.

[0169] In some embodiments, the one or more asymmetric substitutions are _Y407V / T394W.

[0170] In some embodiments, the one or more asymmetric substitutions are T366I_K392M _T394W / F405A_Y407V.

[0171] In some embodiments, the one or more asymmetric substitutions are T366L_K392M _T394W / F405A_Y407V.

[0172] In some embodiments, the one or more asymmetric substitutions are / T366A_K409F.

[0173] In some embodiments, the one or more asymmetric substitutions are / T366V_K409F.

[0174] In some embodiments, the one or more asymmetric substitutions are Y407A / T366A _K409F.

[0175] In some embodiments, the one or more asymmetric substitutions are T350V_L351Y _F405A_Y407V / T350V_T366L_K392L_T394W.

[0176] In some embodiments, the cancer is a hematological malignancy or a solid tumor.

[0177] In some embodiments, the hematological malignancy is multiple myeloma, smoldering multiple myeloma, Benign monoclonal gammopathy of undetermined significance ance (MGUS), acute lymphoblastic leukemia (ALL), and Diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma (BL), follicular lymphoma FL), mantle-cell lymphoma (MCL), Waldenstrom lymphoma Hypergammaglobulinemia, plasma cell leukemia, light chain amyloidosis oidosis, AL), precursor B-cell lymphoblastic leukemia, precursor B-cell lymphoblastic leukemia , acute myeloid leukemia (AML), myelodysplastic syndrome (myelodysplastic syndrome) plastic syndrome (MDS), chronic lymphocytic leukemia (C LL), B-cell malignancy, chronic myeloid leukemia (CML), Hairy cell leukemia (HCL), blastic plasmacytoid dendritic cell neoplasm, Hodgkin's lymphoma, non-Hodgkin's lymphoma, marginal zone B-cell lymphoma lymphoma (MZL), mucosa-associated lymphatic tissue lymphoma sue lymphoma (MALT), plasma cell leukemia, anaplastic large cell lymphoma (anaplastic large cell lymphoma) ALCL), leukemia, or lymphoma.

[0178] In some embodiments, the hematological malignancy is multiple myeloma.

[0179] In some embodiments, the multiple myeloma is newly diagnosed multiple myeloma.

[0180] In some embodiments, the multiple myeloma is relapsed or refractory multiple myeloma.

[0181] In some embodiments, the multiple myeloma is high-risk multiple myeloma. Subjects with primary myeloma are known to relapse early and have poor prognosis and outcome. A subject may be classified as having high-risk multiple myeloma if they have one of the following cytogenetic abnormalities: :t(4;14)(p16;q32), t(14;16)(q32;q23), del1 7p, 1qAmp, t(4;14)(p16;q32) and t(14;16)(q32; q23), t(4;14)(p16;q32) and del17p, t(14;16)(q 32;q23) and del17p, or t(4;14)(p16;q32), t(14; 16)(q32;q23) and del17p do.

[0182] In some embodiments, the subject with high-risk multiple myeloma has t(4;14)(p 16;q32), t(14;16)(q32;q23), del17p, 1qAmp, t (4;14)(p16;q32) and t(14;16)(q32;q23), t(4;1 4) (p16;q32) and del17p, t(14;16)(q32;q23) and d el17p, t(4;14)(p16;q32), t(14;16)(q32;q23) one or more chromosomal abnormalities, including del17p, del2p, and del17p, or any combination thereof It has constancy.

[0183] A variety of qualitative and / or quantitative methods are used to determine disease recurrence or refractory status. Possible associated symptoms include, for example, a decline or plateau in the patient's health, Reversal or worsening of various symptoms associated with the tumor and / or transfer of tumors from one location to other organs or tissues Cancer is the spread of cancerous cells within the body to tissues or cells.

[0184] Cytogenetic abnormalities can be detected, for example, by fluorescence in situ hybridization. Both chromosomal translocations can be detected by in situ hybridization (FISH). As a result, oncogenes are translocated to the IgH region on chromosome 14q32, leading to deregulation of these genes. t(4;14)(p16;q32) results in the deletion of fibroblast growth factor receptor 3 (GFGR3). (FGFR3) and multiple myeloma SET domain-containing protein (MMSET) (a.k.a. WHSC1 / NSD2) translocation, t(14;16)(q32;q23), is associated with MAF It involves translocation of the transcription factor C-MAF. 17p deletion (del17p) results in loss of the p53 locus. It involves loss.

[0185] In some embodiments, the multiple myeloma is treated with anti-CD38 antibody, lenalidomide, bortezomib, or Mib, pomalidomide, carfilzomib, elotozumab, ixazomib, For treatment with melphalan, or thalidomide, or any combination thereof and recurrent or refractory.

[0186] In some embodiments, the multiple myeloma relapses or fails to respond to treatment with an anti-CD38 antibody. In some embodiments, the multiple myeloma is refractory to treatment with lenalidomide. In some embodiments, the multiple myeloma is relapsed or refractory to bortezomib. In some embodiments, the multiple myeloma is relapsed or refractory to treatment with In some embodiments, the tumor is relapsed or refractory to treatment with pomalidomide. Multiple myeloma relapsed or refractory to treatment with carfilzomib. In embodiments, the multiple myeloma is relapsed or refractory to treatment with elotozumab. In some embodiments, the multiple myeloma is relapsed or refractory to treatment with ixazomib. In some embodiments, the multiple myeloma is curable to treatment with melphalan. In some embodiments, the multiple myeloma is relapsed or refractory to thalidomide. relapsed or refractory to current treatment.

[0187] In some embodiments, the hematological malignancy is AML.

[0188] In some embodiments, the AML is AML with at least one genetic abnormality, multilineage AML with dysplasia, therapy-related AML, undifferentiated AML, poorly differentiated AML, differentiated AML L, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroid leukemia, acute megakaryoblastic leukemia leukemia, acute basophilic leukemia, acute panmyelitis with fibrosis, or myeloid sarcoma.

[0189] In some embodiments, the AML is AML with at least one genetic abnormality. In some embodiments, the AML is AML with multilineage dysplasia. In some embodiments, the AML is therapy-associated AML. In some embodiments, the AML is minimally differentiated AML. In some embodiments, the AML is differentiated AML. L is acute myelomonocytic leukemia. In some embodiments, AML is acute monocytic leukemia. In some embodiments, the AML is acute erythroid leukemia. In some embodiments, the AML is acute megakaryoblastic leukemia. ML is acute basophilic leukemia. In some embodiments, AML is associated with fibrosis. In some embodiments, the AML is a myeloid sarcoma.

[0190] In some embodiments, the at least one genetic abnormality is a mutation in chromosomes 8 and 21. translocation between chromosome 15 and 17, translocation or inversion of chromosome 16, translocation, alteration of chromosome 11, or fms-related tyrosine kinase 3 (fms-related tyrosine kinase 3) kinase 3, FLT3), nucleophosmin (NPM1), isoquen Isocitrate dehydrogenase 1 (IDH1), isocitrate dehydrogenase Isocitrate dehydrogenase 2 (IDH2), DNA (cytosine-5)-methyl DNA(cytosine-5)-methyltransferase 3 (DNMT3A), CCAAT / enhancer binding protein alpha lpha, CEBPA), U2 small nuclear RNA auxiliary factor 1 (U2 small nuclear RNA auxiliary ry factor 1, U2AF1), zeste2, a polycomb repressive complex 2 subunit enhancer enhancer (enhancer of zeste 2 polycomb repressive complex 2 subunit, EZH2), Structural maintenance of chromosomes 1A (SMC1A), if In particular, structural maintenance of chromosomes 3 (SMC3) This is a mutation.

[0191] In some embodiments, the at least one genetic abnormality is a mutation in chromosomes 8 and 21. In some embodiments, the at least one genetic abnormality is a translocation between position 16 and position 17. In some embodiments, the at least one genetic abnormality is a chromosomal translocation or inversion. In some embodiments, the translocation is between chromosomes 15 and 17. Another genetic abnormality is an alteration in chromosome 11. In some embodiments, at least Another genetic abnormality is a mutation in fms-related tyrosine kinase 3 (FLT3). In some embodiments, the at least one genetic abnormality is nucleophosmin (NPM1) In some embodiments, the at least one genetic abnormality is a mutation in isocitrate In some embodiments, the mutation is a mutation in at least one of IDH1 and IDH2. One genetic abnormality is a mutation in isocitrate dehydrogenase 2 (IDH2). In some embodiments, the at least one genetic abnormality is a DNA (cytosine-5)-methyltransferase. In some embodiments, the mutation is a mutation in DNMT3A. Another genetic abnormality is CCAAT / enhancer-binding protein alpha (CEBPA In some embodiments, the at least one genetic abnormality is a mutation in U2 nuclear hypoxia. In some embodiments, the mutation is in the molecule RNA cofactor 1 (U2AF1). Another gene mutation is the zeste2 polycomb repressive complex 2 subunit enhancer In some embodiments, the at least one genetic abnormality is a mutation in EZH2. In some embodiments, the mutation is in structural maintenance of chromosomes 1A (SMC1A). One genetic abnormality is a mutation in structural maintenance of chromosomes 3 (SMC3).

[0192] In some embodiments, the at least one genetic abnormality is the translocation t(8;21)(q2 2;q22), inversion inv(16)(p13;q22), translocation t(16;16)(p13 ;q22), translocation t(15;17)(q22;q12), FLT3-ITD mutation, ID R132H or R100Q / R104V / F108L / R119Q / I in H1 130V mutation, or R140Q or R172 mutation in IDH2.

[0193] In some embodiments, the at least one genetic abnormality is the translocation t(8;21)(q2 In some embodiments, the at least one genetic abnormality is an inversion i nv(16)(p13;q22). In some embodiments, at least one gene The genetic abnormality is the translocation t(16;16)(p13;q22). In some embodiments, At least one genetic abnormality is the translocation t(15;17)(q22;q12). In some embodiments, the at least one genetic abnormality is a mutation in FLT3-ITD. In some embodiments, the at least one genetic abnormality is R132 in IDH1 In some embodiments, the at least one genetic abnormality is a mutation in IDH1. The mutations are R100Q / R104V / F108L / R119Q / I130V. In some embodiments, the at least one genetic abnormality is R140Q in IDH2. In some embodiments, the at least one genetic abnormality is a mutation in IDH2. The mutation is R172.

[0194] In some embodiments, the hematological malignancy is ALL.

[0195] In some embodiments, the ALL is B-lineage ALL, T-lineage ALL, adult ALL, L, or childhood ALL.

[0196] In some embodiments, the ALL is B-lineage ALL. In some embodiments, the ALL is T-lineage ALL. In some embodiments, the ALL is adult ALL. L. In some embodiments, the ALL is childhood ALL.

[0197] In some embodiments, the subject with ALL has or does not have the Philadelphia chromosome. or are resistant to or unable to respond to treatment with a BCR-ABL kinase inhibitor It has acquired resistance to the drug.

[0198] In some embodiments, the subject with ALL has the Philadelphia chromosome. In some embodiments, the subject with ALL is treated with a BCR-ABL kinase inhibitor. Resistant to or has acquired resistance to treatment.

[0199] The Ph chromosome is present in approximately 20% of adults with ALL and a small proportion of children with ALL. At relapse, patients with Ph+ positive ALL have tyrosine may be on a kinase inhibitor (TKI) regimen and therefore resistant to the TKI Therefore, anti-CD38 antibodies may selectively or partially selectively target BCR- These inhibitors may be administered to subjects who have become resistant to ABL inhibitors. For example, imatinib, dasatinib, nilotinib, bosutinib, ponatinib, and bafetinib nib, saracatinib, tozasertib, or danusertib.

[0200] Another chromosomal rearrangement identified in patients with B-lineage ALL is t(v;11q23)(M LL rearrangement), t(1;19)(q23;p13.3);TCF3-PBX1(E2A- PBX1), t(12;21)(p13;q22);ETV6-RUNX1(TEL-A ML1) and t(5;14)(q31;q32);IL3-IGH.

[0201] In some embodiments, the subject has t(v;11q23) (MLL rearrangement), t(1; 19)(q23;p13.3);TCF3-PBX1(E2A-PBX1), t(12; 21)(p13;q22);ETV6-RUNX1(TEL-AML1) or t(5;1 4) (q31;q32); ALL with IL3-IGH chromosomal rearrangement.

[0202] Chromosomal rearrangements can be detected by well-known methods, such as fluorescence in situ hybridization, nuclear can be identified using typing, pulsed-field gel electrophoresis, or sequencing. .

[0203] In some embodiments, the hematological malignancy is smoldering multiple myeloma.

[0204] In some embodiments, the hematological malignancy is MGUS.

[0205] In some embodiments, the hematological malignancy is ALL.

[0206] In some embodiments, the hematological malignancy is DLBLC.

[0207] In some embodiments, the hematological malignancy is BL.

[0208] In some embodiments, the hematological malignancy is FL.

[0209] In some embodiments, the hematological malignancy is MCL.

[0210] In some embodiments, the hematological malignancy is Waldenstrom's hypergammaglobulinemia It is a disease.

[0211] In some embodiments, the hematological malignancy is plasma cell leukemia.

[0212] In some embodiments, the hematological malignancy is AL.

[0213] In some embodiments, the hematological malignancy is precursor B-cell lymphoblastic leukemia.

[0214] In some embodiments, the hematological malignancy is precursor B-cell lymphoblastic leukemia.

[0215] In some embodiments, the hematological malignancy is myelodysplastic syndrome (MDS).

[0216] In some embodiments, the hematological malignancy is CLL.

[0217] In some embodiments, the hematological malignancy is a B-cell malignancy.

[0218] In some embodiments, the hematological malignancy is CML.

[0219] In some embodiments, the hematological malignancy is HCL.

[0220] In some embodiments, the hematological malignancy is blastic plasmacytoid dendritic cell neoplasm.

[0221] In some embodiments, the hematological malignancy is Hodgkin's lymphoma.

[0222] In some embodiments, the hematological malignancy is non-Hodgkin's lymphoma.

[0223] In some embodiments, the hematological malignancy is MZL.

[0224] In some embodiments, the hematological malignancy is MALT.

[0225] In some embodiments, the hematological malignancy is plasma cell leukemia.

[0226] In some embodiments, the hematological malignancy is ALCL.

[0227] In some embodiments, the hematological malignancy is leukemia.

[0228] In some embodiments, the hematological malignancy is lymphoma.

[0229] In some embodiments, the solid tumor is prostate cancer, lung cancer, non-small cell lung cancer, or the like. ll 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 carcinoma, epithelial carcinoma, adenocarcinoma, or advanced solid tumor.

[0230] In some embodiments, the solid tumor is prostate cancer.

[0231] In some embodiments, the solid tumor is lung cancer.

[0232] In some embodiments, the solid tumor is non-small cell lung cancer (NSCLC).

[0233] In some embodiments, the solid tumor is liver cancer.

[0234] In some embodiments, the solid tumor is cervical cancer.

[0235] In some embodiments, the solid tumor is colon cancer.

[0236] In some embodiments, the solid tumor is breast cancer.

[0237] In some embodiments, the solid tumor is ovarian cancer.

[0238] In some embodiments, the solid tumor is endometrial cancer.

[0239] In some embodiments, the solid tumor is pancreatic cancer.

[0240] In some embodiments, the solid tumor is melanoma.

[0241] In some embodiments, the solid tumor is esophageal cancer.

[0242] In some embodiments, the solid tumor is gastric cancer.

[0243] In some embodiments, the solid tumor is stomach cancer.

[0244] In some embodiments, the solid tumor is renal carcinoma.

[0245] In some embodiments, the solid tumor is bladder cancer.

[0246] In some embodiments, the solid tumor is hepatocellular carcinoma.

[0247] In some embodiments, the solid tumor is renal cell carcinoma.

[0248] In some embodiments, the solid tumor is a urothelial carcinoma.

[0249] In some embodiments, the solid tumor is head and neck cancer.

[0250] In some embodiments, the solid tumor is a glioma.

[0251] In some embodiments, the solid tumor is a glioblastoma.

[0252] In some embodiments, the solid tumor is colorectal cancer.

[0253] In some embodiments, the solid tumor is thyroid cancer.

[0254] In some embodiments, the solid tumor is an epithelial cancer.

[0255] In some embodiments, the solid tumor is an adenocarcinoma.

[0256] In some embodiments, the solid tumor is an advanced solid tumor.

[0257] In some embodiments, the prostate cancer is recurrent, refractory, aggressive, or castration-resistant. prostate cancer, or any combination thereof.

[0258] 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 pre-malignant. In some embodiments, the prostate cancer is castration-resistant prostate cancer.

[0259] In some embodiments, the anti-CD38 antibody comprises HCDR1 of SEQ ID NO: 6, HCDR2 of SEQ ID NO: 7 HCDR2, HCDR3 of SEQ ID NO: 8, LCDR1 of SEQ ID NO: 9, LCD of SEQ ID NO: 10 R2, and LCDR3 of SEQ ID NO:11.

[0260] In some embodiments, the anti-CD38 antibody comprises a VH of SEQ ID NO: 4 and a VL of SEQ ID NO: 5. Includes.

[0261] In some embodiments, the anti-CD38 antibody is of the IgG1 isotype.

[0262] In some embodiments, the anti-CD38 antibody comprises the HC of SEQ ID NO: 12 and the HC of SEQ ID NO: 13. Contains LC.

[0263] Other anti-CD38 antibodies for use in the methods of the present invention include V and VL of SEQ ID NOs: 14 and 15, respectively. mAb containing H and VL sequences, such as mAb003 described in U.S. Pat. No. 7,829,673 The VH and VL of mAb003 are expressed as IgG1 / κ. 16 and 1, respectively, as described in U.S. Pat. No. 7,829,673. mAb024 comprising the VH and VL sequences of IgG. κ, respectively, as described in U.S. Pat. No. 8,088,896. MOR-202 (MOR-03087) containing the VH and VL sequences of sequences 18 and 19 (The VH and VL of MOR-202 can be expressed as IgG1 / κ); or Tuximab; SEQ ID NO: 20 and SEQ ID NO: 10, respectively, as described in U.S. Pat. No. 8,153,765. It contains 21 VH and VL sequences. The VH and VL of isatuximab are identical to those of IgG1 / κ and It can be expressed as:

[0264] SEQ ID NO: 4 (Daratumumab VH) EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQ APGKGLEWVSAISGSGGGTYYADSVKGRFTISRDNSKNTL YLQMNSLRAEDTAVYFCAKDKILWFGEPVFDYWGQGTLVT VSS

[0265] SEQ ID NO: 5 (Daratumumab VL) EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQK PGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLE PEDFAVYYCQQRSNWPPTFGQGTKVEIK

[0266] SEQ ID NO: 6 (Daratumumab HCDR1) SFAMS

[0267] SEQ ID NO: 7 (Daratumumab HCDR2) AISGSGGGTYYADSVKG

[0268] SEQ ID NO: 8 (Daratumumab HCDR3) DKILWFGEPVFDY

[0269] SEQ ID NO: 9 (Daratumumab LCDR1) RASQSVSSYLA

[0270] SEQ ID NO: 10 (Daratumumab LCDR2) DASNRAT

[0271] SEQ ID NO: 11 (Daratumumab LCDR3) QQRSNWPPTF

[0272] SEQ ID NO: 12 (Daratumumab HC) EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQ APGKGLEWVSAISGSGGGTYYADSVKGRFTISRDNSKNTL YLQMNSLRAEDTAVYFCAKDKILWFGEPVFDYWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG TQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEL LGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK FNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPS REEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK

[0273] SEQ ID NO: 13 (Daratumumab LC) EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQK PGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLE PEDFAVYYCQQRSNWPPTFGQGTKVEIKRTVAAPSVFIFP PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC

[0274] SEQ ID NO: 14 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAFSWVRQ APGQGLEWMGRVIPFLGIANSAQKFQGRVTITADKSTSTA YMDLSSLRSEDTAVYYCARDDIAALGPFDYWGQGTLVTVS SAS

[0275] SEQ ID NO: 15 DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQK PEKAPKSLIYAASSLQSGVPSRFSGSGGSGTDFTLTISSLQ PEDFATYYCQQYNSYPRTFGQGTKVEIK

[0276] SEQ ID NO: 16 EVQLVQSGAEVKKPGESLKISCKGSGYSFSNYWIGWVRQ MPGKGLEWMGIIYPHSDARYSPSFQGQVTFSADKSISTA YLQWSSLKASDTAMYYCARHVGWGSRYWYFDLWGRGTLVT VSS

[0277] SEQ ID NO: 17 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQK PGQAPGLLIYDASNRASGIPARFSGSGSGTDFTLTISSLE PEDFAVYYCQQRSNWPLTFGGGTKVEIK

[0278] SEQ ID NO: 18 QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMNWVRQ APGKGLEWVSGISGDPSNTYYADSVKGRFTISRDNSKNTL YLQMNSLRAEDTAVYYCARDLPLVYTGFAYWGQGTLVTVS S

[0279] SEQ ID NO: 19 DIELTQPPSVSVAPGQTARISCSGDNLRHYYVYWYQQKP GQAPVLVIYGDSKRPSGIPERFSGSNSGNTATLTISGTQA EDEADYYCQTYTGGASLVFGGGGTKLTVLGQ

[0280] SEQ ID NO: 20 QVQLVQSGAEVAKPGTSVKLSCKASGYTFTDYWMQWVKQ RPGQGLEWIGTIYPGDGDTGYAQKFQGKATLTADKSSKTV YMHLSSLASEDSAVYYCARGDYYGSNSLDYWGQGTSVTVS S

[0281] SEQ ID NO: 21 DIVMTQSHLSMSSTSLGDPVSITCKASQDVSTVVAWYQQK PGQSPRRLIYSASYRYIGVPDRFTGSGAGTDFTFTISSVQ AEDLAVYYCQQHYSPPYTFGGGTKLEIK

[0282] In some embodiments, the anti-CD38 antibody VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15, VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17, VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or It comprises a VH of SEQ ID NO:20 and a VL of SEQ ID NO:21.

[0283] In some embodiments, the anti-CD38 antibody is of the IgG1 isotype.

[0284] In some embodiments, the T cell redirecting therapeutic is a BCMAxCD3 bispecific Antibody, GPRC5D×CD3 bispecific antibody, CD33×CD3 bispecific antibody, CD1 9×CD3 bispecific antibody, CD123×CD3 bispecific antibody, PSMA×CD3 bispecific antibody It is a specific antibody or a TMEFF2xCD3 bispecific antibody.

[0285] In some embodiments, the T cell redirecting therapeutic is a BCMAxCD3 bispecific It is an antibody.

[0286] In some embodiments, the T cell redirecting therapeutic is a GPRC5DxCD3 bispecific It is an anti-antibody.

[0287] In some embodiments, the T cell redirecting therapeutic is a CD33xCD3 bispecific an antibody, In some embodiments, the T cell redirecting therapeutic is a CD19xCD3 bispecific It is an antibody.

[0288] In some embodiments, the T cell redirecting therapeutic is a CD123xCD3 bispecific It is a sexual antibody.

[0289] In some embodiments, the T cell redirecting therapeutic is a PSMAxCD3 bispecific It is an antibody.

[0290] In some embodiments, the T cell redirecting therapeutic comprises a TMEFF2xCD3 bispecific It is an anti-antibody.

[0291] In some embodiments, the methods include administering to the subject one or more anti-cancer therapies. Also includes:

[0292] In some embodiments, the one or more anti-cancer therapies include autologous stem cell transplantation. US stem cell transplant (ASCT), radiation, surgery, chemotherapy, immunomodulatory agents, and targeted cancer therapies.

[0293] In some embodiments, the one or more anti-cancer therapies include autologous stem cell transplantation (ASCT). In some embodiments, the one or more anti-cancer treatments is radiation. In some embodiments, the one or more anti-cancer treatments is surgery. In some embodiments, the one or more anti-cancer therapies are chemotherapeutic agents. One or more anti-cancer therapies are immunomodulatory agents. In some embodiments, one or more The two or more anti-cancer treatments are targeted cancer therapies.

[0294] In some embodiments, the one or more anticancer therapies include lenalidomide, thalidomide, , pomalidomide, bortezomib, carfilzomib, elotozumab, ixazomib, Lupharan, dexamethasone, vincristine, cyclophosphamide, hydroxydauno Rubicin, prednisone, rituximab, imatinib, dasatinib, nilotinib, bosutiib nib, ponatinib, bafetinib, saracatinib, tozasertib, or danusertib , cytarabine, daunorubicin, idarubicin, mitoxantrone, hydroxyurea, Decitabine, cladribine, fludarabine, topotecan, etoposide 6-thioguanine, Corticosteroids, methotrexate, 6-mercaptopurine, azacitidine trioxide arsenic, and all-trans retinoic acid, or any combination thereof. It is selected.

[0295] In some embodiments, the anti-CD38 antibody is administered at a dose of about 8 mg / kg to about 16 mg / kg. It is administered in doses.

[0296] In some embodiments, the anti-CD38 antibody is dissolved in about 25 mM acetic acid, about 60 mM sodium chloride, sodium, about 140g mannitol, and about 0.04% w / v polysorbate-20 (po Approximately 20 mg / mL to approximately 120 mg / mL of anti-CD38 antibody in lysorptiform lysorptiform 20 (PS-20). and a pH of about 5.5. It is served.

[0297] In some embodiments, the anti-CD38 antibody comprises about 1,800 mg of anti-CD38 antibody and or in a pharmaceutical composition containing about 30,000 U of rHuPH20. is provided for.

[0298] In some embodiments, the anti-CD38 antibody is about 120 mg / mL of anti-CD38 antibody and and about 2,000 U / mL of rHuPH20; or provided for administration.

[0299] In some embodiments, the -CD38 antibody about 5 mM to about 15 mM histidine, about 100 mM to about 300 mM sorbitol; Approximately 0.01% w / v to approximately 0.04% w / v of PS-20, It contains about 1 mg / mL to about 2 mg / mL of methionine and has a pH of about 5.5 to 5.6. , administered or presented for administration in a pharmaceutical composition.

[0300] In some embodiments, the anti-CD38 antibody Approximately 1,800 mg of anti-CD38 antibody, Approximately 30,000 U of rHuPH20 and Approximately 10 mM histidine, about 300 mM sorbitol; Approximately 0.04% (w / v) PS-20, about 1 mg / mL methionine and a pH of about 5.6. or provided for administration.

[0301] In some embodiments, the anti-CD38 antibody Approximately 120 mg / mL of anti-CD38 antibody; Approximately 2,000 U / mL of rHuPH20 and Approximately 10 mM histidine, about 300 mM sorbitol; Approximately 0.04% (w / v) PS-20, about 1 mg / mL methionine and a pH of about 5.6. or provided for administration.

[0302] Combination of anti-CD38 antibody and BCMAxCD3 bispecific antibody The present disclosure also provides a method of treating cancer in a subject, comprising administering a therapeutically effective amount of BCMAx administering a CD3 bispecific antibody and an anti-CD38 antibody to a subject to treat cancer. A method is also provided.

[0303] The present disclosure also provides a method of treating cancer in a subject, comprising administering a therapeutically effective amount of BCMAx administering a CD3 bispecific antibody to a subject to treat cancer, wherein the subject is Also provided are methods wherein the subject is treated with an anti-CD38 antibody prior to administration of the CD3 bispecific antibody.

[0304] The present disclosure also provides a method of treating cancer in a subject, comprising administering a therapeutically effective amount of BCMAx administering a CD3 bispecific antibody to a subject to treat cancer, wherein the subject has previously undergone anti-cancer therapy. Also provided are methods in which the cancer is relapsed or refractory to treatment with a therapeutic agent.

[0305] T cell redirecting therapies, such as BCMA×CD3 bispecific antibodies such as JNJ-957 The drug redirects T cells to BCMA-positive tumor cells, such as multiple myeloma cells, and then , perforin / granzyme release or activation of the FASL / FAS pathway, and ultimately This is followed by the death of BCMA-positive tumor cells. Therefore, BCMA × CD3 bispecific antibodies, etc. The efficacy of T cell redirecting therapeutics depends on the availability and activity of recruited T cells, as well as This is primarily influenced by the possible regulated expression of tumor-associated antigens such as BCMA on tumor cells. obtain.

[0306] In some embodiments, the cancer is a BCMA-expressing cancer.

[0307] B-cell maturation antigen (BCMA) binds B cells to plasma cells. BCMA is a cell membrane-bound tumor necrosis factor receptor family member involved in differentiation. Expression is restricted to the B cell lineage, where it is primarily located within the intrafollicular regions of germinal centers and BCMA is expressed on differentiated plasma cells and plasmablasts. It is expressed on naive and memory B cells. It is virtually absent on cells (Tai and Anderson, Immunotherapy rapy 7:1187-99,2015).

[0308] In some embodiments, the cancer is a hematological malignancy.

[0309] In some embodiments, the cancer is multiple myeloma, smoldering multiple myeloma, benign monoclonal antibody Myeloadenopathy of Congenital Gammaglobulinemia (MGUS), B-cell acute lymphoblastic leukemia, diffuse large cell lymphoma B-cell lymphoma, Burkitt lymphoma, follicular lymphoma, mantle cell lymphoma, Wart lymphoma Denström's hypergammaglobulinemia, plasma cell leukemia, light chain amyloidosis, or Non-Hodgkin's lymphoma. An experienced doctor will diagnose the cancer.

[0310] In some embodiments, the subject is receiving anti-CD38 antibody or lenalidomide, or The patient is relapsed or refractory to treatment with a combination of

[0311] In some embodiments, the subject is a patient who has relapsed or is refractory to treatment with an anti-CD38 antibody. In some embodiments, the subject has relapsed or refractory disease to treatment with lenalidomide. It is treatable.

[0312] In some embodiments, the subject is receiving chemotherapy for the treatment of multiple myeloma or other hematological malignancies. relapsed or refractory to treatment with previous anti-cancer drugs, such as those used in .

[0313] In some embodiments, the subject is receiving THALOMID® (thalidomide), REVLIMID® (lenalidomide), POMALYST® (pomalyzed Lidomide), VELCADE® (bortezomib), NINLARO (ixazomib) (carfilzomib), KYPROLIS® (carfilzomib), FARADYK® (registered trademark) (Panonostat), AREDIA® (Pamidronate), ZOMETA (R) (zoledronic acid), DARZALEX® (daratumumab), ERO Refractory or relapsed to treatment with tozumab or melphalan.

[0314] In some embodiments, the subject is taking DARZALEX® (daratumumab). It is recurrent to treatment with

[0315] In some embodiments, the BCMAxCD3 bispecific antibody and the anti-CD38 antibody are Exemplary antigen-binding fragments are Fab, F(ab'), Fd, and Fv. It is a fragment.

[0316] In some embodiments, the BCMAxCD3 bispecific antibody is chimeric, humanized, or Human.

[0317] In some embodiments, the BCMAxCD3 bispecific antibody is selected from the group consisting of IgG1, IgG2, It is an IgG3 or IgG4 isotype.

[0318] In some embodiments, the BCMAxCD3 bispecific antibody is an IgG4 isotype is.

[0319] In some embodiments, the BCMAxCD3 bispecific antibody comprises the HCD of SEQ ID NO: 23. R1, HCDR2 of SEQ ID NO: 24, HCDR3 of SEQ ID NO: 25, LCDR of SEQ ID NO: 26 1, a BCMA-binding domain comprising an LCDR2 of SEQ ID NO: 27 and an LCDR3 of SEQ ID NO: 28 HCDR1 of SEQ ID NO: 33, HCDR2 of SEQ ID NO: 34, H of SEQ ID NO: 35 CDR3 of SEQ ID NO: 36, LCDR1 of SEQ ID NO: 37, and LCDR2 of SEQ ID NO: 38 Contains the CD3 binding domain containing LCDR3.

[0320] In some embodiments, the BCMA binding domain comprises a VH of SEQ ID NO: 29 and a VH of SEQ ID NO: 30 VL, and the CD3 binding domain comprises a VH of SEQ ID NO: 39 and a VL of SEQ ID NO: 40 Includes.

[0321] In some embodiments, the BCMAxCD3 bispecific antibody is an IgG4 isotype and the first heavy chain (HC1) contains a phenylalanine at position 405 and an arginine at position 409. and the second heavy chain (HC2) contains a leucine at position 405 and a lysine at position 409, The numbering follows the EU index.

[0322] In some embodiments, the BCMAxCD3 bispecific antibody comprises both HC1 and HC2. It further contains a proline at position 228, an alanine at position 234, and an alanine at position 235.

[0323] In some embodiments, the BCMAxCD3 bispecific antibody comprises HC1 of SEQ ID NO: 31. , the first light chain (LC1) of SEQ ID NO: 32, the second light chain (LC2) of SEQ ID NO: 41, and the third light chain (LC3) of SEQ ID NO: 42. It contains two light chains (LC2).

[0324] In some embodiments, the BCMAxCD3 bispecific antibody is BI836909, P F-06863135, AMG-701, or CC-93269.

[0325] In some embodiments, the anti-CD38 antibody comprises HCDR1 of SEQ ID NO: 6, HCDR2 of SEQ ID NO: 7 HCDR2, HCDR3 of SEQ ID NO: 8, LCDR1 of SEQ ID NO: 9, LCD of SEQ ID NO: 10 R2, and LCDR3 of SEQ ID NO:11.

[0326] In some embodiments, the anti-CD38 antibody comprises a VH of SEQ ID NO: 4 and a VL of SEQ ID NO: 5. Includes.

[0327] In some embodiments, the anti-CD38 antibody has a heavy chain (HC) of SEQ ID NO: 12 and a Contains light chain (LC) No. 13.

[0328] In some embodiments, the anti-CD38 antibody is DARZALEX® (Darzalex Mumab).

[0329] In some embodiments, the anti-CD38 antibody VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15, VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17, VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or It comprises a VH of SEQ ID NO:20 and a VL of SEQ ID NO:21.

[0330] In some embodiments, the anti-CD38 antibody is chimeric, humanized, or human.

[0331] In some embodiments, the anti-CD38 antibody is an IgG1, IgG2, IgG3, or IgG1 antibody. It is the gG4 isotype.

[0332] In some embodiments, the anti-CD38 antibody is of the IgG1 isotype.

[0333] In some embodiments, the anti-CD38 antibody is administered at a dose of about 8 mg / kg to about 16 mg / kg. It is administered in doses.

[0334] In some embodiments, the BCMAxCD3 bispecific antibody and the anti-CD38 antibody are administered intravenously. It is administered by intravenous injection.

[0335] In some embodiments, the BCMAxCD3 bispecific antibody is administered by intravenous injection. The anti-CD38 antibody is administered by subcutaneous injection.

[0336] In some embodiments, the BCMAxCD3 bispecific antibody and the anti-CD38 antibody are administered intradermally. It is administered by subcutaneous injection.

[0337] In some embodiments, the methods include administering to the subject one or more anti-cancer therapies. Also includes:

[0338] In some embodiments, the one or more anti-cancer therapies include autologous stem cell transplantation (ASCT). ), radiation, surgery, chemotherapy, immunomodulatory agents, and targeted cancer therapy. do.

[0339] In some embodiments, the one or more anticancer therapies include lenalidomide, thalidomide, , pomalidomide, bortezomib, carfilzomib, elotozumab, ixazomib, Lupharom, prednisone, or dexamethasone, or any combination thereof is selected from the group consisting of:

[0340] In some embodiments, the anti-CD38 antibody is dissolved in about 25 mM acetic acid, about 60 mM sodium chloride, sodium, about 140g mannitol, and about 0.04% w / v polysorbate-20 (P S-20), containing approximately 20 mg / mL to approximately 120 mg / mL of anti-CD38 antibody, at a pH of approximately 5.5, administered or provided for administration in a pharmaceutical composition.

[0341] In some embodiments, the anti-CD38 antibody comprises about 1,800 mg of anti-CD38 antibody and or in a pharmaceutical composition containing about 30,000 U of rHuPH20. is provided for.

[0342] In some embodiments, the anti-CD38 antibody is about 120 mg / mL of anti-CD38 antibody and and about 2,000 U / mL of rHuPH20; or provided for administration.

[0343] In some embodiments, the anti-CD38 antibody about 5 mM to about 15 mM histidine, about 100 mM to about 300 mM sorbitol; Approximately 0.01% w / v to approximately 0.04% w / v of PS-20, It contains about 1 mg / mL to about 2 mg / mL of methionine and has a pH of about 5.5 to 5.6. , administered or presented for administration in a pharmaceutical composition.

[0344] In some embodiments, the anti-CD38 antibody Approximately 1,800 mg of anti-CD38 antibody, Approximately 30,000 U of rHuPH20 and Approximately 10 mM histidine, about 300 mM sorbitol; Approximately 0.04% (w / v) PS-20, about 1 mg / mL methionine and a pH of about 5.6. or provided for administration.

[0345] In some embodiments, the anti-CD38 antibody Approximately 120 mg / mL of anti-CD38 antibody; Approximately 2,000 U / mL of rHuPH20 and Approximately 10 mM histidine, about 300 mM sorbitol; Approximately 0.04% (w / v) PS-20, about 1 mg / mL methionine and a pH of about 5.6. or provided for administration.

[0346] BCMAxCD3 bispecific antibodies given to subjects with cancer, such as multiple myeloma, and The dose of anti-CD38 antibody is selected to alleviate or at least partially alleviate the disease being treated. A therapeutically effective amount is sufficient to prevent g, for example, about 0.05 mg to about 30 mg / kg or about 5 mg to about 25 mg / kg, or about 4 mg / kg, about 8 mg / kg, about 16 mg / kg, or about 24 mg / kg Suitable doses include, for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 1 0, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 40 , 50, 60, 70, 80, 90, or 100 mg / kg.

[0347] A fixed unit dose of BCMAxCD3 bispecific antibody and / or anti-CD38 antibody, e.g., Doses of 50, 100, 200, 500, or 1000 mg may be administered, or Doses are based on the patient's surface area, e.g., 500, 400, 300, 250, 200 , or 100 mg / m 2 Typically, to treat cancers such as multiple myeloma Between 1 and 8 doses (e.g., 1, 2, 3, 4, 5, 6, 7, or 8 doses) may be administered. But 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 times, or Higher doses may be given.

[0348] The BCMAxCD3 bispecific antibody and / or anti-CD38 antibody were administered on days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, Days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, 2 The treatment may be repeated after 3, 4, 5, 6, or more months. Repeated administration may be performed at the same dose, and long-term administration is also possible. For example, a BCMAxCD3 bispecific antibody and an anti- CD38 antibody was administered by intravenous infusion at 8 mg / kg or 16 mg / kg every 8 weeks. 1 week, followed by 1 additional dose at 8 mg / kg or 16 mg / kg every 2 weeks. Administered for 6 weeks, then 8 mg / kg or 16 mg / kg every 4 weeks It can be done.

[0349] The BCMAxCD3 bispecific antibody and the anti-CD38 antibody may be administered for, e.g., 6 months or more. For example, BCMAxCD may be administered by maintenance therapy, such as once weekly for a period of 3 Bispecific antibodies and anti-CD38 antibodies were administered as a single dose every 24, 12, 8, 6, 4, or 2 hours. about 0.1 mg / dose, using a single dose or divided doses, or a combination thereof A daily dosage of about 100 mg / kg to about 100 mg / kg may be administered, for example, at 0.5, 0.9, or 100 mg / kg per day. , 1.0, 1.1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 , 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90 or 100 mg / kg, after the start of treatment, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 2 7, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or On at least one of the 40 days, or on the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, During the 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, or 20th week may be provided at least once a week, or any combination thereof.

[0350] BCMAxCD3 bispecific antibodies and anti-CD38 antibodies also have potential therapeutic applications in treating cancers such as multiple myeloma. Reduce the risk of developing cancer, delay the onset of events in the progression of cancer, and / or may also be administered prophylactically to reduce the risk of recurrence once the cancer goes into remission.

[0351] In some embodiments, the BCMAxCD3 bispecific antibody is administered to a subject via administration of an anti-CD38 antibody The BCMA×CD3 bispecific antibody is administered to a subject after administration of an anti-CD38 antibody. After administration, 1 week, 2 weeks, 3 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, 2 months, and 3 months , 4 months, 5 months, 6 months, or more. Subjects receiving BCMAxCD3 antibodies are resistant to and / or resistant to treatment with anti-CD38 antibodies. Or it is intractable.

[0352] The present invention also provides a BCMA-binding domain comprising a VH of SEQ ID NO: 29 and a VL of SEQ ID NO: 30. and a CD3 binding domain comprising a VH of SEQ ID NO: 39 and a VL of SEQ ID NO: 40. BCMAxCD3 bispecific antibody and anti-C antibody comprising VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5 Also provided are pharmaceutical compositions comprising the D38 antibody.

[0353] In some embodiments, the pharmaceutical composition comprises an HC1 of SEQ ID NO: 31, an LC of SEQ ID NO: 32, 1. BCMA×CD3 bispecific antibody comprising HC2 of SEQ ID NO: 41 and LC2 of SEQ ID NO: 42 and an anti-CD38 antibody comprising the HC of SEQ ID NO:12 and the LC of SEQ ID NO:13.

[0354] In some embodiments, the pharmaceutical composition is a non-fixed combination.

[0355] In some embodiments, the pharmaceutical composition comprises about 25 mM acetic acid, about 60 mM sodium chloride, mannitol, and about 0.04% w / v polysorbate-20 (PS- 20) containing approximately 20 mg / mL to approximately 120 mg / mL of anti-CD38 antibody, pH approximately 5. It is 5.

[0356] BCMAxCD3 bispecific antibodies, about 20 mg / mL to about 120 mg / mL of antibody; Acetic acid, histidine, sodium chloride, mannitol, and / or polysorbate-20 It can be formulated as a pharmaceutical composition containing

[0357] In some embodiments, the pharmaceutical composition comprises about 1,800 mg of an anti-CD38 antibody and about 3 Contains 0,000U of rHuPH20.

[0358] In some embodiments, the pharmaceutical composition comprises about 120 mg / mL of an anti-CD38 antibody and about Contains 2,000 U / mL rHuPH20.

[0359] In some embodiments, the pharmaceutical composition further comprises one or more excipients.

[0360] In some embodiments, the one or more excipients are histidine, methionine, sodium sorbitol, or polysorbate-20 (PS-20), or any combination thereof It is a combination.

[0361] In some embodiments, the pharmaceutical composition comprises: About 100 mg / mL to about 120 mg / mL formulated in about 5 mM to about 15 mM histidine and anti-CD38 antibody at 100 mg / mL. about 100 mM to about 300 mM sorbitol; Approximately 0.01% w / v to approximately 0.04% w / v of PS-20, It contains about 1 mg / mL to about 2 mg / mL of methionine and has a pH of about 5.5 to 5.6. .

[0362] In some embodiments, the pharmaceutical composition comprises about 10 mM histidine.

[0363] In some embodiments, the pharmaceutical composition comprises about 300 mM sorbitol.

[0364] In some embodiments, the pharmaceutical composition comprises about 0.04% (w / v) PS-20. .

[0365] In some embodiments, the pharmaceutical composition comprises about 1 mg / mL of methionine.

[0366] In some embodiments, the pharmaceutical composition comprises: Approximately 1,800 mg of anti-CD38 antibody, Approximately 30,000 U of rHuPH20 and Approximately 10 mM histidine, about 300 mM sorbitol; Approximately 0.04% (w / v) PS-20, It contains about 1 mg / mL of methionine and has a pH of about 5.6.

[0367] In some embodiments, the pharmaceutical composition comprises: Approximately 120 mg / mL of anti-CD38 antibody; Approximately 2,000 U / mL of rHuPH20 and Approximately 10 mM histidine, about 300 mM sorbitol; Approximately 0.04% (w / v) PS-20, It contains about 1 mg / mL of methionine and has a pH of about 5.6.

[0368] The present disclosure also provides a pharmaceutical composition comprising a BCMAxCD3 bispecific antibody and an anti-CD38 antibody. Also provided is a kit comprising:

[0369] Treatment with BCMAxCD3 bispecific antibodies in relapsed or refractory subjects The present disclosure also provides a method of treating cancer in a subject, comprising administering a therapeutically effective amount of BCMAx administering a CD3 bispecific antibody to a subject to treat cancer, wherein the subject has previously undergone anti-cancer therapy. Also provided are methods in which the cancer is relapsed or refractory to treatment with a therapeutic agent.

[0370] In some embodiments, the BCMAxCD3 bispecific antibody comprises the HCD of SEQ ID NO: 23. R1, HCDR2 of SEQ ID NO: 24, HCDR3 of SEQ ID NO: 25, LCDR of SEQ ID NO: 26 1, a BCMA-binding domain comprising an LCDR2 of SEQ ID NO: 27 and an LCDR3 of SEQ ID NO: 28 HCDR1 of SEQ ID NO: 33, HCDR2 of SEQ ID NO: 34, H of SEQ ID NO: 35 CDR3 of SEQ ID NO: 36, LCDR1 of SEQ ID NO: 37, and LCDR2 of SEQ ID NO: 38 Contains the CD3 binding domain containing LCDR3.

[0371] In some embodiments, the BCMA binding domain comprises a VH of SEQ ID NO: 29 and a VH of SEQ ID NO: 30 VL, and the CD3 binding domain comprises a VH of SEQ ID NO: 39 and a VL of SEQ ID NO: 40 Includes.

[0372] In some embodiments, the BCMAxCD3 bispecific antibody is an IgG4 isotype phenylalanine at position 405 and arginine at position 409 of HC1, and The residue numbering is based on the EU index. Follow the instructions.

[0373] In some embodiments, the BCMAxCD3 bispecific antibody comprises both HC1 and HC2. It further contains a proline at position 228, an alanine at position 234, and an alanine at position 235.

[0374] In some embodiments, the BCMAxCD3 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.

[0375] In some embodiments, the cancer is a hematological malignancy.

[0376] In some embodiments, the hematological malignancy is multiple myeloma.

[0377] In some embodiments, the multiple myeloma is high-risk multiple myeloma.

[0378] In some embodiments, the subject with high-risk multiple myeloma is 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 de have one or more chromosomal abnormalities including l17p, l18p, or any combination of these .

[0379] In some embodiments, the subject is receiving anti-CD38 antibody, lenalidomide, bortezomib, or poliovirus. Maridomide, carfilzomib, elotozumab, ixazomib, melphalan, or relapsed or refractory to treatment with thalidomide, or any combination thereof .

[0380] In some embodiments, the subject is a patient with 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 relapses or fails to respond to treatment with pomalidomide. In some embodiments, the subject is refractory to treatment with carfilzomib. In some embodiments, the subject is relapsed or refractory to treatment with elotozumab. In some embodiments, the subject is relapsed or refractory to treatment with ixazomib. In some embodiments, the subject is relapsed or refractory to melphalan. In some embodiments, the subject is relapsed or refractory to thalidomide. The disease is recurrent or refractory to treatment with steroids.

[0381] In some embodiments, the subject is relapsed to treatment with the anti-CD38 antibody.

[0382] In some embodiments, the anti-CD38 antibody comprises HCDR1 of SEQ ID NO: 6, HCDR2 of SEQ ID NO: 7 HCDR2, HCDR3 of SEQ ID NO: 8, LCDR1 of SEQ ID NO: 9, LCD of SEQ ID NO: 10 R2, and LCDR3 of SEQ ID NO:11.

[0383] In some embodiments, the anti-CD38 antibody comprises a VH of SEQ ID NO: 4 and a VL of SEQ ID NO: 5. Includes.

[0384] In some embodiments, the anti-CD38 antibody is of the IgG1 isotype.

[0385] In some embodiments, the anti-CD38 antibody comprises the HC of SEQ ID NO: 12 and the HC of SEQ ID NO: 13. Contains LC.

[0386] In some embodiments, the anti-CD38 antibody VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15, VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17, VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or It comprises a VH of SEQ ID NO:20 and a VL of SEQ ID NO:21.

[0387] In some embodiments, the anti-CD38 antibody is of the IgG1 isotype.

[0388] In some embodiments, the subject is a human.

[0389] In some embodiments, the methods include administering to the subject one or more anti-cancer therapies. Also includes:

[0390] In some embodiments, the one or more anti-cancer therapies include autologous stem cell transplantation (ASCT). ), radiation, surgery, chemotherapy, immunomodulatory agents, and targeted cancer therapy. do.

[0391] In some embodiments, the one or more anticancer therapies include lenalidomide, thalidomide, , pomalidomide, bortezomib, carfilzomib, elotozumab, ixazomib, Lupharom, prednisone, or dexamethasone, or any combination thereof is selected from the group consisting of:

[0392] Combination therapy with T cell redirecting therapeutic agents that bind to GPRC5D and anti-CD38 antibodies The present disclosure also provides a method of treating cancer in a subject, comprising administering a therapeutically effective amount of GPRC5 The T cell redirecting therapeutic agent that binds to D and an anti-CD38 antibody are administered to the subject to treat cancer. Also provided is a method comprising:

[0393] In some embodiments, the anti-CD38 antibody is a T cell redirecting antibody that binds to GPRC5D. The drug is administered to the subject prior to administration of the active therapeutic agent.

[0394] In some embodiments, the subject has relapsed or refractory disease to treatment with a previous anti-cancer therapeutic agent. It is sex.

[0395] In some embodiments, the cancer is a GPRC5D-expressing cancer.

[0396] In some embodiments, the GPRC5D-expressing cancer is a hematological malignancy or a solid tumor.

[0397] In some embodiments, the hematological malignancy is leukemia, lymphoma, or multiple myeloma. do.

[0398] In some embodiments, the hematological malignancy is leukemia. In some embodiments, the hematological malignancy is lymphoma. In some embodiments, the hematological malignancy is multiple bone marrow tumor. It is myeloma.

[0399] In some embodiments, the solid tumor is ovarian cancer, lung cancer, gastric cancer, prostate cancer, renal cancer, liver cancer, The cancer is pancreatic cancer, colon cancer, esophageal cancer, bladder cancer, cervical cancer, or malignant melanoma.

[0400] GPRC5D has been disclosed to be expressed in these tumors, and has been reported in, for example, See International Publication No. 2018 / 147245.

[0401] In some embodiments, the subject is receiving anti-CD38 antibody, lenalidomide, bortezomib, or poliovirus. Maridomide, carfilzomib, elotozumab, ixazomib, melphalan, or relapsed or refractory to treatment with thalidomide, or any combination thereof .

[0402] In some embodiments, the subject is a patient with 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 relapses or fails to respond to treatment with pomalidomide. In some embodiments, the subject is refractory to treatment with carfilzomib. In some embodiments, the subject is relapsed or refractory to treatment with elotozumab. In some embodiments, the subject is relapsed or refractory to treatment with ixazomib. In some embodiments, the subject is relapsed or refractory to melphalan. In some embodiments, the subject is relapsed or refractory to thalidomide. In some embodiments, the subject is relapsed or refractory to treatment with anti-CD38 Relapsed or refractory to antibody treatment.

[0403] In some embodiments, the multiple myeloma is newly diagnosed multiple myeloma.

[0404] In some embodiments, the multiple myeloma is relapsed or refractory multiple myeloma.

[0405] In some embodiments, the multiple myeloma is high-risk multiple myeloma.

[0406] In some embodiments, the subject with high-risk multiple myeloma is 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 de have one or more chromosomal abnormalities including l17p, l18p, or any combination of these .

[0407] In some embodiments, the T cell redirecting therapeutic is a T cell targeting antibody against CD3, CD3 epsilon ( CD3ε), CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, Binds to CD186, BTNL8, PD-1, CD195, or NKG2C.

[0408] In some embodiments, the T cell redirecting therapeutic 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, GPRC5D binding domain containing LCDR2 of SEQ ID NO: 47 and LCDR3 of SEQ ID NO: 48 and HCDR1 of SEQ ID NO: 33, HCDR2 of SEQ ID NO: 34, HCDR3 of SEQ ID NO: 35. DR3, LCDR1 of SEQ ID NO: 36, LCDR2 of SEQ ID NO: 37, and LCDR3 of SEQ ID NO: 38 It contains a CD3 binding domain including CDR3.

[0409] In some embodiments, the GPRC5D binding domain comprises a VH of SEQ ID NO: 49 and a VH of sequence the CD3 binding domain comprises a VL of SEQ ID NO: 50, a VH of SEQ ID NO: 39 and a VL of SEQ ID NO: 40 Contains VL.

[0410] In some embodiments, the T cell redirecting therapeutic that binds GPRC5C is a multimeric specific antibodies, CARs, or T cells expressing CARs.

[0411] In some embodiments, the multispecific antibody is an IgG1, IgG2, IgG3, or IgG1 antibody. It is the gG4 isotype.

[0412] 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 an IgG3 isotype. The specific antibody is of the IgG4 isotype.

[0413] In some embodiments, the multispecific antibody is a multispecific antibody Fcγ receptor (Fcγ R).

[0414] In some embodiments, the one or more Fc substitutions are F234A / L235A, L234A / L235A on IgG1, V234A / G237 on IgG2 A / P238S / H268A / V309L / A330S / P331S, F2 on IgG4 34A / L235A, S228P / F234A / L235A on IgG4, all IgA N297A on isotype, V234A / G237A on IgG2, K21 on IgG1 4T / E233P / L234V / L235A / G236 deletion / A327G / P331A / D365E / L358M, H268Q / V309L / A330S / P331 on IgG2 S, S267E / L328F on IgG1, L234F / L235E / D2 on IgG1 65A, L234A / L235A / G237A / P238S / H268A / on IgG1 A330S / P331S, S228P / F234A / L235A / G237 on IgG4 A / P238S and S228P / F234A / L235A / G236 deletion on IgG4 / G237A / P238S, and the residue numbering is according to the EU index. Follow the instructions.

[0415] In some embodiments, the multispecific antibody further comprises a S228P substitution.

[0416] In some embodiments, the multispecific antibody comprises a first CH3 domain or a second CH3 domain. In the H3 domain, or in both the first CH3 domain and the second CH3 domain, one or contains two or more asymmetric substitutions.

[0417] In some embodiments, the one or more asymmetric substitutions are F450L / K409R , wild type / F409L_R409K, T366Y / F405A, T366W / F405W , F405W / Y407A, T394W / Y407T, T394S / Y407A, T36 6W / T394S, F405W / T394S and T366W / T366S_L368A_ Y407V, L351Y_F405A_Y407V / T394W, T366I_K392 M_T394W / F405A_Y407V, T366L_K392M_T394W / F4 05A_Y407V, L351Y_Y407A / T366A_K409F, L351Y_ Y407A / T366V_K409F, Y407A / T366A_K409F, and T 350V_L351Y_F405A_Y407V / T350V_T366L_K392L _T394W.

[0418] In some embodiments, the multispecific antibody comprises HC1 of SEQ ID NO: 51, HC2 of SEQ ID NO: 52 LC1, HC2 of SEQ ID NO: 41, and LC2 of SEQ ID NO: 42.

[0419] In some embodiments, the anti-CD38 antibody comprises HCDR1 of SEQ ID NO: 6, HCDR2 of SEQ ID NO: 7 HCDR2, HCDR3 of SEQ ID NO: 8, LCDR1 of SEQ ID NO: 9, LCD of SEQ ID NO: 10 R2, and LCDR3 of SEQ ID NO:11.

[0420] In some embodiments, the anti-CD38 antibody comprises a VH of SEQ ID NO: 4 and a VL of SEQ ID NO: 5. Includes.

[0421] In some embodiments, the anti-CD38 antibody is of the IgG1 isotype.

[0422] In some embodiments, the anti-CD38 antibody comprises the HC of SEQ ID NO: 12 and the HC of SEQ ID NO: 13. Contains LC.

[0423] In some embodiments, the anti-CD38 antibody VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15, VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17, VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or It comprises a VH of SEQ ID NO:20 and a VL of SEQ ID NO:21.

[0424] In some embodiments, the anti-CD38 antibody is of the IgG1 isotype.

[0425] In some embodiments, the anti-CD38 antibody is administered at a dose of about 8 mg / kg to about 16 mg / kg. It is administered in doses.

[0426] In some embodiments, a T cell redirecting therapeutic that binds GPRC5D and an anti-C The D38 antibody is administered by intravenous injection.

[0427] In some embodiments, the T cell redirecting therapeutic that binds GPRC5D is administered intravenously. The anti-CD38 antibody is administered by intravenous injection, and the anti-CD38 antibody is administered by subcutaneous injection.

[0428] In some embodiments, a T cell redirecting therapeutic that binds GPRC5D and an anti-C The D38 antibody is administered by subcutaneous injection.

[0429] In some embodiments, the subject is a human.

[0430] In some embodiments, the T cell redirecting therapeutic that binds GPRC5D is It is a RC5D x CD3 bispecific antibody.

[0431] In some embodiments, the methods include administering to the subject one or more anti-cancer therapies. Also includes:

[0432] In some embodiments, the one or more anti-cancer therapies include autologous stem cell transplantation (ASCT). ), radiation, surgery, chemotherapy, immunomodulatory agents, and targeted cancer therapy. do.

[0433] In some embodiments, the one or more anticancer therapies include lenalidomide, thalidomide, , pomalidomide, bortezomib, carfilzomib, elotozumab, ixazomib, It is selected from the group consisting of flufenathan, dexamethasone, or prednisone.

[0434] In some embodiments, the anti-CD38 antibody is dissolved in about 25 mM acetic acid, about 60 mM sodium chloride, sodium, about 140g mannitol, and about 0.04% w / v polysorbate-20 (P S-20), containing approximately 20 mg / mL to approximately 120 mg / mL of anti-CD38 antibody, at a pH of approximately 5.5, administered or provided for administration in a pharmaceutical composition.

[0435] In some embodiments, the anti-CD38 antibody comprises about 1,800 mg of anti-CD38 antibody and or in a pharmaceutical composition containing about 30,000 U of rHuPH20. is provided for.

[0436] In some embodiments, the anti-CD38 antibody is about 120 mg / mL of anti-CD38 antibody and and about 2,000 U / mL of rHuPH20; or provided for administration.

[0437] In some embodiments, the anti-CD38 antibody about 100 mg / mL to about 120 mg / mL of an anti-CD38 antibody; about 5 mM to about 15 mM histidine, about 100 mM to about 300 mM sorbitol; Approximately 0.01% w / v to approximately 0.04% w / v of PS-20, It contains about 1 mg / mL to about 2 mg / mL of methionine and has a pH of about 5.5 to 5.6. , administered or presented for administration in a pharmaceutical composition.

[0438] In some embodiments, the anti-CD38 antibody Approximately 1,800 mg of anti-CD38 antibody, Approximately 30,000 U of rHuPH20 and Approximately 10 mM histidine, about 300 mM sorbitol; Approximately 0.04% (w / v) PS-20, about 1 mg / mL methionine and a pH of about 5.6. or provided for administration.

[0439] In some embodiments, the anti-CD38 antibody Approximately 120 mg / mL of anti-CD38 antibody; Approximately 2,000 U / mL of rHuPH20 and Approximately 10 mM histidine, about 300 mM sorbitol; Approximately 0.04% (w / v) PS-20, about 1 mg / mL methionine and a pH of about 5.6. or provided for administration.

[0440] The present disclosure also provides HCDR1 of SEQ ID NO: 43, HCDR2 of SEQ ID NO: 44, HCDR3 of SEQ ID NO: 45 HCDR3 of SEQ ID NO: 46, LCDR1 of SEQ ID NO: 47, and LCDR2 of SEQ ID NO: 4 GPRC5D binding domain containing LCDR3 of SEQ ID NO: 8, and HCDR1 of SEQ ID NO: 33, HCDR2 of sequence number 34, HCDR3 of sequence number 35, LCDR1 of sequence number 36, a CD3 binding domain comprising LCDR2 of SEQ ID NO: 37 and LCDR3 of SEQ ID NO: 38 GPRC5D×CD3 bispecific antibody and HCDR1 of SEQ ID NO: 6, HCDR of SEQ ID NO: 7 R2, HCDR3 of SEQ ID NO: 8, LCDR1 of SEQ ID NO: 9, LCDR2 of SEQ ID NO: 10, and an anti-CD38 antibody comprising an LCDR3 of SEQ ID NO: 11. do.

[0441] In some embodiments, the GPRC5D binding domain comprises a VH of SEQ ID NO: 49 and a VH of sequence the CD3 binding domain comprises a VL of SEQ ID NO: 50, a VH of SEQ ID NO: 39 and a VL of SEQ ID NO: 40 The anti-CD38 antibody comprises a VH of SEQ ID NO:4 and a VL of SEQ ID NO:5.

[0442] In some embodiments, the GPRC5DxCD3 bispecific antibody comprises H of SEQ ID NO: 51 C1, LC1 of SEQ ID NO: 52, HC2 of SEQ ID NO: 41, LC2 of SEQ ID NO: 42, The CD38 antibody comprises an HC of SEQ ID NO:12 and an LC of SEQ ID NO:13.

[0443] In some embodiments, the pharmaceutical combination is a non-fixed combination.

[0444] In some embodiments, the pharmaceutical combination comprises about 25 mM acetic acid, about 60 mM sodium chloride sodium, about 140g mannitol, and about 0.04% w / v polysorbate-20 (P S-20), containing approximately 20 mg / mL to approximately 120 mg / mL of anti-CD38 antibody, at a pH of approximately It's 5.5.

[0445] In some embodiments, the pharmaceutical combination comprises about 1,800 mg of an anti-CD38 antibody and Contains approximately 30,000 U of rHuPH20.

[0446] In some embodiments, the pharmaceutical combination comprises about 120 mg / mL of an anti-CD38 antibody and and approximately 2,000 U / mL of rHuPH20.

[0447] In some embodiments, the pharmaceutical combination further comprises one or more excipients.

[0448] In some embodiments, the one or more excipients are histidine, methionine, sodium sorbitol, or polysorbate-20 (PS-20), or any combination thereof It is a combination.

[0449] In some embodiments, the pharmaceutical composition comprises: about 100 mg / mL to about 120 mg / mL of an anti-CD38 antibody; about 5 mM to about 15 mM histidine, about 100 mM to about 300 mM sorbitol; Approximately 0.01% w / v to approximately 0.04% w / v of PS-20, It contains about 1 mg / mL to about 2 mg / mL of methionine and has a pH of about 5.5 to 5.6. .

[0450] In some embodiments, the pharmaceutical combination comprises about 10 mM histidine.

[0451] In some embodiments, the pharmaceutical combination comprises about 300 mM sorbitol.

[0452] In some embodiments, the pharmaceutical combination comprises about 0.04% (w / v) PS-20. include.

[0453] In some embodiments, the pharmaceutical combination comprises about 1 mg / mL of methionine.

[0454] In some embodiments, the pharmaceutical combination comprises: Approximately 1,800 mg of anti-CD38 antibody, Approximately 30,000 U of rHuPH20 and Approximately 10 mM histidine, about 300 mM sorbitol; Approximately 0.04% (w / v) PS-20, It contains about 1 mg / mL of methionine and has a pH of about 5.6.

[0455] In some embodiments, the pharmaceutical combination comprises: Approximately 120 mg / mL of anti-CD38 antibody; Approximately 2,000 U / mL of rHuPH20 and Approximately 10 mM histidine, about 300 mM sorbitol; Approximately 0.04% (w / v) PS-20, It contains about 1 mg / mL of methionine and has a pH of about 5.6.

[0456] The present disclosure also provides T cell redirecting therapeutics and anti-CD38 antibodies that bind to GPRC5D. Also provided is a pharmaceutical combination comprising:

[0457] Treatment with GPRC5DxCD3 bispecific antibody in relapsed or refractory subjects The present disclosure also provides a method of treating cancer in a subject, comprising administering a therapeutically effective amount of GPRC5 administering a DxCD3 bispecific antibody to a subject to treat cancer, wherein the subject has previously Also provided are methods for treating cancer that is relapsed or refractory to treatment with an anti-cancer therapeutic agent.

[0458] In some embodiments, the GPRC5DxCD3 bispecific antibody comprises H of SEQ ID NO: 43 CDR1, HCDR2 of SEQ ID NO: 44, HCDR3 of SEQ ID NO: 45, LC of SEQ ID NO: 46 GPRC5D comprising LCDR1, LCDR2 of SEQ ID NO: 47, and LCDR3 of SEQ ID NO: 48 The binding domain, as well as HCDR1 of SEQ ID NO: 33, HCDR2 of SEQ ID NO: 34, 35, LCDR1 of SEQ ID NO: 36, LCDR2 of SEQ ID NO: 37, and It contains a CD3 binding domain containing LCDR3 of No. 38.

[0459] In some embodiments, the GPRC5D binding domain comprises a VH of SEQ ID NO: 49 and a VH of sequence the CD3 binding domain comprises a VL of SEQ ID NO: 50, a VH of SEQ ID NO: 39 and a VL of SEQ ID NO: 40 Contains VL.

[0460] In some embodiments, the GPRC5DxCD3 bispecific antibody is an IgG4 isotype. phenylalanine at position 405 and arginine at position 409 of HC1, and C2 contains a leucine at position 405 and a lysine at position 409, and the residue numbering is based on the EU index. Follow the instructions.

[0461] In some embodiments, the GPRC5DxCD3 bispecific antibody comprises HC1 and HC2 and further containing a proline at position 228, an alanine at position 234, and an alanine at position 235. .

[0462] In some embodiments, the GPRC5DxCD3 bispecific antibody comprises H of SEQ ID NO: 51 C1, LC1 of SEQ ID NO: 52, HC2 of SEQ ID NO: 41, and LC2 of SEQ ID NO: 42 .

[0463] In some embodiments, the cancer is a hematological malignancy or a solid tumor.

[0464] In some embodiments, the cancer is multiple myeloma, lymphoma, melanoma, breast cancer, endometrial cancer. , ovarian cancer, lung cancer, stomach cancer, prostate cancer, kidney cancer, liver cancer, pancreatic cancer, colon cancer, esophageal cancer, bladder cancer, or children. It is cervical cancer.

[0465] In some embodiments, the multiple myeloma is high-risk multiple myeloma.

[0466] In some embodiments, the subject with high-risk multiple myeloma is 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 de have one or more chromosomal abnormalities including l17p, l18p, or any combination of these .

[0467] In some embodiments, the subject is receiving anti-CD38 antibody, lenalidomide, bortezomib, or poliovirus. Maridomide, carfilzomib, elotozumab, ixazomib, melphalan, or refractory or relapsed to treatment with thalidomide, or any combination thereof .

[0468] In some embodiments, the subject is a patient who has relapsed or is refractory to treatment with an anti-CD38 antibody. is.

[0469] In some embodiments, the anti-CD38 antibody comprises HCDR1 of SEQ ID NO: 6, HCDR2 of SEQ ID NO: 7 HCDR2, HCDR3 of SEQ ID NO: 8, LCDR1 of SEQ ID NO: 9, LCD of SEQ ID NO: 10 R2, and LCDR3 of SEQ ID NO:11.

[0470] In some embodiments, the anti-CD38 antibody comprises a VH of SEQ ID NO: 4 and a VL of SEQ ID NO: 5. Includes.

[0471] In some embodiments, the anti-CD38 antibody is of the IgG1 isotype.

[0472] In some embodiments, the anti-CD38 antibody comprises the HC of SEQ ID NO: 12 and the HC of SEQ ID NO: 13. Contains LC.

[0473] In some embodiments, the anti-CD38 antibody VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15, VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17, VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or It comprises a VH of SEQ ID NO:20 and a VL of SEQ ID NO:21.

[0474] In some embodiments, the anti-CD38 antibody is of the IgG1 isotype.

[0475] In some embodiments, the subject is a human.

[0476] In some embodiments, the methods include administering to the subject one or more anti-cancer therapies. Also includes:

[0477] In some embodiments, the one or more anti-cancer therapies include autologous stem cell transplantation (ASCT). ), radiation, surgery, chemotherapy, immunomodulatory agents, and targeted cancer therapy. do.

[0478] In some embodiments, the one or more anticancer therapies include lenalidomide, thalidomide, , pomalidomide, bortezomib, carfilzomib, elotozumab, ixazomib, Lupharan, dexamethasone, vincristine, cyclophosphamide, hydroxydauno Rubicin, prednisone, rituximab, imatinib, dasatinib, nilotinib, bosutiib nib, ponatinib, bafetinib, saracatinib, tozasertib, or danusertib , cytarabine, daunorubicin, idarubicin, mitoxantrone, hydroxyurea, Decitabine, cladribine, fludarabine, topotecan, etoposide 6-thioguanine, Corticosteroids, methotrexate, 6-mercaptopurine, azacitidine trioxide arsenic, and all-trans retinoic acid, or any combination thereof. It is selected.

[0479] Combination therapy with CD19-binding T cell redirecting therapeutic agents and anti-CD38 antibodies The present disclosure also provides a method of treating cancer in a subject, comprising administering a therapeutically effective amount of CD19 to a subject. A T cell redirecting therapeutic agent and an anti-CD38 antibody combined are administered to a subject to treat cancer. Also provided is a method, which includes:

[0480] In some embodiments, the subject receives administration of a T cell redirecting therapeutic that binds to CD19. The patient had been treated with anti-CD38 antibody before administration.

[0481] The present disclosure also provides a method for redirecting T cells that bind to CD19 in a subject with cancer. a method for improving the efficacy of a T cell-redirecting therapeutic agent that binds to CD19, comprising administering the agent to a subject; Also provided are methods comprising administering an anti-CD38 antibody to the subject prior to administering the drug.

[0482] In some embodiments, the subject has relapsed or refractory disease to treatment with a previous anti-cancer therapeutic agent. It is sex.

[0483] In some embodiments, the cancer is a hematological malignancy or a solid tumor.

[0484] In some embodiments, the hematological malignancy is lymphoma, B-cell malignancy, Hodgkin's lymphoma, or lymphoma, non-Hodgkin's lymphoma, DLBLC, FL, MCL, marginal zone B-cell lymphoma (MZL) ), mucosa-associated lymphoid tissue lymphoma (MALT), CLL, ALL, AML, Waldenstrom Rehm's hypergammaglobulinemia or T-cell lymphoma.

[0485] In some embodiments, the solid tumor is lung cancer, liver cancer, cervical cancer, colon cancer, breast cancer, or ovarian cancer. , pancreatic cancer, melanoma, glioblastoma, prostate cancer, esophageal cancer, or gastric cancer. International Publication No. 2019 / 057124(A1) is a treatment with a T cell redirecting therapeutic agent that binds to CD19. The present invention discloses cancers suitable for

[0486] In some embodiments, the T cell redirecting therapeutic is a CD3 epsilon (CD3ε ), CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD18 6, binds to BTNL8, PD-1, CD195, or NKG2C.

[0487] In some embodiments, the T cell redirecting therapeutic that binds CD19 is Momab, axicabtagene ciloleucel, tisagenlecleucel-t, inebilizumab , Lysocabtagene Maraleucel, XmAb-5574, CIK-CAR.CD19, I CTCAR-011, IM-19, JCAR-014, loncastuximab tesirine, M B-CART2019.1, OXS-1550, PBCAR-0191, PCAR-01 9, PCAR-119, Senl-001, TI-1007, XmAb-5871, PT G-01, PZ01, Senl_1904A, Senl_1904B, UCART-19 , CSG-CD19, DI-B4, ET-190, GC-007F, or GC-022 Contains the CD19 binding domain.

[0488] In some embodiments, the T cell redirecting therapeutic that binds CD19 is Momab, axicabtagene ciloleucel, tisagenlecleucel-t, inebilizumab , Lysocabtagene Maraleucel, XmAb-5574, CIK-CAR.CD19, I CTCAR-011, IM-19, JCAR-014, loncastuximab tesirine, M B-CART2019.1, OXS-1550, PBCAR-0191, PCAR-01 9, PCAR-119, Senl-001, TI-1007, XmAb-5871, PT G-01, PZ01, Senl_1904A, Senl_1904B, UCART-19 , CSG-CD19, DI-B4, ET-190, GC-007F, or GC-022 include.

[0489] In some embodiments, the T cell redirecting therapeutic that binds to CD19 is a multispecific The antibody, CAR, or T cell expressing the CAR.

[0490] In some embodiments, the anti-CD38 antibody comprises HCDR1 of SEQ ID NO: 6, HCDR2 of SEQ ID NO: 7 HCDR2, HCDR3 of SEQ ID NO: 8, LCDR1 of SEQ ID NO: 9, LCD of SEQ ID NO: 10 R2, and LCDR3 of SEQ ID NO:11.

[0491] In some embodiments, the anti-CD38 antibody comprises a VH of SEQ ID NO: 4 and a VL of SEQ ID NO: 5. Includes.

[0492] In some embodiments, the anti-CD38 antibody is of the IgG1 isotype.

[0493] In some embodiments, the anti-CD38 antibody comprises the HC of SEQ ID NO: 12 and the HC of SEQ ID NO: 13. Contains LC.

[0494] In some embodiments, the anti-CD38 antibody VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15, VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17, VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or It comprises a VH of SEQ ID NO:20 and a VL of SEQ ID NO:21.

[0495] In some embodiments, the anti-CD38 antibody is of the IgG1 isotype.

[0496] In some embodiments, the anti-CD38 antibody is administered at a dose of about 8 mg / kg to about 16 mg / kg. It is administered in doses.

[0497] In some embodiments, a T cell redirecting therapeutic that binds CD19 and an anti-CD3 The antibody is administered by intravenous injection.

[0498] In some embodiments, the T cell redirecting therapeutic that binds CD19 is administered intravenously. The anti-CD38 antibody is administered by intravenous injection, and the anti-CD38 antibody is administered by subcutaneous injection.

[0499] In some embodiments, a T cell redirecting therapeutic that binds CD19 and an anti-CD3 The antibody is administered by subcutaneous injection.

[0500] In some embodiments, the subject is a human.

[0501] In some embodiments, the T cell redirecting therapeutic that binds to CD19 ×CD3 bispecific antibody.

[0502] In some embodiments, the methods include administering to the subject one or more anti-cancer therapies. Also includes:

[0503] In some embodiments, the one or more anti-cancer therapies include autologous stem cell transplantation (ASCT). ), radiation, surgery, chemotherapy, immunomodulatory agents, and targeted cancer therapy. do.

[0504] The present disclosure also provides a CD19xCD3 bispecific antibody, including blinatumomab of SEQ ID NO: 53. , HCDR1 of SEQ ID NO: 6, HCDR2 of SEQ ID NO: 7, HCDR3 of SEQ ID NO: 8, An antibody comprising LCDR1 of SEQ ID NO: 9, LCDR2 of SEQ ID NO: 10, and LCDR3 of SEQ ID NO: 11. Pharmaceutical combinations comprising CD38 antibodies are also provided.

[0505] In some embodiments, the anti-CD38 antibody comprises a VH of SEQ ID NO: 4 and a VL of SEQ ID NO: 5. Includes.

[0506] In some embodiments, the anti-CD38 antibody comprises the HC of SEQ ID NO: 12 and the HC of SEQ ID NO: 13. Contains LC.

[0507] In some embodiments, the pharmaceutical combination is a non-fixed combination.

[0508] In some embodiments, the pharmaceutical combination comprises about 25 mM acetic acid, about 60 mM sodium chloride sodium, about 140g mannitol, and about 0.04% w / v polysorbate-20 (P S-20), containing approximately 20 mg / mL to approximately 120 mg / mL of anti-CD38 antibody, at a pH of approximately It's 5.5.

[0509] In some embodiments, the pharmaceutical combination comprises about 1,800 mg of an anti-CD38 antibody and Contains approximately 30,000 U of rHuPH20.

[0510] In some embodiments, the pharmaceutical combination comprises about 120 mg / mL of an anti-CD38 antibody and and approximately 2,000 U / mL of rHuPH20.

[0511] In some embodiments, the pharmaceutical combination further comprises one or more excipients.

[0512] In some embodiments, the one or more excipients are histidine, methionine, sodium sorbitol, or polysorbate-20 (PS-20), or any combination thereof It is a combination.

[0513] In some embodiments, the pharmaceutical combination comprises: about 100 mg / mL to about 120 mg / mL of an anti-CD38 antibody; about 5 mM to about 15 mM histidine, about 100 mM to about 300 mM sorbitol; Approximately 0.01% w / v to approximately 0.04% w / v of PS-20, It contains about 1 mg / mL to about 2 mg / mL of methionine and has a pH of about 5.5 to 5.6. .

[0514] In some embodiments, the pharmaceutical combination comprises: Contains approximately 10 mM histidine.

[0515] In some embodiments, the pharmaceutical combination comprises about 300 mM sorbitol.

[0516] In some embodiments, the pharmaceutical combination comprises about 0.04% (w / v) PS-20. include.

[0517] In some embodiments, the pharmaceutical combination comprises about 1 mg / mL of methionine.

[0518] In some embodiments, the pharmaceutical combination comprises: Approximately 1,800 mg of anti-CD38 antibody, Approximately 30,000 U of rHuPH20 and Approximately 10 mM histidine, about 300 mM sorbitol; Approximately 0.04% (w / v) PS-20, It contains about 1 mg / mL of methionine and has a pH of about 5.6.

[0519] In some embodiments, the pharmaceutical combination comprises: Approximately 120 mg / mL of anti-CD38 antibody; Approximately 2,000 U / mL of rHuPH20 and Approximately 10 mM histidine, about 300 mM sorbitol; Approximately 0.04% (w / v) PS-20, It contains about 1 mg / mL of methionine and has a pH of about 5.6.

[0520] In some embodiments, the pharmaceutical combination comprises citric acid monohydrate (3.35 mg), salt Lysine acetate (23.23 mg), Polysorbate 80 (0.64 mg), Trehalose dihydrate The solution was formulated with benzoyl perchlorate (95.5 mg), and sodium hydroxide to adjust the pH to 7.0. Contains 35 mcg of blinatumomab.

[0521] In some embodiments, blinatumomab is administered in 3 mL of preservative-free sterile water for injection. , Reconstituted per USP.

[0522] Blinatumomab of SEQ ID NO: 53, 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 A kit comprising a pharmaceutical combination comprising an anti-CD38 antibody comprising LCDR3 of sequence number 11.

[0523] T cell redirection therapeutics multispecific antibodies The T cell redirecting therapeutic may be a multispecific molecule, such as a bispecific antibody. Various multispecific and / or bispecific formats include those described herein and recombinant I A IgG-like dual targeting molecule (where each of the two sides of the molecule is a Fab fragment of at least two different antibodies) or part of a Fab fragment), IgG fusion molecules (full-length IgG antibodies with extra Fa Fc fusion molecules (single chain Fv molecules or stabilized Fv molecules) the engineered diabody is fused to a heavy chain constant domain, Fc region, or portion thereof), F Based on ab fusion molecules (different Fab fragments fused together), ScFv and diabodies and heavy chain antibodies (e.g., domain antibodies, nanobodies) (different single chain Fv molecules or different diabodies or different heavy chain antibodies (e.g., domain antibodies, nanobodies) fused to another protein or carrier molecule, or produced by arm exchange. Exemplary multispecific and / or bispecific antibodies include those fused to the antibody or antibody fragments. Specific formats include dual targeting molecules such as Dual Targeting (DT)-Ig (GS K / Domantis), 2in1 (Two-in-one) antibody (Genentech), and m Ab2 (F-Star), dual variable domain (DVD)-Ig (Abbott), Ts2 Ab (MedImmune / AZ) and BsAb (Zymogenetics), HE RCULES (Biogen Idec), and TvAb (Roche), ScFv / F c Fusion (Academic Institution), SCORPION (Emer gent BioSolutions / Trubion, Zymogenetics / B MS), and Dual Affinity Retargeting Technology (Fc-D ART)(MacroGenics), F(ab)2(Medarex / AMGEN), Dual activity or Bis-Fab (Genentech), Dock-and-Lock (D NL) (ImmunoMedics), bivalent bispecific (Biotecnol), and F ab-Fv (UCB-Celltech), bispecific T cell engager (Bispecif ic T Cell Engager, BITE) (Micromet), Tandem Diabody (Tandem Diabody, Tandab) (Affimed), Dual Affinity Retargeting Technology (DART) (M acroGenics), single-chain diabody (Academic), TCR-like antibody (A IT, ReceptorLogics), human serum albumin ScFv fusion (Merr imack), and COMBODY (Epigen Biotech), dual-targeted nanobody Ablynx, a dual-targeting heavy chain-only domain antibody. Various forms of bispecific Antibodies can be prepared, for example, as described in Chames and Baty (2009) Curr Opin D rug Disc Dev 12:276 and Nunez-Prado et al., (2015)Drug Discovery Today 20(5):588-594 is described in.

[0524] Methods for generating antibodies for use in the methods of the invention Antibodies used in the methods of the invention that bind to specific antigens can be prepared, for example, by phage display. Alternatively, the phage may be de novo selected from a library, in which case the phage may be selected from a library of human immunoglobulins. or a portion thereof (Fab, single chain antibody (scFv), or unpaired or paired These are engineered to express specific target genes (e.g., antibody variable regions) (Knappik et al., J Mol Biol296:57-86,2000, Krebs et al., JI mmunol Meth 254:67-84,2001, Vaughan et al. .,Nature Biotechnology14:309-14,1996, She ets et al., PITAS (USA) 95:6157-62, 1998, Hoo genboom and Winter, J Mol Biol 227:381,19 91, Marks et al., J Mol Biol 222:581, 1991). Shi et al(2010)J.Mol.Biol.397:385-96 and International Bacteriophage pIX coat protein as described in Publication No. 2009 / 085462 Phage display line expressing antibody heavy and light chain variable regions as fusion proteins The antibody library is divided into BCMA, CD3, CD38, CD123, CD19, and CD3 3, PSMA, or the TMEFF2 extracellular domain. The resulting positive clones were further characterized and Fab was isolated from the clone lysates. Once isolated, they can be cloned as full-length antibodies. Such phage display methods are well established in the art. US Patent No. 5,223,409, US Patent No. 5,403,484, US Patent No. 5,57 No. 1,698, U.S. Patent No. 5,427,908, U.S. Patent No. 5,580,717, U.S. Patent No. US Patent No. 5,969,108, US Patent No. 6,172,197, US Patent No. 5,88 No. 5,793, U.S. Patent No. 6,521,404, U.S. Patent No. 6,544,731, U.S. Patent No. US Patent No. 6,555,313, US Patent No. 6,582,915, and US Patent No. See No. 593,081.

[0525] T cell redirecting bispecific antibodies are described in WO 2011 / 131746 According to the method, in vitro in a cell-free environment, two monospecific homodimeric antibodies Asymmetrical mutations were introduced into the CH3 region to create different disulfide bonds. The two parent monospecific homodimeric antibodies are converted into bispecific heterodimeric antibodies under reducing conditions that activate the antibody. Alternatively, a heterodimeric antibody may be produced by forming a heterodimeric antibody. Two monospecific bivalent antibodies with specific substitutions in the CH3 domain that facilitate identification These antibodies are engineered to have disulfide bonds formed by cysteines in the hinge region. are incubated together under reducing conditions sufficient to isomerize F Ab arm exchange generates bispecific antibodies. Incubation conditions are optimally: A typical reducing agent that can be used is 2-mercaptoethylamine. (2-MEA), dithiothreitol (DTT), dithioerythritol (DTE), Glutathione, Tris(2-carboxyethyl)phosphine (TCEP), L-cysteine , and β-mercaptoethanol, preferably 2-mercaptoethylamine, di Selected from the group consisting of thiothreitol and tris(2-carboxyethyl)phosphine For example, at least 25 mM of 2-M in the presence of EA or at least 0.5 mM dithiothreitol, pH 5-8, For example, use a pH of 7.0 or 7.4 and incubate for at least 90 minutes. can be done.

[0526] Exemplary CH3 mutations that can be used in the first and second heavy chains of a bispecific antibody are: K409R and / or F405L.

[0527] Additional CH3 mutations that may be used include Duobody® mutations (Genmab ), knob-in-hole mutation (Genentech), electrostatic match mutation (Chugai, A mgen, NovoNordisk, Oncomed), strand exchange manipulation domain body (S EED body) (EMD Serono), and other asymmetric mutations (e.g., Zymewo rks) and other technologies.

[0528] Duobody® mutations (Genmab) are described, for example, in U.S. Pat. No. 91,506 63 and U.S. Patent Application Publication No. 2014 / 0303356, for example: F405L / K409R, wild type / F405L_R409K, T350I_K370T_ F405L / K409R, K370W / K409R, D399AFGHILMNRSTV WY / K409R, T366ADEFGHILMQVY / K409R, L368ADEG HNRSTVQ / K409AGRH, D399FHKRQ / K409AGRH, F405 IKLSTVW / K409AGRH and Y407LWQ / K409AGRH mutations It can be enjoyed.

[0529] Knob-in-hole mutations are disclosed, for example, in WO 1996 / 027011. Thus, amino acids with small side chains (holes) are introduced into the first CH3 region, and amino acids with large side chains are introduced into the second CH3 region. An amino acid having a (knob) is introduced into the second CH3 region, and the first CH3 region and the second C These include mutations on the interface of the CH3 domain that result in preferential interactions with the H3 domain. Exemplary CH3 region mutations that form knobs and holes are T366Y / F405A, T36 6W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y 407A, T366W / T394S, F405W / T394S, and T366W / T36 It is 6S_L368A_Y407V.

[0530] Heavy chain heterodimerization is described in U.S. Patent Application Publication Nos. 2010 / 0015133 and 2010 / 0015135. No. 09 / 0182127, No. 2010 / 028637, or No. 2011 / 0123 As described in US Pat. No. 5,332, the positively charged residues on the first CH3 region and the second CH3 region Facilitated by using electrostatic interactions by substituting negatively charged residues on It can be done.

[0531] Other asymmetric mutations that can be used to promote heavy chain heterodimerization are described in U.S. Pat. L351 described in Patent Publication No. 2012 / 0149876 or Patent Publication No. 2013 / 0195849 Y_F405A_Y407V / T394W, T366I_K392M_T394W / F4 05A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366 V_K409F, Y407A / T366A_K409F, or T350V_L351Y_ F405A_Y407V / T350V_T366L_K392L_T394W.

[0532] SEED body mutations may be induced as described in U.S. Patent Application Publication No. 2007 / 0287170. Additionally, selected IgG residues are replaced with IgA residues to promote heavy chain heterodimerization. accompanied by.

[0533] Other exemplary mutations that can be used are described in WO 2007 / 147901, WO 2007 / 147902, WO 2007 / 147903, WO 2007 / 147904, WO 2007 / 147905, WO 2007 / 147906, WO 2007 / 147907, WO 2007 / 147908, WO 2007 / 147909 ... 2011 / 143545, International Publication No. 2013 / 157954, International Publication No. 2013 / 096291 and R40 described in U.S. Patent Application Publication No. 2018 / 0118849 9D_K370E / D399K_E357K, S354C_T366W / Y349C_T 366S_L368A_Y407V, Y349C_T366W / S354C_T366S _L368A_Y407V, T366K / L351D, L351K / Y349E, L35 1K / Y349D, L351K / L368E, L351Y_Y407A / T366A_K 409F, L351Y_Y407A / T366V_K409F, K392D / D399K , K392D / E356K, K253E_D282K_K322D / D239K_E24 0K_K292D, K392D_K409D / D356K_D399K.

[0534] Additional bispecific or multispecific constructs that may be used as T cell redirecting therapeutics Dual variable domain immunoglobulins (DVDs) (WO 2009 / 134776 , the DVD has a heavy chain having a VH1-linker-VH2-CH structure and a VL1-linker- a full-length antibody comprising a light chain having a VL2-CL structure, and a linker is optional), Two antibodies with different specificities, such as isin zipper or collagen dimerization domains Structures containing various dimerization domains for linking arms (WO 2012 / 022 811, U.S. Patent No. 5,932,448, U.S. Patent No. 6,833,441), together Two or more domain antibodies (dAbs), diabodies, lambda Heavy chain-only antibodies, such as camelid antibodies and engineered camelid antibodies, dual targeting (DT)-Ig ( GSK / Domantis), 2in1 antibody (Genentech), cross-linked Mab (Ka rmanos Cancer Center), mAb2 (F-Star), and Cov X-body (CovX / Pfizer), IgG-like bispecific (InnClone / Eli Lilly), Ts2Ab (MedImmune / AZ), and BsAb (Zymog enetics), HERCULES (Biogen Idec), and TvAb (Ro che), ScFv / Fc fusion (Academic Institution), SC ORPION(Emergent BioSolutions / Trubion, Zym ogenetics / BMS), dual affinity retargeting technology (Fc-DART) (Macro Genics), and dual (ScFv)2-Fab (National Research h Center for Antibody Medicine--China), 2 Heavy activity or Bis-Fab (Genentech), Dock-and-Lock (DN L) (ImmunoMedics), bivalent bispecific (Biotecnol), and Fa ScFv antibodies, diabody-based antibodies, and b-Fv (UCB-Celltech) Bispecific T cell engagers (BiTEs) (Mic romet), Tandem Diabody (Tandab) (Affimed), Dual Affinity Retargeting Technology (DART) (MacroGenics), single-chain diabody (Academy mic), TCR-like antibody (AIT, ReceptorLogics), human serum albumin ScFv fusion (Merrimack), and COMBODY (Epigen Bio tech), dual-targeting nanobodies (Ablynx), and dual-targeting heavy chain-only domain antibodies. Examples include, but are not limited to:

[0535] Fc engineering of antibodies T cell redirecting therapies such as bispecific or multispecific antibodies or anti-CD38 antibodies The Fc region of a drug binds to activating Fcγ receptors (FcγRs) for T cell redirecting therapeutics and / or reduce C1q binding, complement dependent cytotoxicity oxicity (CDC), antibody-dependent cell-mediated cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (CDC); d cytotoxicity (ADCC), or phagocytosis (antibody-dependent cell-mediated p A small amount of Fc in the Fc region reduces Fc effector functions such as haemocytosis and ADCP. It may contain at least one substitution.

[0536] Substitutions that reduce Fc binding to activating FcγRs and subsequently reduce effector function Possible Fc positions are L234A / L235A on IgG1, V234A / V235A on IgG2, G237A / P238S / H268A / V309L / A330S / P331S, IgG4 F234A / L235A on IgG4, S228P / F234A / L235A on IgG4, all N297A on Ig isotypes, V234A / G237A on IgG2, and V234A / G237A on IgG1 K214T / E233P / L234V / L235A / G236 deletion / A327G / P3 31A / D365E / L358M, H268Q / V309L / A330S / on IgG2 P331S, S267E / L328F on IgG1, L234F / L235 on IgG1 E / D265A, L234A / L235A / G237A / P238S / H2 on IgG1 68A / A330S / P331S, S228P / F234A / L235A / on IgG4 G237A / P238S, and S228P / F234A / L235A / G2 on IgG4 36 deletion / G237A / P238S substitution.

[0537] An Fc substitution that can be used to reduce CDC is the K322A substitution.

[0538] To improve the stability of IgG4, the well-known S228P substitution was further made in the IgG4 antibody. It is possible to do so.

[0539] An exemplary wild-type IgG1 comprises the amino acid sequence of SEQ ID NO:103.

[0540] SEQ ID NO:103: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPSRD ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY TQKSLSLSPGK

[0541] An exemplary wild-type IgG4 comprises the amino acid sequence of SEQ ID NO:104.

[0542] SEQ ID NO:104: ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTK TYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYV DGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPSQEEMT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQK SLSLSLGK

[0543] "Antibody-dependent cytotoxicity", "Antibody-dependent cell-mediated cytotoxicity", or "ADCC" Fcγ receptors (FcγR) expressed on effector cells mediate the binding of antibody-coated target cells , natural killer cells (NK), monocytes, macrophages, and neutrophils. This mechanism of cell death induction depends on the interaction with effector cells that possess the , NK cells express FcγRIIIa, whereas monocytes express FcγRI, FcγRII, and The ADCC activity of antibodies is determined by the expression of the protein to which the antibody binds. In vitro immunohistochemistry using target cells and NK cells as effector cells Cytolysis can be assessed using an assay that allows for the release of label (e.g., IgG) from lysed cells. detection by the release of a specific protein (e.g., a radioactive substrate, a fluorescent dye, or a natural intracellular protein) In an exemplary assay, target cells are cultured in a ratio of 1 target cell to 4 effector cells. The target cells were pre-labeled with BATDA and used in the same ratio as the effector cells and test antibody. The samples were incubated for 2 hours and the BATDA released into the supernatant was measured. Cell lysis was measured by adding 0.67% Triton X-100 (Sigma). Data were normalized to the maximum cytotoxicity of any antibody (Aldrich). A minimum control is determined by the spontaneous release of BATDA from target cells in the absence of BATDA.

[0544] "Antibody-dependent cellular phagocytosis" ("ADCP") is a process that involves the phagocytosis of cells, e.g., macrophages or dendritic cells. This refers to the mechanism by which antibody-coated target cells are eliminated by phagocytes such as spleens. CPs are composed of monocyte-derived macrophages as effector cells and proteins to which antibodies bind. The cells expressing the protein are then compared with target cells that are also engineered to express GFP or another marker molecule. In an exemplary assay, effector activity can be assessed by using The effector cell:target cell ratio can be, for example, 4:1. The mixture may be incubated with the target cells for 4 hours with or without the addition of After the extraction, the cells can be detached using sorbase. Macrophages bind to the fluorescent label. Although the phagocytosis rate can be distinguished by the anti-CD11b and anti-CD14 antibodies, the rate of phagocytosis was significantly higher than that of the control group. Using standard methods, CD11 + and CD14 + Percentage of GFP fluorescence in macrophages The ratio can be determined based on the percentage of the total.

[0545] "Complement-dependent cytotoxicity," or "CDC," is a process that induces Fc effector domains of target-bound antibodies. The main component binds to and activates complement component C1q, which then activates complement The mechanism for inducing cell death is to activate the cytotoxic cascade, resulting in the death of target cells. Complement activation can also result in the deposition of complement components on the surface of target cells, leading to the formation of leukocytes. CDC is facilitated by the binding of complement receptors (e.g., CR3) to the cells. For example, Daudi cells were cultured in RPMI-B (RPMI supplemented with 1% BSA). 1 x 10 per well 5 Plated with 50 μL of cells (50 μL / well) Test antibodies were added to the wells at a final concentration of 0-100 μg / mL and the reaction was incubated for 15 min at room temperature. After incubation at 4°C, 11 μL of pooled human serum was added to the wells and the reaction was incubated for 45 min. The percentage of lysed cells can be measured by incubating the cells at 37°C for 1 hour. (%) of propidium iodide stained cells in a FACS assay using standard methods % can be detected.

[0546] Binding of antibodies to FcγR or FcRn was measured using flow cytometry. In an exemplary binding assay, the binding activity can be assessed in cells engineered to express: 2 x 10 per well in a 96-well plate 5 100 cells were seeded and stained with BSA. Buffer (BD Biosciences, San Jose, USA) at 4°C. The cells were then blocked with PBS for 30 minutes. The cells were then incubated with the test antibody on ice for 1.5 hours at 4°C. After washing twice with BSA staining buffer, the cells were incubated with R-PE-labeled anti-human IgG secondary antibody. antibodies (Jackson Immunoresearch Laboratories) and Both are incubated for 45 minutes at 4° C. The cells are washed twice with staining buffer, then DRAQ7 Live / Dead Cell Stain (Cell Signaling Technology) diluted 1:200 150 μL of Stain B containing 100 μL of PBS (BioSciences, Inc., Danvers, USA) The PE and DRAQ7 signals of the stained cells were analyzed by Milt Miltenyi MACSQuant flow cytometer (Miltenyi Biotec , Auburn, USA) using B2 and B4 channels, respectively. Live cells were gated by DRAQ7 exclusion and at least 10,000 live cell events were collected. The geometric mean fluorescence signal was determined for each sample. Analysis was performed using FlowJo software ( Data are expressed as the logarithm of the mean fluorescent signal versus the antibody concentration. Plot as .Perform nonlinear regression analysis.

[0547] Chimeric antigen receptor (CAR) Chimeric antigen receptors (CARs) are genetically engineered receptors. These engineered The receptors can be readily inserted into immune cells, including T cells, according to techniques known in the art. With CAR, a single receptor can be expressed by a specific antigen. When it recognizes and binds to the antigen, it activates immune cells and causes the cells that carry the antigen to These antigens can be programmed to attack and destroy tumor cells. When present, immune cells expressing CAR target and kill tumor cells. It is possible.

[0548] CARs typically comprise an extracellular domain that binds to an antigen (e.g., a prostate neoantigen), Any linker, transmembrane domain, and costimulatory and / or signaling domains It contains a cytoplasmic domain containing the ribosomal domain.

[0549] The extracellular domain of the CAR can be any polypeptide that binds to a desired antigen (e.g., prostate neoantigen). The extracellular domain may comprise a portion of an antibody or an alternative scaffold. The CAR may also comprise scFvs arranged in tandem and separated by a linker sequence. The antibody may be engineered to bind two or more desired antigens. One or more domain antibodies, scFv, llama VHH antibodies, or other VH-only antibody fragments can be configured in tandem via a linker to provide bispecific or multispecificity to the CAR. That's fine.

[0550] The transmembrane domain of CAR is composed of the transmembrane domains of CD8, alpha and beta T cell receptors. Ta or zeta chain, CD28, CD3 epsilon, CD45, CD4, CD5, CD 8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86 , CD134, CD137, CD154, KIRDS2, OX40, CD2, CD27, LFA-1 (CDI la, CD18), ICOS (CD278), 4-1BB (CD1 37), 4-1BBL, GITR, CD40, BAFFR, HVEM(LIGHTR), SLAMF7, NKp80 (KLRFI), CD160, CD19, IL2R beta, I L2R gamma, IL7R a, ITGA1, VLA1, CD49 a, ITGA4, IA4 , CD49D, ITGA6, VLA-6, CD49f, ITGAD, CDI ID, IT GAE, CD103, ITGAL, CDI la, LFA-1, ITGAM, CDI l b, ITGAX, CDI lc, ITGB1, CD29, ITGB2, CD18, LFA -1, ITGB7, TNFR2, DNAM1 (CD226), SLAMF4 (CD244 , 2B4), CD84, CD96 (tactile), CEACAM1, CRT AM, Ly9(C D229), CD160(BY55), PSGL1, CD100(SEMA4D), SL AMF6 (NTB-A, Lyl08), SLAM (SLAMF1, CD150, IPO- 3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​PAG / Cbp, NKp44, NKp30, NKp46, NKG2D, and / or NKG2C It can come.

[0551] The intracellular costimulatory domain of the CAR binds to the intracellular domain of one or more costimulatory molecules. Costimulatory molecules are required for efficient activation and function of T lymphocytes upon antigen binding. A well-known cell surface molecule other than an antigen receptor or an Fc receptor that provides an essential second signal. Exemplary costimulatory domains that can be used in CARs include 4-1BB, CD2, CD7, CD27, CD28, CD30, CD40, CD54(ICAM), CD83, CD13 4 (OX40), CD150 (SLAMF1), CD152 (CTLA4), CD223 (LAG3), CD270(HVEM), CD278(ICOS), DAP10, LAT , the intracellular domains of NKD2C, SLP76, TRIM, and ZAP70.

[0552] The intracellular signaling domain of the CAR can be, for example, O'O3ζ, CD3ε, CD22, It may be derived from the signaling domains of CD79a, CD66d, or CD39. The signaling domain is a domain that binds to the target antigen to induce effector cell function. It is involved in the transduction of CAR-bound messages into immune effector cells, effector cell functions, such as activation, cytokine production, proliferation, and cytotoxic activity ( Release of cytotoxic factors into CAR-bound target cells or antigen binding to the extracellular CAR domain The term "CAR" refers to a portion of a CAR polypeptide that elicits a specific cellular response (including other cellular responses that are subsequently elicited).

[0553] The linker of any CAR located between the extracellular domain and the transmembrane domain may be The linker may be a polypeptide of about 2 to 100 amino acids in length. It contains flexible residues such as glycine and serine so that the domains can move freely relative to each other. It can be seen or consist of two adjacent domains that do not sterically interfere with each other. Longer linkers can be used if desired to ensure that the linker The linker may be cleavable or non-cleavable. Examples of cleavable linkers include , 2A linkers (e.g., T2A), 2A-like linkers, or functional equivalents thereof, and The linker may also be a hinge region or a portion of any immunoglobulin. It may be derived from a portion of the hinge region.

[0554] Exemplary CARs that can be used include, for example, extracellular domains that bind to the prostate neoantigens of the present invention. A CAR containing the main, CD8 transmembrane domain, and CD3ζ signaling domain Other exemplary CARs include an extracellular domain, CD4, that binds to a prostate neoantigen of the present invention. 8 or CD28 transmembrane domain, CD28, 41BB, or OX40 costimulatory domain, and and CD3ζ signaling domains.

[0555] CARs are generated using standard molecular biology techniques. The exodomain may be an antibody or antigen-binding fragment thereof generated using the techniques described herein. It can come from a piece.

[0556] While the invention has been described in general terms, embodiments of the invention are set forth in the following claims. The present invention is further disclosed in the following examples, which should not be construed as limiting.

[0557] Further embodiments of the present invention Certain further embodiments of the present invention, in accordance with the disclosure elsewhere herein, are described below. The features of the embodiments of the invention described above as relating to the invention disclosed herein are , also relates to each and every one of these numbered further embodiments.

[0558] Embodiment 1. Use in treating subjects with cancer in combination with a T cell redirecting therapeutic. Anti-CD38 antibody for

[0559] Embodiment 2. Use for improving the efficacy of T cell redirecting therapeutics in subjects with cancer Anti-CD38 antibody for this purpose.

[0560] Embodiment 3. A method for treating patients with cancer in combination with a T cell redirecting therapy. Use of an anti-CD38 antibody for preparing a drug or pharmaceutical composition for the treatment of cancer.

[0561] Embodiment 4. Use of an anti-CD38 antibody in combination with a T cell redirecting therapy. and to provide a combination useful for treating subjects with cancer in patients in need thereof. A use characterized by functioning to manufacture.

[0562] Embodiment 5. An embodiment in which the anti-CD38 antibody is administered prior to administration of the T cell redirecting therapy. An anti-CD38 antibody for use according to any one of embodiments 1 to 4.

[0563] Embodiment 6. The T cell redirecting therapeutic is a therapeutic agent selected from the group consisting of BCMA, GPRC5D, CD33, CD 123, CD19, PSMA, TMEFF2, or CD20, embodiments 1 to 5. an anti-CD38 antibody for use with any one of

[0564] Embodiment 7. The T cell redirecting therapeutic is selected from the group consisting of CD3, CD3 epsilon (CD3ε), CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, Any of embodiments 1 to 6, which binds to BTNL8, PD-1, CD195, or NKG2C. Anti-CD38 antibody for use with any one of:

[0565] Embodiment 8. The T cell redirecting therapeutic comprises: 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; A heavy chain variable region (VH) of SEQ ID NO: 39 and a light chain variable region (VL) of SEQ ID NO: 40; 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 , VH of SEQ ID NO: 80 and VL of SEQ ID NO: 81; HCDR1, HCDR2, HCDR3, LCDR of the CD3 binding domain of SEQ ID NO: 53 1, LCDR2, and LCDR3, or a CD3 binding domain comprising the VH and VL of the CD3 binding domain of SEQ ID NO: 53; An anti-CD38 antibody for use according to any one of embodiments 1 to 7.

[0566] Embodiment 9. A T cell redirecting therapeutic agent 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 a BCMA binding domain comprising: an HCDR1 of SEQ ID NO: 33; an HCDR2 of SEQ ID NO: 34; R2, HCDR3 of SEQ ID NO: 35, LCDR1 of SEQ ID NO: 36, LCDR of SEQ ID NO: 37 2, and a CD3 binding domain comprising an LCDR3 of SEQ ID NO: 38, and / or A BCMA binding domain comprising a VH of SEQ ID NO: 29 and a VL of SEQ ID NO: 30, and the sequence 39 and a VL of SEQ ID NO: 40. 8. Anti-CD38 antibody for use with any one of

[0567] Embodiment 10. The T cell redirecting therapeutic comprises a first heavy chain (HC1) of SEQ ID NO: 31, A first light chain (LC1) of SEQ ID NO: 32, a second heavy chain (HC2) of SEQ ID NO: 41, and a second light chain (LC3) of SEQ ID NO: 42. For use according to any one of embodiments 1 to 9, comprising a second light chain (LC2) of number 42. Anti-CD38 antibody for immunization.

[0568] Embodiment 11. The T cell redirecting therapeutic 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 GPRC5D binding domain comprising HCDR1 of SEQ ID NO: 33, H of SEQ ID NO: 34 CDR2, HCDR3 of SEQ ID NO: 35, LCDR1 of SEQ ID NO: 36, LC of SEQ ID NO: 37 a CD3 binding domain comprising a DR2 and an LCDR3 of SEQ ID NO: 38, and / or a GPRC5D-binding domain comprising a VH of SEQ ID NO: 49 and a VL of SEQ ID NO: 50; and an embodiment comprising a CD3 binding domain comprising a VH of SEQ ID NO: 39 and a VL of SEQ ID NO: 40 Anti-CD38 antibodies for use with any one of 1 to 10.

[0569] Embodiment 12. The T cell redirecting therapy comprises HC1 of SEQ ID NO: 51, L of SEQ ID NO: 52 112. Any of embodiments 111, comprising C1, HC2 of SEQ ID NO: 41, and LC2 of SEQ ID NO: 42. Anti-CD38 antibody for use with any one of:

[0570] Embodiment 13. The T cell redirecting therapeutic comprises: HCDR1 of SEQ ID NO: 84, HCDR2 of SEQ ID NO: 85, HCDR3 of SEQ ID NO: 86, LCDR1 of SEQ ID NO: 87, LCDR2 of SEQ ID NO: 88, and LCDR3 of SEQ ID NO: 89 and a CD33 binding domain comprising HCDR1 of SEQ ID NO: 74, HCDR of SEQ ID NO: 75 R2, HCDR3 of SEQ ID NO: 76, LCDR1 of SEQ ID NO: 77, LCDR of SEQ ID NO: 78 2, and a CD3 binding domain comprising an LCDR3 of SEQ ID NO: 79, and / or A CD33 binding domain comprising a VH of SEQ ID NO: 90 and a VL of SEQ ID NO: 91, and the sequence 80 and a VL of SEQ ID NO: 81. 12. Anti-CD38 antibody for use with any one of

[0571] Embodiment 14. The T cell redirecting therapy comprises HCl of SEQ ID NO: 92, L of SEQ ID NO: 93 14. Any of embodiments 1 to 13, comprising C1, HC2 of SEQ ID NO: 82, and LC2 of SEQ ID NO: 83. Anti-CD38 antibody for use with either one of:

[0572] Embodiment 15. The T cell redirecting therapeutic 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 a CD123 binding domain comprising HCDR1 of SEQ ID NO: 33, HCDR of SEQ ID NO: 34, R2, HCDR3 of SEQ ID NO: 35, LCDR1 of SEQ ID NO: 36, LCDR of SEQ ID NO: 37 2, and a CD3 binding domain comprising an LCDR3 of SEQ ID NO: 38, and / or a CD123 binding domain comprising a VH of SEQ ID NO: 100 and a VL of SEQ ID NO: 61; and an embodiment comprising a CD3 binding domain comprising a VH of SEQ ID NO: 39 and a VL of SEQ ID NO: 40 1 to 14.

[0573] Embodiment 16. T cell redirecting therapy comprises HCl of SEQ ID NO: 102, HCl of SEQ ID NO: 63 16. The method of any one of embodiments 1 to 15, comprising administering to a subject a HC1 of SEQ ID NO: 41, an LC2 of SEQ ID NO: 42, and an LC3 of SEQ ID NO: 43. Anti-CD38 antibody for use with any one of:

[0574] Embodiment 17. The T cell redirecting therapeutic agent is: HCDR1, HCDR2, HCDR3, LCD of the CD19 binding domain of SEQ ID NO: 53 a CD19 binding domain comprising R1, LCDR2, and LCDR3, and the sequence of SEQ ID NO: 53 HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 of the CD3 binding domain and a CD3 binding domain comprising LCDR3, and / or For use according to any one of embodiments 1 to 16, comprising the amino acid sequence of SEQ ID NO: 53. Anti-CD38 antibody for immunization.

[0575] Embodiment 18. The T cell redirecting therapeutic 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 A PSMA binding domain comprising: HCDR1 of SEQ ID NO: 33; HCDR2 of SEQ ID NO: 34; 2. HCDR3 of SEQ ID NO: 35, LCDR1 of SEQ ID NO: 36, LCDR2 of SEQ ID NO: 37 and a CD3 binding domain comprising an LCDR3 of SEQ ID NO: 38, and / or A PSMA binding domain comprising a VH of SEQ ID NO: 60 and a VL of SEQ ID NO: 61, and the sequence 39 and a VL of SEQ ID NO: 40. 17. An anti-CD38 antibody for use with any one of

[0576] Embodiment 19. The T cell redirecting therapy comprises HCl of SEQ ID NO: 62, L of SEQ ID NO: 63 19. Any of embodiments 1 to 18, comprising C1, HC2 of SEQ ID NO: 41, and LC2 of SEQ ID NO: 42. Anti-CD38 antibody for use with either one of:

[0577] Embodiment 20. The T cell redirecting therapeutic 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 a TMEFF2-binding domain comprising HCDR1 of SEQ ID NO: 74, H of SEQ ID NO: 75, CDR2, HCDR3 of SEQ ID NO: 76, LCDR1 of SEQ ID NO: 77, LC a CD3 binding domain comprising an LCDR2 and an LCDR3 of SEQ ID NO: 79, and / or a TMEFF2-binding domain comprising a VH of SEQ ID NO: 70 and a VL of SEQ ID NO: 71; and an embodiment comprising a CD3 binding domain comprising a VH of SEQ ID NO: 80 and a VL of SEQ ID NO: 81. 1 to 19.

[0578] Embodiment 21. The T cell redirecting therapy comprises HCl of SEQ ID NO: 72, L of SEQ ID NO: 73 21. Any of embodiments 1 to 20, comprising C1, HC2 of SEQ ID NO: 82, and LC2 of SEQ ID NO: 83. Anti-CD38 antibody for use with either one of:

[0579] Embodiment 22. The T cell redirecting therapeutic is selected from the group consisting of a multispecific antibody, a chimeric antigen receptor (CAR) 22. The use according to any one of embodiments 1 to 21, wherein the T cell comprises a T cell comprising a CAR, ... or a T cell comprising a CAR. Anti-CD38 antibody for

[0580] Embodiment 23. The multispecific antibody is an IgG1, IgG2, IgG3, or IgG4 antibody. 23. The anti-CD38 antibody for use according to embodiment 22, which is a genotype.

[0581] Embodiment 24. The multispecific antibody is characterized in that the multispecific antibody binds to Fcγ receptors (FcγR). For use according to embodiment 22 or 23, the antibody comprises one or more Fc substitutions that reduce the Anti-CD38 antibody for immunization.

[0582] Embodiment 25. The one or more Fc substitutions are F234A / L235A on IgG4 , L234A / L235A on IgG1, V234A / G237A / P23 on IgG2 8S / H268A / V309L / A330S / P331S, F234A / L on IgG4 235A, S228P / F234A / L235A on IgG4, all Ig isotypes N297A on IgG1, V234A / G237A on IgG2, K214T / E2 on IgG1 33P / L234V / L235A / G236 deletion / A327G / P331A / D365E / L358M, H268Q / V309L / A330S / P331S on IgG2, IgG S267E / L328F on IgG1, L234F / L235E / D265A on IgG1, I L234A / L235A / G237A / P238S / H268A / A330S on gG1 / P331S, S228P / F234A / L235A / G237A / P23 on IgG4 8S, and S228P / F234A / L235A / G236 deletion / G237 on IgG4 A / P238S, wherein residue numbering is according to the EU index; 25. An anti-CD38 antibody for use according to any one of embodiments 22 to 24.

[0583] Embodiment 26. The use according to embodiment 25, wherein the multispecific antibody further comprises a S228P substitution. Anti-CD38 antibody for use.

[0584] Embodiment 27. The multispecific antibody comprises a first CH3 domain or a second CH3 domain. one or more CH3 domains, or both the first CH3 domain and the second CH3 domain 27. Anti-CD38 for use according to any one of embodiments 22 to 26, comprising an asymmetric substitution of antibody.

[0585] Embodiment 28. One or more asymmetric substitutions are F450L / K409R, wild type / F409L_R409K, T366Y / F405A, T366W / F405W, F405 W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T3 94S, F405W / T394S and T366W / T366S_L368A_Y407V , L351Y_F405A_Y407V / T394W, T366I_K392M_T39 4W / F405A_Y407V, T366L_K392M_T394W / F405A_Y 407V, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F, and T350V_ L351Y_F405A_Y407V / T350V_T366L_K392L_T394 28. The anti-CD38 antibody for use according to embodiment 27, selected from the group consisting of: W.

[0586] Embodiment 29. Any one of embodiments 1 to 28, wherein the subject has newly diagnosed cancer. Anti-CD38 antibody for use by a

[0587] Embodiment 30. The subject is a patient of any of embodiments 1 to 3 who is relapsed or refractory to a previous anti-cancer treatment. 29. An anti-CD38 antibody for use with any one of

[0588] Embodiment 31. Any of embodiments 1 to 30, wherein the cancer is a hematological malignancy or a solid tumor. Anti-CD38 antibody for use by one.

[0589] Embodiment 32. The hematological malignancy is multiple myeloma, smoldering multiple myeloma, benign monoclonal antibody Myeloglobulinemia (MGUS), acute lymphoblastic leukemia (ALL), diffuse large cell lung cancer DLBCL, Burkitt lymphoma (BL), follicular lymphoma (FL) ), mantle cell lymphoma (MCL), Waldenstrom's hypergammaglobulinemia, Stromal cell leukemia, light chain amyloidosis (AL), precursor B-cell lymphoblastic leukemia, precursor Somatic B-cell lymphoblastic leukemia, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) ), chronic lymphocytic leukemia (CLL), B-cell malignancies, chronic myeloid leukemia (CML), Alley cell leukemia (HCL), blastic plasmacytoid dendritic cell neoplasm, Hodgkin's lymphoma, non-Hodgkin's lymphoma JKL 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 32. The anti-CD38 antibody for use according to any one of embodiments 1 to 31, wherein the antibody is a tumor.

[0590] Embodiment 33. The multiple myeloma is a newly diagnosed multiple myeloma. 32. An anti-CD38 antibody for use with any one of

[0591] Embodiment 34. The multiple myeloma is relapsed or refractory multiple myeloma. 2. Anti-CD38 antibody for use with any one of

[0592] Embodiment 35. Any of embodiments 1 to 34, wherein the multiple myeloma is high-risk multiple myeloma. Anti-CD38 antibody for use with either one of:

[0593] Embodiment 36. A subject with high-risk multiple myeloma is 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 de have one or more chromosomal abnormalities including l17p, l18p, or any combination of these 36. An anti-CD38 antibody for use according to embodiment 35.

[0594] Embodiment 37. Multiple myeloma is treated with an anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, or thrombin. Lidomide, carfilzomib, elotozumab, ixazomib, melphalan, or saprostatin relapsed or refractory to treatment with lidomide, or any combination thereof; 37. An anti-CD38 antibody for use according to any one of embodiments 1 to 36.

[0595] Embodiment 38. 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 c cancer), stomach cancer, kidney cancer, colon cancer, bladder cancer, cervical cancer cinoma), melanoma, hepatocellular carcinoma, renal cell carcinoma, urothelial carcinoma, head and neck cancer, glioma, or glioblastoma 38. The anti-CD38 antibody for use according to any one of embodiments 1 to 37, wherein

[0596] Embodiment 39. The prostate cancer is recurrent, refractory, malignant, or castration-resistant prostate cancer, or or any combination thereof.

[0597] Embodiment 40. AML is AML with at least one genetic abnormality, multilineage dysplasia Acute osteoporosis, therapy-associated AML, undifferentiated AML, poorly differentiated AML, differentiated AML, acute osteoporosis Myelomonocytic leukemia, acute monocytic leukemia, acute erythroid leukemia, acute megakaryoblastic leukemia, acute basophilic leukemia, acute panmyelitis with fibrosis, or myeloid sarcoma according to embodiment 32. Anti-CD38 antibody for use in

[0598] Embodiment 41. At least one genetic abnormality is a translocation between chromosomes 8 and 21. translocation or inversion of chromosome 16, translocation between chromosomes 15 and 17, 11 Alterations in chromosome 1, fms-related tyrosine kinase 3 (FLT3), nucleophosmin (NPM1), isocitrate dehydrogenase 1 (IDH1), isocitrate dehydrogenase IDH2, DNA (cytosine-5)-methyltransferase 3 (DNM T3A), CCAAT / enhancer-binding protein alpha (CEBPA), U2 nuclear Small RNA cofactor 1 (U2AF1), zeste2 polycomb repressive complex 2 subunit Enhancer of chromosome maintenance 1A (SMC1A), or chromosome structure 41. The anti-CD38 antibody for use according to embodiment 40, which is a mutation in maintenance of fibrosis 3 (SMC3). antibody.

[0599] Embodiment 42. At least one genetic abnormality is a translocation t(8;21)(q22;q22 ), inversion inv(16)(p13;q22), translocation t(16;16)(p13;q22) , translocation t(15;17)(q22;q12), FLT3-ITD mutation, IDH1 R132H or R100Q / R104V / F108L / R119Q / I130V 42. The method of claim 41, wherein the mutation is a mutation of R140Q or R172 in IDH2. Anti-CD38 antibody for use by

[0600] Embodiment 43. ALL is B-cell lineage ALL, T-cell lineage ALL, adult ALL, or small 33. The anti-CD38 antibody for use according to embodiment 32, wherein the anti-CD38 antibody is a childhood ALL.

[0601] Embodiment 44. The subject with ALL has the Philadelphia chromosome or BC Resistant to or acquired resistance to treatment with R-ABL kinase inhibitors 44. The anti-CD38 antibody for use according to embodiment 43, having the properties

[0602] Embodiment 45. 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 45. For use according to any one of embodiments 1 to 44, comprising an LCDR3 of SEQ ID NO: 11. Anti-CD38 antibody.

[0603] Embodiment 46. An anti-CD38 antibody comprising a VH of SEQ ID NO: 4 and a VL of SEQ ID NO: 5. An anti-CD38 antibody for use according to any one of embodiments 1 to 45.

[0604] Embodiment 47. The method of any one of embodiments 1 to 46, wherein the anti-CD38 antibody is an IgG1 isotype. Anti-CD38 antibody for use with any one of:

[0605] Embodiment 48. The anti-CD38 antibody comprises a HC of SEQ ID NO: 12 and a LC of SEQ ID NO: 13. 48. An anti-CD38 antibody for use according to any one of embodiments 1 to 47.

[0606] Embodiment 49. The anti-CD38 antibody is VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15, VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17, VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or 45. Any one of embodiments 1-44, comprising a VH of SEQ ID NO: 20 and a VL of SEQ ID NO: 21. Anti-CD38 antibody for use by

[0607] Embodiment 50. According to embodiment 49, the anti-CD38 antibody is of the IgG1 isotype. Anti-CD38 antibody for use.

[0608] Embodiment 51. The T cell redirecting therapeutic is a BCMAxCD3 bispecific antibody, a GP RC5D×CD3 bispecific antibody, CD33×CD3 bispecific antibody, CD19×CD3 Bispecific antibody, CD123×CD3 bispecific antibody, PSMA×CD3 bispecific antibody or a TMEFF2×CD3 bispecific antibody. Anti-CD38 antibody for use by

[0609] Embodiment 52. The method of embodiment 1, further comprising administering to the subject one or more anti-cancer therapies. Anti-CD38 antibody for use by ~51.

[0610] Embodiment 53. The one or more anticancer treatments are autologous stem cell transplant (ASCT), radiation , surgery, chemotherapy, immunomodulatory agents, and targeted cancer therapy. 10. An anti-CD38 antibody for use in accordance with any one of aspects 1 to 52.

[0611] Embodiment 54. The one or more anticancer therapies are lenalidomide, thalidomide, pomarin, or thalidomide. Domido, bortezomib, carfilzomib, elotozumab, ixazomib, melphalan , dexamethasone, vincristine, cyclophosphamide, hydroxydaunorubicin, Prednisone, rituximab, imatinib, dasatinib, nilotinib, bosutinib, ponate tinib, bafetinib, saracatinib, tozasertib, or danusertib, citarabine daunorubicin, idarubicin, mitoxantrone, hydroxyurea, decitabine , cladribine, fludarabine, topotecan, etoposide 6-thioguanine, corticosteroids steroids, methotrexate, 6-mercaptopurine, azacitidine, arsenic trioxide, and all-trans retinoic acid, or any combination thereof; 54. An anti-CD38 antibody for use according to any one of embodiments 1 to 53.

[0612] Embodiment 55. The anti-CD38 antibody is administered at a dose of about 8 mg / kg to about 16 mg / kg. 55. An anti-CD38 antibody for use according to any one of embodiments 1 to 54,

[0613] Embodiment 56. The anti-CD38 antibody is prepared in a solution of about 25 mM acetic acid, about 60 mM sodium chloride, Approximately 140% mannitol, and approximately 0.04% w / v polysorbate-20 (PS-20) The solution contains about 20 mg / mL to about 120 mg / mL of anti-CD38 antibody in a pH range of about 5.5. 55. The method of claim 1, wherein the compound is administered or provided for administration in a pharmaceutical composition. an anti-CD38 antibody for use with any one of

[0614] Embodiment 57. The anti-CD38 antibody comprises about 1,800 mg of anti-CD38 antibody and about 30,0 100 U of rHuPH20. 54. The anti-CD38 antibody for use according to any one of embodiments 1 to 53.

[0615] Embodiment 58. The anti-CD38 antibody is a soluble form of an anti-CD38 antibody at about 120 mg / mL and about 2,0 or for administration in a pharmaceutical composition containing 100 U / mL of rHuPH20. 58. The anti-CD38 antibody for use according to embodiment 57, as provided in

[0616] Embodiment 59. The anti-CD38 antibody is about 5 mM to about 15 mM histidine, about 100 mM to about 300 mM sorbitol; Approximately 0.01% w / v to approximately 0.04% w / v of PS-20, It contains about 1 mg / mL to about 2 mg / mL of methionine and has a pH of about 5.5 to 5.6. , administered or provided for administration in a pharmaceutical composition, embodiments 57-58. an anti-CD38 antibody for use with any one of

[0617] Embodiment 60. The anti-CD38 antibody is Approximately 1,800 mg of anti-CD38 antibody, Approximately 30,000 U of rHuPH20 and Approximately 10 mM histidine, about 300 mM sorbitol; Approximately 0.04% (w / v) PS-20, about 1 mg / mL methionine and a pH of about 5.6. Use according to any one of embodiments 57 to 59, wherein the Anti-CD38 antibody for.

[0618] Embodiment 61. The anti-CD38 antibody is Approximately 120 mg / mL of anti-CD38 antibody; Approximately 2,000 U / mL of rHuPH20 and Approximately 10 mM histidine, about 300 mM sorbitol; Approximately 0.04% (w / v) PS-20, about 1 mg / mL methionine and a pH of about 5.6. Use according to any one of embodiments 57 to 60, wherein the Anti-CD38 antibody for.

[0619] Embodiment 62. For use in treating a subject with cancer in combination with an anti-CD38 antibody. BCMA×CD3 bispecific antibody.

[0620] Embodiment 63. The subject is treated with an anti-CD38 antibody prior to administration of the BCMAxCD3 bispecific antibody. 63. The BCMAxCD3 bispecific antibody for use according to embodiment 62, wherein the patient is undergoing treatment.

[0621] Embodiment 64. The BCMAxCD3 bispecific antibody comprises HCDR1 of SEQ ID NO: 23, HCDR2 of SEQ ID NO: 24, HCDR3 of SEQ ID NO: 25, HCDR4 of SEQ ID NO: 26, HCDR5 of SEQ ID NO: 27, HCDR6 of SEQ ID NO: 28, HCDR7 of SEQ ID NO: 29, HCDR8 of SEQ ID NO: 30 HCDR2 of SEQ ID NO: 24, HCDR3 of SEQ ID NO: 25, LCDR1 of SEQ ID NO: 26, a BCMA binding domain comprising an LCDR2 of SEQ ID NO: 27 and an LCDR3 of SEQ ID NO: 28, and 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 BCMAx for use according to embodiment 62 or 63, comprising a CD3 binding domain comprising CD3 bispecific antibody.

[0622] Embodiment 65. The BCMA binding domain comprises a VH of SEQ ID NO: 29 and a VL of SEQ ID NO: 30 and the CD3 binding domain comprises a VH of SEQ ID NO: 39 and a VL of SEQ ID NO: 40. BCMAxCD3 bispecific antibody for use according to any one of embodiments 62 to 64.

[0623] Embodiment 66. The BCMAxCD3 bispecific antibody is of the IgG4 isotype and Phenylanine at position 405 and arginine at position 409 of C1, and HC2 at position 405 leucine at position 104 and lysine at position 409, residue numbering according to the EU index; BCMAxCD3 bispecific antibody for use according to any one of embodiments 62 to 65 .

[0624] Embodiment 67. The BCMAxCD3 bispecific antibody is a 228 62. Further comprising a proline at position 234, an alanine at position 235, and an alanine at position 236. BCMAxCD3 bispecific antibody for use with any one of ~66.

[0625] Embodiment 68. The BCMAxCD3 bispecific antibody comprises HC1 of SEQ ID NO: 31, HC2 of SEQ ID NO: 32, HC3 of SEQ ID NO: 33, HC4 of SEQ ID NO: 34, HC5 of SEQ ID NO: 35, HC6 of SEQ ID NO: 36, HC7 of SEQ ID NO: 37, HC8 of SEQ ID NO: 38, HC9 of SEQ ID 62. The method of claim 61, further comprising administering to said patient an LC1 of SEQ ID NO: 32, an HC2 of SEQ ID NO: 41, and an LC2 of SEQ ID NO: 42. BCMAxCD3 bispecific antibody for use with any one of ~67.

[0626] Embodiment 69. The method according to any one of embodiments 62 to 68, wherein the cancer is a BCMA-expressing cancer. BCMA×CD3 bispecific antibody for use in

[0627] Embodiment 70. According to any one of embodiments 62 to 69, the cancer is a hematological malignancy. BCMAxCD3 bispecific antibody for use.

[0628] Embodiment 71. The subject is receiving anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide. , carfilzomib, elotozumab, ixazomib, melphalan, or thalidomide In embodiments, the patient is relapsed or refractory to treatment with any of the following: BCMAxCD3 bispecific antibody for use with any one of 62 to 70.

[0629] Embodiment 72. A method for treating a subject in which the subject is relapsed or refractory to treatment with an anti-CD38 antibody. BCMAxCD3 bispecific antibody for use according to any one of embodiments 62 to 71.

[0630] Embodiment 73. The hematological malignancy is multiple myeloma, myeloma, DLBLC, CLL, Waldenstrom, In embodiments 62-64, the patient is a patient with rheumatoid arthritis, rheumatoid arthritis, or non-Hodgkin's lymphoma. BCMAxCD3 bispecific antibody for use with any one of 72.

[0631] Embodiment 74. The multiple myeloma is newly diagnosed multiple myeloma. BCMAxCD3 bispecific antibody for use with

[0632] Embodiment 75. The same as in embodiment 74, wherein the multiple myeloma is relapsed or refractory multiple myeloma. BCMA×CD3 bispecific antibody for use by

[0633] Embodiment 76. The use according to embodiment 74, wherein the multiple myeloma is high-risk multiple myeloma. BCMA×CD3 bispecific antibody for use.

[0634] Embodiment 77. A subject with high-risk multiple myeloma is 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 de have one or more chromosomal abnormalities including l17p, l18p, or any combination of these 77. A BCMAxCD3 bispecific antibody for use according to embodiment 76.

[0635] Embodiment 78. 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 For use according to any one of embodiments 62 to 77, comprising an LCDR3 of SEQ ID NO: 11 BCMA×CD3 bispecific antibody.

[0636] Embodiment 79. An anti-CD38 antibody comprising a VH of SEQ ID NO: 4 and a VL of SEQ ID NO: 5. BCMAxCD3 bispecific antibody for use according to any one of embodiments 62 to 78.

[0637] Embodiment 80. Any of embodiments 62 to 79, wherein the anti-CD38 antibody is an IgG1 isotype. BCMA×CD3 bispecific antibody for use with any one of

[0638] Embodiment 81. The anti-CD38 antibody comprises a HC of SEQ ID NO: 12 and a LC of SEQ ID NO: 13. BCMA×CD3 bispecific antibody for use according to any one of embodiments 62 to 80. body.

[0639] Embodiment 82. The anti-CD38 antibody is VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15, VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17, VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or Any one of embodiments 62 to 77, comprising a VH of SEQ ID NO: 20 and a VL of SEQ ID NO: 21. BCMA×CD3 bispecific antibody for use by a patient.

[0640] Embodiment 83. According to embodiment 82, the anti-CD38 antibody is of the IgG1 isotype. BCMAxCD3 bispecific antibody for use.

[0641] Embodiment 84. The anti-CD38 antibody is administered at a dose of about 8 mg / kg to about 16 mg / kg. BCMA×CD3 bispecific antibody for use according to any one of embodiments 62 to 83 sexual antibodies.

[0642] Embodiment 85. A BCMAxCD3 bispecific antibody and an anti-CD38 antibody are administered intravenously. BCMA×C for use according to any one of embodiments 62 to 84, administered by D3 bispecific antibody.

[0643] Embodiment 86. The BCMAxCD3 bispecific antibody is administered by intravenous injection and 85. The method according to any one of embodiments 62 to 84, wherein the CD38 antibody is administered by subcutaneous injection. BCMA×CD3 bispecific antibody for use in

[0644] Embodiment 87. The use according to any one of embodiments 62 to 86, wherein the subject is a human. BCMA×CD3 bispecific antibody for

[0645] Embodiment 88. Embodiment 6 further comprising administering to the subject one or more anti-cancer therapies. BCMAxCD3 bispecific antibody for use with any one of 2 to 87.

[0646] Embodiment 89. The one or more anticancer treatments are autologous stem cell transplant (ASCT), radiation , surgery, chemotherapy, immunomodulatory agents, and targeted cancer therapy. BCMAxCD3 bispecific antibody for use with a patient receiving immunotherapy.

[0647] Embodiment 90. The one or more anticancer therapies is lenalidomide, thalidomide, pomarin, or thalidomide. Domido, bortezomib, carfilzomib, elotozumab, ixazomib, melphalan , prednisone, or dexamethasone, or any combination thereof. BCMAxCD3 for use according to any one of embodiments 88 to 89, selected from Bispecific antibodies.

[0648] Embodiment 91. The anti-CD38 antibody is prepared in a solution of about 25 mM acetic acid, about 60 mM sodium chloride, Approximately 140% mannitol, and approximately 0.04% w / v polysorbate-20 (PS-20) The solution contains about 20 mg / mL to about 120 mg / mL of anti-CD38 antibody in a pH range of about 5.5. 62 to 69, wherein the compound is administered or provided for administration in a pharmaceutical composition. BCMAxCD3 bispecific antibody for use with any one of

[0649] Embodiment 92. The anti-CD38 antibody comprises about 1,800 mg of anti-CD38 antibody and about 30,0 100 U of rHuPH20. BCMA×CD3 bispecific antibody for use according to any one of embodiments 62 to 90. Heterogeneous antibodies.

[0650] Embodiment 93. The anti-CD38 antibody is a soluble form of an anti-CD38 antibody at about 120 mg / mL and about 2,0 or for administration in a pharmaceutical composition containing 100 U / mL of rHuPH20. 93. The BCMAxCD3 bispecific antibody for use according to embodiment 92, as provided in

[0651] Embodiment 94. The anti-CD38 antibody is about 5 mM to about 15 mM histidine, about 100 mM to about 300 mM sorbitol; Approximately 0.01% w / v to approximately 0.04% w / v of PS-20, It contains about 1 mg / mL to about 2 mg / mL of methionine and has a pH of about 5.5 to 5.6. , according to embodiments 92-93, administered or provided for administration in a pharmaceutical composition. BCMAxCD3 bispecific antibody for use with any one of

[0652] Embodiment 95. The anti-CD38 antibody is Approximately 1,800 mg of anti-CD38 antibody, Approximately 30,000 U of rHuPH20 and Approximately 10 mM histidine, about 300 mM sorbitol; Approximately 0.04% (w / v) PS-20, about 1 mg / mL methionine and a pH of about 5.6. Use according to any one of embodiments 92 to 94, wherein the BCMA×CD3 bispecific antibody for

[0653] Embodiment 96. The anti-CD38 antibody is Approximately 120 mg / mL of anti-CD38 antibody; Approximately 2,000 U / mL of rHuPH20 and Approximately 10 mM histidine, about 300 mM sorbitol; Approximately 0.04% (w / v) PS-20, about 1 mg / mL methionine and a pH of about 5.6. Use according to any one of embodiments 92 to 95, wherein the compound is administered or provided for administration. BCMA×CD3 bispecific antibody for

[0654] Embodiment 97. A BCMAxCD3 bispecific antibody for use in treating a subject with cancer. BC, wherein the subject is relapsed or refractory to treatment with a previous anti-cancer therapeutic agent. MA×CD3 bispecific antibody.

[0655] Embodiment 98. The BCMAxCD3 bispecific antibody comprises HCDR1 of SEQ ID NO: 23, HCDR2 of SEQ ID NO: 24, HCDR3 of SEQ ID NO: 25, HCDR4 of SEQ ID NO: 26, HCDR5 of SEQ ID NO: 27, HCDR6 of SEQ ID NO: 28, HCDR7 of SEQ ID NO: 29, HCDR8 of SEQ ID NO: 30, HCDR9 of SEQ ID NO: 31, HCDR1 of SEQ ID NO: 32, HCDR1 of SEQ ID NO: 33, HCDR1 of SEQ ID NO: 34, HCDR1 of SEQ ID NO: 35, HCDR1 of SEQ ID NO: 36, HCDR1 of SEQ ID NO: 37, HCDR1 of SEQ ID NO: 38, HCDR1 of SEQ ID NO: 39, HCDR2 of SEQ ID NO: 24, HCDR3 of SEQ ID NO: 25, LCDR1 of SEQ ID NO: 26, a BCMA binding domain comprising an LCDR2 of SEQ ID NO: 27 and an LCDR3 of SEQ ID NO: 28, and 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 98. A BCMAxCD3 bilayer for use according to embodiment 97, comprising a CD3 binding domain comprising Heavy specific antibody.

[0656] Embodiment 99. The BCMA binding domain comprises a VH of SEQ ID NO: 29 and a VL of SEQ ID NO: 30 and the CD3 binding domain comprises a VH of SEQ ID NO: 39 and a VL of SEQ ID NO: 40. BCMAxCD3 bispecific antibody for use according to embodiment 97 or 98.

[0657] Embodiment 100. The BCMAxCD3 bispecific antibody is of the IgG4 isotype, Phenylanine at position 405 and arginine at position 409 of HC1, and 405 of HC2 Leucine at position 409 and Lysine at position 409; residue numbering is according to the EU index BCMA×CD3 bispecific antibody for use according to any one of embodiments 97 to 99. body.

[0658] Embodiment 101. A BCMAxCD3 bispecific antibody is 1, further comprising a proline at position 8, an alanine at position 234, and an alanine at position 235. BCMAxCD3 bispecific antibody for use with 00.

[0659] Embodiment 102. The BCMAxCD3 bispecific antibody comprises HC1 of SEQ ID NO: 31, HC2 of SEQ ID NO: 32, HC3 of SEQ ID NO: 33, HC4 of SEQ ID NO: 34, HC5 of SEQ ID NO: 35, HC6 of SEQ ID NO: 36, HC7 of SEQ ID NO: 37, HC8 of SEQ ID NO: 38, HC9 of SEQ 32, HC2 of SEQ ID NO: 41, and LC2 of SEQ ID NO: 42. BCMAxCD3 bispecific antibody for use with any one of 7 to 101.

[0660] Embodiment 103. Any one of embodiments 97 to 102, wherein the cancer is a hematological malignancy. BCMA×CD3 bispecific antibody for use by

[0661] Embodiment 104. The use according to embodiment 103, wherein the hematological malignancy is multiple myeloma. BCMA×CD3 bispecific antibody for

[0662] Embodiment 105. The method according to embodiment 104, wherein the multiple myeloma is high-risk multiple myeloma. BCMA×CD3 bispecific antibody for use in

[0663] Embodiment 106. A subject with high-risk multiple myeloma is 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 de have one or more chromosomal abnormalities including l17p, l18p, or any combination of these 106. A BCMAxCD3 bispecific antibody for use according to embodiment 105.

[0664] Embodiment 107. The subject is receiving anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide carfilzomib, elotozumab, ixazomib, melphalan, or thalidomide or any combination thereof, BCMAxCD3 bispecific antibody for use with any one of conditions 97 to 106.

[0665] Embodiment 108. An embodiment in which the subject is relapsed to treatment with an anti-CD38 antibody. BCMAxCD3 bispecific antibody for use with any one of 97 to 107.

[0666] Embodiment 109. The anti-CD38 antibody comprises HCDR1 of SEQ ID NO: 6, HCDR2 of SEQ ID NO: 7 2. HCDR3 of SEQ ID NO: 8, LCDR1 of SEQ ID NO: 9, LCDR2 of SEQ ID NO: 10, and and LCDR3 of SEQ ID NO: 11. BCMA×CD3 bispecific antibody for

[0667] Embodiment 110. The anti-CD38 antibody comprises a VH of SEQ ID NO: 4 and a VL of SEQ ID NO: 5. BCMAxCD3 bispecific antibody for use according to any one of embodiments 97 to 109. body.

[0668] Embodiment 111. The anti-CD38 antibody is an IgG1 isotype, BCMAxCD3 bispecific antibody for use with any one of the ten methods described herein.

[0669] Embodiment 112. The anti-CD38 antibody comprises a HC of SEQ ID NO: 12 and a LC of SEQ ID NO: 13. BCMA×CD3 bispecific antibody for use according to any one of embodiments 97 to 111. sexual antibodies.

[0670] Embodiment 113. The anti-CD38 antibody is VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15, VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17, VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or Any of embodiments 97 to 108, comprising a VH of SEQ ID NO: 20 and a VL of SEQ ID NO: 21. BCMAxCD3 bispecific antibody for use by one.

[0671] Embodiment 114. The method of embodiment 113, wherein the anti-CD38 antibody is an IgG1 isotype. BCMA×CD3 bispecific antibody for use by

[0672] Embodiment 115. The use according to any one of embodiments 97 to 114, wherein the subject is a human. BCMA×CD3 bispecific antibody for use.

[0673] Embodiment 116. An embodiment further comprising administering one or more anti-cancer therapies to the subject. BCMAxCD3 bispecific antibody for use with any one of 97 to 115.

[0674] Embodiment 117. The one or more anticancer treatments are autologous stem cell transplant (ASCT), radiation a cancer treatment selected from the group consisting of radiation, surgery, chemotherapy, immunomodulatory agents, and targeted cancer therapy. BCMAxCD3 bispecific antibody for use with form 116.

[0675] Embodiment 118. The one or more anticancer treatments are lenalidomide, thalidomide, pomalidomide, or thalidomide. Lidomide, bortezomib, carfilzomib, elotozumab, ixazomib, melfala the group consisting of acetaminophen, prednisone, or dexamethasone, or any combination thereof 117. The BCMAxCD3 bispecific antibody for use according to embodiment 116, selected from:

[0676] Embodiment 119. A BCMA-binding domain comprising a VH of SEQ ID NO: 29 and a VL of SEQ ID NO: 30. and a CD3 binding domain comprising a VH of SEQ ID NO: 39 and a VL of SEQ ID NO: 40. a BCMAxCD3 bispecific antibody comprising a VH of SEQ ID NO: 4 and a VL of SEQ ID NO: 5; and a CD38 antibody.

[0677] Embodiment 120. The BCMAxCD3 bispecific antibody comprises HC1 of SEQ ID NO: 31, HC2 of SEQ ID NO: 32, HC3 of SEQ ID NO: 33, HC4 of SEQ ID NO: 34, HC5 of SEQ ID NO: 35, HC6 of SEQ ID NO: 36, HC7 of SEQ ID NO: 37, HC8 of SEQ ID NO: 38, HC9 of SEQ LC1 of SEQ ID NO: 32, HC2 of SEQ ID NO: 41, and LC2 of SEQ ID NO: 42, 120. The pharmaceutical composition of embodiment 119, wherein the antibody comprises a HC of SEQ ID NO: 12 and a LC of SEQ ID NO: 13. thing.

[0678] Embodiment 121. The pharmaceutical composition of embodiment 119 or 120, which is a non-fixed combination.

[0679] Embodiment 122. A mixture of about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mM mannitol and about 20 mg / mL in about 0.04% w / v polysorbate-20 (PS-20). 12. The method of claim 11, wherein the anti-CD38 antibody is present in an amount of from about 100 mg / mL to about 120 mg / mL and has a pH of about 5.5. 1. A pharmaceutical composition.

[0680] Embodiment 123. About 1,800 mg of an anti-CD38 antibody and about 30,000 U of rHuP 122. The pharmaceutical composition of embodiment 121, comprising H20.

[0681] Embodiment 124. A composition comprising about 120 mg / mL of an anti-CD38 antibody and about 2,000 U / mL of r The pharmaceutical composition of embodiment 123, comprising HuPH20.

[0682] Embodiment 125. The pharmaceutical composition of embodiment 124, further comprising one or more excipients. .

[0683] Embodiment 126. The one or more excipients are histidine, methionine, sorbitol, or polysorbate-20 (PS-20), or any combination thereof. The pharmaceutical composition of embodiment 125,

[0684] Embodiment 127. The pharmaceutical composition comprises: about 100 mg / mL to about 120 mg / mL of an anti-CD38 antibody; about 5 mM to about 15 mM histidine, about 100 mM to about 300 mM sorbitol; Approximately 0.01% w / v to approximately 0.04% w / v of PS-20, It contains about 1 mg / mL to about 2 mg / mL of methionine and has a pH of about 5.5 to 5.6. , The pharmaceutical composition of embodiment 126.

[0685] Embodiment 128. The pharmaceutical composition of embodiment 127, comprising about 10 mM histidine.

[0686] Embodiment 129. The pharmaceutical composition of embodiment 127 or 128, comprising about 300 mM sorbitol. Pharmaceutical composition.

[0687] Embodiment 130. Embodiments 127-12, comprising about 0.04% (w / v) PS-20. 9. The pharmaceutical composition of any one of

[0688] Embodiment 131. Any of embodiments 127 to 130, comprising about 1 mg / mL of methionine. Any one of the pharmaceutical compositions.

[0689] Embodiment 132. Approximately 1,800 mg of anti-CD38 antibody, Approximately 30,000 U of rHuPH20 and Approximately 10 mM histidine, about 300 mM sorbitol; Approximately 0.04% (w / v) PS-20, and about 1 mg / mL methionine, and a pH of about 5.6. Any one of the pharmaceutical compositions.

[0690] Embodiment 133. Approximately 120 mg / mL of anti-CD38 antibody; Approximately 2,000 U / mL of rHuPH20 and Approximately 10 mM histidine, about 300 mM sorbitol; Approximately 0.04% (w / v) PS-20, and about 1 mg / mL methionine, and a pH of about 5.6. Any one of the pharmaceutical compositions.

[0691] Embodiment 134. A kit comprising the pharmaceutical composition of any one of embodiments 119 to 133. .

[0692] Embodiment 135. A method for treating a subject with cancer in combination with an anti-CD38 antibody. A T cell redirecting therapeutic agent that binds to GPRC5D for this purpose.

[0693] Embodiment 136. T cell redirection therapy in which an anti-CD38 antibody binds to GPRC5D Binding to GPRC5D for use according to embodiment 135, administered to the subject before administration of the drug. T cell redirection therapy.

[0694] Embodiment 137. The subject is relapsed or refractory to treatment with a previous anticancer therapeutic agent. 137. A T cell redirector binding to GPRC5D for use according to embodiment 135 or 136. Drug treatment.

[0695] Embodiment 138. Any of embodiments 135 to 137, wherein the cancer is a GPRC5D-expressing cancer. or a T cell redirecting therapeutic agent that binds to GPRC5D for use by one of

[0696] Embodiment 139. An embodiment in which the GPRC5D-expressing cancer is a hematological malignancy or a solid tumor. 135 to 138, for use in a T cell redirecting agent that binds to GPRC5D. Rectotherapy.

[0697] Embodiment 140. The hematological malignancy is leukemia, lymphoma, or multiple myeloma. T cell redirecting therapeutics that bind to GPRC5D for use with form 139.

[0698] Embodiment 141. The solid tumor is ovarian cancer, lung cancer, gastric cancer, prostate cancer, kidney cancer, liver cancer, pancreatic cancer, The use according to embodiment 139, wherein the cancer is intestinal cancer, esophageal cancer, bladder cancer, cervical cancer, or malignant melanoma. T cell redirecting therapeutics that bind to GPRC5D for

[0699] Embodiment 142. The subject is receiving anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide carfilzomib, elotozumab, ixazomib, melphalan, or thalidomide or any combination thereof, T cell leader that binds to GPRC5D for use with any one of conditions 135 to 141 Irrector drug.

[0700] Embodiment 143. The subject is relapsed or refractory to treatment with an anti-CD38 antibody. T cells binding to GPRC5D for use according to any one of embodiments 135 to 142 Cell redirection therapy.

[0701] Embodiment 144. The multiple myeloma is newly diagnosed multiple myeloma. T cell redirectors that bind to GPRC5D for use with any one of 40 to 143 Drug treatment.

[0702] Embodiment 145. The multiple myeloma is relapsed or refractory multiple myeloma. T cell redirecting agents that bind to GPRC5D for use with any one of 0 to 143 Treatment drug.

[0703] Embodiment 146. The multiple myeloma is high-risk multiple myeloma. T cell redirection therapy that binds to GPRC5D for use with any one of 45 medicine.

[0704] Embodiment 147. A subject with high-risk multiple myeloma is 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 de have one or more chromosomal abnormalities including l17p, l18p, or any combination of these 147. A T cell redirecting therapeutic agent that binds GPRC5D for use according to embodiment 146. .

[0705] Embodiment 148. The T cell redirecting therapeutic agent is selected from the group consisting of CD3, CD3 epsilon (CD3ε), ), CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD18 6. Binds to BTNL8, PD-1, CD195, or NKG2C, embodiments 135 to 136 147. T cell redirection therapy that binds to GPRC5D for use with any one of Therapeutic medicine.

[0706] Embodiment 149. The T cell redirecting therapeutic comprises HCDR1 of SEQ ID NO: 43, HCDR2 of SEQ ID NO: 44, HCDR3 of SEQ ID NO: 45, HCDR4 of SEQ ID NO: 46, HCDR5 of SEQ ID NO: 47, HCDR6 of SEQ ID NO: 48, HCDR7 of SEQ ID NO: 49, HCDR8 of SEQ ID NO: 50, HCDR9 of SEQ ID NO: 51, HCDR1 of SEQ ID NO: 52, HCDR1 of SEQ ID NO: 53, HCDR1 of SEQ ID NO: 54, HCDR1 of SEQ ID NO: 55, HCDR1 of SEQ ID NO: 56, HCDR1 of SEQ ID NO: 57, HCDR1 of SEQ ID NO: 58, HCDR1 of SEQ ID NO: 59, HCDR1 HCDR2 of SEQ ID NO: 44, HCDR3 of SEQ ID NO: 45, LCDR1 of SEQ ID NO: 46, SEQ ID NO: 4 7, and LCDR3 of SEQ ID NO: 48, and a GPRC5D binding domain comprising LCDR2 of SEQ ID NO: 49; 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: 38 149. The use according to any one of embodiments 135 to 148, comprising a CD3 binding domain comprising T cell redirecting therapeutics that bind to GPRC5D for

[0707] Embodiment 150. The GPRC5D binding domain comprises a VH of SEQ ID NO: 49 and a VH of SEQ ID NO: 50 and the CD3 binding domain comprises a VH of SEQ ID NO: 39 and a VL of SEQ ID NO: 40. Included, coupled to GPRC5D for use according to any one of embodiments 135 to 149. T cell redirecting therapeutics.

[0708] Embodiment 151. The T cell redirecting therapeutic that binds to GPRC5C is a multispecific antibody any one of embodiments 135 to 150, wherein the antibody is a CAR, a T cell expressing a CAR, or a T cell expressing a CAR. EP1317733A1 - T cell redirecting therapeutics that bind to GPRC5D for use by a patient.

[0709] Embodiment 152. The multispecific antibody is an IgG1, IgG2, IgG3, or IgG4 antibody. 151. A T cell receptor that binds to GPRC5D, which is an isotype Direct therapeutic drugs.

[0710] Embodiment 153. The multispecific antibody is a multispecific antibody having a binding site to an Fcγ receptor (FcγR) of the multispecific antibody. Any of embodiments 151-152, comprising one or more Fc substitutions that reduce binding. 10. A T cell redirecting therapeutic that binds to GPRC5D for use by one.

[0711] Embodiment 154. The one or more Fc substitutions are F234A / L235 on IgG4 A, L234A / L235A on IgG1, V234A / G237A / P2 on IgG2 38S / H268A / V309L / A330S / P331S, F234A / on IgG4 L235A, S228P / F234A / L235A on IgG4, all Ig isotypes N297A on IgG1, V234A / G237A on IgG2, K214T / E on IgG1 233P / L234V / L235A / G236 deletion / A327G / P331A / D365 E / L358M, H268Q / V309L / A330S / P331S on IgG2, Ig S267E / L328F on G1, L234F / L235E / D265A on IgG1, L234A / L235A / G237A / P238S / H268A / A330 on IgG1 S / P331S, S228P / F234A / L235A / G237A / P2 on IgG4 38S, and S228P / F234A / L235A / G236 deletion / G23 on IgG4 7A / P238S, wherein residue numbering is according to the EU index , T binding to GPRC5D for use according to any one of embodiments 151 to 153 Cell redirection therapeutics.

[0712] Embodiment 155. The multispecific antibody according to embodiment 154, wherein the antibody further comprises a S228P substitution. 10. A T cell redirecting therapeutic agent that binds to GPRC5D for use in treating a patient suffering from atopic dermatitis.

[0713] Embodiment 156. The multispecific antibody comprises a first CH3 domain or a second CH3 domain. one or more CH3 domains in the first CH3 domain or in both the first CH3 domain and the second CH3 domain GP for use according to any one of embodiments 151 to 155, comprising the above asymmetric substitutions T cell redirecting therapeutics that bind to RC5D.

[0714] Embodiment 157. The one or more asymmetric substitutions are F450L / K409R, wild type / F409L_R409K, T366Y / F405A, T366W / F405W, F40 5W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T 394S, F405W / T394S and T366W / T366S_L368A_Y407 V, L351Y_F405A_Y407V / T394W, T366I_K392M_T3 94W / F405A_Y407V, T366L_K392M_T394W / F405A_ Y407V, L351Y_Y407A / T366A_K409F, L351Y_Y407 A / T366V_K409F, Y407A / T366A_K409F, and T350V _L351Y_F405A_Y407V / T350V_T366L_K392L_T39 4W, coupled to GPRC5D for use according to embodiment 156. T cell redirection therapy.

[0715] Embodiment 158. The multispecific antibody comprises HC1 of SEQ ID NO: 51, LC1 of SEQ ID NO: 52, Any of embodiments 151 to 157, comprising an HC2 of SEQ ID NO: 41 and an LC2 of SEQ ID NO: 42. 10. A T cell redirecting therapeutic that binds to GPRC5D for use with any one of

[0716] Embodiment 159. The anti-CD38 antibody comprises HCDR1 of SEQ ID NO: 6, HCDR2 of SEQ ID NO: 7 2. HCDR3 of SEQ ID NO: 8, LCDR1 of SEQ ID NO: 9, LCDR2 of SEQ ID NO: 10, and and LCDR3 of SEQ ID NO: 11. T cell redirecting therapeutics that bind to GPRC5D for

[0717] Embodiment 160. The anti-CD38 antibody comprises a VH of SEQ ID NO: 4 and a VL of SEQ ID NO: 5. T cells binding to GPRC5D for use according to any one of embodiments 135 to 159 Cell redirection therapy.

[0718] Embodiment 161. The anti-CD38 antibody of embodiment 135-165 is an IgG1 isotype. 160. T cell redirection therapy that binds to GPRC5D for use with any one of Therapeutic medicine.

[0719] Embodiment 162. The anti-CD38 antibody comprises a HC of SEQ ID NO: 12 and a LC of SEQ ID NO: 13. Included, coupled to a GPRC5D for use according to any one of embodiments 135 to 161. T cell redirecting therapeutics.

[0720] Embodiment 163. The anti-CD38 antibody is VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15, VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17, VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or Any of embodiments 135 to 158, comprising a VH of SEQ ID NO: 20 and a VL of SEQ ID NO: 21. or a T cell redirecting therapeutic agent that binds to GPRC5D for use by one of

[0721] Embodiment 164. The method of embodiment 163, wherein the anti-CD38 antibody is an IgG1 isotype. 20. A T cell redirecting therapeutic that binds GPRC5D for use by

[0722] Embodiment 165. The anti-CD38 antibody is administered at a dose of about 8 mg / kg to about 16 mg / kg. 165. The method according to claim 135, wherein the GPRC5D is coupled to the GPRC5D for use according to any one of embodiments 135 to 164. T cell redirection therapy.

[0723] Embodiment 166. T cell redirecting therapeutic agents that bind to GPRC5D and anti-CD38 antibodies The use according to any one of embodiments 135 to 165, wherein the compound is administered by intravenous injection. T cell redirecting therapeutics that bind to GPRC5D for use.

[0724] Embodiment 167. A T cell redirecting therapeutic agent that binds to GPRC5D is administered by intravenous injection. and the anti-CD38 antibody is administered by subcutaneous injection. 65 Binding to GPRC5D for T cell redirection therapy for use with any one of medicine.

[0725] Embodiment 168. The method according to any one of embodiments 135 to 167, wherein the subject is a human. 10. A T cell redirecting therapeutic that binds to GPRC5D for use.

[0726] Embodiment 169. The T cell redirecting therapeutic agent that binds to GPRC5D is For use according to any one of embodiments 135 to 168, the antibody is a β-CD3 bispecific antibody. T cell redirecting therapeutic agents that bind to GPRC5D for

[0727] Embodiment 170. An embodiment further comprising administering one or more anti-cancer therapies to the subject. 135-170, a T cell redirecting agent that binds to GPRC5D for use with any one of Rectotherapy.

[0728] Embodiment 171. The one or more anticancer treatments include autologous stem cell transplantation (ASCT), radiation a cancer treatment selected from the group consisting of radiation, surgery, chemotherapy, immunomodulatory agents, and targeted cancer therapy. T cell redirecting therapeutics that bind to GPRC5D for use with Form 170.

[0729] Embodiment 172. The one or more anticancer treatments are lenalidomide, thalidomide, pomalidomide, or thalidomide. Lenalidomide, bortezomib, carfilzomib, elotuzumab, ixazomib, melphalan, dexamethasone, or prednisone, a T cell redirecting therapeutic agent that binds to GPRC5D for use according to Embodiment 170. Selected from the group consisting of, for use according to Embodiment 170. A T cell redirecting therapeutic agent that binds to GPRC5D for use according to Embodiment 170.

[0730] Embodiment 173. The anti-CD38 antibody is administered or provided for administration in a pharmaceutical composition comprising from about 20 mg / mL to about 120 mg / mL of anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mannitol, and about 0.04% w / v polysorbate-20 (PS-20), at a pH of about 5.5, for use according to any one of Embodiments 135 to 172. Selected from the group consisting of, for use according to Embodiment 170. A T cell redirecting therapeutic agent that binds to GPRC5D for use according to Embodiment 170. A T cell redirecting therapeutic agent that binds to GPRC5D for use according to any one of Embodiments 135 to 172, which is administered or provided for administration in a pharmaceutical composition. Selected from the group consisting of, for use according to Embodiment 170. A T cell redirecting therapeutic agent that binds to GPRC for use according to Embodiment 170. <00​​​​​​​​​​​​​​​​​​​​​​​​​​ about 100 mM to about 300 mM sorbitol; Approximately 0.01% w / v to approximately 0.04% w / v of PS-20, It contains about 1 mg / mL to about 2 mg / mL of methionine and has a pH of about 5.5 to 5.6. , administered or provided for administration in a pharmaceutical composition, or 175. A T cell redirecting therapeutic agent that binds GPRC5D for use by a

[0734] Embodiment 177. The anti-CD38 antibody is Approximately 1,800 mg of anti-CD38 antibody, Approximately 30,000 U of rHuPH20 and Approximately 10 mM histidine, about 300 mM sorbitol; Approximately 0.04% (w / v) PS-20, about 1 mg / mL methionine and a pH of about 5.6. or provided for administration according to any one of embodiments 174 to 176. 10. A T cell redirecting therapeutic that binds to GPRC5D for use.

[0735] Embodiment 178. The anti-CD38 antibody is Approximately 120 mg / mL of anti-CD38 antibody; Approximately 2,000 U / mL of rHuPH20 and Approximately 10 mM histidine, about 300 mM sorbitol; Approximately 0.04% (w / v) PS-20, about 1 mg / mL methionine and a pH of about 5.6. or provided for administration according to any one of embodiments 174 to 177. 10. A T cell redirecting therapeutic that binds to GPRC5D for use.

[0736] Embodiment 179. GPRC5D x CD3 bispecific antibody for use in treating a subject with cancer an alloantibody, and the subject is relapsed or refractory to treatment with a previous anti-cancer therapeutic agent; , GPRC5D×CD3 bispecific antibody.

[0737] Embodiment 180. The GPRC5DxCD3 bispecific antibody 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, GPRC5D binding domain comprising LCDR2 of SEQ ID NO: 47 and LCDR3 of SEQ ID NO: 48 HCDR1 of SEQ ID NO: 33, HCDR2 of SEQ ID NO: 34, H of SEQ ID NO: 35 CDR3 of SEQ ID NO: 36, LCDR1 of SEQ ID NO: 37, and LCDR2 of SEQ ID NO: 38 179. A GPR for use according to embodiment 179, comprising a CD3 binding domain comprising LCDR3. C5D×CD3 bispecific antibody.

[0738] Embodiment 181. The GPRC5D binding domain comprises a VH of SEQ ID NO: 49 and a VH of SEQ ID NO: 50 and the CD3 binding domain comprises a VH of SEQ ID NO: 39 and a VL of SEQ ID NO: 40. GPRC5DxCD3 bispecific antibody for use according to embodiment 179 or 180 .

[0739] Embodiment 182. The GPRC5DxCD3 bispecific antibody is of the IgG4 isotype. HC1 has phenylalanine at position 405 and arginine at position 409, and HC2 has 4 It contains a leucine at position 05 and a lysine at position 409, and the residue numbering is according to the EU index. According to any one of embodiments 179 to 181, GPRC5D×CD3 Bispecific antibodies.

[0740] Embodiment 183. The GPRC5DxCD3 bispecific antibody comprises both HC1 and HC2. Further comprising a proline at position 228, an alanine at position 234, and an alanine at position 235. GPRC5DxCD3 bispecific antibody for use with condition 182.

[0741] Embodiment 184. The GPRC5DxCD3 bispecific antibody comprises HC1 of SEQ ID NO: 51, LC1 of sequence number 52, HC2 of sequence number 41, and LC2 of sequence number 42. GPRC5D×CD3 bispecific antibody for use with any one of conditions 179 to 183 body.

[0742] Embodiment 185. The method of any one of embodiments 179 to 184, wherein the cancer is a hematological malignancy or a solid tumor. GPRC5DxCD3 bispecific antibody for use with any one of

[0743] Embodiment 186. The cancer is multiple myeloma, lymphoma, melanoma, breast cancer, endometrial cancer, or ovarian cancer. , lung cancer, stomach cancer, prostate cancer, kidney cancer, liver cancer, pancreatic cancer, colon cancer, esophageal cancer, bladder cancer, or cervical cancer. A GPRC5DxCD3 bispecific antibody for use according to embodiment 185.

[0744] Embodiment 187. The method according to embodiment 186, wherein the multiple myeloma is high-risk multiple myeloma. GPRC5D×CD3 bispecific antibody for use in

[0745] Embodiment 188. A subject with high-risk multiple myeloma is 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 de have one or more chromosomal abnormalities including l17p, l18p, or any combination of these 188. A GPRC5DxCD3 bispecific antibody for use according to embodiment 187.

[0746] Embodiment 189. The subject is receiving anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide carfilzomib, elotozumab, ixazomib, melphalan, or thalidomide or any combination thereof, GPRC5D×CD3 bispecific antibody for use with any one of conditions 179 to 188 body.

[0747] Embodiment 190. The subject is relapsed or refractory to treatment with an anti-CD38 antibody. GPRC5D×CD3 dual specific for use according to any one of embodiments 179 to 189 Heterogeneous antibodies.

[0748] Embodiment 191. The anti-CD38 antibody comprises HCDR1 of SEQ ID NO: 6, HCDR2 of SEQ ID NO: 7 2. HCDR3 of SEQ ID NO: 8, LCDR1 of SEQ ID NO: 9, LCDR2 of SEQ ID NO: 10, and and LCDR3 of SEQ ID NO: 11. GPRC5D×CD3 bispecific antibody for

[0749] Embodiment 192. The anti-CD38 antibody comprises a VH of SEQ ID NO: 4 and a VL of SEQ ID NO: 5. GPRC5D x CD3 dual specific for use according to any one of embodiments 179 to 191 Heterogeneous antibodies.

[0750] Embodiment 193. The anti-CD38 antibody of embodiment 179 to embodiment 193 is an IgG1 isotype. 192. A GPRC5DxCD3 bispecific antibody for use with any one of

[0751] Embodiment 194. The anti-CD38 antibody comprises a HC of SEQ ID NO: 12 and a LC of SEQ ID NO: 13. GPRC5D×CD3 for use according to any one of embodiments 179 to 193 Heavy specific antibody.

[0752] Embodiment 195. The anti-CD38 antibody is VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15, VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17, VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or Any of embodiments 179 to 190, comprising a VH of SEQ ID NO: 20 and a VL of SEQ ID NO: 21. GPRC5DxCD3 bispecific antibody for use with one or more of:

[0753] Embodiment 196. The method of embodiment 195, wherein the anti-CD38 antibody is an IgG1 isotype. GPRC5DxCD3 bispecific antibody for use by

[0754] Embodiment 197. The method according to any one of embodiments 179 to 196, wherein the subject is a human. GPRC5D x CD3 bispecific antibody for use.

[0755] Embodiment 198. An embodiment further comprising administering one or more anti-cancer therapies to the subject. GPRC5D x CD3 bispecific antibody for use with any one of 179 to 197 .

[0756] Embodiment 199. The one or more anticancer treatments include autologous stem cell transplantation (ASCT), radiation a cancer treatment selected from the group consisting of radiation, surgery, chemotherapy, immunomodulatory agents, and targeted cancer therapy. GPRC5DxCD3 bispecific antibody for use with Form 198.

[0757] Embodiment 200. The one or more anticancer therapies is lenalidomide, thalidomide, pomalidomide, or thalidomide. Lidomide, bortezomib, carfilzomib, elotozumab, ixazomib, melfala , dexamethasone, vincristine, cyclophosphamide, hydroxydaunorubicin , prednisone, rituximab, imatinib, dasatinib, nilotinib, bosutinib, Natinib, bafetinib, saracatinib, tozasertib or danusertib, citara Bin, daunorubicin, idarubicin, mitoxantrone, hydroxyurea, decitabine methicillin, cladribine, fludarabine, topotecan, etoposide 6-thioguanine, corticosteroids Steroids, methotrexate, 6-mercaptopurine, azacitidine, arsenic trioxide, and and all-trans retinoic acid, or any combination thereof 199. A GPRC5DxCD3 bispecific antibody for use according to embodiment 198.

[0758] Embodiment 201. HCDR1 of SEQ ID NO: 43, HCDR2 of SEQ ID NO: 44, SEQ ID NO: 4 5, LCDR1 of SEQ ID NO: 46, LCDR2 of SEQ ID NO: 47, and GPRC5D binding domain comprising LCDR3 of SEQ ID NO: 48, and HCDR1 of SEQ ID NO: 33; HCDR2 of SEQ ID NO: 34, HCDR3 of SEQ ID NO: 35, LCDR1 of SEQ ID NO: 36, A CD3 binding domain comprising LCDR2 of SEQ ID NO: 37 and LCDR3 of SEQ ID NO: 38. GPRC5D×CD3 bispecific antibody containing HCDR1 of SEQ ID NO: 6 and HCDR2 of SEQ ID NO: 7 DR2, HCDR3 of SEQ ID NO: 8, LCDR1 of SEQ ID NO: 9, LCDR2 of SEQ ID NO: 10 and an anti-CD38 antibody comprising an LCDR3 of SEQ ID NO: 11.

[0759] Embodiment 202. The GPRC5D binding domain comprises a VH of SEQ ID NO: 49 and a VH of SEQ ID NO: 50 and the CD3 binding domain comprises a VH of SEQ ID NO: 39 and a VL of SEQ ID NO: 40. 201. The method of claim 200, wherein the anti-CD38 antibody comprises a VH of SEQ ID NO: 4 and a VL of SEQ ID NO: 5. Pharmaceutical combinations.

[0760] Embodiment 203. The GPRC5CxCD3 bispecific antibody comprises HC1 of SEQ ID NO: 51, LC1 of sequence number 52, HC2 of sequence number 41, and LC2 of sequence number 42, 38. The antibody of embodiment 201 or 2, wherein the antibody comprises an HC of SEQ ID NO: 12 and an LC of SEQ ID NO: 13. 02 drug combinations.

[0761] Embodiment 204. Any one of embodiments 201 to 203, which is a non-fixed combination. Pharmaceutical combinations.

[0762] Embodiment 205. A mixture of about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mM mannitol and about 20 mg / mL in about 0.04% w / v polysorbate-20 (PS-20). 20. The method of claim 20, wherein the anti-CD38 antibody is present in an amount of from about 100 mg / mL to about 120 mg / mL and has a pH of about 5.5. 4 pharmaceutical combinations.

[0763] Embodiment 206. About 1,800 mg of an anti-CD38 antibody and about 30,000 U of rHuP. The pharmaceutical combination of embodiment 204, comprising H20.

[0764] Embodiment 207. A composition comprising about 120 mg / mL of an anti-CD38 antibody and about 2,000 U / mL of r 207. The pharmaceutical composition of embodiment 206, comprising HuPH20.

[0765] Embodiment 208. The pharmaceutical combination of embodiment 207, further comprising one or more excipients. Match.

[0766] Embodiment 209. The one or more excipients are histidine, methionine, sorbitol, or polysorbate-20 (PS-20), or any combination thereof. The pharmaceutical combination of embodiment 208,

[0767] Embodiment 210. The pharmaceutical composition comprises: about 100 mg / mL to about 120 mg / mL of an anti-CD38 antibody; about 5 mM to about 15 mM histidine, about 100 mM to about 300 mM sorbitol; Approximately 0.01% w / v to approximately 0.04% w / v of PS-20, It contains about 1 mg / mL to about 2 mg / mL of methionine and has a pH of about 5.5 to 5.6. , The pharmaceutical combination of embodiment 209.

[0768] Embodiment 211. The pharmaceutical composition of embodiment 209 or 210, comprising about 10 mM histidine. Combination.

[0769] Embodiment 212. Any of embodiments 209 to 211, comprising about 300 mM sorbitol. One of these pharmaceutical combinations.

[0770] Embodiment 213. The composition of any of embodiments 209 to 21, comprising about 0.04% (w / v) PS-20. Any one of the two pharmaceutical combinations.

[0771] Embodiment 214. Any of embodiments 209 to 213, comprising about 1 mg / mL of methionine. One of these pharmaceutical combinations.

[0772] Embodiment 215. Approximately 1,800 mg of anti-CD38 antibody, Approximately 30,000 U of rHuPH20 and Approximately 10 mM histidine, about 300 mM sorbitol; Approximately 0.04% (w / v) PS-20, and about 1 mg / mL methionine, and a pH of about 5.6. Any one of the pharmaceutical combinations.

[0773] Embodiment 216. Approximately 120 mg / mL of anti-CD38 antibody; Approximately 2,000 U / mL of rHuPH20 and Approximately 10 mM histidine, about 300 mM sorbitol; Approximately 0.04% (w / v) PS-20, and about 1 mg / mL methionine, and a pH of about 5.6. Any one of the pharmaceutical combinations.

[0774] Embodiment 217. A method for treating a kidney disease comprising administering a combination of any one of embodiments 201 to 215. tt.

[0775] Embodiment 218. A method for treating a subject with cancer in combination with an anti-CD38 antibody. A T cell redirecting therapeutic agent that binds to CD19.

[0776] Embodiment 219. CD19-binding T cell redirection therapy in subjects with cancer An anti-CD38 antibody for use in improving the efficacy of a drug, the antibody binding to CD19 in a subject. have been treated with anti-CD38 antibodies before receiving a T cell redirecting therapy, or have had anti-CD3 8 antibodies.

[0777] Embodiment 220. The subject is refractory or relapsed to treatment with a previous anticancer therapeutic agent. , T cell redirecting therapeutic agent or anti-CD3 for use according to embodiment 218 or 219 8 antibodies.

[0778] Embodiment 221. The method of any of embodiments 218 to 221, wherein the cancer is a hematological malignancy or a solid tumor. For use with any one of a T cell redirecting therapeutic or an anti-CD38 antibody.

[0779] Embodiment 222. The hematological malignancy is selected from the group consisting of lymphoma, B-cell malignancies, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, DLBLC, FL, MCL, marginal zone B-cell lymphoma (MZL), mucosal Associated lymphoid tissue lymphoma (MALT), CLL, ALL, AML, Waldenstrom's high For use according to embodiment 221, the disease is gammopathy or T-cell lymphoma. T cell redirecting therapy or anti-CD38 antibody.

[0780] Embodiment 223. The solid tumor is lung cancer, liver cancer, cervical cancer, colon cancer, breast cancer, ovarian cancer, pancreatic cancer, 222. The use according to embodiment 221, wherein the cancer is melanoma, glioblastoma, prostate cancer, esophageal cancer, or gastric cancer. T cell redirecting therapeutics or anti-CD38 antibodies for

[0781] Embodiment 224. The T cell redirecting therapeutic agent is a CD3 epsilon (CD3εε), C D8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, B Binding to TNL8, PD-1, CD195, or NKG2C, embodiments 218-223 or an anti-CD38 antibody.

[0782] Embodiment 225. The T cell redirecting therapeutic agent that binds to CD19 is blinatumomab, Axicabtagene ciloleucel, tisagenlecleucel-t, inebilizumab, risoca Butagenmaraleucel, XmAb-5574, CIK-CAR.CD19, ICTCA R-011, IM-19, JCAR-014, loncustuximab tesirin, MB-CA RT2019.1, OXS-1550, PBCAR-0191, PCAR-019, PC AR-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 T cells for use according to any one of embodiments 218 to 224, comprising a binding domain Redirective therapeutic agents or anti-CD38 antibodies.

[0783] Embodiment 226. The T cell redirecting therapeutic agent that binds to CD19 is blinatumomab, Axicabtagene ciloleucel, tisagenlecleucel-t, inebilizumab, risoca Butagenmaraleucel, XmAb-5574, CIK-CAR.CD19, ICTCA R-011, IM-19, JCAR-014, loncustuximab tesirin, MB-CA RT2019.1, OXS-1550, PBCAR-0191, PCAR-019, PC AR-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 T cell redirecting therapeutic agent for use according to any one of embodiments 218 to 225 or Anti-CD38 antibody.

[0784] Embodiment 227. The T cell redirecting therapeutic that binds to CD19 is a multispecific antibody, 227. Any one of embodiments 218 to 226, wherein the T cell is a CAR or a T cell expressing a CAR. 20. A T cell redirecting therapeutic or anti-CD38 antibody for use by

[0785] Embodiment 228. The anti-CD38 antibody comprises HCDR1 of SEQ ID NO: 6, HCDR2 of SEQ ID NO: 7 2. HCDR3 of SEQ ID NO: 8, LCDR1 of SEQ ID NO: 9, LCDR2 of SEQ ID NO: 10, and and LCDR3 of SEQ ID NO: 11. T cell redirecting therapeutics or anti-CD38 antibodies for

[0786] Embodiment 229. The anti-CD38 antibody comprises a VH of SEQ ID NO: 4 and a VL of SEQ ID NO: 5. T cell redirecting therapeutic agent or for use according to any one of embodiments 218 to 228 indicates anti-CD38 antibody.

[0787] Embodiment 230. The anti-CD38 antibody is an IgG1 isotype. 229 T cell redirecting therapeutic or anti-CD38 antibody for use with any one of .

[0788] Embodiment 231. The anti-CD38 antibody comprises a HC of SEQ ID NO: 12 and a LC of SEQ ID NO: 13. 230, including T cell redirection therapy for use according to any one of embodiments 218 to 230. Drugs or anti-CD38 antibodies.

[0789] Embodiment 232. The anti-CD38 antibody is VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15, VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17, VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19, or Any of embodiments 218 to 227, comprising a VH of SEQ ID NO: 20 and a VL of SEQ ID NO: 21. or a T cell redirecting therapeutic agent or an anti-CD38 antibody for use by one of:

[0790] Embodiment 233. The method of embodiment 232, wherein the anti-CD38 antibody is an IgG1 isotype. 20. A T cell redirecting therapeutic or anti-CD38 antibody for use by

[0791] Embodiment 234. The anti-CD38 antibody is administered at a dose of about 8 mg / kg to about 16 mg / kg. T cell redirection for use according to any one of embodiments 218 to 233 Therapeutic agents or anti-CD38 antibodies.

[0792] Embodiment 235. A T cell redirecting therapeutic agent that binds to CD19 and an anti-CD38 antibody , the use according to any one of embodiments 218 to 234, wherein the compound is administered by intravenous injection. T cell redirecting therapeutics or anti-CD38 antibodies for

[0793] Embodiment 236. A T cell redirecting therapeutic agent that binds to CD19 is administered by intravenous injection. and the anti-CD38 antibody is administered by subcutaneous injection. or an anti-CD38 antibody.

[0794] Embodiment 237. The method according to any one of embodiments 218 to 236, wherein the subject is a human. A T cell redirecting therapeutic agent or anti-CD38 antibody for use.

[0795] Embodiment 238. The T cell redirecting therapeutic agent that binds to CD19 is CD19xCD3 T cells for use according to any one of embodiments 218 to 237, which are bispecific antibodies Cell redirecting therapy or anti-CD38 antibody.

[0796] Embodiment 239. An embodiment further comprising administering one or more anti-cancer therapies to the subject. T cell redirecting therapeutic agent or anti-CD31 inhibitor for use with any one of 218 to 238 38 antibodies.

[0797] Embodiment 240. The one or more anticancer treatments include autologous stem cell transplantation (ASCT), radiation a cancer treatment selected from the group consisting of radiation, surgery, chemotherapy, immunomodulatory agents, and targeted cancer therapy. 238. A T cell redirecting therapeutic or anti-CD38 antibody for use according to claim 238.

[0798] Embodiment 241. A CD19xCD3 bispecific antibody comprising blinatumomab of SEQ ID NO: 53. HCDR1 of SEQ ID NO: 6, HCDR2 of SEQ ID NO: 7, HCDR3 of SEQ ID NO: 8, sequence LCDR1 of SEQ ID NO: 9, LCDR2 of SEQ ID NO: 10, and LCDR3 of SEQ ID NO: 11 A pharmaceutical combination comprising an anti-CD38 antibody.

[0799] Embodiment 242. The anti-CD38 antibody comprises a VH of SEQ ID NO: 4 and a VL of SEQ ID NO: 5. The pharmaceutical combination of embodiment 241.

[0800] Embodiment 243. The anti-CD38 antibody comprises an HC of SEQ ID NO: 12 and an LC of SEQ ID NO: 13. 243. The pharmaceutical combination of embodiment 241 or 242.

[0801] Embodiment 244. Any one of embodiments 241 to 243, which is a non-fixed combination. Pharmaceutical combinations.

[0802] Embodiment 245. A mixture of about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mM mannitol and about 20 mg / mL in about 0.04% w / v polysorbate-20 (PS-20). 24. The method of claim 24, wherein the anti-CD38 antibody is present in an amount of from about 100 mg / mL to about 120 mg / mL and has a pH of about 5.5. Any one of pharmaceutical combinations 1 to 244.

[0803] Embodiment 246. About 1,800 mg of an anti-CD38 antibody and about 30,000 U of rHuP The pharmaceutical combination of any one of embodiments 241-243, comprising H20.

[0804] Embodiment 247. About 120 mg / mL of an anti-CD38 antibody and about 2,000 U of rHuP The pharmaceutical combination of embodiment 246, comprising H20.

[0805] Embodiment 248. The method of embodiment 246 or 257, further comprising one or more excipients. Pharmaceutical combinations.

[0806] Embodiment 249. The one or more excipients are histidine, methionine, sorbitol, or polysorbate-20 (PS-20), or any combination thereof. The pharmaceutical combination of any one of embodiments 246 to 248.

[0807] Embodiment 250. The pharmaceutical combination comprises: about 100 mg / mL to about 120 mg / mL of an anti-CD38 antibody; about 5 mM to about 15 mM histidine, about 100 mM to about 300 mM sorbitol; Approximately 0.01% w / v to approximately 0.04% w / v of PS-20, It contains about 1 mg / mL to about 2 mg / mL of methionine and has a pH of about 5.5 to 5.6. , The pharmaceutical combination of any one of embodiments 246 to 249.

[0808] Embodiment 251. Any of embodiments 246 to 250, comprising about 10 mM histidine. One pharmaceutical combination.

[0809] Embodiment 252. Any of embodiments 246 to 251, comprising about 300 mM sorbitol. One of these pharmaceutical combinations.

[0810] Embodiment 253. Embodiments 246-25, comprising about 0.04% (w / v) PS-20. Any one of the two pharmaceutical combinations.

[0811] Embodiment 254. Any of embodiments 246 to 253, comprising about 1 mg / mL of methionine. One of these pharmaceutical combinations.

[0812] Embodiment 255. Approximately 1,800 mg of anti-CD38 antibody, Approximately 30,000 U of rHuPH20 and Approximately 10 mM histidine, about 300 mM sorbitol; Approximately 0.04% (w / v) PS-20, and about 1 mg / mL methionine, and a pH of about 5.6. Any one of the pharmaceutical combinations.

[0813] Embodiment 256. Approximately 120 mg / mL of anti-CD38 antibody; Approximately 2,000 U / mL of rHuPH20 and Approximately 10 mM histidine, about 300 mM sorbitol; Approximately 0.04% (w / v) PS-20, and about 1 mg / mL methionine, and a pH of about 5.6. Any one of the pharmaceutical compositions.

[0814] Embodiment 257. A kit comprising the pharmaceutical composition of any one of embodiments 241 to 256. . [Example]

[0815] The following examples are provided to further illustrate some of the embodiments disclosed herein. These examples are intended to illustrate, but not limit, embodiments of the present disclosure. It's not that.

[0816] General Materials and Methods Antibodies and reagents Anti-BCMA / anti-CD3 antibody JNJ-957 (International Publication No. 2017 / 031104(A1 ) and daratumumab are manufactured by Janssen Pharmaceuticals All were CNTO7008 manufactured by Janssen Pharmaceuticals. (CD3×null), BC3B4 (BCMA×null), and 3930 (IgG antibody JNJ-957 (also known as JNJ-7957) was used as a control antibody. be.

[0817] JNJ-957 binds to the BCMA-binding arm BCMB69 and the CD3-binding arm CD3B2 19, the amino acid sequences of which are shown in Tables 3 and 4, respectively.

[0818] [Table 3]

[0819] [Table 4]

[0820] Bone marrow and peripheral blood mononuclear cells Peripheral blood mononuclear cells (PBMCs) from healthy donors and MM patients, as well as BM aspirates from MM patients Bone marrow mononuclear cells (BM-MNC) were isolated by Ficoll-Hypaque density gradient centrifugation. and isolated it.

[0821] Cell lines and culture Luciferase (LUC)-transduced multiple myeloma cell line UM9, R PMI8226, U266, and MM1.S, and the non-transduced multiple myeloma cell line NC I-H929 and RPMI8226 were supplemented with 10% fetal bovine serum (F BS, Lonza) and antibiotics (100 units / mL penicillin, 100 μg / mL RPMI1 supplemented with streptomycin (both Life Technologies) The cells were cultured in 640 (Invitrogen).

[0822] Flow cytometry analysis of bone marrow and blood samples from MM patients Identify BM-localized MM cells and measure 1.0 x 10 6 cells / mL, HuMax-003 (CD 38) FITC (This antibody binds to an epitope different from that bound by daratumumab. pitope, Janssen Pharmaceuticals), CD138 PE, CD56 PC7, CD45 Krome Orange (all Beckman Coulter), CD269 (BCMA) APC (Biolegend), CD27 4 (PD-L1) BV421, and CD19 APC-H7 (both Becton Dermatology). Cell surface marker expression levels were analyzed by staining with IFN-γ (Fragmentinson). Identify BM or PB immune cell subsets and measure 1.0 x 10 6 cells / mL, CD45 Krome Orange, CD56 PC7 (both Beckman Coulter) , CD14 APC-H7, CD19 APC-H7, CD3 V450, CD4 AP C-H7 or PE, CD8 FITC, CD45-RA APC, CD127 PE.C y7, CD62L PE, CD274(PD-1)BV421, CD16 APC, HL A-DR APC-H7 (all Becton Dickinson), and CD25 P Cell surface marker expression levels were analyzed by staining with E (Dako). All BM samples were analyzed within 24 hours from the time of sample collection.

[0823] Flow cytometry was performed using a 7-laser LSRFORTESSA (Becton Digital The assay was performed using fluorescently labeled beads (CS&T beads, Becton). Dickinson) daily to monitor the performance of the flow cytometer and The flow rate was verified. This procedure allows for controlled and standardized results and is Allows determination of long-term drift and random changes in the data that may affect the results Compensation beads were used to determine the spectral overlap, and compensation was performed using Di Calculations were performed automatically using FACS Diva software. The flow cytometry data were then analyzed.

[0824] Flow cytometry-based ex vivo lysis analysis in BM-MNCs Not only BM-MNC derived from MM patients containing tumor cells, but also autologous effector cells Cells were also used in lysis assays. Sample survival during incubation was 7 days. ->98% when assessed using AAD (Becton Dickinson) For the lysis assay, BM-MNCs were cultured in a 96-well U-bottom plate with control antibody or JNJ-957 (0.0064 to 4.0 μg / mL) and / or daratumumab Incubate for 48 hours in RPMI + 10% fetal bovine serum with ribosomal enzyme (10 μg / mL). Primary CD138 in BM-MNC + MM cell survival was assessed as previously described. Sea urchin (van der Veers et al.,Haematologica.20 11;96(2):284-290, van der Veer MS et al. Blood CancerJ.2011;1(10):e41, Nijhof IS e t al., Leukemia2015;29(10):2039-2049, Nijh of IS,et al.,Blood2016;128(7):959-970.), In both assays, viable MM cells were determined by flow cytometry. low-Count Fluorospheres (Beckman Coulter) and LIVE / DEAD Fixable Dead Cell Stain Near CD138 in the presence of -IR fluorescent reactive dye (Invitrogen) + Single cell The complete number of viable MM cells was determined by platform flow cytometry analysis. The logarithm was determined. The percentage of lysis induced by JNJ-957 was then calculated using the following formula: % Lysed MM Cells = 1-(Viable CD138 in the Presence of JNJ-957) + Absolute cell count / unknown Viable CD138 in treated wells + Calculations were made using the absolute number of cells) × 100%.

[0825] CD4 + and CD8 + JNJ-957-induced activation and degranulation of T cells were measured using CD4+ and CD5+, respectively. The expression of CD25 and CD107a on the cell surface was analyzed by flow cytometry.

[0826] Flow cytometry in MM cell lines using PB MNCs as effector cells -based lysis assay. BCMA-positive MM cell lines were cultured in 96-well U-bottom plates with control antibodies or JNJ- in the presence of 957 (0.00256–4.0 μg / mL) at an effector-to-target ratio of 9:1 The cells were co-cultured with PB MNCs from healthy donors or MM patients for 48 hours. The presence was determined by flow cytometry as described above.

[0827] Bioluminescence imaging using LUC-transduced MM cell lines lysis assay based on blue light spectroscopy (BLI) LUC-transduced MM cell lines were obtained from newly diagnosed MM patients (n = 12). In the presence or absence of pooled BM stromal cells (BMSCs), After culturing for 1 h, effector cells (from a healthy donor) were cultured at an effector-to-target ratio of 9:1. Freshly isolated PBMCs were incubated in a 96-well flat-bottom plate (Gre Inner-Bio-One, JNJ-957 (0.00256-4.0 μg / The substrate luciferin (150 μg mL) or control antibody was serially diluted for 48 h. 10 min after adding 1 mL of 1000 ng / mL Promega + -MM cell survival with BLI Lysis of MM cells was determined according to the following formula: % Lysis = 1 - (effector cells and J Mean BLI signal / effector cell in the presence of NJ-957 and untreated antibody The mean BLI signal in the presence of 100% β-glucan was determined using the mean BLI signal in the presence of 100% β-glucan.

[0828] Efficacy of JNJ-957 on PB MNCs with daratumumab monotherapy in vivo To evaluate the effect of pretreatment, LUC-transduced MM cell line 4 was also used in daratumma Results obtained from MM patients before initiation of daratumumab monotherapy and at the time of best response to daratumumab monotherapy PB MNCs were co-cultured (effector to target ratio of 9:1). It was carried out as described above.

[0829] Cytogenetic analysis Fluorescence in situ hybridization (FISH) and single nucleotide polymorphism (si Single nucleotide polymorphism (SNP) arrays were used to identify cytogenetic abnormalities and purified M High-risk disease was assessed in M ​​cells. Defined by the presence of l(1q), t(4;14), or t(14;16) 2 .

[0830] Soluble BCMA assay MSD GOLD™ 96-well Small Spot Streptavidin n SECTOR Plate (Meso Scale Diagnostics) manufacturing The soluble BCMA in the cell culture supernatant was analyzed according to the protocol recommended by the author. BCMA, sBCMA) were measured.

[0831] Granzyme B assay MSD R-Plex Granzyme B Assay Plate (Meso Scale Di Gram-negative antibodies (GlcNAc) were used according to the manufacturer's protocol to detect granulocyte colony formation in cell culture supernatants. Enzyme B was measured.

[0832] Multiplex cytokine assay V-Plex Pro-inflammatory Panel 1 Human Kit (Meso Scale Diagnos tics) according to the manufacturer's protocol to measure cytokines in the cell culture supernatant [ Interferon-gamma (IFN-γ), interleukin (interleukin- rleukin, IL-2, IL-6, IL-8, IL-10, and tumor necrosis factor-alpha (tumor necrosis factor-alpha, TNF-α)] were analyzed.

[0833] Statistics When data do not follow a normal distribution, comparisons between variables are performed using two-tailed (paired) studies. Matched-pairs signed rank test, Mann-Whitney U test, or Wilcoxon matched-pairs signed rank test Correlations between variables were performed using Spearman's rank correlation coefficient. A p value of less than 0.05 was considered significant. For real-life treatments, the expected dissolution value was calculated using the following formula as previously described: % lysis by JNJ-957 + % lysis by daratumumab - (% lysis by JNJ-957 × daratumumab) Using the % lysis by daratumumab, there was no additive effect between JNJ-957 and daratumumab. We tested the null hypothesis that only 20、23、24 The observed value is lower than the expected value. If significantly higher (P<0.05), the null hypothesis of an "additive effect" was rejected.

[0834] Example 1 BCMA +Anti-BCMA / anti-CD3 antibody JNJ-957 in multiple myeloma cell lines Mediated lysis involves T cell activation and degranulation Peripheral blood mononuclear cells from healthy donors (HD) were used as effector cells to generate JNJ-9 RPMI 8226 ( 1), UM9 (Fig. 2), U226 (Fig. 3), and MM1.S (Fig. 4)-mediated lysis. The effect of JNJ-957 on lysis of IL-16 was evaluated. JNJ-957-mediated lysis was observed in a dose-dependent manner. As can be seen in Figures 1, 2, 3, and 4, mediated lysis of all tested cell lines. Depending on the cell line, near 100% maximal efficacy was achieved at an antibody concentration of approximately 0.1 μg / ml. Ta.

[0835] BMSCs respond to various anti-MM agents, including daratumumab and MM-reactive T cells, and stimulate MM cells. Therefore, the efficacy of JNJ-957 The potential impact of BMSC-MM cell interactions was evaluated. The activity of JNJ-957 against UM9 and U266 was not affected by the presence of BMSCs. JNJ-957-mediated MM cell lysis was not observed at low concentrations (data not shown). 1. The effect was moderately inhibited by BMSCs in S cells (P<0.0001). The effect was completely abrogated by increasing the dose of JNJ-7957.

[0836] T cell activation was assessed in the RPMI8226 cell line. Treatment with JNJ-957 are characterized by increased cell surface expression of CD25 and CD107a, respectively, or by double-positive C CD25 and CD107a cells in a dose-dependent manner, as evidenced by the percentage of CD107a cells. 4 + and CD8+ This resulted in both activation and degranulation of CD25+ T cells. Figure 6 shows JNJ-957-mediated increase in the percentage of CD107a+CD4 T cells. Figure 7 shows JNJ-957-mediated increase in the percentage of double-positive CD25+CD1 T cells. Figure 8 shows JNJ-957-mediated increase in the percentage of CD25+ CD4 T cells. Figure 9 shows JNJ-957-mediated increase in the percentage of CD107a+CD8 T cells. Figure 10 shows JNJ-957-mediated increase in the percentage of double-positive CD25+ CD4+ T cells. JNJ-957-mediated increase in the percentage of 107+ CD8 T cells is shown.

[0837] Example 2 Daratumumab Improved the Efficacy of T Cell-Redirecting Antibodies patient BCMA expression levels, immune cell subset composition, and ex vivo activity of JNJ-957 Efficacy was evaluated in 11 newly diagnosed MM patients and 21 daratumumab-naive relapsed / refractory patients. 17 patients with relapsed / refractory MM and 17 patients with daratumumab-refractory MM (daratumumab-refractory / Refractory patients are treated with all-trans retinoic acid (ATRA) and Enrolled in phase 1 and 2 trials of combined daratumumab; clinical trial identifier NCT0 2751255), and 55BM obtained from primary plasma cell leukemia (pPCL; n = 6). Assessed in aspirate. Immediately before initiation of daratumumab monotherapy and progression during daratumumab treatment. At the time of active disease, sequential BM samples were obtained from eight patients treated in the DARA / ATRA trial. In the same study, we found that the serotonin-releasing hormone (SHR) levels achieved with daratumumab monotherapy were significantly higher than those achieved with daratumumab monotherapy. At the time of the estimated maximum response, serial peripheral blood samples were obtained from 10 patients.

[0838] In the DARA / ATRA trial (NCT02751255), patients were randomly assigned to receive systemic therapy. Patients with MM who have relapsed from or are refractory to two or more prior treatments Patients were aged 18 or 19 years or older, had a life expectancy of 3 or 4 months or more, and had a 2 or had an activity index of 1 or less and measurable disease.

[0839] During Phase 1 trials, the recommended dose and schedule (16 mg / kg weekly for 8 weeks, Daratumumab was administered according to the following schedule: every 2 weeks for 16 weeks, then every 4 weeks until PD. The ethics committee or institutional review board of the study site approved the protocol, which is tion of Helsinki, International Conference e on Harmonization and Guidelines for Good All patients were followed in accordance with the principles of clinical practice. Informed consent was provided.

[0840] Baseline characteristics of patients enrolled in the phase 1 and 2 study NCT02751255 were: The results are shown in Tables 5 and 6. Patients with RRMM had received an average of 5 (range 1–9) previous treatments. RMM patients had received an average of six (range, 3–12) previous treatments. Table 7 shows the An updated summary of the baseline characteristics of patients enrolled in the Phase 1 and Phase 2 studies is presented.

[0841] [Table 5]

[0842] [Table 6]

[0843] [Table 7] * High-risk disease includes del(17p), del(1p), ampl(1q), t(4; 14), or the presence of t(14;16). ** Refractory disease is defined as progression during therapy according to the International Standards for Assessment of Multiple Myeloma Therapy Response. Progressive disease was defined as progressive disease, no response (less than PR), or progressive disease within 60 days after stopping treatment. do. #BM aspirates were obtained immediately at the onset of progressive disease during daratumumab monotherapy (n=1 5) However, the two BM samples were obtained after 3 and 5 other treatments, respectively, and after daratumumab monotherapy. Patients were obtained 22 and 48 months after the onset of progression during the study. Additionally, 1 in 19 patients was lenalidomide intolerant. † Additionally, 4 of 17 patients were bortezomib intolerant. ‡ Additionally, 3 of 16 patients were bortezomib intolerant. Abbreviations: MM, multiple myeloma; NDMM, newly diagnosed MM; RRMM, relapsed / refractory. Sex MM, Daratumumab, pPCL, primary plasma cell leukemia, n, number, IgG, immune IgA, immunoglobulin G, FLC, free light chain, del, deletion, amp, Amplification, t, translocation, PI, proteasome inhibitors, IMiDs, immunomodulators,

[0844] result Daratumumab is indicated for patients with newly diagnosed (NDMM) and relapsed / refractory (RR) myeloma. mediated efficient lysis of MM cells in EVE patients, but not in daratumumab-refractory patients with RRMM The cells were resistant to lysis (Figure 11).

[0845] In newly diagnosed (ND) MM patient samples (n=8), JNJ-957 4.0 The mean lysis of MM cells at 1 μg / mL was 79% (range: 66–92%, Figure 12 Similar, but more variable, MM lysis was observed in lenalidomide (LEN)-refractory patients. Patient samples (n=15, mean lysis at 4.0 μg / mL: 69%, range: 24-98%) %, Figure 13), and these patients also received bortezomib (73%), pomalidomide (81%), and Most patients were refractory to ramosetron (82%) and carfilzomib (9%). In addition, samples from MM patients who were refractory to daratumumab (DARA) (n=11, 4.0 μg / mL: mean lysis: 83%, range: 52-99%, Figure 14). NK and T cell frequencies were not affected in any of the samples tested.

[0846] CD3xnull and BCMAxnull control antibodies compared to JNJ-957 showed significantly lower activity in different patient samples, suggesting that MM cells and effector These results demonstrate the need for cross-linking with target T cells and the absence of a direct effect of BCMA blockade. Ta.

[0847] JNJ-957-mediated lysis of primary MM cells was assessed by expression of the CD25 activation antigen. If evaluated, activated CD4 + and CD8 + This was associated with a dose-dependent increase in the proportion of T cells. JNJ-957 treatment also inhibited CD4 as determined by cell surface expression of CD107a. + and CD8 + This resulted in T cell degranulation. There was a significant difference in T cell activation and degranulation between patients with RMM and those with daratumumab-refractory RRMM. Figure 15 shows the JNJ-957-mediated increase in the percentage of CD25+CD4 T cells. Figure 16 shows JNJ-957-mediated increase in the percentage of CD107a+CD4 T cells. Figure 17 shows an increase in the percentage of double-positive CD25+CD107+CD4 T cells. Figure 18 shows JNJ-957-mediated increase in the percentage of CD25+CD8 T cells. Figure 19 shows JNJ-957-mediated increase in the percentage of CD107a+CD8 T cells. Figure 20 shows the mediated increase in the percentage of double positive CD25+CD107+CD8 T cells. JNJ-957-mediated increase is shown.

[0848] Daratumumab-naive and daratumumab-refractory RRMM patients treated with JNJ-957 The levels of granzyme B and various cytokines in the supernatants of treated BM-MNCs were also evaluated. JNJ-957-mediated T cell activation was mediated by granzyme B, IFN-γ, IL-2, Produces a dose-dependent increase in the levels of IL-6, IL-8, IL-10, and TNF-α (data not shown).

[0849] The efficacy of JNJ-957 in mediating MM cell killing was assessed by tumor characteristics (BCMA or PD). -L1 expression, presence of standard or high-risk cytogenetic abnormalities) in all BM samples effector:target ratio across the T cell lineage, the composition of T cell lines, or PD-1 / HLA- There was no association with patient characteristics such as DR development. However, when analyzing patient categories separately, In the 2016 study, the expression levels of BCMA (Figure 21) and PD-L1 (Figure 22) were significantly higher after daratumumab exposure. Regardless of the etiology, it was significantly higher in RRMM patients compared with NDMM patients. Although the number of patients was small, JNJ-957 activity was observed in daratumumab-naive RRMM patients. There was an inverse correlation with PD-L1 expression level (P=0.045).

[0850] BM aspirate NDMM, daratumumab-naive RRMM, and daratumumab-RRMM We assessed the immune cell composition of the pools and compared the results of the pools of samples from three patient subgroups. We gained insight into the differential effects of JNJ-957. The frequency of cysts (P = 0.034) and the high E:T ratio (P = 0.029) were significantly higher in JNJ- associated with improved 7957-mediated lysis. Other immune parameters (T cells, Tregs, PD- 1 + T cells, HLA-DR + The number of T cells or naive T cells was measured using JNJ-7957 mediator. It had no effect on MM cell lysis mediated by MM.

[0851] In subgroup analyses, RRMM patients had higher Treg ( 23) and activated T cells (defined by HLA-DR expression) (Fig. 24). In addition, daratumumab had a higher frequency of naive T cells and a lower frequency of naive T cells. Refractory patient samples had significantly more TEMRA than daratumumab-naive samples. However, activated, naive, and central memory ( The frequency of effector memory (CM), effector memory (EM), or TEMRA T cells in this subgroup Loop analysis showed that high Treg levels were not associated with response to JNJ-7957. Baseline rates were assessed for JNJ-957-mediated MM cell lysis in RRMM patient samples. showed a negative impact on Treg baseline, which was overcome by optimal dosing. NDMM mediated by autologous effector cells, dichotomized by the proportion of patients with NDMM (Figure 26) , daratumumab-naive RRMM (Figure 27), and daratumumab-refractory RRMM (Figure 28) ) JNJ-597-mediated lysis of patient samples was assessed. The 50th percentile was used. Samples were then classified as "low" or "high" in terms of Treg content. ≦7.34%, high:>7.34%. Daratumumab naive RRMM: low ≦15.57%, High >15.57%. Daratumumab-refractory RRMM: Low ≤11.24%, High >11.24% Higher Treg concentrations were associated with daratumumab-naive RRMM and daratumumab-refractory RRMM. Attenuated JNJ-957-mediated lysis of MM cells in MM samples. was inhibited at higher JNJ-957 concentrations.

[0852] PD-1 + The proportion of T cells and E:T ratios were similar in the three patient groups. Only in M ​​patients were there low frequencies of T cells (P=0.010) and high frequencies of PD-1 + T cells (P=0.048) but impaired JNJ-957-mediated lysis of MM cells (data not shown). ).

[0853] The effect of daratumumab treatment on the efficacy of JNJ-957 was assessed after 48 hours of incubation. After treatment, NDMM (n=9), daratumumab-naive RRMM (n=18), and daratumumab-naive RRMM (n=18) were JNJ-957-mediated BM samples from patients with ratumumab-refractory RRMM (n=13) The results were evaluated by assessing the solubility of the drug. ~0.032μg / mL) in daratumumab-naive RRMM patients and NDMM patients Tumor cell lysis was significantly better in daratumumab-exposed patients compared with both. 29 indicates the percentage of lysis in the patient population. Data are presented as mean ± SEM, with P values is calculated using the Student's t-test.

[0854] Improved tumor reduction may be aided by the recently discovered immune-stimulating effects of DARA. To investigate the efficacy of DARA, serial BM aspirates from MM patients were analyzed before and after DARA treatment (n = 5). Therefore, we compared the samples obtained after disease progression during DARA with those obtained before DARA initiation. In the MM samples, BCMA expression was comparable, but JNJ-957-induced MM cell lysis was improved. We observed that the mean lysis at 4.0 μg / mL was 93 vs. 74%, Figure 30. In the BM aspirate of our study, Treg (Figure 31) and CD4 + The proportion of cells (Figure 32) is small Although the percentage of CD8+ cells (Figure 33) decreased significantly in the daratumumab-exposed patient samples, In this study, the incidence of daratumumab in patients with daratumumab was Samples were collected from patients with a median duration of tumab monotherapy treatment of 3 months (range 1-7 months). A follow-up study of eight RRMM patient samples revealed that CD38 + Treg and B The proportion of reg in daratumumab-naive patient samples was 100% compared to daratumumab-refractory patient samples. was significantly reduced in (data not shown).

[0855] JNJ-957-mediated lysis of RPMI8226 multiple myeloma cell line was observed after daratumumab treatment. Sequential PB MNC samples from RRMM patients before and during treatment were used as effector cells. Daratumumab-exposed PB MNCs were treated with daratumumab for a median duration of 11 months. (range 7-14 months) and good response (partial response, very good partial response, or complete response). Figure 34 shows the results of RPMI822 obtained from patients with daratumumab treatment. JNJ-957-mediated lysis of 6 was enhanced using PB MNCs from Dara-exposed patients. In PB-MNC samples, the percentage of Treg (Fig. 35) and CD4+ cells (Fig. 3 6) slightly decreased, but the percentage of CD8+ cells (Figure 37) was significantly higher in daratumumab-exposed patients. In this study, the increase was observed in daratumumab-naive patient samples compared with the control sample. The median duration of daratumumab treatment for patients was 3 months (range 1-7 months). Got a pull.

[0856] The combination of JNJ-957 and daratumumab also demonstrated efficacy in patients with NDMM or RRMM daratumumab. JNJ-95 was tested for its efficacy in killing MM cells obtained from MM patients. 7 (0.032-0.8 μg / mL) alone or in combination with daratumumab 10 μg / mL Bone marrow tumors in newly diagnosed MM (NDMM) patients (n=8) treated with a combination of steroids for 48 hours The percentage of NC lysis is shown. Observation of MM cells with JNJ-957 and daratumumab (ob s) Compare the dissolution levels to the expected (exp) dissolution levels and use the additive method indicated in the method. The calculations were made assuming that the combinatorial effect was achieved by the effect. Mean values ​​± SEM are shown. P values ​​are calculated using a paired Student's t-test. Figure 39 shows the percentage of BM MNC lysis in RRNN dara-naive patients. Figure 1 shows the rate of lysis of BM MNCs in RRMM daratumumab-refractory patients.

[0857] Therefore, this study demonstrates that JNJ-957 is effective in newly diagnosed MM patient samples and demonstrated efficacy in a large sample of previously treated MM patients. Regulatory T cells may also negatively affect the efficacy of low-dose JNJ-957. The effect was overcome by increasing the dose of JNJ-957. improved the efficacy of JNJ-957 against MM cells.

[0858] Ex vivo combination of JNJ-957 and daratumumab demonstrated additive efficacy Furthermore, in vivo daratumumab pretreatment significantly inhibited the ex vivo expression of BCMA×CD3. Increased efficacy.

[0859] Example 3 Daratumumab Treatment Improved the Ex Vivo Efficacy of Blinatumomab To assess whether daratumumab treatment may also benefit other T-cell redirecting therapies, To investigate the efficacy and safety of daratumumab-naive and daratumumab-exposed PB- Using MNCs, CD19 + Raji cells, FD for the treatment of acute lymphoblastic leukemia Patients were treated with blinatumomab, an approved CD19×CD3 BiTE. Similar to the observations by

[14] , the activity of blinatumomab was significantly higher in daratumumab-naive PB-MNC compared with that in

[15] . When the PB-MNCs were co-incubated with daratumumab, the PB-MNCs showed a significant improvement. (P<0.0001, FIG. 41). Blinatumomab has the amino acid sequence of SEQ ID NO: 53. Includes.

[0860] SEQ ID NO:53 DIQLTQSPASLAVSLGQRATISCKASQSVDYDGDSYLNW YQQIPGQPPKL LIYDASNLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAAT YHCQQSTEDPW TFGGGTKLEIKGGGGGSGGGGSGGGGSQVQLQQSGAELVR PGSSVKISCKA SGYAFSSYWMNWVKQRPGQGLEWIGQIWPGDGDTNYNGK FKGKATLTADE SSSTAYMQLSSLASEDSAVYFCARRETTTVGRYYYAMDY WGQGTTVTVSS GGGGSDIKLQQSGAELARPGASVKMSCKTSGYTFTRYTM HWVKQRPGQGL EWIGYINPSRGYTNYNQKFKDKATLTTDKSSSTAYMQLS SLTSEDSAVYY CARYYDDHYCLDYWGQGTTLTVSSVEGGSGGSGGSGSG GVDDIQLTQSP AIMSASPGEKVTMTCRASSSVSYMNWYQQKSGTSPKRWI YDTSKVASGVP YRFSGSGGSTSYSLTISSMEAEDAATYYCQQWSSNPLTF GAGTKLELKHH HHHH

[0861] Example 4 JNJ-957 effectively kills primary pPCL cells The ex vivo activity of JNJ-957 was evaluated in newly diagnosed patients characterized by aggressive clinical behavior. The results were evaluated in BM samples from six patients with pPCL. JNJ-957-mediated tumor cell lysis in pull was significantly associated with NDMM and daratumumab-naive RR The lysis was similar to that observed in MM samples, but not in daratumumab-refractory RRMM samples. This was lower than that observed in the pPCL sample (P = 0.0014) (Figure 42). The median E:T ratio in the 144 patients was approximately 8 times lower, but the CD4 + (P=0.0040) and and CD8 + The degree of activation of both T cells (P<0.0001) as well as CD8 + T cell The degree of degranulation (P=0.0141) was significantly greater in pPCL compared with NDMM. CD4 + T cell degranulation was similar to that observed in NDMM.

[0862] BM-MNCs were obtained from six pPCL patients and treated with JNJ-957 (0.0064–4.0 μg / mL). g / mL) or with control antibodies 3930, BC3B4, and 7008 (4.0 μg / mL) After 48 h incubation, viable CD138 + Tumor cells, as well as T cells and NK cells Cells were counted using flow cytometry analysis. Data are presented as the mean number of cells ± SEM. The results were expressed as % solution. All experiments were performed in duplicate.

[0863] Example 5 Combination of GPRC5DxCD3 Bispecific Antibody with Daratumumab To further evaluate whether daratumumab treatment may also benefit other T-cell redirecting therapies In this study, paired daratumumab-naive and daratumumab-exposed PB-M were compared in 11 MM patients. NC (samples were obtained from the same patient as described in the above example) using RPMI MM cells were treated with GPRC5DxCD3 bispecific antibody. The GPRC5D-binding VH / VL domains were linked to an unrelated antigen (gp120). An antibody in which the null domain was substituted with a matching null domain was used (control mAb 3930null×nu ll, control mAb 7008: Null × CD3, control mAb GPRC5D × null) Antibodies were tested over a range of concentrations from 0.00064 to 4.0 μg / ml. ×CD3 bispecific antibody showed similar efficacy in daratumumab-naive and daratumumab-refractory patients mediated MM cell lysis in both sex samples (Figure 43).

[0864] The combination of GPRC5DxCD3 bispecific antibody and daratumumab also demonstrated efficacy in NDMM The efficacy of the compound in killing MM cells obtained from RRMM naive patients was also tested. 44 is GPRC5D × CD3 bispecific antibody (0.0128-0.8 μg / mL) alone or in combination with daratumumab 0.1 μg / mL for 48 hours. The percentage of MM cells lysing BM MNC is shown. The observed (O) lysis level of MM cells by daratumumab was compared to the expected (E) lysis level. , which assumes that the combinatorial effect is achieved by the additive effect shown in the method. Black bars indicate group means ± SEM. P values ​​were calculated using a paired Student's Co-incubation with daratumumab was additive and calculated using a t-test. enhanced MM cell lysis by GPRC5D×CD3 bispecific antibody.

[0865] The GPRC5D×CD3 bispecific antibody has the GPRC5D binding arm GC5B596 and The amino acid sequence of GC5B596 is shown in Table 8. The amino acid sequence of CD3B219 is shown in Table 4.

[0866] The GPRC5D×CD3 bispecific antibody used in these experiments was 8 / 0037651(A1) and has the following sequence: HCDR1, HCDR2, HCDR3, HCDR4, HCDR5, HCDR6, HCDR7, HCDR8, HCDR9, HCDR10, HCDR11, HCDR12, HCDR13, HCDR14, HCDR15, HCDR16, HCDR17, HCDR18, HCDR19, HCDR111, HCDR121, HCDR131, 2. GPRC5D binding domain containing HCDR3, LCDR1, LCDR2, and LCDR3 HCDR1 of SEQ ID NOs: 33, 34, 35, 36, 37, and 38, respectively; CD3-binding domain containing HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 The main course and a GPRC5D-binding domain comprising a VH of SEQ ID NO: 49 and a VL of SEQ ID NO: 50; and a CD3 binding domain comprising a VH of SEQ ID NO: 39 and a VL of SEQ ID NO: 40; The first heavy chain (HC1) of SEQ ID NO: 51, the first light chain (LC1) of SEQ ID NO: 52, The second heavy chain (HC2) has SEQ ID NO: 41, and the second light chain (LC2) has SEQ ID NO: 42.

[0867] The GPRC5DxCD3 bispecific antibody is of the IgG4 isotype.

[0868] HC1 contains S228P, F234A, and L235A substitutions.

[0869] HC2 contains S228P, F234A, L235A, F405L, and R409K substitutions. include.

[0870] [Table 8]

[0871] Example 6 Combination of T cell redirection therapy with anti-CD38 antibody The effect of combining additional T cell redirection therapy with anti-CD38 antibodies is shown in Examples 1 to 4. These combinations will be evaluated similarly to those described in 5. tumor cells targeted by T cell redirection therapy (i.e., Testing for their additive or synergistic effects in mediating killing of tumor cells expressing the antigen The effect of pretreatment with anti-CD38 antibodies on the efficacy of T cell redirection therapy is discussed herein. The results are evaluated as described in the Examples.

[0872] T-cell redirecting therapies being tested in combination with anti-CD38 antibodies include PSMAxC D3, TMEFF2×CD3, CD123×CD3, and CD33×CD3 bispecific antibodies Body included.

[0873] An exemplary PSMAxCD3 bispecific antibody comprises the PSMA binding domains PSMB127 and and PS3B27, which contains the CD3-binding domain CD3B219. The amino acid sequence of CD3B219 is shown in Table 4.

[0874] The exemplary PSMAxCD3 bispecific antibody used in these experiments has the following sequence: HCDR1 and HCDR2 of SEQ ID NOs: 54, 55, 56, 9, 10, and 59, respectively; a PSMA-binding domain comprising HCDR3, LCDR1, LCDR2, and LCDR3, and and HCDR1, HCDR2, HCDR3, HCDR4, HCDR5, HCDR6, HCDR7, HCDR8, HCDR9, HCDR10, HCDR11, HCDR12, HCDR13, HCDR14, HCDR15, HCDR16, HCDR17, HCDR18, HCDR19, HCDR111, HCDR121, HCDR131, HCDR141, HCDR151, HCDR161, HCDR172, HCDR183, HCDR191, HCDR192, HCDR193, HCDR194, HCDR195, HCDR196, HCDR197, HCDR198, HCDR199, HCDR199, HCDR199, HCDR191, HCDR199, HC 2, a CD3-binding domain including HCDR3, LCDR1, LCDR2, and LCDR3; , A PSMA binding domain comprising a VH of SEQ ID NO: 60 and a VL of SEQ ID NO: 61, and the sequence a CD3 binding domain comprising a VH of SEQ ID NO: 39 and a VL of SEQ ID NO: 40; The first heavy chain (HC1) of SEQ ID NO: 62, the first light chain (LC1) of SEQ ID NO: 63, The second heavy chain (HC2) has SEQ ID NO: 41, and the second light chain (LC2) has SEQ ID NO: 42.

[0875] The anti-PSMAxCD3 bispecific antibody is of the IgG4 isotype.

[0876] HC1 contains S228P, F234A, and L235A substitutions.

[0877] HC2 contains S228P, F234A, L235A, F405L, and R409K substitutions. include.

[0878] [Table 9]

[0879] An exemplary TMEFF2xCD3 bispecific antibody comprises the TMEFF2-binding arm TMEB7 62 and TMCB150, which contains the CD3-binding arm CD3B376. Table 11 shows the amino acid sequence of CD3B376.

[0880] The representative TMEFF2 × CD3 bispecific antibody used in these experiments is TMCB 150 and the following sequence: HCDR1 and HCDR2 of SEQ ID NOs: 64, 65, 66, 67, 68, and 69, respectively TMEFF2-binding domain containing HCDR3, LCDR1, LCDR2, and LCDR3 and HCDR1, H of SEQ ID NOs: 74, 75, 76, 77, 78, and 79, respectively. CD3-binding domain containing CDR2, HCDR3, LCDR1, LCDR2, and LCDR3 In and, a TMEFF2-binding domain comprising a VH of SEQ ID NO: 70 and a VL of SEQ ID NO: 71; and a CD3 binding domain comprising a VH of SEQ ID NO: 80 and a VL of SEQ ID NO: 81; 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) has SEQ ID NO: 82, and the second light chain (LC2) has SEQ ID NO: 83.

[0881] The anti-TMEFF2xCD3 bispecific antibody is of the IgG4 isotype.

[0882] HC1 contains S228P, F234A, and L235A substitutions.

[0883] HC2 contains S228P, F234A, L235A, F405L, and R409K substitutions. include.

[0884] [Table 10]

[0885] [Table 11]

[0886] An exemplary CD33xCD3 bispecific antibody comprises the CD33 binding arm C33B904 and C3CB189, which contains the CD3 binding arm CD3B376. The amino acid sequence of CD3B376 is shown in Table 11.

[0887] The representative CD33 × CD3 bispecific antibody used in these experiments is C3CB18 9 and the following sequence: HCDR1 and HCDR2 of SEQ ID NOs: 84, 85, 86, 87, 88, and 89, respectively a CD33 binding domain comprising HCDR3, LCDR1, LCDR2, and LCDR3; and HCDR1, HCD of SEQ ID NOs: 74, 75, 76, 77, 78, and 79, respectively. CD3-binding domain containing R2, HCDR3, LCDR1, LCDR2, and LCDR3 and, A CD33 binding domain comprising a VH of SEQ ID NO: 90 and a VL of SEQ ID NO: 91, and the sequence a CD3 binding domain comprising a VH of SEQ ID NO: 80 and a VL of SEQ ID NO: 81; 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) has SEQ ID NO: 82, and the second light chain (LC2) has SEQ ID NO: 83.

[0888] The anti-CD33xCD3 bispecific antibody is of the IgG4 isotype.

[0889] HC1 contains S228P, F234A, and L235A substitutions.

[0890] HC2 contains S228P, F234A, L235A, F405L, and R409K substitutions. include.

[0891] [Table 12]

[0892] An exemplary CD123xCD3 bispecific antibody comprises the CD123 binding arm I3RB218 and 8747, which contains the CD3 binding arm CD3B219. 8747 is described in WO 2007 / 023496. Table 13 shows the amino acid sequence of I3RB218. The amino acid sequence of CD3B219 is shown in Table 4.

[0893] The representative CD123xCD3 bispecific antibody used in these experiments is 8747 Yes, the following array: HCDR1, HCDR2 of SEQ ID NOs: 94, 95, 96, 9, 10, and 59, respectively; a CD123 binding domain comprising HCDR3, LCDR1, LCDR2, and LCDR3; and HCDR1, HCD of SEQ ID NOs: 33, 34, 35, 36, 37, and 38, respectively. CD3-binding domain containing R2, HCDR3, LCDR1, LCDR2, and LCDR3 and, a CD123 binding domain comprising a VH of SEQ ID NO: 100 and a VL of SEQ ID NO: 61; and a CD3 binding domain comprising a VH of SEQ ID NO: 39 and a VL of SEQ ID NO: 40; The first heavy chain (HC1) of SEQ ID NO: 102, the first light chain (LC1) of SEQ ID NO: 63, the sequence It comprises a second heavy chain (HC2) of sequence number 41, and a second light chain (LC2) of sequence number 42.

[0894] The anti-CD123xCD3 bispecific antibody is of the IgG4 isotype.

[0895] HC1 contains S228P, F234A, and L235A substitutions.

[0896] HC2 contains S228P, F234A, L235A, F405L, and R409K substitutions. include.

[0897] [Table 13]

[0898] Pretreatment with anti-CD38 antibody improves the efficacy of tumor killing by T cell redirecting therapeutics To assess the efficacy of the treatment, tumor cells were transfected with CD123, CD33, PSMA, and TMEFF. isolated from a subject with a tumor expressing an antigen to which a T cell redirecting therapeutic agent such as 2 binds. Alternatively, established tumor cell lines are used. Tumor cell killing is performed by using tumor cells as described in the examples. with PB-MNCs obtained from anti-CD38 antibody-exposed or anti-CD38 antibody-naive subjects as described The percentage of tumor cell lysis was assessed ex vivo by co-incubation with 100 μg of ... In a separate example, the T cell redirecting therapeutic and the anti-CD38 antibody are evaluated in: Incubate target and effector cells together or separately, and compare combined vs. individual Therapy-mediated tumor cell killing is assessed.

[0899] CD123-positive tumor cells such as AML tumors, or AML cell lines KG1a, HL60, and young Alternatively, cell lines such as MOLM13 may be used as target cells to express CD123 × CD3 double specificity. The effect of anti-CD38 antibodies on alloantibody-mediated tumor cell killing is evaluated.

[0900] CD33-positive tumor cells, such as AML tumors, or AML cell lines KG1a, HL60, or CD33×CD3 bispecific antibodies were used to target cell lines such as MOLM13. The effect of anti-CD38 antibodies on antibody-mediated tumor cell killing is evaluated.

[0901] TMEFF2-positive tumor cells, such as ...

Claims

1. 1. A pharmaceutical composition for treating multiple myeloma in a subject, said composition comprising a GPRC5DxCD3 bispecific antibody; the subject is relapsed or refractory to treatment with a previous anti-cancer therapeutic; The pharmaceutical composition, wherein the GPRC5DxCD3 bispecific antibody comprises a 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 a CD3 binding domain comprising HCDR1 of SEQ ID NO: 33, HCDR2 of SEQ ID NO: 34, HCDR3 of SEQ ID NO: 35, LCDR1 of SEQ ID NO: 36, LCDR2 of SEQ ID NO: 37, and LCDR3 of SEQ ID NO:

38.

2. The pharmaceutical composition of claim 1, wherein the GPRC5D binding domain comprises a VH of SEQ ID NO: 49 and a VL of SEQ ID NO: 50, and the CD3 binding domain comprises a VH of SEQ ID NO: 39 and a VL of SEQ ID NO:

40.

3. 3. The pharmaceutical composition of claim 1, wherein the GPRC5DxCD3 bispecific antibody is of the IgG4 isotype and comprises a phenylalanine at position 405 and an arginine at position 409 of HC1, and a leucine at position 405 and a lysine at position 409 of HC2, the numbering of the residues being according to the EU index.

4. 4. The pharmaceutical composition of claim 1, wherein the GPRC5DxCD3 bispecific antibody further comprises a proline at position 228, an alanine at position 234, and an alanine at position 235 of both the HC1 and the HC2.

5. 5. The pharmaceutical composition of claim 1, wherein the GPRC5DxCD3 bispecific antibody comprises an HC1 of SEQ ID NO: 51, an LC1 of SEQ ID NO: 52, an HC2 of SEQ ID NO: 41, and an LC2 of SEQ ID NO:

42.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the multiple myeloma is high-risk multiple myeloma.

7. the subject with high-risk multiple myeloma: a) t(4;14)(p16;q32), b) t(14;16)(q32;q23), c) del17p, d) 1qAmp; e) t(4;14)(p16;q32) and t(14;16)(q32;q23), f) t(4;14)(p16;q32) and del17p; g) t(14;16)(q32;q23) and del17p, or h) The pharmaceutical composition of claim 6, wherein the patient has one or more chromosomal abnormalities including t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p, or any combination thereof.

8. 8. The pharmaceutical composition of any one of claims 1 to 7, wherein the subject is refractory or relapsed to treatment with an anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotozumab, ixazomib, melphalan, or thalidomide, or any combination thereof.

9. The pharmaceutical composition of claim 8, wherein the subject is relapsed or refractory to treatment with the anti-CD38 antibody.

10. The pharmaceutical composition of claim 8 or 9, wherein the anti-CD38 antibody comprises an HCDR1 of SEQ ID NO: 6, an HCDR2 of SEQ ID NO: 7, an HCDR3 of SEQ ID NO: 8, an LCDR1 of SEQ ID NO: 9, an LCDR2 of SEQ ID NO: 10, and an LCDR3 of SEQ ID NO:

11.

11. The pharmaceutical composition of any one of claims 8 to 10, wherein the anti-CD38 antibody comprises a VH of SEQ ID NO: 4 and a VL of SEQ ID NO:

5.

12. The pharmaceutical composition according to any one of claims 8 to 11, wherein the anti-CD38 antibody is of the IgG1 isotype.

13. The pharmaceutical composition of any one of claims 8 to 12, wherein the anti-CD38 antibody comprises a HC of SEQ ID NO: 12 and a LC of SEQ ID NO:

13.

14. the anti-CD38 antibody a) a VH of SEQ ID NO: 14 and a VL of SEQ ID NO: 15; b) VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17; c) a VH of SEQ ID NO: 18 and a VL of SEQ ID NO: 19, or d) A pharmaceutical composition according to claim 8 or 9, comprising a VH of SEQ ID NO: 20 and a VL of SEQ ID NO:

21.

15. The pharmaceutical composition of claim 14, wherein the anti-CD38 antibody is of the IgG1 isotype.

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein the subject is a human.

17. The pharmaceutical composition of any one of claims 1 to 16, further comprising administering to the subject one or more anti-cancer therapies.

18. 18. The pharmaceutical composition of claim 17, wherein the one or more anti-cancer treatments are selected from the group consisting of autologous stem cell transplant (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulatory agents, and targeted cancer therapies.

19. The one or more anticancer therapies are lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, elotozumab, ixazomib, melphalan, dexamethasone, vincristine, cyclophosphamide, hydroxydaunorubicin, prednisone, rituximab, imatinib, dasatinib, nilotinib, bosutinib, ponatinib, bafetinib, saracatinib, tozasertib, or dasatinib.

18. The pharmaceutical composition of claim 17, wherein the medicament is selected from the group consisting of nusertib, 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.

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