Methods for treating cancer and methods to improve the efficacy of T-cell re-induction therapies

Abstract

The present invention provides a method for treating cancer in a subject and / or killing tumor cells, said method comprising the step of treating said cancer by administering a therapeutically effective amount of an anti-CD38 antibody and a T-cell redirecting therapeutic to said subject. The present invention provides a method for enhancing the efficacy of a T-cell redirecting therapeutic in a subject having cancer, said method comprising the step of administering an anti-CD38 antibody to said subject. The present invention also provides a method for treating multiple myeloma in a subject, said method comprising the step of treating said multiple myeloma by administering a therapeutically effective amount of a BCMAxCD3 bispecific antibody and an anti-CD38 antibody to said subject. The present invention also provides a pharmaceutical combination comprising a GPRC5DxCD3 bispecific antibody. The present invention also provides a kit comprising a pharmaceutical composition comprising a BCMAxCD3 bispecific antibody and an anti-CD38 antibody.

Description

Technology Field

[0001] A method for treating cancer and a method for improving the efficacy of a T-cell re-induction therapy are disclosed. Background Technology

[0002] T-cell re-induced apoptosis is a desirable mode of action in many therapeutic fields. Generally, T-cell re-induction molecules are engineered to have at least two antigen-binding sites, where one site binds to a surface antigen on a target cell and the other binds to a T cell surface antigen. Among T cell surface antigens, the human CD3 epsilon subunit from the TCR protein complex has been the most frequently targeted to re-induce T-cell apoptosis. Various bispecific antibody formats have been found to mediate T-cell re-induction in both preclinical and clinical studies (Reference [May C et al., Biochem Pharmacol, 84: 1105-12, 2012; Frankel SR & Baeuerle PA, Curr Opin Chem Biol, 17(3): 385-92, 2013]).

[0003] Tumors evade immune recognition by creating an immunosuppressive tumor microenvironment (TME). In the TME, under conditions of persistent antigens and inflammation, T cells become exhausted or dysfunctional, progressively losing their effector function and proliferative capacity. The impaired function and number of available T cells binding to therapies that mediate T-cell re-induced apoptosis can impair the anti-tumor efficacy of such therapies. Therefore, there is a need to enhance T cell functionality for the optimal efficacy of therapies that mediate T-cell re-induced apoptosis.

[0004] The present invention provides a method for treating cancer in a subject, wherein the method comprises the step of treating said cancer by administering a therapeutically effective amount of an anti-CD38 antibody and a T-cell re-induction therapeutic agent to said subject.

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

[0006] The present invention provides a method for enhancing the efficacy of a T-cell re-induction therapeutic agent in a subject having cancer, said method comprising the step of administering an anti-CD38 antibody to said subject.

[0007] The present invention also provides a method for treating cancer in a subject, said method comprising the step of treating said cancer by administering a therapeutically effective amount of a BCMAxCD3 bispecific antibody and an anti-CD38 antibody to said subject.

[0008] The present invention also provides a method for treating cancer in a subject, the method comprising the step of treating said cancer by administering a therapeutically effective amount of a BCMAxCD3 bispecific antibody to said subject, said subject has been treated with an anti-CD38 antibody prior to administering said BCMAxCD3 bispecific antibody.

[0009] The present invention also provides a method for treating cancer in a subject, the method comprising the step of treating said cancer by administering a therapeutically effective amount of a BCMAxCD3 bispecific antibody to said subject, said subject being relapsed or refractory to previous treatment with an anticancer agent.

[0010] The present invention also provides a method for treating multiple myeloma in a subject, said method comprising the step of treating said multiple myeloma by administering a therapeutically effective amount of a BCMAxCD3 bispecific antibody and an anti-CD38 antibody to said subject.

[0011] The present invention also provides a method for treating multiple myeloma in a subject, the method comprising the step of treating said multiple myeloma by administering a therapeutically effective amount of a BCMAxCD3 bispecific antibody to said subject, said subject has been treated with an anti-CD38 antibody prior to administering said BCMAxCD3 bispecific antibody.

[0012] The present invention also provides a method for treating multiple myeloma in a subject, the method comprising the step of treating said multiple myeloma by administering a therapeutically effective amount of a BCMAxCD3 bispecific antibody to said subject, said subject being relapsed or refractory to previous treatment with a multiple myeloma treatment agent.

[0013] The present invention also provides a pharmaceutical composition comprising a BCMA-xCD3 bispecific antibody comprising a BCMA-binding domain comprising VH of SEQ ID NO. 29 and VL of SEQ ID NO. 30, a CD3-binding domain comprising VH of SEQ ID NO. 39 and VL of SEQ ID NO. 40, and an anti-CD38 antibody comprising VH of SEQ ID NO. 4 and VL of SEQ ID NO. 5.

[0014] The present invention also provides a method for treating cancer in a subject, the method comprising the step of treating the cancer by administering a therapeutically effective amount of a T-cell re-induction therapeutic agent that binds to GPRC5D and an anti-CD38 antibody to the subject.

[0015] The present invention also provides a method for treating cancer in a subject, the method comprising the step of treating the cancer by administering a therapeutically effective amount of a GPRC5DxCD3 bispecific antibody to the subject, wherein the subject is relapsed or refractory to treatment with a previous anticancer agent.

[0016] The present invention also provides a pharmaceutical combination comprising 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, and an anti-CD38 antibody comprising HCDR1 of SEQ ID NO. 6, HCDR2 of SEQ ID NO. 7, HCDR3 of SEQ ID NO. 8, LCDR1 of SEQ ID NO. 9, LCDR2 of SEQ ID NO. 10, and LCDR3 of SEQ ID NO. 11.

[0017] The present invention also provides a method for treating cancer in a subject, said method comprising the step of treating said cancer by administering to said subject a therapeutically effective amount of a T-cell re-induction therapeutic agent binding to CD19 and an anti-CD38 antibody.

[0018] The present invention also provides a method for enhancing the efficacy of a T-cell re-induction therapeutic agent that binds to CD19 in a subject having cancer, wherein the method comprises the step of administering an anti-CD38 antibody to the subject before administering the T-cell re-induction therapeutic agent that binds to CD19.

[0019] The present invention also provides a pharmaceutical combination comprising a CD19xCD3 bispecific antibody comprising blinatumomab of SEQ ID NO. 53, and an anti-CD38 antibody comprising HCDR1 of SEQ ID NO. 6, HCDR2 of SEQ ID NO. 7, HCDR3 of SEQ ID NO. 8, LCDR1 of SEQ ID NO. 9, LCDR2 of SEQ ID NO. 10, and LCDR3 of SEQ ID NO. 11.

[0020] The present invention also provides a kit comprising the pharmaceutical composition of the present invention. Brief explanation of the drawing

[0021] Fig. 1 ... represents JNJ-957-mediated lysis of the multiple myeloma (MM) cell line RPMI8226. Healthy donor peripheral blood mononuclear cells (PB MNCs) were used as effector cells. Fig. 2 ...represents JNJ-957-mediated lysis of the multiple myeloma (MM) cell line UM9. Healthy donor peripheral blood mononuclear cells (PB MNCs) were used as effector cells. Fig. 3 ... represents JNJ-957-mediated lysis of multiple myeloma (MM) cell line U226. Healthy donor peripheral blood mononuclear cells (PB MNCs) were used as effector cells. Fig. 4 ...represents JNJ-957-mediated lysis of multiple myeloma (MM) cell line MM1. Healthy donor peripheral blood mononuclear cells (PB MNCs) were used as effector cells. Fig. 5 In a representative example (n=2) of RPMI 8226 cells incubated with healthy donor PB MNCs, CD4, as determined by the increased surface expression (activation) of CD25, was observed in JNJ-957-mediated MM cell lysis. + It indicates that T cell activation and degranulation were involved. Fig. 6In a representative example (n=2) of RPMI 8226 cells incubated with healthy donor PB MNCs, CD4, as determined by increased surface expression (degranulation) of CD107a in JNJ-957-mediated MM cell lysis. + It indicates that T cell activation and degranulation were involved. Fig. 7 In a representative example (n=2) of RPMI 8226 cells incubated with healthy donor PB MNCs, JNJ-957-mediated MM cell lysis showed CD25 and CD107a double-positive CD4 + CD4 as determined by the ratio of T cells + It indicates that T cell activation and degranulation were involved. Fig. 8 In a representative example (n=2) of RPMI 8226 cells incubated with healthy donor PB MNCs, CD8, as determined by the increased surface expression (activation) of CD25, was observed in JNJ-957-mediated MM cell lysis. + It indicates that T cell activation and degranulation were involved. Fig. 9 In a representative example (n=2) of RPMI 8226 cells incubated with healthy donor PB MNCs, CD8, as determined by increased surface expression (degranulation) of CD107a in JNJ-957-mediated MM cell lysis. + It indicates that T cell activation and degranulation were involved. Fig. 10 In a representative example (n=2) of RPMI 8226 cells incubated with healthy donor PB MNCs, JNJ-957-mediated MM cell lysis showed CD25 and CD107a double-positive CD4 + CD8 as determined by the increased proportion of T cells + It indicates that T cell activation and degranulation were involved. Fig. 11 is newly diagnosed multiple myeloma (NDMM) and daratumumab insensitization ( ) Shows in vitro daratumumab-mediated lysis of MM cells from patients with relapsed / refractory MM (RRMM). Multiple myeloma cells from daratumumab-refractory RRMM patients show resistance to daratumumab-mediated lysis (**** P <0.0001). Fig. 12 Figure 1 shows the dose-response of JNJ-957-mediated lysis of plasma cells, T cells, and NK cells in whole autologous bone marrow (BM) MNCs obtained from newly diagnosed multiple myeloma patients (NDMM, n=8). % lysis was measured at various antibody concentrations (0.0064 to 4.0 µg / mL) as shown in this figure. Circle (top line): Plasma cells; Square (middle line): T cells; Triangle (bottom line): NK cells. Fig. 13 Figure 1 shows the dose-response of JNJ-957-mediated lysis of plasma cells, T cells, and NK cells in complete autologous bone marrow (BM) mNNCs obtained from multiple myeloma (MM) patients (n=15) refractory to lenalidomide treatment. % lysis was measured at various antibody concentrations (0.0064 to 4.0 µg / mL) as shown in this figure. Circle (top line): Plasma cells; Square (middle line): T cells; Triangle (bottom line): NK cells. Fig. 14 Figure 1 shows the dose-response of JNJ-957-mediated lysis of plasma cells, T cells, and NK cells in whole autologous bone marrow (BM) MNCs obtained from MM patients (n=11) refractory to treatment with lenalidomide and daratumumab. % lysis was measured at various antibody concentrations (0.0064 to 4.0 µg / mL) as shown in this figure. Circle (top line): Plasma cells; Square (middle line): T cells; Triangle (bottom line): NK cells. Fig. 15 JNJ-957-mediated MM cell lysis in CD4 in BM samples from NDMM, daratumumab-insensitive RRMM (RRMM), and daratumumab-refractory RRMM (RRMM dara R) patients +Indicates that it was achieved by T cell activation (as assessed by increased CD25 surface expression). 3930: Allotypical control; BC3B4: BCMA x null bispecific antibody; 7008: null x CD3 bispecific antibody. Fig. 16 JNJ-957-mediated MM cell lysis in CD4 in BM samples from NDMM, daratumumab-insensitive RRMM (RRMM), and daratumumab-refractory RRMM (RRMM dara R) patients + Indicates that this was achieved by T cell degranulation (as assessed by increased CD107a surface expression). 3930: Allotype control; BC3B4: BCMA x null bispecific antibody; 7008: null x CD3 bispecific antibody. Fig. 17 CD4 in BM samples from NDMM, daratumumab-insensitive RRMM (RRMM), and daratumumab-refractory RRMM (RRMM dara R) patients treated with JNJ-957 at the indicated concentrations + Double-positive CD25 as a percentage of T cells + CD107a + Represents cells. 3930: Allotype control; BC3B4: BCMAx null bispecific antibody; 7008: null xCD3 bispecific antibody. Double-positive: CD25 and CD107a double-positive CD4 + T cells. Fig. 18 JNJ-957-mediated MM cell lysis in CD8 in BM samples from NDMM, daratumumab-insensitive RRMM (RRMM), and daratumumab-refractory RRMM (RRMM dara R) patients + Indicates that this was achieved by T cell activation (as assessed by increased CD25 surface expression). 3930: Allotypical control; BC3B4: BCMA x null bispecific antibody; 7008: null x CD3 bispecific antibody. Fig. 19JNJ-957-mediated MM cell lysis in CD8 in BM samples from NDMM, daratumumab-insensitive RRMM (RRMM), and daratumumab-refractory RRMM (RRMM dara R) patients + Indicates that this was achieved by T cell degranulation (as assessed by increased CD107a surface expression). 3930: Allotype control; BC3B4: BCMA x null bispecific antibody; 7008: null x CD3 bispecific antibody. Fig. 20 CD8 in BM samples from NDMM, daratumumab-insensitive RRMM (RRMM), and daratumumab-refractory RRMM (RRMM dara R) patients treated with the indicated concentrations of JNJ-957 + Double-positive CD25 as a percentage of T cells + CD107a + Represents cells. 3930: Allotype control; BC3B4: BCMAx null bispecific antibody; 7008: null xCD3 bispecific antibody. Double-positive: CD25 and CD107a double-positive CD8 + T cells. Fig. 21 Figure represents the BCMA expression levels (mean MFI ± SEM) on MM cells in NDMM, daratumumab-insensitive RRMM, and daratumumab-refractory RRMM subjects. Among the indicated groups P - value Mann-Whitney U Test (Mann-Whitney) U Calculated using test); * P <0.05; ns: Not significant. Fig. 22 represents the PD-L1 expression levels (mean MFI ± SEM) on MM cells in NDMM, daratumumab-insensitive RRMM, and daratumumab-refractory RRMM subjects. Among the indicated groups P - value Mann-Whitney U Calculated using a test; * P <0.05; ns: Not significant. Fig. 23represents the baseline percentage of Tregs in BM MNCs from NDMM, daratumumab-unsensitive RRMM, and daratumumab-refractory RRMM. **p<0.01; ns: not significant. Fig. 24 represents the baseline percentage of activated T cells (as assessed by HLA-DR positivity) in BM MNCs from NDMM, daratumumab-unsensitive RRMM, and daratumumab-refractory RRMM. **p<0.01; ns: not significant. Fig. 25 represents the baseline percentages of various T cell subsets in BM MNCs from NDMM, daratumumab-unsensitized RRMM, and daratumumab-refractory RRMM. *p<0.05; **p<0.01; ns: not significant. TEMRA: CD45RA + CCR7 - T cell; EM: Effector memory; CM: Central memory; N: Unsensitized T cell. Fig. 26 represents JNJ-957-mediated lysis of multiple myeloma cells from NDMM patients mediated by autologous BM MNCs. Samples were dichotomized by the frequency of Treg at baseline (low ≤50th percentile, high >50th percentile). ns: not significant. Fig. 27 This represents JNJ-957-mediated lysis of multiple myeloma cells from daratumumab-unsensitive RRMM patients mediated by autologous BM MNCs. Samples were dichotomized by the frequency of Tregs at baseline (low ≤50th percentile, high >50th percentile). *p<0.05; **p<0.01; ns: not significant. Fig. 28 This represents JNJ-957-mediated lysis of multiple myeloma cells from daratumumab-refractory RRMM patients mediated by autologous BM MNCs. Samples were dichotomized by the frequency of Tregs at baseline (low ≤50th percentile, high >50th percentile). *p<0.05; ns: not significant. Fig. 29This represents the JNJ-957-mediated lysis of MM cells from BM samples from NDMM (n=9), daratumumab-unsensitive RRMM (n=18), and daratumumab-refractory RRMM (n=13) patients after 48 hours of incubation. Data are expressed as mean ± SEM, P The value is student t -Test(Student t It was calculated using -test). ** P <0.01. Fig. 30 This indicates that JNJ-957-mediated lysis of MM cells from bone marrow (BM) samples obtained from patients with relapsed / refractory multiple myeloma (RRMM) (n=8) was enhanced in samples from patients who received daratumumab ("Dara exposed") compared to samples from the same patients prior to the initiation of daratumumab treatment ("Dara unsensitized"). Data are presented as mean ± SEM; P Values ​​are pairwise t- Calculated using a test. ns: Not significant; * P <0.05, ** P <0.01. Fig. 31 represents the percentage of Tregs in sequential BM aspirates from RRMM patients prior to the initiation of daratumumab (before dara treatment) and at the time of onset of daratumumab-refractory disease (dara exposure). ns: Not significant. Fig. 32 CD4 in sequential BM aspirates from RRMM patients prior to the initiation of daratumumab (prior to dara treatment) and at the time of the onset of daratumumab-refractory disease (dara exposure). + Represents the percentage of cells. ns: Not significant. Fig. 33 CD8 in sequential BM aspirates from RRMM patients prior to the initiation of daratumumab (prior to dara treatment) and at the time of the onset of daratumumab-refractory disease (dara exposure). + It represents the percentage of T cells. Fig. 34This shows that JNJ-957-mediated lysis of RPMI8226 multiple myeloma cells using patient-derived PB MNCs as effector cells was enhanced by PB MNCs from patients who received daratumumab ("dara-treated with PBMNCs") compared to samples from the same patients prior to the initiation of daratumumab treatment ("unsensitized with PBMNCs") (n=5). Data are presented as mean ± SEM; P Values ​​are pairwise t- Calculated using a test. ns: Not significant; * P <0.05. Fig. 35 represents the percentage of Treg in PB-MNC samples from RRMM patients who were irritated to daratumumab (before dara treatment) and daratumumab refractory (dara treatment). Fig. 36 CD4 in PB-MNC samples from RRMM patients who were daratumumab irritated (before dara treatment) and daratumumab refractory (dara treatment) + Represents the percentage of T cells. ns: Not significant. Fig. 37 CD8 in PB-MNC samples from RRMM patients who were daratumumab irritated (before dara treatment) and daratumumab refractory (dara treatment) + Represents the percentage of T cells. ns: Not significant. Fig. 38 This indicates that the addition of daratumumab enhanced JNJ-957-mediated MM cell lysis. BM mononuclear cells (MNCs) from NDMM patients (n=8) were treated for 48 hours with JNJ-957 (0.032 to 0.8 µg / mL) alone or in combination with 10 µg / mL daratumumab. The observed (Obs) lysis levels of MM cells induced by JNJ-957 and daratumumab were compared to the predicted (Exp) lysis levels, which were calculated under the assumption that the combination effect is achieved by an additive effect as described in Methods. Black bars represent the group mean ± SEM. P The value is pairwise studentt- Calculated using a test. ns: Not significant. Fig. 39 This indicates that the addition of daratumumab enhanced JNJ-957-mediated MM cell lysis. MM MNCs from daratumumab-insensitive RRMM patients (n=17) were treated for 48 hours with JNJ-957 (0.032 to 0.8 µg / mL) alone or in combination with 10 µg / mL daratumumab. The observed (Obs) lysis levels of MM cells by JNJ-957 and daratumumab were compared to the predicted (Exp) lysis levels, which were calculated under the assumption that the combination effect is achieved by an additive effect as described in Methods. Black bars represent the group mean ± SEM. P The value is pairwise student t- Calculated using a test. ns: Not significant. Fig. 40 ... indicates that the addition of daratumumab enhanced JNJ-957-mediated MM cell lysis. BM MNCs from daratumumab-refractory RRMM patients (n=14) were treated for 48 hours with JNJ-957 (0.032 to 0.8 µg / mL) alone or in combination with 10 µg / mL daratumumab. The observed (O) lysis levels of MM cells by JNJ-957 and daratumumab were compared to the predicted (E) lysis levels, which were calculated under the assumption that the combination effect is achieved by an additive effect as described in Methods. Black bars represent the group mean ± SEM. P The value is pairwise student t- Calculated using a test. JNJ-957 is referred to as JNJ-7957 in this figure. Dara: Daratumumab. ns: Not significant. Fig. 41Figure 1 shows the blinatumomab-mediated lysis of Raji cell lines using sequential PB samples from 11 RRMM patients as effector cells (E:T = 10:1), wherein the sequential PB samples were obtained immediately before the initiation of daratumomab treatment (black, bottom line) and during daratumomab treatment (gray, top line); the median duration of treatment was 7 months, ranging from 2 to 14 months. Blinatumomab-based cytotoxicity assays were performed after incubating Raji cells with blinatumomab (0.01 to 10 µg / mL) for 48 hours in the presence of these PB-MNCs. Data are expressed as mean ± SEM, and the experiment was repeated twice. Statistical significance between the indicated groups ( P- The value was calculated using non-linear regression analysis. Fig. 42 This figure shows the dose-response of JNJ-957-mediated lysis of plasma cells, T cells, and NK cells from BM-MNC cells obtained from six patients with primary plasma cell leukemia (pPCL). % lysis was measured at various antibody concentrations (0.0064 to 4.0 μg / mL) as shown in this figure. Top line: plasma cells; bottom line: overlapping lines for T cells and NK cells. JNJ-957 is referred to as JNJ-7957 in this figure. Fig. 43 Figure 1 shows the anti-GPRC5DxCD3 antibody-mediated lysis of MM cell lines using sequential PB samples from 11 RRMM patients as effector cells (E:T = 10:1), wherein the sequential PB samples were obtained immediately before the initiation of daratumumab treatment (bottom line) and during daratumumab treatment (top line); the median duration of treatment was 7 months, ranging from 2 to 14 months. After incubating Raji cells with blinatumumab (0.01 to 10 µg / mL) for 48 hours in the presence of these PB-MNCs, a blinatumumab-based cytotoxicity assay was performed. Data are expressed as mean ± SEM, and the experiment was repeated twice. Fig. 44This indicates that the addition of daratumumab was additive to anti-GPRC5DxCD3 bispecific antibody (JNJ-7564)-mediated MM cell lysis. BM MNCs from daratumumab-unsensitive RRMM patients (n=17) were treated for 48 hours with anti-GPRC5DxCD3 bispecific antibody (0.00128 to 0.8 µg / mL) alone or in combination with 0.1 µg / mL daratumumab. The observed (O) lysis levels of MM cells induced by the anti-GPRC5DxCD3 bispecific antibody and daratumumab were compared to the predicted (E) lysis levels, which were calculated under the assumption that the combination effect is achieved through additive action as described in Methods. Black bars represent the group mean ± SEM. P The value is pairwise student t- Calculated using a test. ns: Not significant. Dara: Daratumumab. Specific details for implementing the invention

[0022] The method disclosed herein may be more easily understood by referring to the following detailed description taken in connection with the accompanying drawings, which form part of this specification. The method disclosed herein is not limited to the specific methods described and / or shown herein, and it should be understood that the terms used herein are merely illustrative of specific embodiments and are not intended to limit the claimed method. All patents, published patent applications, and publications cited herein are incorporated by reference as if they were fully described herein.

[0023] As used in this specification, the singular forms (“a,” “an,” and “the”) include the plural.

[0024] Various terms relating to the details of the description are used throughout this specification and claims. Unless otherwise indicated, these terms should be given in their ordinary meaning in the art. Other specifically defined terms are interpreted in a manner consistent with the definitions provided in this specification.

[0025] When used in reference to a numerical range, cutoff, or specific value, “about” means that the specific value, as determined by a person skilled in the art, is within an acceptable margin of error, which will depend in part on how the value is measured or determined (i.e., limitations of the measurement system). Unless otherwise explicitly stated in the examples or elsewhere in the specification in relation to the test, result, or embodiment, “about” means within one standard deviation or up to 5%, whichever is greater, according to the practice of the art.

[0026] "Antibody""Broadly defined" includes monoclonal antibodies, including murine, human, humanized, and chimeric monoclonal antibodies; antigen-binding fragments; multispecific antibodies (e.g., bispecific, trispecific, quadrspecific, etc.); dimeric, tetrameric, or multimeric antibodies; immunoglobulin molecules, including single-strand antibodies and domain antibodies; and any other modified configuration of immunoglobulin molecules containing antigen-binding sites of the required specificity. "Whole-length antibody" consists of two heavy chains (HC) and two light chains (LC) interconnected by disulfide bonds, as well as their multimers (e.g., IgM). Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region (composed of domains CH1, hinge, CH2, and CH3). Each light chain consists of a light chain variable region (VL) and a light chain constant region (CL). The VH and VL regions can be further subdivided into hypervariable regions called complementarity determining regions (CDRs), which are interspersed with framework regions (FRs). Each VH and VL consists of three CDRs and four FR segments, arranged from the amino-terminus to the carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. Immunoglobulins can be classified into five major classes, IgA, IgD, IgE, IgG, and IgM, based on the heavy chain constant domain amino acid sequence. IgA and IgG are further subdivided into isotypes IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. The antibody light chain of any vertebrate species can be determined as one of two distinct types, namely kappa (κ) and lambda (λ), based on the amino acid sequence of its constant domain.

[0027] " Antigen-binding fragment " or " antigen binding domain"Refers to a portion of an immunoglobulin molecule that binds to an antigen. The antigen-binding fragment may be a synthetic polypeptide, an enzymatically obtainable polypeptide, or a genetically engineered polypeptide, and includes VH, VL, VH and VL, Fab, F(ab')2, Fd and Fv fragments; domain antibodies (dAbs) consisting of one VH domain or one VL domain; shark variable IgNAR domains; camelized VH domains; minimal recognition units consisting of amino acid residues mimicking the antibody's CDR, e.g., FR3-CDR3-FR4 portions; HCDR1, HCDR2 and / or HCDR3; and LCDR1, LCDR2 and / or LCDR3. VH and VL domains may be linked together via a synthetic linker to form various types of single-strand antibody designs, wherein the VH / VL domains are paired intramolecularly or intermolecularly when the VH and VL domains are expressed by separate single-strand antibody constructs to form monovalent antigen-binding fragments. The site may form, for example, a single-stranded Fv (scFv) or a diabody, which is described, for example, in international patent applications WO1998 / 44001, WO1988 / 01649, WO1994 / 13804, and WO1992 / 01047.

[0028] " BCMA " refers to the human B-cell maturation antigen also known as CD269 or TNFRSF17 (UniProt Q02223). The extracellular domain of BCMA contains residues 1-54 of Q02223. Human BCMA is Sequence No. 2 It includes the amino acid sequence of.

[0029] Sequence No. 2

[0030] MLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPLTCQRYCNASVTNSVKGTNAILWTCLGLSLIISLAVFVLMFLLRKINSEPLKDEFKNTGSGLLGMANIDLEKSRTGDEIILPRGLEYTVEECTCEDCIKSKPKVDSDHCFPLPAMEEGATILVTTKTNDYCKSLPAALSATEIEKSISAR

[0031] " double specificity "It refers to an antibody that specifically binds to two distinct antigens or two distinct epitopes within the same antigen. Bispecific antibodies are those that bind to other related antigens, for example, different species (homologous), such as humans or monkeys, for example, macaca cynomolgus ( Macaca cynomolgus )(cynomolgus, cyno), or pantroglodites( Pan troglodytes It can have cross-reactivity to the same antigen from ) or can bind to an epitope shared between two or more distinct antigens.

[0032] " cancer "It refers to a broad group of various diseases characterized by the uncontrolled growth of abnormal cells in the body. Uncontrolled cell division and growth lead to the formation of malignant tumors that can invade neighboring tissues and also metastasize to distant parts of the body via the lymphatic system or bloodstream. "Cancer" or "cancer tissue" may include tumors.

[0033] " CD123 " refers to human interleukin-3 receptor subunit alpha (IR3RA) having the amino acid sequence presented in SEQ ID NO. 57. The extracellular domain of CD123 extends across residues 19-305 of SEQ ID NO. 57.

[0034] CD123 (Sequence No. 57)

[0035] MVLLWLTLLLIALPCLLQTKEDPNPPITNLRMKAKAQQLTWDLNRNVTDIECVKDADYSMPAVNNSYCQFGAISLCEVTNYTVRVANPPFSTWILFPENSGKPWAGAENLTCWIHDVDFLSCSWAVGPGAPADVQYDLYLNVANRRQQYECLHYKTDAQGTRIGCRFDDISRLSSGSQSSHILVRGRSA AFGIPCTDKFVVFSQIEILTPPNMTAKCNKTHSFMHWKMRSHFNRKFRYELQIQKRMQPVITEQVRDRTSFQLLNPGTYTVQIRARERVYEFLS AWSTPQRFECDQEEGANTRAWRTSLLIALGTLLALVCVFVICRRYLVMQRLFPRIPHMKDPIGDSFQNDKLVVWEAGKAGLEECLVTEVQVVQKT

[0036] " CD19 " refers to human B-lymphocyte antigen CD19 having the amino acid sequence of sequence number 58. The extracellular domain of CD19 extends across residues 20–291 of sequence number 58.

[0037] CD19 (Sequence No. 58)

[0038] MPPPRLLFFLLFLTPMEVRPEEPLVVKVEEGDNAVLQCLKGTSDGPTQQLTWSRESPLKP

[0039] FLKLSLGLPGLGIHMRPLAIWLFIFNVSQQMGGFYLCQPGPPSEKAWQPGWTVNVEGSGE

[0040] LFRWNVSDLGGLGCGLKNRSSEGPSSPSGKLMSPKLYVWAKDRPEIWEGEPPCLPPRDSL

[0041] NQSLSQDLTMAPGSTLWLSCGVPPDSVSRGPLSWTHVHPKGPKSLLSLELKDDRPARDMW

[0042] VMETGLLLPRATAQDAGKYYCHRGNLTMSFHLEITARPVLWHWLLRTGGWKVSAVTLAYL

[0043] IFCLCSLVGILHLQRALVLRRKRKRMTDPTRFFKVTPPPGSGPQNQYGNVLSLPTPTSG

[0044] LGRAQRWAAGLGGTAPSYGNPSSDVQADGALGSRSPPGVGPEEEEGEGYEEPDSEEDSEF

[0045] YENDSNLGQDQLSQDGSGYENPEDEPLGPEDEDSFSNAESYENEDEELTQPVARTMDFLS

[0046] PHGSAWDPSREATSLGSQSYEDMRGILYAAPQLRSIRGQPGPNHEEDADSYENMDNPDGP

[0047] DPAWGGGGRMGTWSTR

[0048] " CD3 " refers to a human antigen expressed on T cells as part of a multimolecular T cell receptor (TCR) complex and composed of a homodimer or heterodimer formed from the association of the following two or four receptor chains: CD3 epsilon, CD3 delta, CD3 zeta, and CD3 gamma. Human CD3 epsilon is Sequence No. 3 It includes the amino acid sequence of. Sequence number 22 represents the extracellular domain of CD3 epsilon.

[0049] Sequence No. 3

[0050] MQSGTHWRVLGLCLLSVGVWGQDGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGS KPEDANFYLYLRARVCENCMEMDVMSVATIVIVDICITGGLLLLLVYYWSKNRKAKAKPVTRGAGAGGRQRGQNKERPPPVPNPDYEPIRKGQRDLYSGLNQRRI

[0051] Sequence number 22

[0052] DGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENCMEMD

[0053] " CD33 " refers to the myeloid cell surface antigen CD33 having the amino acid sequence of sequence number 97. The extracellular domain of CD33 extends across residues 18-259 of sequence number 97.

[0054] CD33 (Sequence No. 97)

[0055] MPLLLLLPLLWAGALAMDPNFWLQVQESVTVQEGLCVLVPCTFFHPIPYYDKNSPVHGYWFREGAIISRDSPVATNKLDQEVQEETQGRFRLLGDPSRNNCSLSIVDARRRDNGSYFFRMERGSTKYSYKSPQLSVHVTDLTHRPKILIPGTLEPGHSKNLTCSVSWACEQGTPPIFSWLSA APTSLGPRTTHSSVLIITPRPQDHGTNLTCQVKFAGAGVTTERTIQLNVTYVPQNPTTGIFPGDGSGKQETRAGVVHGAIGGAGVTALLALCLCLIFFIVKTHRRKAARTAVGRNDTHPTTGSASPKHQKKSKLHGPTETSSCSGAAPTVEMDEELHYASLNFHGMNPSKDTSTEYSEVRTQ

[0056] " CD38 " refers to the human CD38 protein (UniProt accession number P28907) (synonyms: ADP-ribosyl cyclase 1, cADPr hydrolase 1, cyclic ADP-ribose hydrolase 1). Human CD38 has the amino acid sequence as presented in SEQ ID NO. 1. CD38 is a single-pass type II transmembrane protein having amino acid residues 1-21 representing a cytoplasmic domain, amino acid residues 22-42 representing a transmembrane domain, and residues 43-300 representing an extracellular domain.

[0057] Sequence No. 1

[0058] MANCEFSPVSGDKPCCRLSRRAQLCLGVSILVLILVVVLAVVVPRWRQQWSGPGTTKRFPETVLARCVKYTEIHPEMRHVDCQSVWDAF㎏AFISKHPCNITEEDYQPLMKLGTQTVPCNKILLWSRIKDLAHQFTQVQRDMFTLEDTLLGYLADDLTWCGEFNTSKINYQSCPDWRKDCSNNPVSVFWKTVSRRFAEAACDVVHVMLNGSRSKIFDKNSTFGSVEVHNLQPEKVQTLEAWVIHGGREDSRDLCQDPTIKELESIISKRNIQFSCKNIYRPDKFLQCVKNPEDSSCTSEI

[0059] " CH3 area " or " CH3 domain " refers to the CH3 region of the immunoglobulin. The CH3 region of the human IgG1 antibody corresponds to amino acid residues 341-446. However, the CH3 region may also be any other antibody isotype as described herein.

[0060] " Chimeric antigen receptor " or " CAR"CAR refers to an engineered T cell receptor that implants ligand or antigen specificity onto T cells (e.g., unsensitized T cells, central memory T cells, effector memory T cells, or combinations thereof). CAR is also known as an artificial T-cell receptor, a chimeric T-cell receptor, or a chimeric immune receptor. A CAR comprises an extracellular domain, a transmembrane domain, and at least one intracellular domain capable of binding to an antigen. The CAR intracellular domain comprises a polypeptide known to function as a domain that transmits signals to cause the activation or inhibition of biological processes in the cell. The transmembrane domain comprises any peptide or polypeptide known to span the cell membrane and capable of functioning to link the extracellular domain and the signaling domain. The chimeric antigen receptor may optionally comprise a hinge domain that acts as a linker between the extracellular domain and the transmembrane domain.

[0061] " Combined use "This means that two or more therapeutic agents are administered to a subject together as a mixture, simultaneously as a single agent, or sequentially as a single agent in any order."

[0062] " Complementarity determination region "(CDR) is the antibody region that binds to the antigen. The CDR can be defined using various delineations as follows: Kabat (Literature [Wu et al. J Exp Med 132: 211-50, 1970]) (Literature[Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991], Chothia (Reference [Chothia et al. J Mol Biol 196: 901-17, 1987]), IMGT (Literature [Lefranc et al. Dev Comp Immunol 27: 55-77, 2003]) and AbM (Literature [Martin and Thornton J Bmol Biol [263: 800-15, 1996]). The correspondence between these various illustrations and variable area numbering is explained (e.g., the literature [Lefranc et al. Dev Comp Immunol 27: 55-77, 2003]; literature[Honegger and Pluckthun, J Mol Biol [309:657-70, 2001]; International ImMunoGeneTics (IMGT) database; Web resource, see http: / / www_imgt_org). A CDR can be described in detail using available programs such as abYsis of UCL Business PLC. As used herein, the terms “CDR”, “HCDR1”, “HCDR2”, “HCDR3”, “LCDR1”, “LCDR2”, and “LCDR3” include a CDR defined by any of the methods described above, such as Kavat, Chotia, IMGT, or AbM, unless otherwise expressly stated in this specification.

[0063] " including "is intended to include examples covered by the terms "essentially composed of" and "composed of"; similarly, the term "essentially composed of" is intended to include examples covered by the term "composed of". Unless otherwise clearly required by the context, throughout the detailed description and claims, words such as "include," "including," etc., should be interpreted in an inclusive sense; that is, "includes but is not limited to" as opposed to an exclusive or all-encompassing sense.

[0064] " improve " or " Improved“Improved” refers to an improvement in one or more functions of the test molecule or of the combination of test molecules compared to one or more control molecules. Exemplary functions that may be measured are tumor cell death, T cell activation, relative or absolute T cell number, Fc-mediated effector function (e.g., ADCC, CDC, and / or ADCP), or binding to the Fcγ receptor (FcγR) or FcRn. “Improved” may be an improvement of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or greater, or a statistically significant improvement.

[0065] " Fc gamma receptor "( FcγR ) refers to the well-known FcγRI, FcγRIIa, FcγRIIb, or FcγRIII. Activated FcγR includes FcγRI, FcγRIIa, and FcγRIII.

[0066] " GPRC5D " refers to human G-protein coupled receptor family C group 5 member D having the amino acid sequence presented in sequence number 98.

[0067] GPRC5D (Sequence No. 98)

[0068] MYKDCIESTGDYFLLCDAEGPWGIILESLAILGIVVTILLLLAFLFLMRKIQDCSQWNVL

[0069] PTQLLFLLSVLGLFGLAFAFFIIELNQQTAPVRYFLFGVLFALCFSCLLAHASNLVKLVRG

[0070] CVSFSWTTILCIAIGCSLLQIIIATEYVTLIMTRGMMFVNMTPCQLNVDFVVLLVYVLFL

[0071] MALTFFVSKATFCGPCENWKQHGRLIFITVLFSIIIWVVWISMLLRGNPQFQRQPQWDDP

[0072] VVCIALVTNAWVFLLLYIVPELCILYRSCRQECPLQGNACPVTAYQHSFQVENQELSRAR

[0073] DSDGAEEDVALTSYGTPIQPQTVDPTQECFIPQAKLSPQQDAGGV

[0074] " Human antibodies"Human antibody" refers to an antibody optimized to produce a minimal immune response when administered to a human subject. The variable region of the human antibody is derived from the human immunoglobulin sequence. If the human antibody contains a constant region or a portion of the constant region, the constant region is also derived from the human immunoglobulin sequence. The human antibody includes heavy and light chain variable regions derived from "sequences of human origin" where the variable region of the human antibody is obtained from a system using human germline immunoglobulin or a rearranged immunoglobulin gene. Such exemplary systems include a library of human immunoglobulin genes displayed on phages, and genetically modified non-human animals, such as mice or rats, carrying the human immunoglobulin locus. The "human antibody" typically contains amino acid differences compared to immunoglobulin expressed in humans due to differences between the human antibody and the system used to obtain the human immunoglobulin locus, the introduction of somatic mutations or the intentional introduction of substitutions into the framework or CDR, or both. Typically, the human antibody The amino acid sequence encoded by human germline immunoglobulin or rearranged immunoglobulin genes is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence. In some cases, the "human antibody" contains a common framework sequence derived from human framework sequence analysis, for example, as described in the literature [Knappik et al., (2000) J Mol Biol 296:57-86], or, for example, in the literature [Shi et al.It may contain synthetic HCDR3 introduced into a human immunoglobulin gene library displayed on a phage as described in [J Mol Biol 397:385-96] (2010) and International Patent Application Publication WO2009 / 085462. Antibodies in which at least one CDR is derived from a non-human species are not included in the definition of "human antibody".

[0075] " Humanized antibodies " refers to an antibody in which one or more CDRs are derived from a non-human species and at least one framework is derived from a human immunoglobulin sequence. Since humanized antibodies may contain substitutions within the framework, the framework may not be an exact copy of the expressed human immunoglobulin or human immunoglobulin germline gene sequence.

[0076] " isolated "Refers to a homologous group of molecules (e.g., synthetic polynucleotides or proteins, e.g., antibodies) that have undergone at least one purification or isolation step, as well as molecules that have been substantially separated from and / or purified from other components of the system in which the molecules are generated, e.g., recombinant cells. "Isolated antibody" refers to an antibody that is substantially free of other cellular material and / or chemicals, and includes antibodies isolated to a higher purity, e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%.

[0077] " monoclonal antibodies"Refers to antibodies obtained from a substantially homogeneous population of antibody molecules, that is, the individual antibodies constituting the population are identical except for possible well-known alterations, such as the removal of C-terminal lysine from the antibody heavy chain, or post-translational modifications, such as amino acid isomerization or deamidation, methionine oxidation, or asparagine or glutamine deamidation. Monoclonal antibodies typically bind to a single antigen epitope. Bispecific monoclonal antibodies bind to two distinct antigen epitopes. Monoclonal antibodies may have heterogeneous glycosylation within the antibody population. Monoclonal antibodies can be monospecific or multispecific, such as bispecific monovalent, divalent, or multivalent.

[0078] " Mutation " refers to a manipulated or naturally occurring alteration in a polypeptide or polynucleotide sequence when compared to a reference sequence. The alteration may be a substitution, insertion, or deletion of one or more amino acids or polynucleotides.

[0079] " Non-fixed conjugate " refers to separate pharmaceutical compositions of a T-cell re-induction therapeutic agent and an anti-CD38 antibody administered as separate entities simultaneously, in parallel, or sequentially without specific intervention time limits, wherein such administration provides effective levels of these two compounds in the body of the subject.

[0080] " Multiple specificity " refers to an antibody that specifically binds to at least two distinct antigens or at least two distinct epitopes within the same antigen. A multispecific antibody may bind to, for example, two, three, four, or five distinct antigens or distinct epitopes within the same antigen.

[0081] " Pharmaceutical composition " refers to a composition comprising an active ingredient and a pharmaceutically acceptable carrier.

[0082] " Pharmaceutically acceptable carrier" or " Brothers " refers to a component in a pharmaceutical composition other than the active ingredient that is non-toxic to the subject.

[0083] " Philadelphia chromosome " or "Ph" refers to a well-known chromosomal translocation between chromosomes 9 and 22, resulting in an oncogenic BCR-ABL gene fusion with constitutively active tyrosine kinase activity. The translocation causes a portion of the BCR gene from chromosome 22q11 to fuse with a portion of the ABL gene from chromosome 9q34 and is designated as t(9;22)(q34;q11) under the International System for Human Cytogenetic Nomenclature (ISCN). Depending on the exact location of the fusion, the molecular weight of the resulting fusion protein may range from 185 to 210 kDa. "Philadelphia chromosome" refers to all BCR-ABL fusion proteins formed as a result of the (9;22)(q34;q11) translocation.

[0084] " PSMA " refers to a human prostate-specific membrane antigen having the amino acid sequence of SEQ No. 99. The extracellular domain extends across residues 44-750 of SEQ No. 99.

[0085] PSMA (Sequence No. 99)

[0086] MWNLLHETDSAVATARRPRWLCAGALVLAGGFFLLGFLFGWFIKSSNEATNITPKHNMKAFLDELKAENIKKFLYNFTQIPHLAGTEQNFQLAKQIQSQWKEFGLDSVELAHYDVLLSYPNKTHPNYISIINEDGNEIFNTSLFEPPPPGYENVSDIVPPFSAFSPQGMPEGDLVYVNYARTEDFFK LERDMKINCSGKIVIARYGKVFRGNKVKNAQLAGAKGVILYSDPADYFAPGVKSYPDGWNLPGGGVQRGNILNLNGAGDPLTPGYPANEYAYRRGIAEAVGLPSIPVHPIGYYDAQKLLEKMGGSAPPDSSWRGSLKVPYNVGPGFTGNFSTQKVKMHIHSTNEVTRIYNVIGTLRGAVEPDRYVILG GHRDSWVFGGIDPQSGAAVVHEIVRSFGTLKKEGWRPRRTILFASWDAEEFGLLGSTEWAEENSRLLQERGVAYINADSSIEGNYTLRVDCTPLMYSLVHNLTKELKSPDEGFEGKSLYESWTKKSPSPEFSGMPRISKLGSGNDFEVFFQRLGIASGRARYTKNWETNKFSGYPLYHSVYETYELV EKFYDPMFKYHLTVAQVRGGMVFELANSIVLPFDCRDYAVVLRKYADKIYSISMKHPQEMKTYSVSFDSLFSAVKNFTEIASKFSERLQDFDKSNPIVLRMMNDQLMFLERAFIDPLGLPDRPFYRHVIYAPSSHNKYAGESFPGIYDALFDIESKVDPSKAWGEVKRQIYVAAFTVQAAAETLSEVA

[0087] " recombination " refers to DNA, antibodies, and other proteins produced, expressed, generated, or isolated by a recombinant means when segments from different sources are combined to produce recombinant DNA, antibodies, or proteins."

[0088] " to decrease " or " Reduced“Decreases” refers to a reduction in one or more functions of the test molecule or of the combination of test molecules compared to one or more control molecules. Exemplary functions that may be measured are tumor cell death, T cell activation, relative or absolute T cell number, Fc-mediated effector function (e.g., ADCC, CDC, and / or ADCP), or binding to the Fcγ receptor (FcγR) or FcRn. “Decreases” may be a reduction of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or greater, or a statistically significant improvement.

[0089] " rHuPh20 "is a recombinant hyaluronidase (HYLENEX) described in International Patent Application Publication WO2004 / 078140" ® It refers to recombinant human hyalurodinase having the amino acid sequence of sequence number 105, which is a recombinant.

[0090] rHuPH20 (sequence number 105)

[0091] MGVLKFKHIFFRSFVKSSGVSQIVFTFLLIPCCLTLNFRAPPVIPNVPFLWAWNAPSEFCLGKFDEPLDMSLFSFIGSPRINATGQGVTIFYVDRLGYYPYIDSITGVTVNGGIPQKISLQDHLDKA KKDITFYMPVDNLGMAVIDWEEWRPTWARNWKPKDVYKNRSIELVQQQNVQLSLTEATEKAKQEFEKAGKDFLVETIKLGKLLRPNHLWGYYLFPDCYNHHYKKPGYNGSCFNVEIKRNDDLSWLWN ESTALYPSIYLNTQQSPVAATLYVRNRVREAIRVSKIPDAKSPLPVFAYTRIVFTDQVLKFLSQDELVYTFGETVALGASGIVIWGTLSIMRSMKSCLLLDNYMETILNPYIINVTLAAKMCSQVLC QEQGVCIRKNWNSSDYLHLNPDNFAIQLEKGGKFTVRGKPTLEDLEQFSEKFYCSCYSTLSCKEKADVKDTDAVDVCIADGVCIDAFLKPPMETEEPQIFYNASPSTLSATMFIVSILFLIISSVASL

[0092] " Refractory It refers to cancer that is not suitable for surgical intervention and is unresponsive to therapy in the early stages.

[0093] " recurrent It refers to cancer that responded to treatment but subsequently reverted.

[0094] " object " includes any human or non-human animal. "Non-human animal" includes all vertebrates, e.g., mammals and non-mammals, e.g., non-human primates, sheep, dogs, cats, horses, cattle, chickens, amphibians, reptiles, etc. Unless otherwise noted, the terms "patient" or "subject" are used interchangeably.

[0095] " T-cell re-induction therapy" refers to a molecule containing two or more binding regions, wherein one of the binding regions specifically binds to a cell surface antigen on a target cell or tissue (e.g., tumor-associated antigen), and the second binding region of the molecule specifically binds to a T cell antigen (e.g., CD3). This dual / multi-target binding ability mobilizes T cells to the target cell or tissue, leading to the eradication of the target cell or tissue.

[0096] " TMEFF2 " refers to a human transmembrane protein having EGF-like and two follistatin-like domains 2, also known as tomoregulin 2. The amino acid sequence of the full-length human TMEFF2 is presented in Sequence No. 101. The extracellular domain of TMEFF2 extends across residues 40–374 of sequence number 101.

[0097] TMEFF2 (Sequence No. 101)

[0098] MVLWESPRQCSSWTLCEGFCWLLLLPVMLLIVARPVKLAAFPTSLSDCQTPTGWNCSGYDDRENDLFLCDTNTCKFDGECLRIGDTVTCVCQFKCNNDYVPVCGSNGESYQNECYLRQAACKQQSEILVVSEGSCATDAGSGSGDGVHEGSGETSQKETSTCDICQFGAECDEDAEDVWCVCNIDCS QTNFNPLCASDGKSYDNACQIKEASCQKQEKIEVMSLGRCQDNTTTTTKSEDGHYARTDYAENANKLEESAREHHIPCPEHYNGFCMHGKCEHSINMQEPSCRCDAGYTGQHCEKKDYSVLYVVPGPVRFQYVLIAAVIGTIQIAVICVVVLCITRKCPRSNRIHRQKQNTGHYSSDNTTRASTRLI

[0099] " Therapeutic effective dose"It refers to an amount effective for achieving the desired therapeutic outcome at the required dose and for the required time. The therapeutic effective dose may vary depending on factors such as the individual's disease state, age, sex, and weight, and the ability of the therapeutic agent or combination of therapeutic agents to induce the desired response in the individual. Exemplary indicators of an effective therapeutic agent or combination of therapeutic agents include, for example, the patient's improved well-being."

[0100] " treat "Or "treatment" refers to both therapeutic treatment and prophylactic or preventive measures, the purpose of which is to prevent or mitigate unwanted physiological changes or disorders. Beneficial or desired clinical outcomes, whether detectable or undetectable, include relief of symptoms, reduction of the severity of the disease, a stabilized (i.e., non-deteriorating) disease state, delay or slowing of disease progression, improvement or palliative of the disease state, and remission (whether partial or whole). "Treatment" may also mean extended survival compared to the survival expected if the subject were not receiving treatment. Those requiring treatment include not only those who already have the disease or disorder, but also those who are prone to the disease or disorder or for whom the disease or disorder must be prevented.

[0101] " tumor cells "or "cancer cells" are in vivo ( in vivo ), in vitro ( ex vivoIt refers to cancerous, precancerous, or transformed cells in tissue culture, which possess spontaneous or induced phenotypic changes. These changes do not necessarily involve the uptake of new genetic material. Although transformation can occur from infection by transforming viruses, the introduction of new genomic nucleic acids, or the uptake of exogenous nucleic acids, it can also occur spontaneously or after exposure to carcinogens, thereby mutating endogenous genes. Transformation / cancer is exemplified in vitro, in vivo, and in vitro by morphological changes, cell immortalization, control of abnormal growth, lesion formation, proliferation, malignancy, regulation of tumor-specific marker levels, invasiveness, and tumor growth in suitable animal hosts such as nude mice.

[0102] Unless otherwise explicitly stated, throughout this specification, the numbering of amino acid residues within the antibody constant region follows the EU index as described in the literature [Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)]. The numbering of the antibody constant chains can be found, for example, on the ImMunoGeneTics website, in IMGT web resources, and in IMGT Scientific charts.

[0103] Substitutions within the CH3 region are expressed as modified position(s) within the first CH3 domain of the first heavy chain / modified position(s) within the second CH3 domain of the second heavy chain. For example, F405L / K409R refers to the F405L mutation within the first CH3 region and the K09R mutation within the second CH3 region. L351Y_F405A_Y407V / T394W refers to the L351Y, F40FA, and Y407V mutations within the first CH3 region and the T394W mutation within the second CH3 region. D399FHKRQ / K409AGRH refers to a mutation in which D399 can be replaced with F, H, KR, or Q, and K409 can be replaced with A, G, R, or H.

[0104] Table 1 Conventional 1-character and 3-character amino acid codes as shown in are used herein:

[0105] [Table 1]

[0106]

[0107] Combination of anti-CD38 antibody and T-cell re-induction therapy and its use

[0108] The present invention relates to the therapeutic agent JNJ-957 or GPRC5DxCD3 antibody and the anti-CD38 antibody DARZALEX ® (Daratumumab) — each of these mediates the death of multiple myeloma cells upon target binding on the same cell — are based at least in part on the finding that they did not antagonize each other in terms of competition for binding to MM cells, mechanisms of action on MM cells, or reciprocal downregulation of targets, and thus are suitable for use as combination therapy. The present invention also relates to DARZALEX ®The invention is at least partially based on the finding that prior treatment with (daratumumab) enhanced JNJ-957-mediated apoptosis of multiple myeloma cells obtained from intensively treated relapsed / refractory multiple myeloma subjects. The invention also includes DARZALEX ® This is based at least in part on the finding that daratumumab enhanced the death of tumor cells other than multiple myeloma cells induced by T-cell re-induction therapies targeting non-multiple myeloma tumor cells. Therefore, the combination of an anti-CD38 antibody and a T-cell re-induction therapies, and / or pretreatment of subjects with an anti-CD38 antibody prior to the administration of the T-cell re-induction therapies, may enhance the anti-tumor efficacy of these monotherapy regimens. Furthermore, considering that cancer is typically a heterogeneous disease, parts of the tumor may exclusively exhibit sufficient expression of a single target in contrast to others; in such cases, combination therapy will aid in the deeper eradication of this disease.

[0109] CD38 is a multifunctional protein that not only functions in receptor-mediated adhesion and signaling but also catalyzes the formation of cyclic ADP-ribose (cADPR) and ADPR by mediating calcium mobilization through ecto-enzymatic activity. CD38 mediates cytokine secretion and the activation and proliferation of lymphocytes (Funaro et al., J Immunol 145:2390-6, 1990]; literature[Terhorst et al., Cell 771-80, 1981]; Literature[Guse et al., [Nature 398:70-3, 1999]). CD38 also [activates] extracellular NAD through its NAD glycohydrolase activity. + These extracellular NADs regulate levels + Levels have been involved in regulating regulatory T-cell compartments (Literature [Adriouch] et al., Microbes infect 14:1284-92, 2012]; Literature[Chiarugi et al., Nature Reviews 12:741-52, 2012]). Ca 2+ In addition to signal transduction via [the method], CD38 signaling occurs through cross-talk with antigen-receptor complexes or other types of receptor complexes, such as MHC molecules, on T- and B-cells, thereby involving CD38 in various cellular responses as well as in the switching and secretion of IgG1. In this specification, the anti-CD38 antibody DARZALEX ® It has been confirmed that (daratumumab) enhances the anti-tumor effect of T-cell re-induction therapies. Although I do not wish to be bound by any specific theory, DARZALEX ® (Daratumumab) exerts its immunomodulatory activity in human subjects (i.e., by reducing the number of immunosuppressive Treg, MDSC, and Breg, CD8 + T cell count and CD8 + By increasing the ratio of Treg to CD8 + By promoting the formation of central memory cells and increasing T cell clonality, an enhanced immune response can be induced even in subjects, thereby promoting T cell binding to T-cell re-induction therapies.

[0110] The present invention provides a method for treating cancer in a subject, wherein the method comprises the step of treating said cancer by administering a therapeutically effective amount of an anti-CD38 antibody and a T-cell re-induction therapeutic agent to said subject.

[0111] The present invention also provides a method for killing tumor cells in a subject, the method comprising the step of administering to the subject an anti-CD38 antibody that binds to an antigen on the tumor cells and a T-cell re-induction therapeutic agent for a time sufficient to kill the tumor cells.

[0112] The present invention also provides a method for enhancing the efficacy of a T-cell re-induction therapeutic agent in a subject having cancer, said method comprising the step of administering an anti-CD38 antibody to said subject.

[0113] In some embodiments, the anti-CD38 antibody is administered before the administration of the T-cell re-induction therapy.

[0114] T-cell re-induction therapy may be administered 1 day, 2 days, 3 days, 4 days, 5 days, 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 longer before administering anti-CD38 antibodies.

[0115] In some embodiments, the T-cell re-induction therapeutic agent binds to an antigen on the tumor cell.

[0116] In some embodiments, the antigens on the tumor cells are BCMA, GPRC5D, CD33, CD123, CD19, PSMA, TMEFF2, CD20, CD10, CD21, CD22, CD25, CD30, CD34, CD37, CD44v6, CD45, CD52, CD133, ROR1, B7-H6, B7-H3, HM1.24, SLAMF7, Fms-like tyrosine kinase 3 (FLT-3, CD135), chondroitin sulfate proteoglycan 4 (CSPG4, melanoma-associated chondroitin sulfate proteoglycan), epidermal growth factor receptor (EGFR), Her2, Her3, IGFR, IL3R, fibroblast-activated protein (FAP), CDCP1, Derlin 1, Tenacine, Frizzled 1-10, VEGFR2(KDR / FLK1), VEGFR3(FLT4, CD309), PDGFR-alpha(CD140a), PDGFR-beta(CD140b), endoglin, CLEC14, Tem1-8, or Tie2. Additional exemplary antigens on tumor cells include A33, CAMPATH-1 (CDw52), carcinoembryonic antigen (CEA), carboanhydrase IX (MN / CA IX), de2-7, EGFRvIII, EpCAM, Ep-CAM, folate-binding protein, G250, c-Kit (CD117), CSF1R (CD115), HLA-DR, IGFR, IL-2 receptor, IL3R, MCSP (melanoma-associated cell surface chondroitin sulfate proteoglycan), Muc-1, prostate stem cell antigen (PSCA), prostate-specific antigen (PSA), hK2, TAG-72, or tumor cell neoantigen.

[0117] In some embodiments, the T-cell re-induction therapeutic agent binds to BCMA, GPRC5D, CD33, CD123, CD19, PSMA, TMEFF2, CD20, CD22, CD25, CD52, ROR1, HM1.24, CD38, or SLAMF7.

[0118] In some embodiments, the T-cell re-induction therapeutic agent binds to CD3 epsilon (CD3ε).

[0119] In some embodiments, the T-cell re-induction therapeutic binds to CD3.

[0120] In some embodiments, the T-cell re-induction therapeutic binds to CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, BTNL8, PD-1, CD195, or NKG2C. These antigens are CD8 compared to CD3. + It is more specific for T cells (see, for example, International Patent Application Publication WO2018 / 187215).

[0121] In some embodiments, the T-cell re-induction therapeutic agent comprises a CD3 binding domain, and said CD3 binding domain

[0122] 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;

[0123] The heavy chain variable region (VH) of sequence number 39 and the light chain variable region (VL) of sequence number 40;

[0124] HCDR1 of sequence number 74, HCDR2 of sequence number 75, HCDR3 of sequence number 76, LCDR1 of sequence number 77, LCDR2 of sequence number 78, and LCDR3 of sequence number 79;

[0125] VH of sequence number 80 and VL of sequence number 81;

[0126] HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of the CD3 binding domain of sequence no. 53; or

[0127] Includes VH and VL of the CD3 binding domain of sequence number 53.

[0128] In some embodiments, the T-cell re-induction therapeutic binds to BCMA.

[0129] In some embodiments, the T-cell re-induction therapeutic agent

[0130] A BCMA binding domain comprising HCDR1 of SEQ ID NO. 23, HCDR2 of SEQ ID NO. 24, HCDR3 of SEQ ID NO. 25, LCDR1 of SEQ ID NO. 26, LCDR2 of SEQ ID NO. 27, and LCDR3 of SEQ ID NO. 28, and a CD3 binding domain comprising HCDR1 of SEQ ID NO. 33, HCDR2 of SEQ ID NO. 34, HCDR3 of SEQ ID NO. 35, LCDR1 of SEQ ID NO. 36, LCDR2 of SEQ ID NO. 37, and LCDR3 of SEQ ID NO. 38, and / or;

[0131] It includes a BCMA binding domain comprising VH of sequence number 29 and VL of sequence number 30, and a CD3 binding domain comprising VH of sequence number 39 and VL of sequence number 40.

[0132] In some embodiments, the T-cell re-induction therapeutic agent that binds to BCMA comprises a first heavy chain (HC1) of SEQ ID NO. 31, a first light chain (LC1) of SEQ ID NO. 32, a second heavy chain (HC2) of SEQ ID NO. 41, and a second light chain (LC2) of SEQ ID NO. 42.

[0133] In some embodiments, BCMA-binding T-cell re-induction therapies are ACTR cancer therapy (Seattle Genetics), AFM-26, ALLO-715, anti-BCMA allogeneic CAR-T cell therapy (CRISPR Therapeutics), anti-BCMA CAR-T therapy (Sorrento Therapeutics), anti-CD19 / BCMA CAR-T cell therapy (Hrain Biotechnology), BCMA CAR-T therapy (Chineo Med, Beijing, China), BCMA TAC-T cell therapy (Triumvira Immunologics), BCMA-CAR T-cell therapy (Shanghai Unicar-Therapy Biomed), BCMA / CD3 antibody (Regeneron), CAR-NK cell therapy (NantKwest), CC-93629, CMD-505, CTX-4419, CYAD-211, HDP-101, HPN-217, P-BCMA-ALLO1, TNB-383B, Includes bb-2121, AUTO-2, BCMA chimeric antigen receptor therapy (Pregene), BCMA-CAR T cell (Shanghai Bioray Laboratory), BCMA-CAR-T cell (CARsgen Therapeutics), CAR-T / TCR-T cell immunotherapy (Shenzhen BinDeBio), ET-140, P-BCMA-101, REGN-5458, AMG-701, anti-BCMA CAR-T cell therapy (Cellular Biomedicine Group), bb-21217, BI-836909, CC-93269, Descartes-08, IM-21, JNJ-64007957, MEDI-2228, or PF-06863135.

[0134] In some embodiments, the T-cell re-induction therapeutic agent comprises any one of the BCMA binding domains described in International Patent Application Publication WO2017 / 031104.

[0135] In some embodiments, the T-cell re-induction therapeutic agent binds to GPRC5D.

[0136] In some embodiments, the T-cell re-induction therapeutic agent

[0137] GPRC5D binding domains 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 CD3 binding domains comprising HCDR1 of SEQ ID NO. 33, HCDR2 of SEQ ID NO. 34, HCDR3 of SEQ ID NO. 35, LCDR1 of SEQ ID NO. 36, LCDR2 of SEQ ID NO. 37, and LCDR3 of SEQ ID NO. 38, and / or;

[0138] It includes a GPRC5D binding domain comprising VH of sequence number 49 and VL of sequence number 50, and a CD3 binding domain comprising VH of sequence number 39 and VL of sequence number 40.

[0139] In some embodiments, the T-cell re-induction therapeutic agent that binds to GPRC5D comprises HC1 of SEQ ID NO. 51, LC1 of SEQ ID NO. 52, HC2 of SEQ ID NO. 41, and LC2 of SEQ ID NO. 42.

[0140] In some embodiments, the T-cell re-induction therapeutic agent comprises a GPRC5D antibody by Eureka Therapeutics.

[0141] In some embodiments, the T-cell re-induction therapeutic agent comprises any one of the GPRC5D binding domains described in International Patent Application Publication WO2018 / 0037651.

[0142] In some embodiments, the T-cell re-induction therapeutic binds to CD33.

[0143] In some embodiments, the T-cell re-induction therapeutic agent comprises a CD33 binding domain comprising HCDR1 of SEQ ID NO. 84, HCDR2 of SEQ ID NO. 85, HCDR3 of SEQ ID NO. 86, LCDR1 of SEQ ID NO. 87, LCDR2 of SEQ ID NO. 88, and LCDR3 of SEQ ID NO. 89, and a CD3 binding domain comprising HCDR1 of SEQ ID NO. 74, HCDR2 of SEQ ID NO. 75, HCDR3 of SEQ ID NO. 76, LCDR1 of SEQ ID NO. 77, LCDR2 of SEQ ID NO. 78, and LCDR3 of SEQ ID NO. 79, and / or;

[0144] It includes a CD33 binding domain comprising VH of sequence number 90 and VL of sequence number 91, and a CD3 binding domain comprising VH of sequence number 80 and VL of sequence number 81.

[0145] In some embodiments, the T-cell re-induction therapeutic agent that binds to CD33 comprises HC1 of SEQ ID NO. 92, LC1 of SEQ ID NO. 93, HC2 of SEQ ID NO. 82, and LC2 of SEQ ID NO. 83.

[0146] In some embodiments, T-cell re-induction therapies binding to CD33 include CAR-T / TCR-T cell immunotherapy (Shenzhen BinDeBio), AMG-330, AMV-564, JNJ-67571244, ICG-144, AMG-673, CD33 CAR-T therapy INXN 3004 (Ziopharm); huCD33-BsAb, VOR-33, HMBD-004A, GEM-333, TGB-3550, or CD33.taNK.

[0147] In some embodiments, the T-cell re-induction therapeutic binds to CD123.

[0148] In some embodiments, the T-cell re-induction therapeutic agent

[0149] A CD123 binding domain comprising HCDR1 of SEQ ID NO. 94, HCDR2 of SEQ ID NO. 95, HCDR3 of SEQ ID NO. 96, LCDR1 of SEQ ID NO. 9, LCDR2 of SEQ ID NO. 10, and LCDR3 of SEQ ID NO. 59, and a CD3 binding domain comprising HCDR1 of SEQ ID NO. 33, HCDR2 of SEQ ID NO. 34, HCDR3 of SEQ ID NO. 35, LCDR1 of SEQ ID NO. 36, LCDR2 of SEQ ID NO. 37, and LCDR3 of SEQ ID NO. 38, and / or;

[0150] It includes a CD123 binding domain comprising VH of sequence number 100 and VL of sequence number 61, and a CD3 binding domain comprising VH of sequence number 39 and VL of sequence number 40.

[0151] In some embodiments, the T-cell re-induction therapeutic agent that binds to CD123 comprises HC1 of SEQ ID NO. 102, LC1 of SEQ ID NO. 63, HC2 of SEQ ID NO. 41, and LC2 of SEQ ID NO. 42.

[0152] In some embodiments, T-cell re-induction therapies that bind to CD123 include rapid myeloid leukemia therapy (TheraVectys), APVO-437, anti-CD123 CAR-T cell therapy (Nanjing Legend Biotech), APVO-436, CD123 CAR-T cell therapy (Hebei Senlang Biotechnology), flotetuzumab, IM-23, JNJ-63709178, MB-102 (Mustang Bio), UCART-123, XmAb-14045, or CD3-CD123 bispecific T-cell engager (Sanofi).

[0153] In some embodiments, the T-cell re-induction therapeutic agent comprises any one of the CD123 binding domains described in International Patent Application Publication WO2016 / 036937.

[0154] In some embodiments, the T-cell re-induction therapeutic binds to CD19.

[0155] In some embodiments, the T-cell re-induction therapeutic agent

[0156] A CD19 binding domain comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of the CD19 binding domain of SEQ NO. 53, and a CD3 binding domain comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of the CD3 binding domain of SEQ NO. 53, and / or;

[0157] Includes the amino acid sequence of sequence number 53.

[0158] In some embodiments, CD19-binding T-cell re-induction therapies are axicarbatagen ciloleucel, blinatumomab, tisagen recleucel-t, AMG-562, AUTO-1 CAR-T CD19 (Cellular Biomedicine Group), CD19 chimeric antigen receptor T-cell therapy (Ziopharm), CD19-CAR-T cell therapy (ioceltech Therapeutics), CD19-CAR-T cell therapy (Marino Biotechnology), CD19-CAR-T2 cell therapy (Guangdong Zhaotai InVivo), CD19 / 4-1BBL enhanced CAR T-cell therapy (Juno Therapeutics), CSG-CD19, DI-B4, ET-190, GC-007F, GC-022, human CD19 T-cell therapy (HRAIN Biotechnology), humanized anti-CD19 control CAR (3rd generation) (Kite Pharma), ICAR-19 CAR-T Cell (Immune Cell Therapy), ICTCAR-003, iPD1 CD19 eCAR T Cell (Marino Biotechnology), JWCAR029, PTG-01, PZ01, Senl_1904A, Senl_1904B, UCART-19, UWC-19, AUTO-3, BinD-19, CAR-T Cell Therapy (Shanghai Unicar-Therapy Biomed), CAR-T / TCR-T Cell Immunotherapy (Shenzhen BinDeBio), CD-19 CAR-T Cell Therapy (Miltenyi Biotec), CD19 CAR-T Cell (Shanghai Unicar-Therapy Biomed), CD19-CAR T Cell Therapy (Takara Bio), CD19-CART (Shanghai Bioray Laboratory), CD19-Targeted Chimeric Antigen Receptor T-Cell (Sinobioway), CD19 / CD20 CAR-T Cell Therapy (Shanghai Longyao Biotechnology), CIK-CAR.CD19, ICTCAR-011, IM-19, JCAR-014, Roncastuximab Tesirin, MB-CART2019.1, OXS-1550, PBCAR-0191, PCAR-019, PCAR-119, Senl-001, TI-1007, XmAb-5871, Inevillizumab, Lisocarbatagen Maralucel, XmAb-5574, 3rd Generation CD19-CART Cells + mbIL15 (Eden BioCell), A-329, ALLO-501, Anti-CD19 Anti-CD20 Bispecific CAR Re-induced Autologous T-cells (Beijing Doing Biomedical Co), Anti-CD19 CAR NK Cell Therapy (Allife Medical Science), Anti-CD19 / BCMA CAR-T Cell Therapy (Hrain Biotechnology), ATA-2431, ATA-3219, AVA-008, CD19 CAR-T cell therapy (Celularity), CD19 Chimeric Antigen Receptor T-cell Therapy (3rd Generation) (Ziopharm), CD19 dBiTE (Inovio), CD19 TCR-cell therapy (Bellicum), CD19-ATAC (Wilex), CD19 / 20 CAR-T therapy (Chineo Med, Beijing, China), CD19 / CD22 dual-targeting therapy (Eureka Therapeutics), Chimeric Antigen Receptor T-cell (CAR-T) therapy (Helix BioPharma), CMD-502, CTX-110, CYAD-04, CYAD-221, ET-019002, FT-596, FT-819, Gamma-Delta CAR-T therapy (TC Biopharm), ICTCAR-014, iDD-002, KITE-037, Includes NI-2201, RB-1916, Senl_002, TAC01-CD19, TC-110, TC-310, TCB-003, or TI-7007.

[0159] In some embodiments, the T-cell re-induction therapeutic agent binds to PSMA.

[0160] In some embodiments, the T-cell re-induction therapeutic agent

[0161] PSMA binding domains comprising HCDR1 of SEQ ID NO. 54, HCDR2 of SEQ ID NO. 55, HCDR3 of SEQ ID NO. 56, LCDR1 of SEQ ID NO. 9, LCDR2 of SEQ ID NO. 10, and LCDR3 of SEQ ID NO. 59, and CD3 binding domains comprising HCDR1 of SEQ ID NO. 33, HCDR2 of SEQ ID NO. 34, HCDR3 of SEQ ID NO. 35, LCDR1 of SEQ ID NO. 36, LCDR2 of SEQ ID NO. 37, and LCDR3 of SEQ ID NO. 38, and / or;

[0162] It includes a PSMA binding domain comprising VH of sequence number 60 and VL of sequence number 61, and a CD3 binding domain comprising VH of sequence number 39 and VL of sequence number 40.

[0163] In some embodiments, the T-cell re-induction therapeutic agent that binds to PSMA comprises HC1 of SEQ ID NO. 62, LC1 of SEQ ID NO. 63, HC2 of SEQ ID NO. 41, and LC2 of SEQ ID NO. 42.

[0164] In some embodiments, the T-cell re-induction therapeutic binds to TMEFF2.

[0165] In some embodiments, the T-cell re-induction therapeutic agent

[0166] A TMEFF2 binding domain comprising HCDR1 of SEQ ID NO. 64, HCDR2 of SEQ ID NO. 65, HCDR3 of SEQ ID NO. 66, LCDR1 of SEQ ID NO. 67, LCDR2 of SEQ ID NO. 68, and LCDR3 of SEQ ID NO. 69, and a CD3 binding domain comprising HCDR1 of SEQ ID NO. 74, HCDR2 of SEQ ID NO. 75, HCDR3 of SEQ ID NO. 76, LCDR1 of SEQ ID NO. 77, LCDR2 of SEQ ID NO. 78, and LCDR3 of SEQ ID NO. 79, and / or;

[0167] It includes a TMEFF2 binding domain comprising VH of sequence number 70 and VL of sequence number 71, and a CD3 binding domain comprising VH of sequence number 80 and VL of sequence number 81.

[0168] In some embodiments, the T-cell re-induction therapeutic agent that binds to TMEFF2 comprises HC1 of SEQ ID NO. 72, LC1 of SEQ ID NO. 73, HC2 of SEQ ID NO. 82, and LC2 of SEQ ID NO. 83.

[0169] In some embodiments, the T-cell re-induction therapeutic binds to CD20.

[0170] In some embodiments, the T-cell re-induction therapeutic binds to CD22.

[0171] In some embodiments, the T-cell re-induction therapeutic binds to CD25.

[0172] In some embodiments, the T-cell re-induction therapeutic binds to CD52.

[0173] In some embodiments, the T-cell re-induction therapeutic binds to ROR1.

[0174] In some embodiments, a T-cell re-induction therapeutic agent binds to HM1.24.

[0175] In some embodiments, the T-cell re-induction therapeutic binds to SLAMF7.

[0176] In some embodiments, the T-cell re-induction therapeutic agent is a multispecific antibody, a chimeric antigen receptor (CAR), or a T cell containing a CAR.

[0177] In some embodiments, the T-cell re-induction therapeutic agent is a CAR.

[0178] In some embodiments, the T-cell re-induction therapeutic agent is a T cell expressing CAR.

[0179] In some embodiments, the T-cell re-induction therapeutic agent is a multispecific antibody.

[0180] In some embodiments, the multispecific antibody is an IgG1, IgG2, IgG3, or IgG4 allotype.

[0181] In some embodiments, the multispecific antibody is an IgG1 allotype.

[0182] In some embodiments, the multispecific antibody is an IgG2 allotype.

[0183] In some embodiments, the multispecific antibody is an IgG3 allotype.

[0184] In some embodiments, the multispecific antibody is an IgG4 allotype.

[0185] Multispecific antibodies may be of any allotype. The allotype is not expected to affect the characteristics of the multispecific antibody, such as binding or Fc-mediated effector function. The immunogenicity of therapeutic antibodies is associated with an increased risk of infusion reaction and a reduced duration of the therapeutic response (Literature [Baert et al., (2003) N Engl J Med The extent to which therapeutic antibodies induce an immune response in the host can be partially determined by the allotype of the antibody (Stickler et al., (2011) Genes and Immunity [12:213-21]). Antibody homologous types are associated with amino acid sequence variations at specific positions in the sequence of the antibody's constant region. Table 2 represents the selected IgG1, IgG2, and IgG4 homologous factors.

[0186] [Table 2]

[0187]

[0188] In some embodiments, the multispecific antibody comprises one or more Fc substitutions that reduce the binding of the multispecific antibody to the Fcγ receptor (FcγR). The substitutions that reduce the binding of the multispecific antibody to FcγR reduce the Fc effector functions of the multispecific antibody, e.g., ADCC, ADCP, and / or CDC. Specific substitutions may be made in comparison to the wild-type IgG1 of SEQ NO. 103 or the wild-type IgG4 of SEQ NO. 104.

[0189] In some embodiments, one or more Fc substitutions are F234A / L235A on IgG4, L234A / L235A on IgG1, V234A / G237A / P238S / H268A / V309L / A330S / P331S on IgG2, F234A / L235A on IgG4, S228P / F234A / L235A on IgG4, N297A on all Ig isotypes, V234A / G237A on IgG2, K214T / E233P / L234V / L235A / G236-deletion / A327G / P331A / D365E / L358M on IgG1, H268Q / V309L / A330S / P331S on IgG2, and IgG1 Selected from the group consisting of S267E / L328F, L234F / L235E / D265A on IgG1, L234A / L235A / G237A / P238S / H268A / A330S / P331S on IgG1, S228P / F234A / L235A / G237A / P238S on IgG4, and S228P / F234A / L235A / G236-deletion / G237A / P238S on IgG4, and residue numbering follows the EU index.

[0190] In some embodiments, one or more Fc substitutions are F234A / L235A on IgG4.

[0191] In some embodiments, one or more Fc substitutions are L234A / L235A on IgG1.

[0192] In some embodiments, one or more Fc substitutions are V234A / G237A / P238S / H268A / V309L / A330S / P331S on IgG2.

[0193] In some embodiments, one or more Fc substitutions are F234A / L235A on IgG4.

[0194] In some embodiments, one or more Fc substitutions are S228P / F234A / L235A on IgG4.

[0195] In some embodiments, one or more Fc substitutions are N297A on all Ig isomorphs.

[0196] In some embodiments, one or more Fc substitutions are V234A / G237A on IgG2.

[0197] In some embodiments, one or more Fc substitutions are K214T / E233P / L234V / L235A / G236-deletion / A327G / P331A / D365E / L358M on IgG1.

[0198] In some embodiments, one or more Fc substitutions are H268Q / V309L / A330S / P331S on IgG2.

[0199] In some embodiments, one or more Fc substitutions are S267E / L328F on IgG1. In some embodiments, one or more Fc substitutions are L234F / L235E / D265A on IgG1.

[0200] In some embodiments, one or more Fc substitutions are L234A / L235A / G237A / P238S / H268A / A330S / P331S on IgG1.

[0201] In some embodiments, one or more Fc substitutions are S228P / F234A / L235A / G237A / P238S on IgG4 and S228P / F234A / L235A / G236-deletion / G237A / P238S on IgG4.

[0202] In some embodiments, the multispecific antibody further comprises an S228P substitution.

[0203] In some embodiments, the multispecific antibody comprises one or more asymmetric substitutions in the first CH3 domain or in the second CH3 domain, or in both the first CH3 domain and the second CH3 domain.

[0204] In some embodiments, one or more asymmetric substitutions are F450L / K409R, wild-type / F409L_R409K, T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S and T366W / T366S_L368A_Y407V, L351Y_F405A_Y407V / T394W, T366I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, It is selected from the group consisting of L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F, and T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W.

[0205] In some embodiments, one or more asymmetric substitutions are F450L / K409R.

[0206] In some embodiments, one or more asymmetric substitutions are wild-type / F409L_R409K.

[0207] In some embodiments, one or more asymmetric substitutions are T366Y / F405A.

[0208] In some embodiments, one or more asymmetric substitutions are T366W / F405W.

[0209] In some embodiments, one or more asymmetric substitutions are F405W / Y407A.

[0210] In some embodiments, one or more asymmetric substitutions are T394W / Y407T.

[0211] In some embodiments, one or more asymmetric substitutions are T394S / Y407A.

[0212] In some embodiments, one or more asymmetric substitutions are T366W / T394S.

[0213] In some embodiments, one or more asymmetric substitutions are F405W / T394S.

[0214] In some embodiments, one or more asymmetric substitutions are T366W / T366S_L368A_Y407V.

[0215] In some embodiments, one or more asymmetric substitutions are L351Y_F405A_Y407V / T394W.

[0216] In some embodiments, one or more asymmetric substitutions are T366I_K392M_T394W / F405A_Y407V.

[0217] In some embodiments, one or more asymmetric substitutions are T366L_K392M_T394W / F405A_Y407V.

[0218] In some embodiments, one or more asymmetric substitutions are L351Y_Y407A / T366A_K409F.

[0219] In some embodiments, one or more asymmetric substitutions are L351Y_Y407A / T366V_K409F.

[0220] In some embodiments, one or more asymmetric substitutions are Y407A / T366A_K409F.

[0221] In some embodiments, one or more asymmetric substitutions are T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W.

[0222] In some embodiments, the cancer is a hematological malignancy or a solid tumor.

[0223] In some embodiments, hematological malignancies include multiple myeloma, asymptomatic multiple myeloma, monoclonal gammapathia of unknown significance (MGUS), acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), follicular lymphoma (FL), mantle-cell lymphoma (MCL), Waldenström macroglobulinemia, plasma cell leukemia, light chain amyloidosis (AL), precursor B-cell lymphoblastic leukemia, precursor B-cell lymphoblastic leukemia, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic lymphocytic leukemia (CLL), B-cell malignancy, chronic myeloid leukemia (CML), hairy cell leukemia (HCL), blastocystoid dendritic neoplasm, Hodgkin lymphoma, non-Hodgkin lymphoma, marginal zone B-cell lymphoma (MZL), mucosa-associated lymphoid tissue lymphoma (MALT), plasma cell It is leukemia, anaplastic large cell lymphoma (ALCL), leukemia, or lymphoma.

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

[0225] In some embodiments, multiple myeloma is newly diagnosed multiple myeloma.

[0226] In some embodiments, the multiple myeloma is relapsed or refractory multiple myeloma.

[0227] In some embodiments, multiple myeloma is high-risk multiple myeloma. Subjects with high-risk multiple myeloma are known to experience early relapse and have poor prognosis and outcomes. Subjects may be classified as having high-risk multiple myeloma if they have one or more of the following cytogenetic abnormalities: t(4;14)(p16;q32), t(14;16)(q32;q23), del17p, 1qAmp, t(4;14)(p16;q32) and t(14;16)(q32;q23), t(4;14)(p16;q32) and del17p, t(14;16)(q32;q23) and del17p, or t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p.

[0228] In some embodiments, a subject having high-risk multiple myeloma has one or more chromosomal abnormalities comprising: t(4;14)(p16;q32), t(14;16)(q32;q23), del17p, 1qAmp, t(4;14)(p16;q32) and t(14;16)(q32;q23), t(4;14)(p16;q32) and del17p, t(14;16)(q32;q23) and del17p; or t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p, or any combination thereof.

[0229] Various qualitative and / or quantitative methods may be used to determine the recurrent or refractory nature of this disease. Relevant symptoms may include, for example, a decrease or stagnation in the patient's well-being, the re-establishment or worsening of various symptoms associated with solid tumors, and / or the spread of cancerous cells from one location within the body to other organs, tissues, or cells.

[0230] Cytogenetic abnormalities can be detected, for example, by fluorescent in situ hybridization (FISH). In chromosomal translocations, oncogenes are translocated to the IgH region on chromosome 14q32, resulting in dysregulation of these genes. t(4;14)(p16;q32) entails the translocation of fibroblast growth factor receptor 3 (FGFR3) and multiple myeloma SET domain-containing protein (MMSET) (also called WHSC1 / NSD2), and t(14;16)(q32;q23) entails the translocation of the MAF transcription factor C-MAF. The deletion of 17p(del17p) entails the loss of the p53 locus.

[0231] In some embodiments, multiple myeloma is relapsed or refractory to treatment with an anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, erlotozumab, ixazomib, melphalan, or thalidomide, or any combination thereof.

[0232] In some embodiments, multiple myeloma is relapsed or refractory to treatment with an anti-CD38 antibody. In some embodiments, multiple myeloma is relapsed or refractory to treatment with lenalidomide. In some embodiments, multiple myeloma is relapsed or refractory to treatment with bortezomib. In some embodiments, multiple myeloma is relapsed or refractory to treatment with pomalidomide. In some embodiments, multiple myeloma is relapsed or refractory to treatment with carfilzomib. In some embodiments, multiple myeloma is relapsed or refractory to treatment with erlotozumab. In some embodiments, multiple myeloma is relapsed or refractory to treatment with ixazomib. In some embodiments, multiple myeloma is relapsed or refractory to treatment with melphalan. In some embodiments, multiple myeloma is relapsed or refractory to treatment with thalidomide.

[0233] In some embodiments, the hematological malignancy is AML.

[0234] In some embodiments, AML is AML with at least one genetic abnormality, AML with multilineage dysplasia, therapy-associated AML, undifferentiated AML, AML with minimal maturation, AML with maturation, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, acute megakaryoblastic leukemia, acute basophilic leukemia, acute panmyeloma or myeloid sarcoma with fibrosis.

[0235] In some embodiments, AML is AML having at least one genetic abnormality. In some embodiments, AML is AML having multiple lineages of dysplasia. In some embodiments, AML is therapy-associated AML. In some embodiments, AML is undifferentiated AML. In some embodiments, AML is AML having minimal maturation. In some embodiments, AML is mature AML. In some embodiments, AML is graded myelomonocytic leukemia. In some embodiments, AML is graded mononucleic leukemia. In some embodiments, AML is acute erythroleukemia. In some embodiments, AML is acute megakaryoblastic leukemia. In some embodiments, AML is acute basophilic leukemia. In some embodiments, AML is acute panmyelosis with fibrosis. In some embodiments, AML is myeloid sarcoma.

[0236] In some embodiments, at least one genetic abnormality is a translocation between chromosome 8 and chromosome 21, a translocation or inversion on chromosome 16, a translocation between chromosome 15 and chromosome 17, a change on chromosome 11, or a mutation in fms-associated tyrosine kinase 3 (FLT3), nucleophosmin (NPM1), isocitrate dehydrogenase 1 (IDH1), isocitrate dehydrogenase 2 (IDH2), DNA (cytosine-5)-methyltransferase 3 (DNMT3A), CCAAT / enhancer binding protein alpha (CEBPA), U2 small nuclear RNA cofactor 1 (U2AF1), enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), chromosome structure maintenance protein 1A (SMC1A) or chromosome structure maintenance protein 3 (SMC3).

[0237] In some embodiments, at least one genetic abnormality is a translocation between chromosome 8 and chromosome 21. In some embodiments, at least one genetic abnormality is a translocation or inversion on chromosome 16. In some embodiments, at least one genetic abnormality is a translocation between chromosome 15 and chromosome 17. In some embodiments, at least one genetic abnormality is a change on chromosome 11. In some embodiments, at least one genetic abnormality is a mutation in fms-associated tyrosine kinase 3 (FLT3). In some embodiments, at least one genetic abnormality is a mutation in nucleophosphin (NPM1). In some embodiments, at least one genetic abnormality is a mutation in isocitrate dehydrogenase 1 (IDH1). In some embodiments, at least one genetic abnormality is a mutation in isocitrate dehydrogenase 2 (IDH2). In some embodiments, at least one genetic abnormality is a mutation in DNA (cytosine-5)-methyltransferase 3 (DNMT3A). In some embodiments, at least one genetic abnormality is a mutation in CCAAT / enhancer binding protein alpha (CEBPA). In some embodiments, at least one genetic abnormality is a mutation in U2 small nuclear RNA cofactor 1 (U2AF1). In some embodiments, at least one genetic abnormality is a mutation in the enhancer of the Zest 2 Polycomb repression complex 2 subunit (EZH2). In some embodiments, at least one genetic abnormality is a mutation in chromosome structure maintenance protein 1A (SMC1A). In some embodiments, at least one genetic abnormality is a mutation in chromosome structure maintenance protein 3 (SMC3).

[0238] In some embodiments, at least one genetic abnormality is a translocation t(8; 21)(q22; q22), an inversion inv(16)(p13; q22), a translocation t(16; 16)(p13; q22), a translocation t(15; 17)(q22; q12), a mutation FLT3-ITD, a mutation R132H or R100Q / R104V / F108L / R119Q / I130V in IDH1 or a mutation R140Q or R172 in IDH2.

[0239] In some embodiments, at least one genetic abnormality is a translocation t(8; 21)(q22; q22). In some embodiments, at least one genetic abnormality is an inversion inv(16)(p13; q22). In some embodiments, at least one genetic abnormality is a translocation t(16; 16)(p13; q22). In some embodiments, at least one genetic abnormality is a translocation t(15; 17)(q22; q12). In some embodiments, at least one genetic abnormality is a mutation FLT3-ITD. In some embodiments, at least one genetic abnormality is a mutation R132H in IDH1. In some embodiments, at least one genetic abnormality is a mutation R100Q / R104V / F108L / R119Q / I130V in IDH1. In some embodiments, at least one genetic abnormality is mutation R140Q in IDH2. In some embodiments, at least one genetic abnormality is mutation R172 in IDH2.

[0240] In some embodiments, the hematological malignancy is ALL.

[0241] In some embodiments, ALL is a B-cell lineage ALL, a T-cell lineage ALL, an adult ALL, or a pediatric ALL.

[0242] In some embodiments, ALL is a B-cell lineage ALL. In some embodiments, ALL is a T-cell lineage ALL. In some embodiments, ALL is an adult ALL. In some embodiments, ALL is a pediatric ALL.

[0243] In some embodiments, subjects having ALL have the Philadelphia chromosome, or exhibit resistance to treatment with a BCR-ABL kinase inhibitor or have acquired resistance.

[0244] In some embodiments, subjects having ALL have the Philadelphia chromosome. In some embodiments, subjects having ALL exhibit resistance or acquired resistance to treatment with a BCR-ABL kinase inhibitor.

[0245] The Ph chromosome is present in approximately 20% of adults with ALL and a small percentage of children with ALL, and is associated with a poor prognosis. Upon relapse, patients with Ph+ positive ALL may be on a tyrosine kinase inhibitor (TKI) regimen and may have consequently developed resistance to the TKI. Accordingly, anti-CD38 antibodies may be administered to subjects who have developed resistance to selective or partially selective BCR-ABL inhibitors. Exemplary BCR-ABL inhibitors are, for example, imatinib, dasatinib, nilotinib, bosutinib, ponatinib, bafetinib, saracatinib, tozasertip, or danucertip.

[0246] Other chromosomal rearrangements identified in patients with B-lineage ALL are t(v;11q23)(MLL rearrangement), t(1;19)(q23;p13.3); TCF3-PBX1(E2A-PBX1), t(12;21)(p13;q22); ETV6-RUNX1(TEL-AML1) and t(5;14)(q31;q32); IL3-IGH.

[0247] In some embodiments, the subject has ALL having t(v;11q23)(MLL rearrangement), t(1;19)(q23;p13.3); TCF3-PBX1(E2A-PBX1), t(12;21)(p13;q22); ETV6-RUNX1(TEL-AML1) or t(5;14)(q31;q32); IL3-IGH chromosomal rearrangement.

[0248] Chromosome rearrangements can be identified using well-known methods, such as fluorescence in situ hybridization, karyotyping, pulsed field gel electrophoresis, or sequencing.

[0249] In some embodiments, the hematological malignancy is asymptomatic multiple myeloma.

[0250] In some embodiments, the hematological malignancy is MGUS.

[0251] In some embodiments, the hematological malignancy is ALL.

[0252] In some embodiments, the hematological malignancy is DLBLC.

[0253] In some embodiments, the hematological malignancy is BL.

[0254] In some embodiments, the hematological malignancy is FL.

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

[0256] In some embodiments, the hematological malignancy is Waldenström macroglobulinemia.

[0257] In some embodiments, the hematological malignancy is plasma cell leukemia.

[0258] In some embodiments, the hematological malignancy is AL.

[0259] In some embodiments, the hematological malignancy is precursor B-cell lymphoblastic leukemia.

[0260] In some embodiments, the hematological malignancy is precursor B-cell lymphoblastic leukemia.

[0261] In some embodiments, the hematological malignancy is myelodysplastic syndrome (MDS).

[0262] In some embodiments, the hematological malignancy is CLL.

[0263] In some embodiments, the hematological malignancy is a B-cell malignancy.

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

[0265] In some embodiments, the hematological malignancy is HCL.

[0266] In some embodiments, the hematological malignancy is a blastocystic plasmacytic dendritic neoplasm.

[0267] In some embodiments, the hematological malignancy is Hodgkin lymphoma.

[0268] In some embodiments, the hematological malignancy is non-Hodgkin lymphoma.

[0269] In some embodiments, the hematological malignancy is MZL.

[0270] In some embodiments, the hematological malignancy is MALT.

[0271] In some embodiments, the hematological malignancy is plasma cell leukemia.

[0272] In some embodiments, the hematological malignancy is ALCL.

[0273] In some embodiments, the hematological malignancy is leukemia.

[0274] In some embodiments, the hematological malignancy is lymphoma.

[0275] In some embodiments, the solid tumor is prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), liver cancer, cervical cancer, colon cancer, breast cancer, ovarian cancer, endometrial cancer, pancreatic cancer, melanoma, esophageal cancer, gastric cancer, stomach cancer, renal carcinoma, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, urothelial carcinoma, head and neck cancer, glioma, glioblastoma, colorectal cancer, thyroid cancer, epithelial carcinoma, adenocarcinoma, or advanced solid tumor.

[0276] In some embodiments, the solid tumor is prostate cancer.

[0277] In some embodiments, the solid tumor is lung cancer.

[0278] In some embodiments, the solid tumor is non-small cell lung cancer (NSCLC).

[0279] In some embodiments, the solid tumor is liver cancer.

[0280] In some embodiments, the solid tumor is cervical cancer.

[0281] In some embodiments, the solid tumor is colon cancer.

[0282] In some embodiments, the solid tumor is breast cancer.

[0283] In some embodiments, the solid tumor is ovarian cancer.

[0284] In some embodiments, the solid tumor is endometrial cancer.

[0285] In some embodiments, the solid tumor is pancreatic cancer.

[0286] In some embodiments, the solid tumor is melanoma.

[0287] In some embodiments, the solid tumor is esophageal cancer.

[0288] In some embodiments, the solid tumor is gastric cancer.

[0289] In some embodiments, the solid tumor is gastric adenocarcinoma.

[0290] In some embodiments, the solid tumor is a renal carcinoma.

[0291] In some embodiments, the solid tumor is bladder cancer.

[0292] In some embodiments, the solid tumor is a hepatocellular carcinoma.

[0293] In some embodiments, the solid tumor is a renal cell carcinoma.

[0294] In some embodiments, the solid tumor is a urothelial carcinoma.

[0295] In some embodiments, the solid tumor is head and neck cancer.

[0296] In some embodiments, the solid tumor is a glioma.

[0297] In some embodiments, the solid tumor is a glioblastoma.

[0298] In some embodiments, the solid tumor is colorectal cancer.

[0299] In some embodiments, the solid tumor is thyroid cancer.

[0300] In some embodiments, the solid tumor is an epithelial carcinoma.

[0301] In some embodiments, the solid tumor is an adenocarcinoma.

[0302] In some embodiments, the solid tumor is a progressive solid tumor.

[0303] In some embodiments, the prostate cancer is recurrent, refractory, malignant, or castration-resistant prostate cancer, or any combination thereof.

[0304] In some embodiments, the prostate cancer is recurrent prostate cancer. In some embodiments, the prostate cancer is refractory prostate cancer. In some embodiments, the prostate cancer is malignant prostate cancer. In some embodiments, the prostate cancer is castration-resistant prostate cancer.

[0305] In some embodiments, the anti-CD38 antibody comprises HCDR1 of SEQ ID NO. 6, HCDR2 of SEQ ID NO. 7, HCDR3 of SEQ ID NO. 8, LCDR1 of SEQ ID NO. 9, LCDR2 of SEQ ID NO. 10, and LCDR3 of SEQ ID NO. 11.

[0306] In some embodiments, the anti-CD38 antibody comprises VH of sequence number 4 and VL of sequence number 5.

[0307] In some embodiments, the anti-CD38 antibody is an IgG1 allotype.

[0308] In some embodiments, the anti-CD38 antibody comprises HC of sequence number 12 and LC of sequence number 13.

[0309] Other anti-CD38 antibodies used in the method of the present invention may be known antibodies such as the following: mAb003, comprising the VH and VL sequences of SEQ ID NOs. 14 and 15, respectively, as described in U.S. Patent No. 7,829,673, wherein the VH and VL of mAb003 may be expressed as IgG1 / κ; mAb024, comprising the VH and VL sequences of SEQ ID NOs. 16 and 17, respectively, as described in U.S. Patent No. 7,829,673, wherein the VH and VL of mAb024 may be expressed as IgG1 / κ; MOR-202 (MOR-03087), comprising the VH and VL sequences of SEQ ID NOs. 18 and 19, respectively, as described in U.S. Patent No. 8,088,896, wherein the VH and VL of MOR-202 may be expressed as IgG1 / κ; Or isatuximab described in U.S. Patent No. 8,153,765, comprising the VH and VL sequences of SEQ ID NOs. 20 and 21, respectively. The VH and VL of isatuximab may be expressed as IgG1 / κ.

[0310] Sequence No. 4 (Daratumumab VH)

[0311] EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQAPGKGLEWVSAISGSGGGTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCAKDKILWFGEPVFDYWGQGTLVTVSS

[0312] Sequence number 5 (Daratumumab VL)

[0313] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPTFGQGTKVEIK

[0314] Sequence number 6 (Daratumumab HCDR1)

[0315] SFAMS

[0316] Sequence number 7 (Daratumumab HCDR2)

[0317] AISGSGGGTYYADSVKG

[0318] Sequence number 8 (Daratumumab HCDR3)

[0319] DKILWFGEPVFDY

[0320] Sequence number 9 (Daratumumab LCDR1)

[0321] RASQSVSSYLA

[0322] Sequence number 10 (Daratumumab LCDR2)

[0323] DASNRAT

[0324] Sequence number 11 (Daratumumab LCDR3)

[0325] QQRSNWPPTF

[0326] Sequence number 12 (Daratumumab HC)

[0327] EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQAPGKGLEWVSAISGSGGGTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCAKDKILWFGEPVFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0328] Sequence number 13 (다라투무맙 LC)

[0329] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0330] Sequence number 14

[0331] QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAFSWVRQAPGQGLEWMGRVIPFLGIANSAQKFQGRVTITADKSTSTAYMDLSSLRSEDTAVYYCARDDIAALGPFDYWGQGTLVTVSSAS

[0332] Sequence number 15

[0333] DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQKPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPRTFGQGTKVEIK

[0334] Sequence number 16

[0335] EVQLVQSGAEVKKPGESLKISCKGSGYSFSNYWIGWVRQMPGKGLEWMGIIYPHDSDARYSPSFQGQVTFSADKSISTAYLQWSSLKASDTAMYYCARHVGWGSRYWYFDLWGRGTLVTVSS

[0336] Sequence number 17

[0337] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPGLLIYDASNRASGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK

[0338] Sequence number 18

[0339] QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMNWVRQAPGKGLEWVSGISGDPSNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDLPLVYTGFAYWGQGTLVTVSS

[0340] Sequence number 19

[0341] DIELTQPPSVSVAPGQTARISCSGDNLRHYYVYWYQQKPGQAPVLVIYGDSKRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQTYTGGASLVFGGGTKLTVLGQ

[0342] Sequence number 20

[0343] QVQLVQSGAEVAKPGTSVKLSCKASGYTFTDYWMQWVKQRPGQGLEWIGTIYPGDGDTGYAQKFQGKATLTADKSSKTVYMHLSSLASEDSAVYYCARGDYYGSNSLDYWGQGTSVTVSS

[0344] Sequence number 21

[0345] DIVMTQSHLSMSTSLGDPVSITCKASQDVSTVVAWYQQKPGQSPRRLIYSASYRYIGVPDRFTGSGAGTDFTFTISSVQAEDLAVYYCQQHYSPPYTFGGGTKLEIK

[0346] In some embodiments, the anti-CD38 antibody is

[0347] VH of sequence number 14 and VL of sequence number 15;

[0348] VH of sequence number 16 and VL of sequence number 17;

[0349] VH of SEQ ID NO. 18 and VL of SEQ ID NO. 19; or

[0350] Includes VH of sequence number 20 and VL of sequence number 21.

[0351] In some embodiments, the anti-CD38 antibody is an IgG1 allotype.

[0352] In some embodiments, the T-cell re-induction therapeutic agent is a BCMAxCD3 bispecific antibody, a GPRC5DxCD3 bispecific antibody, a CD33xCD3 bispecific antibody, a CD19xCD3 bispecific antibody, a CD123xCD3 bispecific antibody, a PSMAxCD3 bispecific antibody, or a TMEFF2xCD3 bispecific antibody.

[0353] In some embodiments, the T-cell re-induction therapeutic is a BCMAxCD3 bispecific antibody.

[0354] In some embodiments, the T-cell re-induction therapeutic agent is a GPRC5DxCD3 bispecific antibody.

[0355] In some embodiments, the T-cell re-induction therapeutic is a CD33xCD3 bispecific antibody.

[0356] In some embodiments, the T-cell re-induction therapeutic is a CD19xCD3 bispecific antibody.

[0357] In some embodiments, the T-cell re-induction therapeutic is a CD123xCD3 bispecific antibody.

[0358] In some embodiments, the T-cell re-induction therapeutic is a PSMAxCD3 bispecific antibody.

[0359] In some embodiments, the T-cell re-induction therapeutic is a TMEFF2xCD3 bispecific antibody.

[0360] In some embodiments, the method further includes the step of administering one or more anticancer therapies to a subject.

[0361] In some embodiments, one or more anticancer therapies are selected from the group consisting of autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapy agents, immunomodulators, and targeted cancer therapies.

[0362] In some embodiments, one or more anticancer therapies are autologous stem cell transplantation (ASCT). In some embodiments, one or more anticancer therapies are radiation. In some embodiments, one or more anticancer therapies are surgery. In some embodiments, one or more anticancer therapies are chemotherapy agents. In some embodiments, one or more anticancer therapies are immunomodulators. In some embodiments, one or more anticancer therapies are targeted cancer therapies.

[0363] In some embodiments, one or more anticancer therapies include lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, erlotozumab, ixazomib, melphalan, dexamethasone, vincristine, cyclophosphamide, hydroxyidaunorubicin, prednisone, rituximab, imatinib, dasatinib, nilotinib, bosutinib, ponatinib, bafetinib, saracatinib, tozasertip or danucertip, cytarabine, daunorubicin, idarubicin, mitoxantrone, hydroxyurea, decitabine, cladribine, fludarabine, topotecan, etoposide, 6-thioguanine, corticosteroids, methotrexate, 6-mercaptopurine, azacitidine, arsenic trioxide, and It is selected from the group consisting of all-trans retinoic acid or any combination thereof.

[0364] In some embodiments, the anti-CD38 antibody is administered at a dose of about 8 mg / kg to about 16 mg / kg.

[0365] In some embodiments, the anti-CD38 antibody is administered or provided for administration into a pharmaceutical composition having a pH of about 5.5 comprising about 20 mg / mL to about 120 mg / mL of the anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mg mannitol, and about 0.04% w / v polysorbate-20 (PS-20).

[0366] In some embodiments, the anti-CD38 antibody is administered or provided for administration into a pharmaceutical composition comprising about 1,800 mg of the anti-CD38 antibody and about 30,000 U of rHuPH20.

[0367] In some embodiments, the anti-CD38 antibody is administered or provided for administration into a pharmaceutical composition comprising about 120 mg / mL of the anti-CD38 antibody and about 2,000 U / mL of rHuPH20.

[0368] In some embodiments, the anti-CD38 antibody is

[0369] About 5 mM to about 15 mM histidine;

[0370] About 100 mM to about 300 mM sorbitol;

[0371] About 0.01% w / v to about 0.04% w / v PS-20; and

[0372] It is administered as a pharmaceutical composition having a pH of about 5.5 to 5.6 containing about 1 mg / mL to about 2 mg / mL of methionine, or is provided for administration as said pharmaceutical composition.

[0373] In some embodiments, the anti-CD38 antibody is

[0374] Approximately 1,800 mg of the above anti-CD38 antibody;

[0375] Approximately 30,000 U of rHuPH20;

[0376] Approximately 10 mM histidine;

[0377] Approximately 300 mM sorbitol;

[0378] Approximately 0.04% (w / v) PS-20; and

[0379] It is administered as a pharmaceutical composition having a pH of about 5.6 containing about 1 mg / mL of methionine, or is provided for administration as said pharmaceutical composition.

[0380] In some embodiments, the anti-CD38 antibody is

[0381] Approximately 120 mg / mL of the above anti-CD38 antibody;

[0382] Approximately 2,000 U / mL of rHuPH20;

[0383] Approximately 10 mM histidine;

[0384] Approximately 300 mM sorbitol;

[0385] Approximately 0.04% (w / v) PS-20; and

[0386] It is administered as a pharmaceutical composition having a pH of about 5.6 containing about 1 mg / mL of methionine, or is provided for administration as said pharmaceutical composition.

[0387] Combination of anti-CD38 antibody and BCMAxCD3 bispecific antibody

[0388] The present invention also provides a method for treating cancer in a subject, said method comprising the step of treating said cancer by administering a therapeutically effective amount of a BCMAxCD3 bispecific antibody and an anti-CD38 antibody to said subject.

[0389] The present invention also provides a method for treating cancer in a subject, the method comprising the step of treating said cancer by administering a therapeutically effective amount of a BCMAxCD3 bispecific antibody to said subject, said subject has been treated with an anti-CD38 antibody prior to administering said BCMAxCD3 bispecific antibody.

[0390] The present invention also provides a method for treating cancer in a subject, the method comprising the step of treating said cancer by administering a therapeutically effective amount of a BCMAxCD3 bispecific antibody to said subject, said subject being relapsed or refractory to previous treatment with an anticancer agent.

[0391] T-cell re-induction therapies, such as BCMAxCD3 bispecific antibodies like JNJ-957, re-induce T cells into BCMA-positive tumor cells, such as multiple myeloma cells, which subsequently lead to perforin / granzyme release or activation of the FASL / FAS pathways, and ultimately death in the form of BCMA-positive tumor cell apoptosis. Therefore, the efficacy of T-cell re-induction therapies, such as BCMAxCD3 bispecific antibodies, can be influenced not only by the availability and activity of mobilized T cells but also by possible regulated expression of tumor-associated antigens, such as BCMA, on the tumor cells.

[0392] In some embodiments, the cancer is a BCMA-expressing cancer.

[0393] B-cell maturation antigen (BCMA) is a member of the membrane-bound tumor necrosis factor receptor family involved in the differentiation of B-cells into plasma cells. Expression of BCMA is restricted to B-cell lineages, where it is primarily expressed in the interfollicular region of the germinal center and on differentiated plasma cells and plasmablasts. BCMA is virtually absent on unsensitized and memory B cells (Reference [Tai and Anderson, Immunotherapy 7: 1187-99, 2015]).

[0394] In some embodiments, the cancer is a hematological malignancy.

[0395] In some embodiments, the cancer is multiple myeloma, asymptomatic myeloma, monoclonal gamma of unknown significance (MGUS), B-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, Burkitt lymphoma, follicular lymphoma, mantle-cell lymphoma, Waldenström macroglobulinemia, plasma cell leukemia, light chain amyloidosis, or non-Hodgkin lymphoma. A skilled physician performs the diagnosis of cancer.

[0396] In some embodiments, the subject is relapsed or refractory to treatment with an anti-CD38 antibody or lenalidomide, or a combination thereof.

[0397] In some embodiments, the subject is relapsed or refractory to treatment with an anti-CD38 antibody. In some embodiments, the subject is relapsed or refractory to treatment with lenalidomide.

[0398] In some embodiments, the subject is relapsed or refractory to treatment with a previous anticancer agent, such as one used to treat multiple myeloma or other hematological malignancies.

[0399] In some embodiments, the object is THALOMID ® (Talidomide), REVLIMID ®(Renalid), POMALYST ® (Formalidomide), VELCADE ® (Bortezomib), NINLARO (Ixazomib), KYPROLIS ® (Carfilzomib), FARADYK ® (Panobinostat), AREDIA ® (Pamidronate), ZOMETA ® (Zoledronic acid), DARZALEX ® It is refractory or relapsed to treatment with (daratumumab), erlotozumab, or melphalan.

[0400] In some embodiments, the subject is DARZALEX ® It is recurrent to treatment with (daratumumab).

[0401] In some embodiments, the BCMAxCD3 bispecific antibody and the anti-CD38 antibody are antigen-binding fragments. Exemplary antigen-binding fragments are the Fab, F(ab')2, Fd, and Fv fragments.

[0402] In some embodiments, the BCMAxCD3 bispecific antibody is a chimeric, humanized, or human antibody.

[0403] In some embodiments, the BCMAxCD3 bispecific antibody is an IgG1, IgG2, IgG3, or IgG4 allotype.

[0404] In some embodiments, the BCMAxCD3 bispecific antibody is an IgG4 allotype.

[0405] In some embodiments, the BCMAxCD3 bispecific antibody comprises a BCMA binding domain comprising HCDR1 of SEQ ID NO. 23, HCDR2 of SEQ ID NO. 24, HCDR3 of SEQ ID NO. 25, LCDR1 of SEQ ID NO. 26, LCDR2 of SEQ ID NO. 27, and LCDR3 of SEQ ID NO. 28, and 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.

[0406] In some embodiments, the BCMA binding domain comprises VH of SEQ ID NO. 29 and VL of SEQ ID NO. 30, and the CD3 binding domain comprises VH of SEQ ID NO. 39 and VL of SEQ ID NO. 40.

[0407] In some embodiments, the BCMAxCD3 bispecific antibody is an IgG4 homotype and comprises phenylalanine at position 405 and arginine at position 409 in the first heavy chain (HC1) and leucine at position 405 and lysine at position 409 in the second heavy chain (HC2), and residue numbering follows the EU index.

[0408] In some embodiments, the BCMAxCD3 bispecific antibody further comprises proline at position 228, alanine at position 234, and alanine at position 235 in both HC1 and HC2.

[0409] In some embodiments, the BCMAxCD3 bispecific antibody comprises HC1 of sequence no. 31, a first light chain (LC1) of sequence no. 32, HC2 of sequence no. 41, and a second light chain (LC2) of sequence no. 42.

[0410] In some embodiments, the BCMAxCD3 bispecific antibody is BI 836909, PF-06863135, AMG-701, or CC-93269.

[0411] In some embodiments, the anti-CD38 antibody comprises HCDR1 of SEQ ID NO. 6, HCDR2 of SEQ ID NO. 7, HCDR3 of SEQ ID NO. 8, LCDR1 of SEQ ID NO. 9, LCDR2 of SEQ ID NO. 10, and LCDR3 of SEQ ID NO. 11.

[0412] In some embodiments, the anti-CD38 antibody comprises VH of sequence number 4 and VL of sequence number 5.

[0413] In some embodiments, the anti-CD38 antibody comprises the heavy chain (HC) of sequence number 12 and the light chain (LC) of sequence number 13.

[0414] In some embodiments, the anti-CD38 antibody is DARZALEX ® It is (daratumumab).

[0415] In some embodiments, the anti-CD38 antibody is

[0416] VH of sequence number 14 and VL of sequence number 15;

[0417] VH of sequence number 16 and VL of sequence number 17;

[0418] VH of SEQ ID NO. 18 and VL of SEQ ID NO. 19; or

[0419] Includes VH of sequence number 20 and VL of sequence number 21.

[0420] In some embodiments, the anti-CD38 antibody is a chimeric, humanized, or human antibody.

[0421] In some embodiments, the anti-CD38 antibody is an IgG1, IgG2, IgG3, or IgG4 allotype.

[0422] In some embodiments, the anti-CD38 antibody is an IgG1 allotype.

[0423] In some embodiments, the anti-CD38 antibody is administered at a dose of about 8 mg / kg to about 16 mg / kg.

[0424] In some embodiments, the BCMAxCD3 bispecific antibody and the anti-CD38 antibody are administered by intravenous injection.

[0425] In some embodiments, the BCMAxCD3 bispecific antibody is administered by intravenous injection, and the anti-CD38 antibody is administered by subcutaneous injection.

[0426] In some embodiments, the BCMAxCD3 bispecific antibody and the anti-CD38 antibody are administered by subcutaneous injection.

[0427] In some embodiments, the method further includes the step of administering one or more anticancer therapies to a subject.

[0428] In some embodiments, one or more anticancer therapies are selected from the group consisting of autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapy agents, immunomodulators, and targeted cancer therapies.

[0429] In some embodiments, one or more anticancer therapies are selected from the group consisting of lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, erlotozumab, ixazomib, melphalan, prednisone or dexamethasone, or any combination thereof.

[0430] In some embodiments, the anti-CD38 antibody is administered or provided for administration into a pharmaceutical composition having a pH of about 5.5 comprising about 20 mg / mL to about 120 mg / mL of the anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mg mannitol, and about 0.04% w / v polysorbate-20 (PS-20).

[0431] In some embodiments, the anti-CD38 antibody is administered or provided for administration into a pharmaceutical composition comprising about 1,800 mg of the anti-CD38 antibody and about 30,000 U of rHuPH20.

[0432] In some embodiments, the anti-CD38 antibody is administered or provided for administration into a pharmaceutical composition comprising about 120 mg / mL of the anti-CD38 antibody and about 2,000 U / mL of rHuPH20.

[0433] In some embodiments, the anti-CD38 antibody is

[0434] About 5 mM to about 15 mM histidine;

[0435] About 100 mM to about 300 mM sorbitol;

[0436] About 0.01% w / v to about 0.04% w / v PS-20; and

[0437] It is administered as a pharmaceutical composition having a pH of about 5.5 to 5.6 containing about 1 mg / mL to about 2 mg / mL of methionine, or is provided for administration as said pharmaceutical composition.

[0438] In some embodiments, the anti-CD38 antibody is

[0439] Approximately 1,800 mg of the above anti-CD38 antibody;

[0440] Approximately 30,000 U of rHuPH20;

[0441] Approximately 10 mM histidine;

[0442] Approximately 300 mM sorbitol;

[0443] Approximately 0.04% (w / v) PS-20; and

[0444] It is administered as a pharmaceutical composition having a pH of about 5.6 containing about 1 mg / mL of methionine, or is provided for administration as said pharmaceutical composition.

[0445] In some embodiments, the anti-CD38 antibody is

[0446] Approximately 120 mg / mL of the above anti-CD38 antibody;

[0447] Approximately 2,000 U / mL of rHuPH20;

[0448] Approximately 10 mM histidine;

[0449] Approximately 300 mM sorbitol;

[0450] Approximately 0.04% (w / v) PS-20; and

[0451] It is administered as a pharmaceutical composition having a pH of about 5.6 containing about 1 mg / mL of methionine, or is provided for administration as said pharmaceutical composition.

[0452] The doses of BCMAxCD3 bispecific antibody and anti-CD38 antibody provided to a subject having cancer, e.g., multiple myeloma, are sufficient to alleviate or at least partially stop the disease being treated ("therapeutic effective dose") and include about 0.005 mg / kg to about 100 mg / kg, e.g., about 0.05 mg / kg to about 30 mg / kg or about 5 mg / kg to about 25 mg / kg, or about 4 mg / kg, about 8 mg / kg, about 16 mg / kg, or about 24 mg / kg of antibody. Suitable doses include, for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 40, 50, 60, 70, 80, 90, or 100 mg / kg.

[0453] Fixed unit doses of BCMAxCD3 bispecific antibody and / or anti-CD38 antibody, e.g., 50, 100, 200, 500, or 1000 mg, may also be provided, or the dose may be based on the patient's surface area, e.g., 500, 400, 300, 250, 200, or 100 mg / m² 2 It may be. To treat cancer, e.g., multiple myeloma, a dose of 1 to 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 doses or more may be provided.

[0454] Administration of BCMAxCD3 bispecific antibodies and / or anti-CD38 antibodies may be repeated after 1, 2, 3, 4, 5, 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 longer periods. As with chronic administration, repeated courses of treatment are also possible. Repeated administration may be performed at the same dose or at different doses. For example, BCMAxCD3 bispecific antibodies and anti-CD38 antibodies may be administered by intravenous infusion at weekly intervals of 8 mg / kg or 16 mg / kg for 8 weeks, then at 8 mg / kg or 16 mg / kg every 2 weeks for an additional 16 weeks, and then at 8 mg / kg or 16 mg / kg every 4 weeks.

[0455] BCMAxCD3 bispecific antibodies and anti-CD38 antibodies may be administered once a week for a period of, for example, 6 months or longer as maintenance therapy. For example, BCMAxCD3 bispecific antibody and anti-CD38 antibody as daily doses for at least one of days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 after the initiation of treatment, or alternatively, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, For at least one of weeks 17, 18, 19, or 20, using a single or divided dose every 24, 12, 8, 6, 4, or 2 hours, or any combination thereof, about 0.1 mg / kg to about 100 mg / kg per day, e.g., 0.5, 0.9, 1.0, 1.1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90, or 100 It may be provided in an amount of mg / kg or any combination thereof.

[0456] BCMAxCD3 bispecific antibodies and anti-CD38 antibodies may also be administered prophylactically to reduce the risk of developing cancer (e.g., multiple myeloma), delay the onset of events in cancer progression, or reduce the risk of recurrence when the cancer is in remission.

[0457] In some embodiments, the BCMAxCD3 bispecific antibody is administered to the subject after the subject has been administered an anti-CD38 antibody. The BCMAxCD3 bispecific antibody may be administered after 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 a longer period after administration of the anti-CD38 antibody. In some embodiments, the subject to whom the BCMAxCD3 antibody is administered is resistant and / or refractory to treatment with the anti-CD38 antibody.

[0458] The present invention also provides a pharmaceutical composition comprising a BCMA-xCD3 bispecific antibody comprising a BCMA-binding domain comprising VH of SEQ ID NO. 29 and VL of SEQ ID NO. 30, a CD3-binding domain comprising VH of SEQ ID NO. 39 and VL of SEQ ID NO. 40, and an anti-CD38 antibody comprising VH of SEQ ID NO. 4 and VL of SEQ ID NO. 5.

[0459] In some embodiments, the pharmaceutical composition comprises a BCMAxCD3 bispecific antibody comprising HC1 of SEQ ID NO. 31, LC1 of SEQ ID NO. 32, HC2 of SEQ ID NO. 41, and LC2 of SEQ ID NO. 42, and an anti-CD38 antibody comprising HC of SEQ ID NO. 12 and LC of SEQ ID NO. 13.

[0460] In some embodiments, the pharmaceutical composition is a non-fixed combination.

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

[0462] BCMAxCD3 bispecific antibody can be formulated as a pharmaceutical composition comprising about 20 mg / mL to about 120 mg / mL of antibody, acetic acid, histidine, sodium chloride, mannitol and / or polysorbate-20.

[0463] In some embodiments, the pharmaceutical composition comprises about 1,800 mg of the anti-CD38 antibody and about 30,000 U of rHuPH20.

[0464] In some embodiments, the pharmaceutical composition comprises about 120 mg / mL of the anti-CD38 antibody and about 2,000 U / mL of rHuPH20.

[0465] In some embodiments, the pharmaceutical composition further comprises one or more excipients.

[0466] In some embodiments, one or more excipients are histidine, methionine, sorbitol or polysorbate-20 (PS-20), or any combination thereof.

[0467] In some embodiments, the pharmaceutical composition is

[0468] About 5 mM to about 15 mM histidine;

[0469] About 100 mM to about 300 mM sorbitol;

[0470] About 0.01% w / v to about 0.04% w / v PS-20; and

[0471] It comprises about 100 mg / mL to about 120 mg / mL of the above anti-CD38 antibody formulated in about 1 mg / mL to about 2 mg / mL of methionine, and has a pH of about 5.5 to 5.6.

[0472] In some embodiments, the pharmaceutical composition contains about 10 mM histidine.

[0473] In some embodiments, the pharmaceutical composition contains about 300 mM sorbitol.

[0474] In some embodiments, the pharmaceutical composition contains about 0.04% (w / v) PS-20.

[0475] In some embodiments, the pharmaceutical composition contains about 1 mg / mL of methionine.

[0476] In some embodiments, the pharmaceutical composition is

[0477] Approximately 1,800 mg of the above anti-CD38 antibody;

[0478] Approximately 30,000 U of rHuPH20;

[0479] Approximately 10 mM histidine;

[0480] Approximately 300 mM sorbitol;

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

[0482] It contains about 1 mg / mL of methionine and has a pH of about 5.6.

[0483] In some embodiments, the pharmaceutical composition is

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

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

[0486] Approximately 10 mM histidine;

[0487] Approximately 300 mM sorbitol;

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

[0489] It contains about 1 mg / mL of methionine and has a pH of about 5.6.

[0490] The present invention also provides a kit comprising a pharmaceutical composition comprising a BCMAxCD3 bispecific antibody and an anti-CD38 antibody.

[0491] Treatment with BCMAxCD3 bispecific antibodies in relapsed or refractory subjects

[0492] The present invention also provides a method for treating cancer in a subject, the method comprising the step of treating said cancer by administering a therapeutically effective amount of a BCMAxCD3 bispecific antibody to said subject, said subject being relapsed or refractory to previous treatment with an anticancer agent.

[0493] In some embodiments, the BCMAxCD3 bispecific antibody comprises a BCMA binding domain comprising HCDR1 of SEQ ID NO. 23, HCDR2 of SEQ ID NO. 24, HCDR3 of SEQ ID NO. 25, LCDR1 of SEQ ID NO. 26, LCDR2 of SEQ ID NO. 27, and LCDR3 of SEQ ID NO. 28, and 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.

[0494] In some embodiments, the BCMA binding domain comprises VH of SEQ ID NO. 29 and VL of SEQ ID NO. 30, and the CD3 binding domain comprises VH of SEQ ID NO. 39 and VL of SEQ ID NO. 40.

[0495] In some embodiments, the BCMAxCD3 bispecific antibody is IgG4 homotype and comprises phenylalanine at position 405 and arginine at position 409 in HC1 and leucine at position 405 and lysine at position 409 in HC2, and residue numbering follows the EU index.

[0496] In some embodiments, the BCMAxCD3 bispecific antibody further comprises proline at position 228, alanine at position 234, and alanine at position 235 in both HC1 and HC2.

[0497] In some embodiments, the BCMAxCD3 bispecific antibody comprises HC1 of sequence no. 31, LC1 of sequence no. 32, HC2 of sequence no. 41, and LC2 of sequence no. 42.

[0498] In some embodiments, the cancer is a hematological malignancy.

[0499] In some embodiments, the hematological malignancy is multiple myeloma.

[0500] In some embodiments, multiple myeloma is high-risk multiple myeloma.

[0501] In some embodiments, a subject having high-risk multiple myeloma has one or more chromosomal abnormalities comprising the following:

[0502] t(4;14)(p16;q32);

[0503] t(14;16)(q32;q23);

[0504] del17p;

[0505] 1qAmp;

[0506] t(4;14)(p16;q32) and t(14;16)(q32;q23);

[0507] t(4;14)(p16;q32) and del17p;

[0508] t(14;16)(q32;q23) and del17p; or

[0509] t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p, or any combination thereof.

[0510] In some embodiments, the subject is relapsed or refractory to treatment with an anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, erlotozumab, ixazomib, melphalan, or thalidomide, or any combination thereof.

[0511] In some embodiments, the subject is relapsed or refractory to treatment with lenalidomide. In some embodiments, the subject is relapsed or refractory to treatment with bortezomib. In some embodiments, the subject is relapsed or refractory to treatment with pomalidomide. In some embodiments, the subject is relapsed or refractory to treatment with carfilzomib. In some embodiments, the subject is relapsed or refractory to treatment with erlotozumab. In some embodiments, the subject is relapsed or refractory to treatment with ixazomib. In some embodiments, the subject is relapsed or refractory to treatment with melphalan. In some embodiments, the subject is relapsed or refractory to treatment with thalidomide.

[0512] In some embodiments, the subject is relapsed in response to treatment with an anti-CD38 antibody.

[0513] In some embodiments, the anti-CD38 antibody comprises HCDR1 of SEQ ID NO. 6, HCDR2 of SEQ ID NO. 7, HCDR3 of SEQ ID NO. 8, LCDR1 of SEQ ID NO. 9, LCDR2 of SEQ ID NO. 10, and LCDR3 of SEQ ID NO. 11.

[0514] In some embodiments, the anti-CD38 antibody comprises VH of sequence number 4 and VL of sequence number 5.

[0515] In some embodiments, the anti-CD38 antibody is an IgG1 allotype.

[0516] In some embodiments, the anti-CD38 antibody comprises HC of sequence number 12 and LC of sequence number 13.

[0517] In some embodiments, the anti-CD38 antibody is

[0518] VH of sequence number 14 and VL of sequence number 15;

[0519] VH of sequence number 16 and VL of sequence number 17;

[0520] VH of SEQ ID NO. 18 and VL of SEQ ID NO. 19; or

[0521] Includes VH of sequence number 20 and VL of sequence number 21.

[0522] In some embodiments, the anti-CD38 antibody is an IgG1 allotype.

[0523] In some embodiments, the subject is a human.

[0524] In some embodiments, the method further includes the step of administering one or more anticancer therapies to a subject.

[0525] In some embodiments, one or more anticancer therapies are selected from the group consisting of autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapy agents, immunomodulators, and targeted cancer therapies.

[0526] In some embodiments, one or more anticancer therapies are selected from the group consisting of lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, erlotozumab, ixazomib, melphalan, prednisone or dexamethasone, or any combination thereof.

[0527] Combination therapy with a T-cell re-induction therapy binding to GPRC5D and an anti-CD38 antibody

[0528] The present invention also provides a method for treating cancer in a subject, the method comprising the step of treating the cancer by administering a therapeutically effective amount of a T-cell re-induction therapeutic agent that binds to GPRC5D and an anti-CD38 antibody to the subject.

[0529] In some embodiments, an anti-CD38 antibody is administered to the subject before administering a T-cell re-induction therapeutic agent that binds to GPRC5D.

[0530] In some embodiments, the subject is relapsed or refractory to treatment with a previous anticancer agent.

[0531] In some embodiments, the cancer is a GPRC5D-expressing cancer.

[0532] In some embodiments, GPRC5D-expressing cancer is a hematological malignancy or a solid tumor.

[0533] In some embodiments, the hematological malignancy is leukemia, lymphoma, or multiple myeloma.

[0534] In some embodiments, the hematological malignancy is leukemia. In some embodiments, the hematological malignancy is lymphoma. In some embodiments, the hematological malignancy is multiple myeloma.

[0535] In some embodiments, the solid tumor is ovarian cancer, lung cancer, gastric adenocarcinoma, prostate cancer, renal carcinoma, liver cancer, pancreatic cancer, colon cancer, esophageal cancer, bladder cancer, cervical cancer, or malignant melanoma.

[0536] GPRC5D is disclosed as being expressed in these tumors, see, for example, International Patent Application Publication WO2018 / 147245.

[0537] In some embodiments, the subject is relapsed or refractory to treatment with an anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, erlotozumab, ixazomib, melphalan, or thalidomide, or any combination thereof.

[0538] In some embodiments, the subject is relapsed or refractory to treatment with lenalidomide. In some embodiments, the subject is relapsed or refractory to treatment with bortezomib. In some embodiments, the subject is relapsed or refractory to treatment with pomalidomide. In some embodiments, the subject is relapsed or refractory to treatment with carfilzomib. In some embodiments, the subject is relapsed or refractory to treatment with erlotozumab. In some embodiments, the subject is relapsed or refractory to treatment with ixazomib. In some embodiments, the subject is relapsed or refractory to treatment with melphalan. In some embodiments, the subject is relapsed or refractory to treatment with thalidomide. In some embodiments, the subject is relapsed or refractory to treatment with an anti-CD38 antibody.

[0539] In some embodiments, multiple myeloma is newly diagnosed multiple myeloma.

[0540] In some embodiments, the multiple myeloma is relapsed or refractory multiple myeloma.

[0541] In some embodiments, multiple myeloma is high-risk multiple myeloma.

[0542] In some embodiments, a subject having high-risk multiple myeloma has one or more chromosomal abnormalities comprising the following:

[0543] t(4;14)(p16;q32);

[0544] t(14;16)(q32;q23);

[0545] del17p;

[0546] 1qAmp;

[0547] t(4;14)(p16;q32) and t(14;16)(q32;q23);

[0548] t(4;14)(p16;q32) and del17p;

[0549] t(14;16)(q32;q23) and del17p; or

[0550] t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p, or any combination thereof.

[0551] In some embodiments, the T-cell re-induction therapeutic agent binds to CD3, CD3 epsilon (CD3ε), CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, BTNL8, PD-1, CD195, or NKG2C.

[0552] In some embodiments, the T-cell re-induction therapeutic agent 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.

[0553] In some embodiments, the GPRC5D binding domain comprises VH of sequence number 49 and VL of sequence number 50, and the CD3 binding domain comprises VH of sequence number 39 and VL of sequence number 40.

[0554] In some embodiments, the T-cell re-induction therapeutic agent that binds to GPRC5C is a multispecific antibody, a CAR, or a T cell expressing a CAR.

[0555] In some embodiments, the multispecific antibody is an IgG1, IgG2, IgG3, or IgG4 allotype.

[0556] In some embodiments, the multispecific antibody is an IgG1 allotype. In some embodiments, the multispecific antibody is an IgG2 allotype. In some embodiments, the multispecific antibody is an IgG3 allotype. In some embodiments, the multispecific antibody is an IgG4 allotype.

[0557] In some embodiments, the multispecific antibody comprises one or more Fc substitutions that reduce the binding of the multispecific antibody to the Fcγ receptor (FcγR).

[0558] In some embodiments, one or more Fc substitutions are F234A / L235A on IgG4, L234A / L235A on IgG1, V234A / G237A / P238S / H268A / V309L / A330S / P331S on IgG2, F234A / L235A on IgG4, S228P / F234A / L235A on IgG4, N297A on all Ig isotypes, V234A / G237A on IgG2, K214T / E233P / L234V / L235A / G236-deletion / A327G / P331A / D365E / L358M on IgG1, H268Q / V309L / A330S / P331S on IgG2, and IgG1 Selected from the group consisting of S267E / L328F, L234F / L235E / D265A on IgG1, L234A / L235A / G237A / P238S / H268A / A330S / P331S on IgG1, S228P / F234A / L235A / G237A / P238S on IgG4, and S228P / F234A / L235A / G236-deletion / G237A / P238S on IgG4, and residue numbering follows the EU index.

[0559] In some embodiments, the multispecific antibody further comprises an S228P substitution.

[0560] In some embodiments, the multispecific antibody comprises one or more asymmetric substitutions in the first CH3 domain or in the second CH3 domain, or in both the first CH3 domain and the second CH3 domain.

[0561] In some embodiments, one or more asymmetric substitutions are F450L / K409R, wild-type / F409L_R409K, T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S and T366W / T366S_L368A_Y407V, L351Y_F405A_Y407V / T394W, T366I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, It is selected from the group consisting of L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F, and T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W.

[0562] In some embodiments, the multispecific antibody comprises HC1 of SEQ ID NO. 51, LC1 of SEQ ID NO. 52, HC2 of SEQ ID NO. 41, and LC2 of SEQ ID NO. 42.

[0563] In some embodiments, the anti-CD38 antibody comprises HCDR1 of SEQ ID NO. 6, HCDR2 of SEQ ID NO. 7, HCDR3 of SEQ ID NO. 8, LCDR1 of SEQ ID NO. 9, LCDR2 of SEQ ID NO. 10, and LCDR3 of SEQ ID NO. 11.

[0564] In some embodiments, the anti-CD38 antibody comprises VH of sequence number 4 and VL of sequence number 5.

[0565] In some embodiments, the anti-CD38 antibody is an IgG1 allotype.

[0566] In some embodiments, the anti-CD38 antibody comprises HC of sequence number 12 and LC of sequence number 13.

[0567] In some embodiments, the anti-CD38 antibody is

[0568] VH of sequence number 14 and VL of sequence number 15;

[0569] VH of sequence number 16 and VL of sequence number 17;

[0570] VH of SEQ ID NO. 18 and VL of SEQ ID NO. 19; or

[0571] Includes VH of sequence number 20 and VL of sequence number 21.

[0572] In some embodiments, the anti-CD38 antibody is an IgG1 allotype.

[0573] In some embodiments, the anti-CD38 antibody is administered at a dose of about 8 mg / kg to about 16 mg / kg.

[0574] In some embodiments, a T-cell re-induction therapeutic agent and an anti-CD38 antibody that bind to GPRC5D are administered by intravenous injection.

[0575] In some embodiments, a T-cell re-induction therapeutic agent that binds to GPRC5D is administered by intravenous injection, and an anti-CD38 antibody is administered by subcutaneous injection.

[0576] In some embodiments, a T-cell re-induction therapeutic agent and an anti-CD38 antibody that bind to GPRC5D are administered by subcutaneous injection.

[0577] In some embodiments, the subject is a human.

[0578] In some embodiments, the T-cell re-induction therapeutic agent that binds to GPRC5D is a GPRC5DxCD3 bispecific antibody.

[0579] In some embodiments, the method further includes the step of administering one or more anticancer therapies to a subject.

[0580] In some embodiments, one or more anticancer therapies are selected from the group consisting of autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapy agents, immunomodulators, and targeted cancer therapies.

[0581] In some embodiments, one or more anticancer regimens are selected from the group consisting of lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, erlotozumab, ixazomib, melphalan, dexamethasone, or prednisone.

[0582] In some embodiments, the anti-CD38 antibody is administered or provided for administration into a pharmaceutical composition having a pH of about 5.5 comprising about 20 mg / mL to about 120 mg / mL of the anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mg mannitol, and about 0.04% w / v polysorbate-20 (PS-20).

[0583] In some embodiments, the anti-CD38 antibody is administered or provided for administration into a pharmaceutical composition comprising about 1,800 mg of the anti-CD38 antibody and about 30,000 U of rHuPH20.

[0584] In some embodiments, the anti-CD38 antibody is administered or provided for administration into a pharmaceutical composition comprising about 120 mg / mL of the anti-CD38 antibody and about 2,000 U / mL of rHuPH20.

[0585] In some embodiments, the anti-CD38 antibody is

[0586] About 100 mg / mL to about 120 mg / mL of the above anti-CD38 antibody;

[0587] About 5 mM to about 15 mM histidine;

[0588] About 100 mM to about 300 mM sorbitol;

[0589] About 0.01% w / v to about 0.04% w / v PS-20; and

[0590] It is administered as a pharmaceutical composition having a pH of about 5.5 to 5.6 containing about 1 mg / mL to about 2 mg / mL of methionine, or is provided for administration as said pharmaceutical composition.

[0591] In some embodiments, the anti-CD38 antibody is

[0592] Approximately 1,800 mg of the above anti-CD38 antibody;

[0593] Approximately 30,000 U of rHuPH20;

[0594] Approximately 10 mM histidine;

[0595] Approximately 300 mM sorbitol;

[0596] Approximately 0.04% (w / v) PS-20; and

[0597] It is administered as a pharmaceutical composition having a pH of about 5.6 containing about 1 mg / mL of methionine, or is provided for administration as said pharmaceutical composition.

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

[0599] Approximately 120 mg / mL of the above anti-CD38 antibody;

[0600] Approximately 2,000 U / mL of rHuPH20;

[0601] Approximately 10 mM histidine;

[0602] Approximately 300 mM sorbitol;

[0603] Approximately 0.04% (w / v) PS-20; and

[0604] It is administered as a pharmaceutical composition having a pH of about 5.6 containing about 1 mg / mL of methionine, or is provided for administration as said pharmaceutical composition.

[0605] The present invention also provides a pharmaceutical combination comprising 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, and an anti-CD38 antibody comprising HCDR1 of SEQ ID NO. 6, HCDR2 of SEQ ID NO. 7, HCDR3 of SEQ ID NO. 8, LCDR1 of SEQ ID NO. 9, LCDR2 of SEQ ID NO. 10, and LCDR3 of SEQ ID NO. 11.

[0606] In some embodiments, the GPRC5D binding domain comprises VH of SEQ ID NO. 49 and VL of SEQ ID NO. 50, the CD3 binding domain comprises VH of SEQ ID NO. 39 and VL of SEQ ID NO. 40, and the anti-CD38 antibody comprises VH of SEQ ID NO. 4 and VL of SEQ ID NO. 5.

[0607] In some embodiments, the GPRC5DxCD3 bispecific antibody comprises HC1 of SEQ ID NO. 51, LC1 of SEQ ID NO. 52, HC2 of SEQ ID NO. 41, and LC2 of SEQ ID NO. 42, and the anti-CD38 antibody comprises HC of SEQ ID NO. 12 and LC of SEQ ID NO. 13.

[0608] In some embodiments, the pharmaceutical combination is a non-fixed combination.

[0609] In some embodiments, the pharmaceutical combination comprises about 20 mg / mL to about 120 mg / mL of the anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mg mannitol, and about 0.04% w / v polysorbate-20 (PS-20), and the pH is about 5.5.

[0610] In some embodiments, the pharmaceutical combination comprises about 1,800 mg of the anti-CD38 antibody and about 30,000 U of rHuPH20.

[0611] In some embodiments, the pharmaceutical combination comprises about 120 mg / mL of the anti-CD38 antibody and about 2,000 U / mL of rHuPH20.

[0612] In some embodiments, the pharmaceutical combination further comprises one or more excipients.

[0613] In some embodiments, one or more excipients are histidine, methionine, sorbitol or polysorbate-20 (PS-20), or any combination thereof.

[0614] In some embodiments, the pharmaceutical composition is

[0615] About 100 mg / mL to about 120 mg / mL of the above anti-CD38 antibody;

[0616] About 5 mM to about 15 mM histidine;

[0617] About 100 mM to about 300 mM sorbitol;

[0618] About 0.01% w / v to about 0.04% w / v PS-20; and

[0619] It contains about 1 mg / mL to about 2 mg / mL of methionine, and has a pH of about 5.5 to 5.6.

[0620] In some embodiments, the pharmaceutical combination contains about 10 mM histidine.

[0621] In some embodiments, the pharmaceutical combination contains about 300 mM sorbitol.

[0622] In some embodiments, the pharmaceutical combination contains about 0.04% (w / v) PS-20.

[0623] In some embodiments, the pharmaceutical combination contains about 1 mg / mL of methionine.

[0624] In some embodiments, the pharmaceutical combination is

[0625] Approximately 1,800 mg of the above anti-CD38 antibody;

[0626] Approximately 30,000 U of rHuPH20;

[0627] Approximately 10 mM histidine;

[0628] Approximately 300 mM sorbitol;

[0629] Approximately 0.04% (w / v) PS-20; and

[0630] It contains about 1 mg / mL of methionine and has a pH of about 5.6.

[0631] In some embodiments, the pharmaceutical combination is

[0632] Approximately 120 mg / mL of the above anti-CD38 antibody;

[0633] Approximately 2,000 U / mL of rHuPH20;

[0634] Approximately 10 mM histidine;

[0635] Approximately 300 mM sorbitol;

[0636] Approximately 0.04% (w / v) PS-20; and

[0637] It contains about 1 mg / mL of methionine and has a pH of about 5.6.

[0638] The invention also provides a pharmaceutical combination comprising a T-cell re-induction therapeutic agent that binds to GPRC5D and an anti-CD38 antibody.

[0639] Treatment with GPRC5DxCD3 bispecific antibodies in relapsed or refractory subjects

[0640] The present invention also provides a method for treating cancer in a subject, the method comprising the step of treating the cancer by administering a therapeutically effective amount of a GPRC5DxCD3 bispecific antibody to the subject, wherein the subject is relapsed or refractory to treatment with a previous anticancer agent.

[0641] In some embodiments, 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.

[0642] In some embodiments, the GPRC5D binding domain comprises VH of sequence number 49 and VL of sequence number 50, and the CD3 binding domain comprises VH of sequence number 39 and VL of sequence number 40.

[0643] In some embodiments, the GPRC5DxCD3 bispecific antibody is an IgG4 homotype and comprises phenylalanine at position 405 and arginine at position 409 in HC1 and leucine at position 405 and lysine at position 409 in HC2, and residue numbering follows the EU index.

[0644] In some embodiments, the GPRC5DxCD3 bispecific antibody further comprises proline at position 228, alanine at position 234, and alanine at position 235 in both HC1 and HC2.

[0645] In some embodiments, the GPRC5DxCD3 bispecific antibody comprises HC1 of sequence no. 51, LC1 of sequence no. 52, HC2 of sequence no. 41, and LC2 of sequence no. 42.

[0646] In some embodiments, the cancer is a hematological malignancy or a solid tumor.

[0647] In some embodiments, the cancer is multiple myeloma, lymphoma, melanoma, breast cancer, endometrial cancer, ovarian cancer, lung cancer, gastric adenocarcinoma, prostate cancer, renal carcinoma, liver cancer, pancreatic cancer, colon cancer, esophageal cancer, bladder cancer, or cervical cancer.

[0648] In some embodiments, multiple myeloma is high-risk multiple myeloma.

[0649] In some embodiments, a subject having high-risk multiple myeloma has one or more chromosomal abnormalities comprising the following:

[0650] t(4;14)(p16;q32);

[0651] t(14;16)(q32;q23);

[0652] del17p;

[0653] 1qAmp;

[0654] t(4;14)(p16;q32) and t(14;16)(q32;q23);

[0655] t(4;14)(p16;q32) and del17p;

[0656] t(14;16)(q32;q23) and del17p; or

[0657] t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p, or any combination thereof.

[0658] In some embodiments, the subject is refractory or relapsed to treatment with an anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, erlotozumab, ixazomib, melphalan, or thalidomide, or any combination thereof.

[0659] In some embodiments, the subject is relapsed or refractory to treatment with anti-CD38 antibodies.

[0660] In some embodiments, the anti-CD38 antibody comprises HCDR1 of SEQ ID NO. 6, HCDR2 of SEQ ID NO. 7, HCDR3 of SEQ ID NO. 8, LCDR1 of SEQ ID NO. 9, LCDR2 of SEQ ID NO. 10, and LCDR3 of SEQ ID NO. 11.

[0661] In some embodiments, the anti-CD38 antibody comprises VH of sequence number 4 and VL of sequence number 5.

[0662] In some embodiments, the anti-CD38 antibody is an IgG1 allotype.

[0663] In some embodiments, the anti-CD38 antibody comprises HC of sequence number 12 and LC of sequence number 13.

[0664] In some embodiments, the anti-CD38 antibody is

[0665] VH of sequence number 14 and VL of sequence number 15;

[0666] VH of sequence number 16 and VL of sequence number 17;

[0667] VH of SEQ ID NO. 18 and VL of SEQ ID NO. 19; or

[0668] Includes VH of sequence number 20 and VL of sequence number 21.

[0669] In some embodiments, the anti-CD38 antibody is an IgG1 allotype.

[0670] In some embodiments, the subject is a human.

[0671] In some embodiments, the method further includes the step of administering one or more anticancer therapies to a subject.

[0672] In some embodiments, one or more anticancer therapies are selected from the group consisting of autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapy agents, immunomodulators, and targeted cancer therapies.

[0673] In some embodiments, one or more anticancer therapies include lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, erlotozumab, ixazomib, melphalan, dexamethasone, vincristine, cyclophosphamide, hydroxyidaunorubicin, prednisone, rituximab, imatinib, dasatinib, nilotinib, bosutinib, ponatinib, bafetinib, saracatinib, tozasertip or danucertip, cytarabine, daunorubicin, idarubicin, mitoxantrone, hydroxyurea, decitabine, cladribine, fludarabine, topotecan, etoposide, 6-thioguanine, corticosteroids, methotrexate, 6-mercaptopurine, azacitidine, arsenic trioxide, and It is selected from the group consisting of all-trans retinoic acid, or any combination thereof.

[0674] Combination therapy with a CD19-binding T-cell re-induction therapy and an anti-CD38 antibody

[0675] The present invention also provides a method for treating cancer in a subject, said method comprising the step of treating said cancer by administering to said subject a therapeutically effective amount of a T-cell re-induction therapeutic agent binding to CD19 and an anti-CD38 antibody.

[0676] In some embodiments, subjects have been treated with an anti-CD38 antibody prior to administration of a T-cell re-induction therapy that binds to CD19.

[0677] The present invention also provides a method for enhancing the efficacy of a T-cell re-induction therapeutic agent that binds to CD19 in a subject having cancer, wherein the method comprises the step of administering an anti-CD38 antibody to the subject before administering the T-cell re-induction therapeutic agent that binds to CD19.

[0678] In some embodiments, the subject is relapsed or refractory to treatment with a previous anticancer agent.

[0679] In some embodiments, the cancer is a hematological malignancy or a solid tumor.

[0680] In some embodiments, the hematological malignancy is lymphoma, B-cell malignancy, Hodgkin lymphoma, non-Hodgkin lymphoma, DLBLC, FL, MCL, marginal zone B-cell lymphoma (MZL), mucosa-associated lymphoid tissue lymphoma (MALT), CLL, ALL, AML, Waldenström macroglobulinemia, or T-cell lymphoma.

[0681] In some embodiments, the solid tumor is lung cancer, liver cancer, cervical cancer, colon cancer, breast cancer, ovarian cancer, pancreatic cancer, melanoma, glioblastoma, prostate cancer, esophageal cancer, or gastric cancer. International patent application publication WO2019057124A1 discloses a cancer suitable for treatment with a T-cell re-induction therapy that binds to CD19.

[0682] In some embodiments, the T-cell re-induction therapeutic agent binds to CD3 epsilon (CD3ε), CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, BTNL8, PD-1, CD195, or NKG2C.

[0683] In some embodiments, the T-cell re-induction therapeutic binding to CD19 is blinatumomab, axicarbatagen ciloleucel, tisagen recleucel-t, inebilizumab, lysocarbatagen marareucel, XmAb-5574, CIK-CAR.CD19, ICTCAR-011, IM-19, JCAR-014, loncastuximab tesirin, MB-CART2019.1, OXS-1550, PBCAR-0191, PCAR-019, PCAR-119, Senl-001, TI-1007, XmAb-5871, PTG-01, PZ01, Senl_1904A, Senl_1904B, UCART-19, CSG-CD19, DI-B4, ET-190, GC-007F or It includes the CD19 binding domain of GC-022.

[0684] In some embodiments, the T-cell re-induction therapeutic binding to CD19 is blinatumomab, axicarbatagen ciloleucel, tisagen recleucel-t, inebilizumab, lysocarbatagen marareucel, XmAb-5574, CIK-CAR.CD19, ICTCAR-011, IM-19, JCAR-014, loncastuximab tesirin, MB-CART2019.1, OXS-1550, PBCAR-0191, PCAR-019, PCAR-119, Senl-001, TI-1007, XmAb-5871, PTG-01, PZ01, Senl_1904A, Senl_1904B, UCART-19, CSG-CD19, DI-B4, ET-190, GC-007F or Includes GC-022.

[0685] In some embodiments, the T-cell re-induction therapeutic agent that binds to CD19 is a multispecific antibody, a CAR, or a T cell expressing a CAR.

[0686] In some embodiments, the anti-CD38 antibody comprises HCDR1 of SEQ ID NO. 6, HCDR2 of SEQ ID NO. 7, HCDR3 of SEQ ID NO. 8, LCDR1 of SEQ ID NO. 9, LCDR2 of SEQ ID NO. 10, and LCDR3 of SEQ ID NO. 11.

[0687] In some embodiments, the anti-CD38 antibody comprises VH of sequence number 4 and VL of sequence number 5.

[0688] In some embodiments, the anti-CD38 antibody is an IgG1 allotype.

[0689] In some embodiments, the anti-CD38 antibody comprises HC of sequence number 12 and LC of sequence number 13.

[0690] In some embodiments, the anti-CD38 antibody is

[0691] VH of sequence number 14 and VL of sequence number 15;

[0692] VH of sequence number 16 and VL of sequence number 17;

[0693] VH of SEQ ID NO. 18 and VL of SEQ ID NO. 19; or

[0694] Includes VH of sequence number 20 and VL of sequence number 21.

[0695] In some embodiments, the anti-CD38 antibody is an IgG1 allotype.

[0696] In some embodiments, the anti-CD38 antibody is administered at a dose of about 8 mg / kg to about 16 mg / kg.

[0697] In some embodiments, a T-cell re-induction therapeutic agent binding to CD19 and an anti-CD38 antibody are administered by intravenous injection.

[0698] In some embodiments, a T-cell re-induction therapeutic agent binding to CD19 is administered by intravenous injection, and an anti-CD38 antibody is administered by subcutaneous injection.

[0699] In some embodiments, a T-cell re-induction therapeutic agent binding to CD19 and an anti-CD38 antibody are administered by subcutaneous injection.

[0700] In some embodiments, the subject is a human.

[0701] In some embodiments, the T-cell re-induction therapeutic agent that binds to CD19 is a CD19xCD3 bispecific antibody.

[0702] In some embodiments, the method further includes the step of administering one or more anticancer therapies to a subject.

[0703] In some embodiments, one or more anticancer therapies are selected from the group consisting of autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapy agents, immunomodulators, and targeted cancer therapies.

[0704] The present invention also provides a pharmaceutical combination comprising a CD19xCD3 bispecific antibody comprising blinatumomab of SEQ ID NO. 53, and an anti-CD38 antibody comprising HCDR1 of SEQ ID NO. 6, HCDR2 of SEQ ID NO. 7, HCDR3 of SEQ ID NO. 8, LCDR1 of SEQ ID NO. 9, LCDR2 of SEQ ID NO. 10, and LCDR3 of SEQ ID NO. 11.

[0705] In some embodiments, the anti-CD38 antibody comprises VH of sequence number 4 and VL of sequence number 5.

[0706] In some embodiments, the anti-CD38 antibody comprises HC of sequence number 12 and LC of sequence number 13.

[0707] In some embodiments, the pharmaceutical combination is a non-fixed combination.

[0708] In some embodiments, the pharmaceutical combination comprises about 20 mg / mL to about 120 mg / mL of the anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mg mannitol, and about 0.04% w / v polysorbate-20 (PS-20), and the pH is about 5.5.

[0709] In some embodiments, the pharmaceutical combination comprises about 1,800 mg of the anti-CD38 antibody and about 30,000 U of rHuPH20.

[0710] In some embodiments, the pharmaceutical combination comprises about 120 mg / mL of the anti-CD38 antibody and about 2,000 U / mL of rHuPH20.

[0711] In some embodiments, the pharmaceutical combination further comprises one or more excipients.

[0712] In some embodiments, one or more excipients are histidine, methionine, sorbitol or polysorbate-20 (PS-20), or any combination thereof.

[0713] In some embodiments, the pharmaceutical combination is

[0714] About 100 mg / mL to about 120 mg / mL of the above anti-CD38 antibody;

[0715] About 5 mM to about 15 mM histidine;

[0716] About 100 mM to about 300 mM sorbitol;

[0717] About 0.01% w / v to about 0.04% w / v PS-20; and

[0718] It contains about 1 mg / mL to about 2 mg / mL of methionine, and has a pH of about 5.5 to 5.6.

[0719] In some embodiments, the pharmaceutical combination contains about 10 mM histidine.

[0720] In some embodiments, the pharmaceutical combination contains about 300 mM sorbitol.

[0721] In some embodiments, the pharmaceutical combination contains about 0.04% (w / v) PS-20.

[0722] In some embodiments, the pharmaceutical combination contains about 1 mg / mL of methionine.

[0723] In some embodiments, the pharmaceutical combination is

[0724] Approximately 1,800 mg of the above anti-CD38 antibody;

[0725] Approximately 30,000 U of rHuPH20;

[0726] Approximately 10 mM histidine;

[0727] Approximately 300 mM sorbitol;

[0728] Approximately 0.04% (w / v) PS-20; and

[0729] It contains about 1 mg / mL of methionine and has a pH of about 5.6.

[0730] In some embodiments, the pharmaceutical combination is

[0731] Approximately 120 mg / mL of the above anti-CD38 antibody;

[0732] Approximately 2,000 U / mL of rHuPH20;

[0733] Approximately 10 mM histidine;

[0734] Approximately 300 mM sorbitol;

[0735] Approximately 0.04% (w / v) PS-20; and

[0736] It contains about 1 mg / mL of methionine and has a pH of about 5.6.

[0737] In some embodiments, the pharmaceutical combination comprises 35 mcg of blinatumomab formulated with citric acid monohydrate (3.35 mg), lysine hydrochloride (23.23 mg), polysorbate 80 (0.64 mg), trehalose dihydrate (95.5 mg), and sodium hydroxide to adjust the pH to 7.0.

[0738] In some embodiments, blinatumomab is reconstituted using 3 mL of preservative-free sterile water for injection (USP).

[0739] The kit comprises a pharmaceutical combination comprising blinatumomab of sequence number 53, and anti-CD38 antibodies including HCDR1 of sequence number 6, HCDR2 of sequence number 7, HCDR3 of sequence number 8, LCDR1 of sequence number 9, LCDR2 of sequence number 10, and LCDR3 of sequence number 11.

[0740] T-cell re-induction therapy

[0741] Multispecific antibodies

[0742] T-cell re-induction therapeutic agents may be multispecific molecules, such as bispecific antibodies. Various multispecific and / or bispecific formats include the formats described herein and recombinant IgG-like bispecific targeting molecules—wherein each of the two sides of the molecule contains at least two Fab fragments or parts of Fab fragments of different antibodies—; IgG fusion molecules—wherein a full-length IgG antibody is fused to an additional Fab fragment or part of a Fab fragment—; Fc fusion molecules—wherein a single-stranded Fv molecule or a stabilized diabody is fused to a heavy-stranded constant-domain, Fc-region, or part thereof—; Fab fusion molecules—wherein different Fab fragments are fused together—; ScFv- and diabody-based and heavy-chain antibodies (e.g., domain antibodies, nanobodies) - wherein different single-chain Fv molecules or different diabodies or different heavy-chain antibodies (e.g., domain antibodies, nanobodies) are fused to each other or to different proteins or carrier molecules - or include multispecific antibodies produced by arm exchange.Exemplary multispecificity and / or bispecificity formats include dual-targeting molecules, including Dual Targeting (DT)-Ig (GSK / Domantis), Two-in-one Antibody (Genentech) and mAb2 (F-Star), Dual Variable Domain (DVD)-Ig (Abbott), Ts2Ab (MedImmune / AZ) and BsAb (Zymogenetics), HERCULES (Biogen Idec) and TvAb (Roche), ScFv / Fc fusion (Academic Institution), SCORPION (Emergent BioSolutions / Trubion, Zymogenetics / BMS) and Dual Affinity Retargeting Technology (Fc-DART) (MacroGenics), F(ab)2 (Medarex / AMGEN), dual-action or Bis-Fab (Genentech), Dock-and-Lock (DNL) (ImmunoMedics), bivalent bispecific (Biotecnol) and Fab-Fv (UCB-Celltech), bispecific T cell engager (BITE) (Micromet), tandem diabody (Tandab) (Affimed), dual affinity retargeting technology (DART) (MacroGenics), single-chain diabody (Academic), TCR-like antibody (AIT, ReceptorLogics), human serum albumin ScFv fusion (Merrimack) and COMBODY (Epigen Biotech), dual-targeting nanobody (Ablynx), and dual-targeting heavy-chain single-domain antibody are included. Various formats of bispecific antibodies, for example [Chames and Baty (2009) Curr Opin Drug Disc Dev 12: 276] and [Nunez-Prado et al.It is listed in [ , (2015) Drug Discovery Today 20(5):588-594].

[0743] A method for generating antibodies used in the method of the present invention

[0744] The antibody that binds to a specific antigen used in the method of the present invention is, for example, a de novo (from a phage display library) de novo It can be selected as ), wherein the phage is engineered to express human immunoglobulin or parts thereof, e.g. Fab, single-stranded antibody (scFv), or unpaired or paired antibody variable regions (reference [Knappik et al., J Mol Biol 296:57-86, 2000]; literature[Krebs et al., J Immunol Meth 254:67-84, 2001]; literature[Vaughan et al., Nature Biotechnology 14:309-14, 1996]; Literature[Sheets et al., PITAS (USA) 95:6157-62, 1998]; Hoogenboom and Winter, J Mol Biol 227:381, 1991]; Literature[Marks et al., J Mol Biol[222:581, 1991]). Phage display libraries express antibody heavy and light chain variable regions as fusion proteins with bacteriophage pIX envelope proteins, as described in the literature [Shi et al (2010) J. Mol. Biol. 397:385-96] and International Patent Application Publication WO2009 / 085462. Antibody libraries can be screened for binding to desired antigens, e.g., BCMA, CD3, CD38, CD123, CD19, CD33, PSMA, or TMEFF2 extracellular domains, and the resulting positive clones can be further characterized, Fab can be isolated from clone lysates, and subsequently cloned as full-length antibodies. Such phage display methods for isolating human antibodies are established in the art. For example, U.S. Patent No. 5,223,409; U.S. Patent No. 5,403,484; U.S. Patent No. 5,571,698; See U.S. Patent No. 5,427,908; U.S. Patent No. 5,580,717; U.S. Patent No. 5,969,108; U.S. Patent No. 6,172,197; U.S. Patent No. 5,885,793; U.S. Patent No. 6,521,404; U.S. Patent No. 6,544,731; U.S. Patent No. 6,555,313; U.S. Patent No. 6,582,915; and U.S. Patent No. 6,593,081.

[0745] T-cell re-induction bispecific antibodies can be generated in vitro in a cell-free environment by introducing asymmetric mutations into the CH3 domains of two monospecific homodimeric antibodies and forming bispecific heterodimeric antibodies from two parental monospecific homodimeric antibodies under reducing conditions that enable disulfide-binding isomerization, which is in accordance with the method described in International Patent Application Publication WO2011 / 131746. In these methods, two monospecific divalent antibodies are engineered to have a specific substitution in the CH3 domain that promotes heterodimeric stability; these antibodies are incubated together under reducing conditions sufficient to allow cysteine ​​in the hinge domain to undergo disulfide-binding isomerization; thereby generating bispecific antibodies by Fab arm exchange. The incubation conditions can be optimally restored to a non-reducing state. Exemplary reducing agents that may be used are 2-mercaptoethylamine (2-MEA), dithiothreitol (DTT), dithioerythritol (DTE), glutathione, tris(2-carboxyethyl)phosphine (TCEP), L-cysteine, and beta-mercaptoethanol, preferably the reducing agent is selected from the group consisting of 2-mercaptoethylamine, dithiothreitol, and tris(2-carboxyethyl)phosphine. For example, incubation for at least 90 minutes at a temperature of 20°C or higher may be used at pH 5 to 8, for example at pH 7.0 or pH 7.4 in the presence of at least 25 mM 2-MEA or at least 0.5 mM dithiothreitol.

[0746] Exemplary CH3 mutations that can be used for the first and second heavy chains of bispecific antibodies are K409R and / or F405L.

[0747] Additional CH3 mutations that can be used include techniques such as Duobody® mutations (Genmab), Knob-in-Hole mutations (Genentech), electrostatically matched mutations (Chugai, Amgen, NovoNordisk, Oncomed), Strand Exchange Engineered Domain Body (SEEDbody) (EMD Serono), and other asymmetric mutations (e.g., Zymeworks).

[0748] Duobody® mutations (Genmab) are disclosed, for example, in U.S. Patent No. 9150663 and U.S. Patent Application Publication No. 2014 / 0303356, and include the mutations F405L / K409R, wild-type / F405L_R409K, T350I_K370T_F405L / K409R, K370W / K409R, D399AFGHILMNRSTVWY / K409R, T366ADEFGHILMQVY / K409R, L368ADEGHNRSTVQ / K409AGRH, D399FHKRQ / K409AGRH, F405IKLSTVW / K409AGRH, and Y407LWQ / K409AGRH.

[0749] Knob-in-hole mutations are disclosed, for example, in International Patent Application Publication WO1996 / 027011 and include mutations at the interface of the CH3 region, wherein an amino acid having a small side chain (hole) is introduced into the first CH3 region and an amino acid having a large side chain (knob) is introduced into the second CH3 region, resulting in a preferential interaction between the first CH3 region and the second CH3 region. Exemplary CH3 region mutations forming the knob and hole are T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S, and T366W / T366S_L368A_Y407V.

[0750] The formation of a heavy chain heteromer can be facilitated by using electrostatic interactions by substituting a positively charged residue on a first CH3 region and a negatively charged residue on a second CH3 region, as described in U.S. Patent Application Publication No. 2010 / 0015133, U.S. Patent Application Publication No. 2009 / 0182127, U.S. Patent Application Publication No. 2010 / 028637 or U.S. Patent Application Publication No. 2011 / 0123532.

[0751] Other asymmetric mutations that may be used to promote heavy chain heteromerization are L351Y_F405A_Y407V / T394W, T366I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F, or as described in U.S. Patent Application Publication No. 2012 / 0149876 or U.S. Patent Application Publication No. 2013 / 0195849. It is T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W.

[0752] As described in U.S. Patent Application Publication No. 20070287170, SEEDbody mutations involve promoting heavy chain heteromerization by substituting selected IgG residues with IgA residues.

[0753] Other exemplary mutations that may be used include R409D_K370E / D399K_E357K, S354C_T366W / Y349C_T366S_L368A_Y407V, Y349C_T366W / S354C_T366S_L368A_Y407V, T366K / L351D, L351K / Y349E, L351K / Y349D, L351K / L368E, as described in International Patent Application Publications WO2007 / 147901, WO 2011 / 143545, WO2013157954, WO2013096291 and U.S. Patent Application Publication No. 2018 / 0118849, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, K392D / D399K, K392D / E356K, K253E_D282K_K322D / D239K_E240K_K292D, It is K392D_K409D / D356K_D399K.

[0754] Additional bispecific or multispecific structures that may be used as T-cell re-induction therapies include Dual Variable Domain Immunoglobulin (DVD) (International Patent Application Publication WO2009 / 134776; DVD is a full-length antibody comprising a heavy chain having the structure VH1-linker-VH2-CH and a light chain having the structure VL1-linker-VL2-CL; the linker is optional), structures comprising various dimerization domains for linking two antibody arms having different specificities, e.g., leucine zipper or collagen dimerization domains (International Patent Application Publication WO2012 / 022811, U.S. Patent No. 5,932,448; U.S. Patent No. 6,833,441), two or more domain antibodies (dAbs) conjugated together, diabodies, heavy-chain monoclonal antibodies, e.g., camel antibodies and engineered camel antibodies, dual Targeting (DT)-Ig (GSK / Domantis), Two-in-One Antibody (Genentech), Cross-linked Mab (Karmanos Cancer Center), mAb2 (F-Star) and CovX-Body (CovX / Pfizer), IgG-like Bispecificity (InnClone / Eli Lilly), Ts2Ab (MedImmune / AZ) and BsAb (Zymogenetics), HERCULES (Biogen Idec) and TvAb (Roche), ScFv / Fc Conjugate (Academic Institution), SCORPION (Emergent BioSolutions / Trubion, Zymogenetics / BMS), Dual Affinity Retargeting Technology (Fc-DART) (MacroGenics) and Dual (ScFv)2-Fab (National Research Center for Antibody Medicine - China), Dual-Action or Bis-Fab (Genentech), Dog-and-Lock (DNL) Includes (ImmunoMedics), divalent bispecific (Biotecnol) and Fab-Fv (UCB-Celltech).ScFv-, diabody-based and domain antibodies include, but are not limited to, bispecific T cell engagers (BiTE) (Micromet), tandem diabody (Tandab) (Affimed), dual-affinity retargeting technology (DART) (MacroGenics), single-strand diabody (Academic), TCR-like antibodies (AIT, ReceptorLogics), human serum albumin ScFv fusions (Merrimack) and COMBODY (Epigen Biotech), dual-targeting nanobodies (Ablynx), and dual-targeting heavy-strand single-domain antibodies.

[0755] Manipulation of antibody Fc

[0756] The Fc region of a T-cell re-induction therapeutic agent, such as a bispecific or multispecific antibody or an anti-CD38 antibody, may contain at least one substitution within the Fc region that reduces the binding of the T-cell re-induction therapeutic agent to the activated Fcγ receptor (FcγR) and / or reduces Fc effector functions, such as C1q binding, complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), or phagocytosis (ADCP).

[0757] Fc positions that can be substituted to reduce the binding of Fc to activating FcγR and subsequently reduce effector function are substitutions L234A / L235A on IgG1, V234A / G237A / P238S / H268A / V309L / A330S / P331S on IgG2, F234A / L235A on IgG4, S228P / F234A / L235A on IgG4, N297A on all Ig isoforms, V234A / G237A on IgG2, K214T / E233P / L234V / L235A / G236-deletion / A327G / P331A / D365E / L358M on IgG1, H268Q / V309L / A330S / P331S on IgG2, and IgG1 These are S267E / L328F, L234F / L235E / D265A on IgG1, L234A / L235A / G237A / P238S / H268A / A330S / P331S on IgG1, S228P / F234A / L235A / G237A / P238S on IgG4, and S228P / F234A / L235A / G236-deleted / G237A / P238S on IgG4.

[0758] The Fc substitution that can be used to reduce CDC is the K322A substitution.

[0759] The well-known S228P substitution can be additionally performed in IgG4 antibodies to enhance IgG4 stability.

[0760] An exemplary wild-type IgG1 contains the amino acid sequence of sequence number 103.

[0761] Sequence number 103:

[0762] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0763] 예시적인 야생형 IgG4는 서열 번호 104의 아미노산 서열을 포함한다.

[0764] Sequence number 104:

[0765] ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0766] " Antibody-dependent cellular cytotoxicity"Antibody-dependent cell-mediated cytotoxicity" or "ADCC" is a mechanism for inducing apoptosis that relies on the interaction between antibody-coated target cells and lytic effector cells, such as natural killer (NK) cells, monocytes, macrophages, and neutrophils, via the Fc gamma receptor (FcγR) expressed on effector cells. For example, NK cells express FcγRIIIa, while monocytes express FcγRI, FcγRII, and FcγRIIIa. The ADCC activity of an antibody can be evaluated using an in vitro assay in which cells expressing the protein to which the antibody binds are used as target cells, and NK cells are used as effector cells. Cell lysis can be detected by the release of a label (e.g., radioactive substrate, fluorescent dye, or natural intracellular protein) from the lysed cells. In an exemplary assay, target cells are used in a ratio of 1 target cell to 4 effector cells. The target cells are pre-treated with BATDA Labeled and combined with effector cells and test antibodies. Samples are incubated for 2 hours, and cell lysis is measured by measuring the BATDA released into the supernatant. Data are normalized against the maximum cytotoxicity by 0.67% Triton X-100 (Sigma Aldrich) and the minimum control determined by the spontaneous release of BATDA from target cells in the absence of any antibody.

[0767] " Antibody-dependent phagocytosis"("ADCP") refers to the mechanism of removal of antibody-coated target cells by internalization by phagocytes, such as macrophages or dendritic cells. ADCP can be evaluated by using monocyte-derived macrophages as effector cells and cells engineered to express the protein to which the antibody binds, as well as GFP or other labeled molecules, as target cells. In an exemplary assay, the effector:target cell ratio may be, for example, 4:1. Effector cells may be incubated with target cells for 4 hours with or without the antibody of the present invention. After incubation, the cells may be detached using accutase. Macrophages may be identified with anti-CD11b and anti-CD14 antibodies coupled to fluorescent labels, and % phagocytosis may be performed using standard methods for CD11 + CD14 + It can be determined based on % GFP fluorescence in macrophages.

[0768] " Complement-dependent cytotoxicity "Or "CDC" refers to a mechanism of apoptosis induction in which the Fc effector domain of a target-bound antibody binds to and activates the complement component C1q, which in turn activates the complement cascade to lead to target cell death. Complement activation can also result in the deposition of complement components on the surface of target cells, which facilitates CDC by binding to complement receptors on leukocytes (e.g., CR3). Cellular CDC, for example, in RPMI-B (RPMI supplemented with 1% BSA), 1 × 10 5The percentage of lysed cells can be measured by plating Dowdy cells at a rate of 50 μL / well, adding 50 μL of test antibody to the wells at a final concentration of 0 to 100 μg / mL, incubating the reaction mixture at room temperature for 15 minutes, adding 11 μL of pooled human serum to the wells, and incubating the reaction mixture at 37°C for 45 minutes. The percentage of lysed cells (%) can be detected as % propidium iodide-stained cells in a FACS assay using standard methods.

[0769] The binding of antibodies to FcγR or FcRn can be evaluated using flow cytometry in cells genetically engineered to express the respective receptors. In an exemplary binding assay, 2 × 10⁶ per well 5Cells were seeded into a 96-well plate and blocked in BSA staining buffer (BD Biosciences, San Jose, USA) at 4°C for 30 minutes. Cells were incubated with the test antibody on ice at 4°C for 1.5 hours. After washing twice with BSA staining buffer, cells were incubated with R-PE-labeled anti-human IgG secondary antibody (Jackson Immunoresearch Laboratories) at 4°C for 45 minutes. After washing twice with staining buffer, cells were resuspended in 150 μL of staining buffer containing 1:200 diluted DRAQ7 live / dead stain (Cell Signaling Technology, Denver, USA). PE and DRAQ7 signals of the stained cells were detected using a Miltenyi MACSQuant flow cytometer (Miltonyi Biotec, Auburn, USA) using B2 and B4 channels, respectively. Live cells are gated for DRAQ7 exclusion, and the geometric mean fluorescence signal is determined for at least 10,000 collected live events. FlowJo software (Tree Star) is used for the analysis. Data are plotted as the logarithm of antibody concentration versus mean fluorescence signal. Non-linear regression analysis is performed.

[0770] Chimeric Antigen Receptor (CAR)

[0771] Chimeric antigen receptors (CARs) are genetically engineered receptors. These engineered receptors can be easily inserted into immune cells, including T cells, and expressed by them according to techniques known in the art. In the case of CARs, a single receptor can be programmed to recognize a specific antigen and, when it binds to that antigen, to activate the immune cell to attack and destroy the cell possessing that antigen. When these antigens are present on tumor cells, immune cells expressing CARs can target and kill the tumor cells.

[0772] CAR typically comprises an extracellular domain that binds to an antigen (e.g., prostate neoantigen), a selective linker, a transmembrane domain, and a cytosolic domain comprising a co-stimulatory domain and / or a signaling domain.

[0773] The extracellular domain of the CAR may contain any polypeptide that binds to a desired antigen (e.g., prostate neoantigen). The extracellular domain may include scFv, a portion of an antibody, or an alternative scaffold. The CAR may also be engineered to bind to two or more desired antigens that can be arranged in a tandem form and separated by a linker sequence. For example, one or more domain antibodies, scFv, lamella VHH antibodies, or other VH monoantibody fragments may be organized in a tandem form via a linker to provide bispecificity or multispecificity to the CAR.

[0774] The transmembrane domain of the CAR is CD8, the alpha, beta, or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, KIRDS2, OX40, CD2, CD27, LFA-1 (CD18), ICOS (CD278), 4-1 BB (CD137), 4-1 BBL, GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRFI), CD160, CD19, IL2R beta, IL2R gamma, IL7R a, ITGA1, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CDI Id, ITGAE, CD103, ITGAL, CDI la, LFA-1, ITGAM, CDI lb, ITGAX, CDI lc, ITGB1, CD29, ITGB2, CD1 8, LFA-1, ITGB7, TNFR2, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRT AM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), SLAMF6 (NTB-A, Lyl08), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, PAG / Cbp, NKp44, NKp30, It may be derived from the transmembrane domains of NKp46, NKG2D, and / or NKG2C.

[0775] The intracellular co-stimulatory domain of a CAR can be derived from the intracellular domains of one or more co-stimulatory molecules. Co-stimulatory molecules are well-known cell surface molecules other than antigen receptors or Fc receptors that provide a secondary signal necessary for the efficient activation and function of T lymphocytes upon binding to an antigen. Exemplary co-stimulatory domains that can be used in a CAR are the intracellular domains of 4-1BB, CD2, CD7, CD27, CD28, CD30, CD40, CD54 (ICAM), CD83, CD134 (OX40), CD150 (SLAMF1), CD152 (CTLA4), CD223 (LAG3), CD270 (HVEM), CD278 (ICOS), DAP10, LAT, NKD2C, SLP76, TRIM, and ZAP70.

[0776] The intracellular signaling domain of the CAR may be derived from, for example, the signaling domains of O-3ζ, CD3ε, CD22, CD79a, CD66d, or CD39. The "intracellular signaling domain" refers to a part of the CAR polypeptide that participates in inducing other cellular responses induced after antigen binding to the extracellular CAR domain by transmitting the message of effective CAR binding to a target antigen into the immune effector cell to induce effector cell functions, e.g., activation, cytokine production, proliferation, and cytotoxic activity—including the release of cytotoxic factors to CAR-bound target cells—or other cellular responses induced after antigen binding to the extracellular CAR domain.

[0777] An optional linker of the CAR located between the extracellular domain and the transmembrane domain may be a polypeptide of about 2 to 100 amino acids in length. The linker may include or be composed of flexible residues, such as glycine and serine, to allow adjacent protein domains to move freely relative to each other. A longer linker may be used when it is desirable to ensure that two adjacent domains do not sterically interfere with each other. The linker may be cleavable or non-cleavable. Examples of cleavable linkers include 2A linkers (e.g., T2A), 2A-like linkers, or their functional equivalents, and combinations thereof. The linker may also be derived from the hinge region of any immunoglobulin or a portion of said hinge region.

[0778] Exemplary CARs that can be used include, for example, an extracellular domain binding to the prostate neoantigen of the present invention, a CD8 transmembrane domain, and CD3 It is a CAR containing a signaling domain. Other exemplary CARs include an extracellular domain that binds to the prostate neoantigen of the present invention, a CD8 or CD28 transmembrane domain, a CD28, 41BB or OX40 co-stimulatory domain, and CD3 It includes a signaling domain.

[0779] CAR is generated by standard molecular biology techniques. The extracellular domain that binds to the desired antigen may be derived from an antibody or its antigen-binding fragment generated using the techniques described herein.

[0780] Although the present invention has been described in a general sense, embodiments of the invention will be further disclosed in the following examples, provided that such examples are not to be interpreted as limiting the scope of the claims.

[0781] Further embodiments of the present invention

[0782] Specific additional embodiments of the present invention according to the present disclosure located elsewhere in this specification are listed below. Features from the embodiments of the present invention listed above, described as related to the present invention disclosed in this specification, also relate to each of these additional numbered embodiments.

[0783] Embodiment 1. An anti-CD38 antibody for use in combination with a T-cell re-induction therapy to treat a subject with cancer.

[0784] Embodiment 2. Anti-CD38 antibody for use in enhancing the efficacy of a T-cell re-induction therapeutic agent in subjects with cancer.

[0785] Embodiment 3. Use of an anti-CD38 antibody for the preparation of a drug or pharmaceutical composition for treating a patient with cancer in combination with a T-cell re-induction therapy.

[0786] Embodiment 4. Use of an anti-CD38 antibody in combination with a T-cell re-induction therapeutic agent, wherein the anti-CD38 antibody is provided to produce a combination useful for treating a subject having cancer in a patient requiring treatment for cancer.

[0787] Embodiment 5. In any one of Embodiments 1 to 4, the anti-CD38 antibody for use is administered before administering the T-cell re-induction therapeutic agent.

[0788] Embodiment 6. In any one of Embodiments 1 to 5, the T-cell re-induction therapeutic agent is an anti-CD38 antibody for said use that binds to BCMA, GPRC5D, CD33, CD123, CD19, PSMA, TMEFF2, or CD20.

[0789] Embodiment 7. In any one of Embodiments 1 to 6, the T-cell re-induction therapeutic agent is an anti-CD38 antibody for use that binds to CD3, CD3 epsilon (CD3ε), CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, BTNL8, PD-1, CD195, or NKG2C.

[0790] Embodiment 8. In any one of Embodiments 1 to 7, the T-cell re-induction therapeutic agent comprises a CD3 binding domain, and the CD3 binding domain

[0791] 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;

[0792] The heavy chain variable region (VH) of sequence number 39 and the light chain variable region (VL) of sequence number 40;

[0793] HCDR1 of sequence number 74, HCDR2 of sequence number 75, HCDR3 of sequence number 76, LCDR1 of sequence number 77, LCDR2 of sequence number 78, and LCDR3 of sequence number 79;

[0794] VH of sequence number 80 and VL of sequence number 81;

[0795] HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of the CD3 binding domain of sequence no. 53; or

[0796] An anti-CD38 antibody for the above use, comprising VH and VL of the CD3 binding domain of sequence number 53.

[0797] Embodiment 9. In any one of Embodiments 1 to 8, the T-cell re-induction therapeutic agent

[0798] A BCMA binding domain comprising HCDR1 of SEQ ID NO. 23, HCDR2 of SEQ ID NO. 24, HCDR3 of SEQ ID NO. 25, LCDR1 of SEQ ID NO. 26, LCDR2 of SEQ ID NO. 27, and LCDR3 of SEQ ID NO. 28, and a CD3 binding domain comprising HCDR1 of SEQ ID NO. 33, HCDR2 of SEQ ID NO. 34, HCDR3 of SEQ ID NO. 35, LCDR1 of SEQ ID NO. 36, LCDR2 of SEQ ID NO. 37, and LCDR3 of SEQ ID NO. 38, and / or;

[0799] An anti-CD38 antibody for the above use, comprising a BCMA binding domain including VH of SEQ ID NO. 29 and VL of SEQ ID NO. 30, and a CD3 binding domain including VH of SEQ ID NO. 39 and VL of SEQ ID NO. 40.

[0800] Embodiment 10. In any one of Embodiments 1 to 9, the T-cell re-induction therapeutic agent comprises a first heavy chain (HC1) of SEQ ID NO. 31, a first light chain (LC1) of SEQ ID NO. 32, a second heavy chain (HC2) of SEQ ID NO. 41, and a second light chain (LC2) of SEQ ID NO. 42, an anti-CD38 antibody for said use.

[0801] Embodiment 11. In any one of Embodiments 1 to 10, the T-cell re-induction therapeutic agent

[0802] GPRC5D binding domains 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 CD3 binding domains comprising HCDR1 of SEQ ID NO. 33, HCDR2 of SEQ ID NO. 34, HCDR3 of SEQ ID NO. 35, LCDR1 of SEQ ID NO. 36, LCDR2 of SEQ ID NO. 37, and LCDR3 of SEQ ID NO. 38, and / or;

[0803] An anti-CD38 antibody for the above use, comprising a GPRC5D binding domain comprising VH of SEQ ID NO. 49 and VL of SEQ ID NO. 50, and a CD3 binding domain comprising VH of SEQ ID NO. 39 and VL of SEQ ID NO. 40.

[0804] Embodiment 12. In any one of Embodiments 111, the T-cell re-induction therapeutic agent comprises HC1 of SEQ ID NO. 51, LC1 of SEQ ID NO. 52, HC2 of SEQ ID NO. 41, and LC2 of SEQ ID NO. 42, an anti-CD38 antibody for said use.

[0805] Embodiment 13. In any one of Embodiments 1 to 12, the T-cell re-induction therapeutic agent

[0806] A CD33 binding domain comprising HCDR1 of SEQ ID NO. 84, HCDR2 of SEQ ID NO. 85, HCDR3 of SEQ ID NO. 86, LCDR1 of SEQ ID NO. 87, LCDR2 of SEQ ID NO. 88, and LCDR3 of SEQ ID NO. 89, and a CD3 binding domain comprising HCDR1 of SEQ ID NO. 74, HCDR2 of SEQ ID NO. 75, HCDR3 of SEQ ID NO. 76, LCDR1 of SEQ ID NO. 77, LCDR2 of SEQ ID NO. 78, and LCDR3 of SEQ ID NO. 79, and / or;

[0807] An anti-CD38 antibody for the above use, comprising a CD33 binding domain comprising VH of SEQ ID NO. 90 and VL of SEQ ID NO. 91, and a CD3 binding domain comprising VH of SEQ ID NO. 80 and VL of SEQ ID NO. 81.

[0808] Embodiment 14. In any one of Embodiments 1 to 13, the T-cell re-induction therapeutic agent comprises HC1 of SEQ ID NO. 92, LC1 of SEQ ID NO. 93, HC2 of SEQ ID NO. 82, and LC2 of SEQ ID NO. 83, an anti-CD38 antibody for said use.

[0809] Embodiment 15. In any one of Embodiments 1 to 14, the T-cell re-induction therapeutic agent

[0810] A CD123 binding domain comprising HCDR1 of SEQ ID NO. 94, HCDR2 of SEQ ID NO. 95, HCDR3 of SEQ ID NO. 96, LCDR1 of SEQ ID NO. 9, LCDR2 of SEQ ID NO. 10, and LCDR3 of SEQ ID NO. 59, and a CD3 binding domain comprising HCDR1 of SEQ ID NO. 33, HCDR2 of SEQ ID NO. 34, HCDR3 of SEQ ID NO. 35, LCDR1 of SEQ ID NO. 36, LCDR2 of SEQ ID NO. 37, and LCDR3 of SEQ ID NO. 38, and / or;

[0811] An anti-CD38 antibody for the above use, comprising a CD123 binding domain comprising VH of SEQ ID NO. 100 and VL of SEQ ID NO. 61, and a CD3 binding domain comprising VH of SEQ ID NO. 39 and VL of SEQ ID NO. 40.

[0812] Embodiment 16. In any one of Embodiments 1 to 15, the T-cell re-induction therapeutic agent comprises HC1 of SEQ ID NO. 102, LC1 of SEQ ID NO. 63, HC2 of SEQ ID NO. 41, and LC2 of SEQ ID NO. 42, an anti-CD38 antibody for said use.

[0813] Embodiment 17. In any one of Embodiments 1 to 16, the T-cell re-induction therapeutic agent

[0814] A CD19 binding domain comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of the CD19 binding domain of SEQ NO. 53, and a CD3 binding domain comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of the CD3 binding domain of SEQ NO. 53, and / or;

[0815] Anti-CD38 antibody for the above use, comprising the amino acid sequence of SEQ No. 53.

[0816] Embodiment 18. In any one of Embodiments 1 to 17, the T-cell re-induction therapeutic agent

[0817] PSMA binding domains comprising HCDR1 of SEQ ID NO. 54, HCDR2 of SEQ ID NO. 55, HCDR3 of SEQ ID NO. 56, LCDR1 of SEQ ID NO. 9, LCDR2 of SEQ ID NO. 10, and LCDR3 of SEQ ID NO. 59, and CD3 binding domains comprising HCDR1 of SEQ ID NO. 33, HCDR2 of SEQ ID NO. 34, HCDR3 of SEQ ID NO. 35, LCDR1 of SEQ ID NO. 36, LCDR2 of SEQ ID NO. 37, and LCDR3 of SEQ ID NO. 38, and / or;

[0818] An anti-CD38 antibody for the above use, comprising a PSMA binding domain comprising VH of SEQ ID NO. 60 and VL of SEQ ID NO. 61, and a CD3 binding domain comprising VH of SEQ ID NO. 39 and VL of SEQ ID NO. 40.

[0819] Embodiment 19. In any one of Embodiments 1 to 18, the T-cell re-induction therapeutic agent comprises HC1 of SEQ ID NO. 62, LC1 of SEQ ID NO. 63, HC2 of SEQ ID NO. 41, and LC2 of SEQ ID NO. 42, an anti-CD38 antibody for said use.

[0820] Embodiment 20. In any one of Embodiments 1 to 19, the T-cell re-induction therapeutic agent

[0821] A TMEFF2 binding domain comprising HCDR1 of SEQ ID NO. 64, HCDR2 of SEQ ID NO. 65, HCDR3 of SEQ ID NO. 66, LCDR1 of SEQ ID NO. 67, LCDR2 of SEQ ID NO. 68, and LCDR3 of SEQ ID NO. 69, and a CD3 binding domain comprising HCDR1 of SEQ ID NO. 74, HCDR2 of SEQ ID NO. 75, HCDR3 of SEQ ID NO. 76, LCDR1 of SEQ ID NO. 77, LCDR2 of SEQ ID NO. 78, and LCDR3 of SEQ ID NO. 79, and / or;

[0822] An anti-CD38 antibody for the above use, comprising a TMEFF2 binding domain comprising VH of SEQ ID NO. 70 and VL of SEQ ID NO. 71, and a CD3 binding domain comprising VH of SEQ ID NO. 80 and VL of SEQ ID NO. 81.

[0823] Embodiment 21. In any one of Embodiments 1 to 20, the T-cell re-induction therapeutic agent comprises HC1 of SEQ ID NO. 72, LC1 of SEQ ID NO. 73, HC2 of SEQ ID NO. 82, and LC2 of SEQ ID NO. 83, an anti-CD38 antibody for said use.

[0824] Embodiment 22. In any one of Embodiments 1 to 21, the T-cell re-induction therapeutic agent is an anti-CD38 antibody for said use, which is a multispecific antibody, a chimeric antigen receptor (CAR), or a T cell comprising said CAR.

[0825] Embodiment 23. The anti-CD38 antibody for use in Embodiment 22, wherein the multispecific antibody is an IgG1, IgG2, IgG3, or IgG4 homotype.

[0826] Embodiment 24. An anti-CD38 antibody for use in Embodiment 22 or Embodiment 23, wherein the multispecific antibody comprises one or more Fc substitutions that reduce the binding of the multispecific antibody to the Fcγ receptor (FcγR).

[0827] Embodiment 25. In any one of Embodiments 22 to 24, the one or more Fc substitutions are F234A / L235A on IgG4, L234A / L235A on IgG1, V234A / G237A / P238S / H268A / V309L / A330S / P331S on IgG2, F234A / L235A on IgG4, S228P / F234A / L235A on IgG4, N297A on all Ig isotypes, V234A / G237A on IgG2, K214T / E233P / L234V / L235A / G236-deletion / A327G / P331A / D365E / L358M on IgG1, and on IgG2 An anti-CD38 antibody for the above use, selected from the group consisting of H268Q / V309L / A330S / P331S, S267E / L328F on IgG1, L234F / L235E / D265A on IgG1, L234A / L235A / G237A / P238S / H268A / A330S / P331S on IgG1, S228P / F234A / L235A / G237A / P238S on IgG4, and S228P / F234A / L235A / G236-deleted / G237A / P238S on IgG4, wherein the residue numbering follows the EU index.

[0828] Embodiment 26. The anti-CD38 antibody for use in Embodiment 25, wherein the multispecific antibody further comprises an S228P substitution.

[0829] Embodiment 27. An anti-CD38 antibody for use, wherein in any one of Embodiments 22 to 26, the multispecific antibody comprises one or more asymmetric substitutions in a first CH3 domain or in a second CH3 domain, or in both the first CH3 domain and the second CH3 domain.

[0830] Embodiment 28. In Embodiment 27, the one or more asymmetric substitutions are F450L / K409R, wild type / F409L_R409K, T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S and T366W / T366S_L368A_Y407V, L351Y_F405A_Y407V / T394W, T366I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, An anti-CD38 antibody for the above use, selected from the group consisting of L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F and T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W.

[0831] Embodiment 29. Any one of Embodiments 1 to 28, wherein the subject has newly diagnosed cancer, an anti-CD38 antibody for said use.

[0832] Embodiment 30. In any one of Embodiments 1 to 29, the subject is relapsed or refractory to previous anticancer therapy, and the anti-CD38 antibody for said use.

[0833] Embodiment 31. An anti-CD38 antibody for use in any one of Embodiments 1 to 30, wherein the cancer is a hematological malignant tumor or a solid tumor.

[0834] Embodiment 32. In any one of Embodiments 1 to 31, the hematological malignancy is multiple myeloma, asymptomatic multiple myeloma, monoclonal gammapathia of unknown significance (MGUS), acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), follicular lymphoma (FL), mantle-cell lymphoma (MCL), Waldenström macroglobulinemia, plasma cell leukemia, light chain amyloidosis (AL), precursor B-cell lymphoblastic leukemia, precursor B-cell lymphoblastic leukemia, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic lymphocytic leukemia (CLL), B-cell malignancy, chronic myeloid leukemia (CML), hairy cell leukemia (HCL), blastocystoid plasmacytic dendritic neoplasm, Hodgkin lymphoma, non-Hodgkin lymphoma, marginal zone B-cell Anti-CD38 antibody for use in lymphoma (MZL) or mucosa-associated lymphoid tissue lymphoma (MALT), plasma cell leukemia, anaplastic large cell lymphoma (ALCL), leukemia or lymphoma.

[0835] Embodiment 33. An anti-CD38 antibody for use in any one of Embodiments 1 to 32, wherein the multiple myeloma is a newly diagnosed multiple myeloma.

[0836] Embodiment 34. An anti-CD38 antibody for use in any one of Embodiments 1 to 32, wherein the multiple myeloma is relapsed or refractory multiple myeloma.

[0837] Embodiment 35. An anti-CD38 antibody for use in any one of Embodiments 1 to 34, wherein the multiple myeloma is a high-risk multiple myeloma.

[0838] Embodiment 36. In Embodiment 35, the subject having high-risk multiple myeloma has one or more chromosomal abnormalities comprising the following, an anti-CD38 antibody for use:

[0839] t(4;14)(p16;q32);

[0840] t(14;16)(q32;q23);

[0841] del17p;

[0842] 1qAmp;

[0843] t(4;14)(p16;q32) and t(14;16)(q32;q23);

[0844] t(4;14)(p16;q32) and del17p;

[0845] t(14;16)(q32;q23) and del17p; or

[0846] t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p, or any combination thereof.

[0847] Embodiment 37. Any one of Embodiments 1 to 36, wherein the multiple myeloma is relapsed or refractory to treatment with the anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, erlotozumab, ixazomib, melphalan, or thalidomide, or any combination thereof, the anti-CD38 antibody for use.

[0848] Embodiment 38. An anti-CD38 antibody for use in any one of Embodiments 1 to 37, wherein the solid tumor is prostate cancer, lung cancer, liver cancer, cervical cancer, colon cancer, breast cancer, ovarian cancer, endometrial cancer, pancreatic cancer, melanoma, glioblastoma, esophageal cancer, gastric cancer, gastric adenocarcinoma, renal carcinoma, colon cancer, bladder cancer, cervical carcinoma, melanoma, hepatocellular carcinoma, renal cell carcinoma, urothelial carcinoma, head and neck cancer, glioma, or glioblastoma.

[0849] Embodiment 39. The anti-CD38 antibody for use in Embodiment 38, wherein the prostate cancer is recurrent, refractory, malignant or castration-resistant prostate cancer, or any combination thereof.

[0850] Embodiment 40. The anti-CD38 antibody for use in Embodiment 32, wherein the AML is AML having at least one genetic abnormality, AML having multiple lineage atypicality, therapy-associated AML, undifferentiated AML, AML having minimal maturation, AML having maturation, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, acute megakaryoblastic leukemia, acute basophilic leukemia, acute panmyelosis with fibrosis, or myeloid sarcoma.

[0851] Embodiment 41. The anti-CD38 antibody for use in Embodiment 40, wherein the at least one genetic abnormality is a translocation between chromosome 8 and chromosome 21, a translocation or inversion in chromosome 16, a translocation between chromosome 15 and chromosome 17, a change in chromosome 11, or a mutation in fms-associated tyrosine kinase 3 (FLT3), nucleophosmin (NPM1), isocitrate dehydrogenase 1 (IDH1), isocitrate dehydrogenase 2 (IDH2), DNA (cytosine-5)-methyltransferase 3 (DNMT3A), CCAAT / enhancer binding protein alpha (CEBPA), U2 small nuclear RNA cofactor 1 (U2AF1), Zest 2 Polycomb repression complex 2 subunit enhancer (EZH2), chromosome structure maintenance protein 1A (SMC1A) or chromosome structure maintenance protein 3 (SMC3).

[0852] Embodiment 42. The anti-CD38 antibody for use in Embodiment 41, wherein at least one genetic abnormality is a translocation t(8; 21)(q22; q22), an inversion inv(16)(p13; q22), a translocation t(16; 16)(p13; q22), a translocation t(15; 17)(q22; q12), a mutant FLT3-ITD, a mutant R132H or R100Q / R104V / F108L / R119Q / I130V in IDH1 or a mutant R140Q or R172 in IDH2.

[0853] Embodiment 43. An anti-CD38 antibody for use in Embodiment 32, wherein the ALL is a B-cell lineage ALL, a T-cell lineage ALL, an adult ALL, or a pediatric ALL.

[0854] Embodiment 44. The anti-CD38 antibody for use in Embodiment 43, wherein the subject having ALL has a Philadelphia chromosome or exhibits resistance to treatment with a BCR-ABL kinase inhibitor or has acquired resistance.

[0855] Embodiment 45. An anti-CD38 antibody for use in any one of Embodiments 1 to 44, wherein the anti-CD38 antibody comprises HCDR1 of SEQ ID NO. 6, HCDR2 of SEQ ID NO. 7, HCDR3 of SEQ ID NO. 8, LCDR1 of SEQ ID NO. 9, LCDR2 of SEQ ID NO. 10, and LCDR3 of SEQ ID NO. 11.

[0856] Embodiment 46. An anti-CD38 antibody for use in any one of Embodiments 1 to 45, wherein the anti-CD38 antibody comprises VH of SEQ ID NO. 4 and VL of SEQ ID NO. 5.

[0857] Embodiment 47. In any one of Embodiments 1 to 46, the anti-CD38 antibody for use is an IgG1 isotype.

[0858] Embodiment 48. An anti-CD38 antibody for use in any one of Embodiments 1 to 47, wherein the anti-CD38 antibody comprises the HC of SEQ ID NO. 12 and the LC of SEQ ID NO. 13.

[0859] Embodiment 49. In any one of Embodiments 1 to 44, the anti-CD38 antibody

[0860] VH of sequence number 14 and VL of sequence number 15;

[0861] VH of sequence number 16 and VL of sequence number 17;

[0862] VH of SEQ ID NO. 18 and VL of SEQ ID NO. 19; or

[0863] Anti-CD38 antibody for the above use, comprising VH of SEQ ID NO. 20 and VL of SEQ ID NO. 21.

[0864] Embodiment 50. In Embodiment 49, the anti-CD38 antibody for use is an IgG1 isotype.

[0865] Embodiment 51. In any one of Embodiments 1 to 50, the T-cell re-induction therapeutic agent is an anti-CD38 antibody for use, wherein the anti-CD38 antibody is a BCMAxCD3 bispecific antibody, a GPRC5DxCD3 bispecific antibody, a CD33xCD3 bispecific antibody, a CD19xCD3 bispecific antibody, a CD123xCD3 bispecific antibody, a PSMAxCD3 bispecific antibody, or a TMEFF2xCD3 bispecific antibody.

[0866] Embodiment 52. An anti-CD38 antibody for said use, wherein in any one of Embodiments 1 to 51, the step of administering one or more anticancer therapies to said subject is further included.

[0867] Embodiment 53. An anti-CD38 antibody for use in any one of Embodiments 1 to 52, wherein one or more anticancer therapies are selected from the group consisting of autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapy agents, immunomodulators, and targeted cancer therapies.

[0868] Embodiment 54. In any one of Embodiments 1 to 53, the one or more anticancer therapies are lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, erlotozumab, ixazomib, melphalan, dexamethasone, vincristine, cyclophosphamide, hydroxyidaunorubicin, prednisone, rituximab, imatinib, dasatinib, nilotinib, bosutinib, ponatinib, bafetinib, saracatinib, tozasertip or danucertip, cytarabine, daunorubicin, idarubicin, mitoxantrone, hydroxyurea, decitabine, cladribine, fludarabine, topotecan, etoposide, 6-thioguanine, corticosteroid, methotrexate, An anti-CD38 antibody for said use, selected from the group consisting of 6-mercaptopurine, azacitidine, arsenic trioxide and all-trans retinoic acid, or any combination thereof.

[0869] Embodiment 55. An anti-CD38 antibody for use, wherein in any one of Embodiments 1 to 54, the anti-CD38 antibody is administered at a dose of about 8 mg / kg to about 16 mg / kg.

[0870] Embodiment 56. The anti-CD38 antibody for use, wherein in any one of Embodiments 1 to 55, the anti-CD38 antibody is administered into a pharmaceutical composition having a pH of about 5.5 comprising about 20 mg / mL to about 120 mg / mL of the anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mg / mL mannitol, and about 0.04% w / v polysorbate-20 (PS-20), or provided for administration into said pharmaceutical composition.

[0871] Embodiment 57. An anti-CD38 antibody for use, wherein in any one of Embodiments 1 to 53, the anti-CD38 antibody is administered as a pharmaceutical composition comprising about 1,800 mg of the anti-CD38 antibody and about 30,000 U of rHuPH20, or provided for administration to said pharmaceutical composition.

[0872] Embodiment 58. The anti-CD38 antibody for use in Embodiment 57, wherein the anti-CD38 antibody is administered as a pharmaceutical composition comprising about 120 mg / mL of the anti-CD38 antibody and about 2,000 U / mL of rHuPH20, or provided for administration to said pharmaceutical composition.

[0873] Embodiment 59. In Embodiment 57 or Embodiment 58, the anti-CD38 antibody is

[0874] About 5 mM to about 15 mM histidine;

[0875] About 100 mM to about 300 mM sorbitol;

[0876] About 0.01% w / v to about 0.04% w / v PS-20; and

[0877] An anti-CD38 antibody for said use, administered to a pharmaceutical composition having a pH of about 5.5 to 5.6 containing about 1 mg / mL to about 2 mg / mL of methionine, or provided for administration to said pharmaceutical composition.

[0878] Embodiment 60. In any one of Embodiments 57 to 59, the anti-CD38 antibody

[0879] Approximately 1,800 mg of the above anti-CD38 antibody;

[0880] Approximately 30,000 U of rHuPH20;

[0881] Approximately 10 mM histidine;

[0882] Approximately 300 mM sorbitol;

[0883] Approximately 0.04% (w / v) PS-20; and

[0884] An anti-CD38 antibody for said use, administered as a pharmaceutical composition having a pH of about 5.6 containing about 1 mg / mL of methionine, or provided for administration as said pharmaceutical composition.

[0885] Embodiment 61. In any one of Embodiments 57 to 60, the anti-CD38 antibody

[0886] Approximately 120 mg / mL of the above anti-CD38 antibody;

[0887] Approximately 2,000 U / mL of rHuPH20;

[0888] Approximately 10 mM histidine;

[0889] Approximately 300 mM sorbitol;

[0890] Approximately 0.04% (w / v) PS-20; and

[0891] An anti-CD38 antibody for said use, administered as a pharmaceutical composition having a pH of about 5.6 containing about 1 mg / mL of methionine, or provided for administration as said pharmaceutical composition.

[0892] Embodiment 62. A BCMAxCD3 bispecific antibody for use in combination with an anti-CD38 antibody to treat a subject with cancer.

[0893] Embodiment 63. The BCMAxCD3 bispecific antibody for use in Embodiment 62, wherein the subject has been treated with an anti-CD38 antibody prior to administration of the BCMAxCD3 bispecific antibody.

[0894] Embodiment 64. The BCMAxCD3 bispecific antibody for use in Embodiment 62 or Embodiment 63, wherein the BCMAxCD3 bispecific antibody comprises a BCMA binding domain comprising HCDR1 of SEQ ID NO. 23, HCDR2 of SEQ ID NO. 24, HCDR3 of SEQ ID NO. 25, LCDR1 of SEQ ID NO. 26, LCDR2 of SEQ ID NO. 27, and LCDR3 of SEQ ID NO. 28, and 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.

[0895] Embodiment 65. A BCMAxCD3 bispecific antibody for use, wherein in any one of Embodiments 62 to 64, the BCMA binding domain comprises VH of SEQ ID NO. 29 and VL of SEQ ID NO. 30, and the CD3 binding domain comprises VH of SEQ ID NO. 39 and VL of SEQ ID NO. 40.

[0896] Embodiment 66. A BCMAxCD3 bispecific antibody for use in any one of Embodiments 62 to 65, wherein the BCMAxCD3 bispecific antibody is IgG4 homotype and comprises phenylalanine at position 405 and arginine at position 409 in HC1 and leucine at position 405 and lysine at position 409 in HC2, and the residue numbering follows the EU index.

[0897] Embodiment 67. A BCMAxCD3 bispecific antibody for use, wherein in any one of Embodiments 62 to 66, the BCMAxCD3 bispecific antibody further comprises proline at position 228, alanine at position 234, and alanine at position 235 in both HC1 and HC2.

[0898] Embodiment 68. A BCMAxCD3 bispecific antibody for use in any one of Embodiments 62 to 67, wherein 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.

[0899] Embodiment 69. A BCMAxCD3 bispecific antibody for use in any one of Embodiments 62 to 68, wherein the cancer is a BCMA-expressing cancer.

[0900] Embodiment 70. A BCMAxCD3 bispecific antibody for use, wherein in any one of Embodiments 62 to 69, the cancer is a hematological malignant tumor.

[0901] Embodiment 71. Any one of Embodiments 62 to 70, wherein the subject is a BCMAxCD3 bispecific antibody for said use that is relapsed or refractory to treatment with the anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, erlotozumab, ixazomib, melphalan or thalidomide, or any combination thereof.

[0902] Embodiment 72. In any one of Embodiments 62 to 71, the subject is a BCMAxCD3 bispecific antibody for said use that is relapsed or refractory to treatment with said anti-CD38 antibody.

[0903] Embodiment 73. A BCMAxCD3 bispecific antibody for use in any one of Embodiments 62 to 72, wherein the hematological malignancy is multiple myeloma, myeloma, DLBLC, CLL, Waldenström hypergammaglobulinemia, or non-Hodgkin lymphoma.

[0904] Embodiment 74. The BCMAxCD3 bispecific antibody for use in Embodiment 73, wherein the multiple myeloma is a newly diagnosed multiple myeloma.

[0905] Embodiment 75. A BCMAxCD3 bispecific antibody for use in Embodiment 74, wherein the multiple myeloma is relapsed or refractory multiple myeloma.

[0906] Embodiment 76. In Embodiment 74, the BCMAxCD3 bispecific antibody for use, wherein the multiple myeloma is a high-risk multiple myeloma.

[0907] Embodiment 77. In Embodiment 76, the subject having high-risk multiple myeloma has one or more chromosomal abnormalities comprising the following, a BCMAxCD3 bispecific antibody for use:

[0908] t(4;14)(p16;q32);

[0909] t(14;16)(q32;q23);

[0910] del17p;

[0911] 1qAmp;

[0912] t(4;14)(p16;q32) and t(14;16)(q32;q23);

[0913] t(4;14)(p16;q32) and del17p;

[0914] t(14;16)(q32;q23) and del17p; or

[0915] t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p, or any combination thereof.

[0916] Embodiment 78. A BCMAxCD3 bispecific antibody for use in any one of Embodiments 62 to 77, wherein the anti-CD38 antibody comprises HCDR1 of SEQ ID NO. 6, HCDR2 of SEQ ID NO. 7, HCDR3 of SEQ ID NO. 8, LCDR1 of SEQ ID NO. 9, LCDR2 of SEQ ID NO. 10, and LCDR3 of SEQ ID NO. 11.

[0917] Embodiment 79. A BCMAxCD3 bispecific antibody for use in any one of Embodiments 62 to 78, wherein the anti-CD38 antibody comprises VH of SEQ ID NO. 4 and VL of SEQ ID NO. 5.

[0918] Embodiment 80. In any one of Embodiments 62 to 79, the anti-CD38 antibody is an IgG1 homotype, a BCMAxCD3 bispecific antibody for said use.

[0919] Embodiment 81. A BCMAxCD3 bispecific antibody for use in any one of Embodiments 62 to 80, wherein the anti-CD38 antibody comprises the HC of SEQ ID NO. 12 and the LC of SEQ ID NO. 13.

[0920] Embodiment 82. In any one of Embodiments 62 to 77, the anti-CD38 antibody

[0921] VH of sequence number 14 and VL of sequence number 15;

[0922] VH of sequence number 16 and VL of sequence number 17;

[0923] VH of SEQ ID NO. 18 and VL of SEQ ID NO. 19; or

[0924] A BCMAxCD3 bispecific antibody for the above use comprising VH of SEQ ID NO. 20 and VL of SEQ ID NO. 21.

[0925] Embodiment 83. In Embodiment 82, the anti-CD38 antibody is an IgG1 isotype, a BCMAxCD3 bispecific antibody for the above use.

[0926] Embodiment 84. A BCMAxCD3 bispecific antibody for use, wherein in any one of Embodiments 62 to 83, the anti-CD38 antibody is administered at a dose of about 8 mg / kg to about 16 mg / kg.

[0927] Embodiment 85. In any one of Embodiments 62 to 84, the BCMAxCD3 bispecific antibody and the anti-CD38 antibody for use are administered by intravenous injection.

[0928] Embodiment 86. A BCMAxCD3 bispecific antibody for use in any one of Embodiments 62 to 84, wherein the BCMAxCD3 bispecific antibody is administered by intravenous injection and the anti-CD38 antibody is administered by subcutaneous injection.

[0929] Embodiment 87. A BCMAxCD3 bispecific antibody for use, wherein the subject is a human, in any one of Embodiments 62 to 86.

[0930] Embodiment 88. A BCMAxCD3 bispecific antibody for said use, wherein in any one of Embodiments 62 to 87, the step of administering one or more anticancer therapies to said subject is further included.

[0931] Embodiment 89. The BCMAxCD3 bispecific antibody for use in Embodiment 88, wherein one or more anticancer therapies are selected from the group consisting of autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapy agents, immunomodulators, and targeted cancer therapies.

[0932] Embodiment 90. In Embodiment 88 or Embodiment 89, the one or more anticancer therapies are selected from the group consisting of lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, erlotozumab, ixazomib, melphalan, prednisone, or dexamethasone, or any combination thereof, a BCMAxCD3 bispecific antibody for said use.

[0933] Embodiment 91. A BCMAxCD3 bispecific antibody for said use, wherein in any one of Embodiments 62 to 90, the anti-CD38 antibody is administered into a pharmaceutical composition having a pH of about 5.5 comprising about 20 mg / mL to about 120 mg / mL of said anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mg / mL mannitol and about 0.04% w / v polysorbate-20 (PS-20), or provided for administration into said pharmaceutical composition.

[0934] Embodiment 92. A BCMAxCD3 bispecific antibody for said use, wherein in any one of Embodiments 62 to 90, the anti-CD38 antibody is administered as a pharmaceutical composition comprising about 1,800 mg of said anti-CD38 antibody and about 30,000 U of rHuPH20, or provided for administration to said pharmaceutical composition.

[0935] Embodiment 93. The anti-CD38 antibody of Embodiment 92, wherein the anti-CD38 antibody is administered as a pharmaceutical composition comprising about 120 mg / mL of the anti-CD38 antibody and about 2,000 U / mL of rHuPH20, or provided for administration to said pharmaceutical composition, a BCMAxCD3 bispecific antibody for said use.

[0936] Embodiment 94. In Embodiment 92 or Embodiment 93, the anti-CD38 antibody is

[0937] About 5 mM to about 15 mM histidine;

[0938] About 100 mM to about 300 mM sorbitol;

[0939] About 0.01% w / v to about 0.04% w / v PS-20; and

[0940] A BCMAxCD3 bispecific antibody for said use, administered with a pharmaceutical composition having a pH of about 5.5 to 5.6 containing about 1 mg / mL to about 2 mg / mL of methionine, or provided for administration with said pharmaceutical composition.

[0941] Embodiment 95. In any one of Embodiments 92 to 94, the anti-CD38 antibody

[0942] Approximately 1,800 mg of the above anti-CD38 antibody;

[0943] Approximately 30,000 U of rHuPH20;

[0944] Approximately 10 mM histidine;

[0945] Approximately 300 mM sorbitol;

[0946] Approximately 0.04% (w / v) PS-20; and

[0947] A BCMAxCD3 bispecific antibody for said use, administered with a pharmaceutical composition having a pH of about 5.6 containing about 1 mg / mL of methionine or provided for administration with said pharmaceutical composition.

[0948] Embodiment 96. In any one of Embodiments 92 to 95, the anti-CD38 antibody

[0949] Approximately 120 mg / mL of the above anti-CD38 antibody;

[0950] Approximately 2,000 U / mL of rHuPH20;

[0951] Approximately 10 mM histidine;

[0952] Approximately 300 mM sorbitol;

[0953] Approximately 0.04% (w / v) PS-20; and

[0954] A BCMAxCD3 bispecific antibody for said use, administered with a pharmaceutical composition having a pH of about 5.6 containing about 1 mg / mL of methionine or provided for administration with said pharmaceutical composition.

[0955] Embodiment 97. A BCMAxCD3 bispecific antibody for use in treating a subject having cancer,

[0956] The above subject is a BCMAxCD3 bispecific antibody that is relapsed or refractory to previous anticancer treatment.

[0957] Embodiment 98. The BCMAxCD3 bispecific antibody for use in Embodiment 97, wherein the BCMAxCD3 bispecific antibody comprises a BCMA binding domain comprising HCDR1 of SEQ ID NO. 23, HCDR2 of SEQ ID NO. 24, HCDR3 of SEQ ID NO. 25, LCDR1 of SEQ ID NO. 26, LCDR2 of SEQ ID NO. 27, and LCDR3 of SEQ ID NO. 28, and 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.

[0958] Embodiment 99. A BCMAxCD3 bispecific antibody for use, wherein, in Embodiment 97 or Embodiment 98, the BCMA binding domain comprises VH of SEQ ID NO. 29 and VL of SEQ ID NO. 30, and the CD3 binding domain comprises VH of SEQ ID NO. 39 and VL of SEQ ID NO. 40.

[0959] Embodiment 100. A BCMAxCD3 bispecific antibody for use, wherein in any one of Embodiments 97 to 99, the BCMAxCD3 bispecific antibody is IgG4 homotype and comprises phenylalanine at position 405 and arginine at position 409 in HC1 and leucine at position 405 and lysine at position 409 in HC2, and the residue numbering follows the EU index.

[0960] Embodiment 101. The BCMAxCD3 bispecific antibody for use in Embodiment 100, wherein the BCMAxCD3 bispecific antibody further comprises proline at position 228, alanine at position 234, and alanine at position 235 in both HC1 and HC2.

[0961] Embodiment 102. A BCMAxCD3 bispecific antibody for use in any one of Embodiments 97 to 101, wherein 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.

[0962] Embodiment 103. A BCMAxCD3 bispecific antibody for use, wherein in any one of Embodiments 97 to 102, the cancer is a hematological malignant tumor.

[0963] Embodiment 104. A BCMAxCD3 bispecific antibody for use in Embodiment 103, wherein the hematological malignancy is multiple myeloma.

[0964] Embodiment 105. In Embodiment 104, the BCMAxCD3 bispecific antibody for use, wherein the multiple myeloma is a high-risk multiple myeloma.

[0965] Embodiment 106. The BCMAxCD3 bispecific antibody for use in Embodiment 105, wherein the subject having high-risk multiple myeloma has one or more chromosomal abnormalities comprising the following:

[0966] t(4;14)(p16;q32);

[0967] t(14;16)(q32;q23);

[0968] del17p;

[0969] 1qAmp;

[0970] t(4;14)(p16;q32) and t(14;16)(q32;q23);

[0971] t(4;14)(p16;q32) and del17p;

[0972] t(14;16)(q32;q23) and del17p; or

[0973] t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p, or any combination thereof.

[0974] Embodiment 107. Any one of Embodiments 97 to 106, wherein the subject is a BCMAxCD3 bispecific antibody for said use that is refractory or relapsed to treatment with the anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, erlotozumab, ixazomib, melphalan, or thalidomide, or any combination thereof.

[0975] Embodiment 108. In any one of Embodiments 97 to 107, the subject is a BCMAxCD3 bispecific antibody for use that is recurrent to treatment with the anti-CD38 antibody.

[0976] Embodiment 109. A BCMAxCD3 bispecific antibody for use in any one of Embodiments 97 to 108, wherein the anti-CD38 antibody comprises HCDR1 of SEQ ID NO. 6, HCDR2 of SEQ ID NO. 7, HCDR3 of SEQ ID NO. 8, LCDR1 of SEQ ID NO. 9, LCDR2 of SEQ ID NO. 10, and LCDR3 of SEQ ID NO. 11.

[0977] Embodiment 110. A BCMAxCD3 bispecific antibody for use in any one of Embodiments 97 to 109, wherein the anti-CD38 antibody comprises VH of SEQ ID NO. 4 and VL of SEQ ID NO. 5.

[0978] Embodiment 111. In any one of Embodiments 97 to 110, the anti-CD38 antibody is an IgG1 homotype, a BCMAxCD3 bispecific antibody for said use.

[0979] Embodiment 112. A BCMAxCD3 bispecific antibody for use in any one of Embodiments 97 to 111, wherein the anti-CD38 antibody comprises the HC of SEQ ID NO. 12 and the LC of SEQ ID NO. 13.

[0980] Embodiment 113. In any one of Embodiments 97 to 108, the anti-CD38 antibody

[0981] VH of sequence number 14 and VL of sequence number 15;

[0982] VH of sequence number 16 and VL of sequence number 17;

[0983] VH of SEQ ID NO. 18 and VL of SEQ ID NO. 19; or

[0984] A BCMAxCD3 bispecific antibody for the above use comprising VH of SEQ ID NO. 20 and VL of SEQ ID NO. 21.

[0985] Embodiment 114. In Embodiment 113, the anti-CD38 antibody is an IgG1 isotype, a BCMAxCD3 bispecific antibody for the above use.

[0986] Embodiment 115. A BCMAxCD3 bispecific antibody for use, wherein the subject is a human, in any one of Embodiments 97 to 114.

[0987] Embodiment 116. A BCMAxCD3 bispecific antibody for said use, wherein in any one of Embodiments 97 to 115, the step of administering one or more anticancer therapies to said subject is further included.

[0988] Embodiment 117. The BCMAxCD3 bispecific antibody for use in Embodiment 116, wherein one or more anticancer therapies are selected from the group consisting of autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapy agents, immunomodulators, and targeted cancer therapies.

[0989] Embodiment 118. In Embodiment 116, the one or more anticancer therapies are selected from the group consisting of lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, erlotozumab, ixazomib, melphalan, prednisone or dexamethasone, or any combination thereof, a BCMAxCD3 bispecific antibody for said use.

[0990] Embodiment 119. A pharmaceutical composition comprising a BCMA-xCD3 bispecific antibody comprising a BCMA-binding domain comprising VH of SEQ ID NO. 29 and VL of SEQ ID NO. 30, a CD3-binding domain comprising VH of SEQ ID NO. 39 and VL of SEQ ID NO. 40, and an anti-CD38 antibody comprising VH of SEQ ID NO. 4 and VL of SEQ ID NO. 5.

[0991] Embodiment 120. A pharmaceutical composition according to Embodiment 119, wherein 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, and the anti-CD38 antibody comprises HC of SEQ ID NO. 12 and LC of SEQ ID NO. 13.

[0992] Embodiment 121. A pharmaceutical composition that is a non-fixed combination in Embodiment 119 or Embodiment 120.

[0993] Embodiment 122. A pharmaceutical composition according to Embodiment 121, comprising about 20 mg / mL to about 120 mg / mL of the anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mg mannitol, and about 0.04% w / v polysorbate-20 (PS-20), wherein the pH is about 5.5.

[0994] Embodiment 123. A pharmaceutical composition comprising about 1,800 mg of the anti-CD38 antibody and about 30,000 U of rHuPH20 in Embodiment 121.

[0995] Embodiment 124. A pharmaceutical composition comprising about 120 mg / mL of the anti-CD38 antibody and about 2,000 U / mL of rHuPH20 in Embodiment 123.

[0996] Embodiment 125. A pharmaceutical composition according to Embodiment 124, further comprising one or more excipients.

[0997] Embodiment 126. A pharmaceutical composition according to Embodiment 125, wherein one or more excipients are histidine, methionine, sorbitol or polysorbate-20 (PS-20), or any combination thereof.

[0998] Embodiment 127. In Embodiment 126, the pharmaceutical composition is

[0999] About 100 mg / mL to about 120 mg / mL of the above anti-CD38 antibody;

[1000] About 5 mM to about 15 mM histidine;

[1001] About 100 mM to about 300 mM sorbitol;

[1002] About 0.01% w / v to about 0.04% w / v PS-20; and

[1003] A pharmaceutical composition comprising about 1 mg / mL to about 2 mg / mL of methionine and having a pH of about 5.5 to 5.6.

[1004] Embodiment 128. A pharmaceutical composition according to Embodiment 127, comprising about 10 mM histidine.

[1005] Embodiment 129. A pharmaceutical composition comprising about 300 mM sorbitol in Embodiment 127 or Embodiment 128.

[1006] Embodiment 130. A pharmaceutical composition comprising about 0.04% (w / v) PS-20 in any one of Embodiments 127 to 129.

[1007] Embodiment 131. A pharmaceutical composition comprising about 1 mg / mL of methionine in any one of Embodiments 127 to 130.

[1008] Embodiment 132. In any one of Embodiments 127 to 131,

[1009] Approximately 1,800 mg of the above anti-CD38 antibody;

[1010] Approximately 30,000 U of rHuPH20;

[1011] Approximately 10 mM histidine;

[1012] Approximately 300 mM sorbitol;

[1013] Approximately 0.04% (w / v) PS-20; and

[1014] A pharmaceutical composition containing about 1 mg / mL of methionine and having a pH of about 5.6.

[1015] Embodiment 133. In any one of Embodiments 127 to 132,

[1016] Approximately 120 mg / mL of the above anti-CD38 antibody;

[1017] Approximately 2,000 U / mL of rHuPH20;

[1018] Approximately 10 mM histidine;

[1019] Approximately 300 mM sorbitol;

[1020] Approximately 0.04% (w / v) PS-20; and

[1021] A pharmaceutical composition containing about 1 mg / mL of methionine and having a pH of about 5.6.

[1022] Embodiment 134. A kit comprising a pharmaceutical composition of any one of Embodiments 119 to 133.

[1023] Embodiment 135. A T-cell re-induction therapeutic agent that binds to GPRC5D for use in combination with an anti-CD38 antibody to treat a subject with cancer.

[1024] Embodiment 136. In Embodiment 135, the anti-CD38 antibody is a T-cell re-induction therapeutic agent that binds to GPRC5D for use, administered to a subject before administering the T-cell re-induction therapeutic agent that binds to GPRC5D.

[1025] Embodiment 137. The embodiment of Embodiment 135 or Embodiment 136, wherein the subject is a T-cell re-induction therapeutic agent that binds to GPRC5D for said use, which is relapsed or refractory to treatment with a previous anticancer therapeutic agent.

[1026] Embodiment 138. A T-cell re-induction therapeutic agent that binds to GPRC5D for use, wherein in any one of Embodiments 135 to 137, the cancer is a GPRC5D-expressing cancer.

[1027] Embodiment 139. A T-cell re-induction therapeutic agent binding to GPRC5D for use, wherein in any one of Embodiments 135 to 138, the GPRC5D-expressing cancer is a hematological malignant tumor or a solid tumor.

[1028] Embodiment 140. A T-cell re-induction therapeutic agent that binds to GPRC5D for use in Embodiment 139, wherein the hematological malignancy is leukemia, lymphoma, or multiple myeloma.

[1029] Embodiment 141. A T-cell re-induction therapeutic agent that binds to GPRC5D for use in Embodiment 139, wherein the solid tumor is ovarian cancer, lung cancer, gastric adenocarcinoma, prostate cancer, renal carcinoma, liver cancer, pancreatic cancer, colon cancer, esophageal cancer, bladder cancer, cervical cancer, or malignant melanoma.

[1030] Embodiment 142. Any one of Embodiments 135 to 141, wherein the subject is a T-cell re-induction therapeutic agent binding to GPRC5D for said use, which is relapsed or refractory to treatment with the anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, erlotozumab, ixazomib, melphalan or thalidomide, or any combination thereof.

[1031] Embodiment 143. In any one of Embodiments 135 to 142, the subject is a T-cell re-induction therapeutic agent that binds to GPRC5D for use, which is relapsed or refractory to treatment with the anti-CD38 antibody.

[1032] Embodiment 144. A T-cell re-induction therapeutic agent that binds to GPRC5D for use in any one of Embodiments 140 to 143, wherein the multiple myeloma is newly diagnosed multiple myeloma.

[1033] Embodiment 145. A T-cell re-induction therapeutic agent that binds to GPRC5D for use, wherein in any one of Embodiments 140 to 143, the multiple myeloma is relapsed or refractory multiple myeloma.

[1034] Embodiment 146. A T-cell re-induction therapeutic agent that binds to GPRC5D for use in any one of Embodiments 140 to 145, wherein the multiple myeloma is a high-risk multiple myeloma.

[1035] Embodiment 147. In Embodiment 146, the subject having high-risk multiple myeloma has one or more chromosomal abnormalities comprising the following, and the T-cell re-induction therapeutic agent binding to GPRC5D for use:

[1036] t(4;14)(p16;q32);

[1037] t(14;16)(q32;q23);

[1038] del17p;

[1039] 1qAmp;

[1040] t(4;14)(p16;q32) and t(14;16)(q32;q23);

[1041] t(4;14)(p16;q32) and del17p;

[1042] t(14;16)(q32;q23) and del17p; or

[1043] t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p, or any combination thereof.

[1044] Embodiment 148. In any one of Embodiments 135 to 147, the T-cell re-induction therapeutic agent is a T-cell re-induction therapeutic agent that binds to GPRC5D for use, which binds to CD3, CD3 epsilon (CD3ε), CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, BTNL8, PD-1, CD195, or NKG2C.

[1045] Embodiment 149. A T-cell re-induction therapeutic agent for use that binds to GPRC5D, wherein in any one of Embodiments 135 to 148, the T-cell re-induction therapeutic agent 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.

[1046] Embodiment 150. A T-cell re-induction therapeutic agent for use that binds to GPRC5D, wherein in any one of Embodiments 135 to 149, the GPRC5D binding domain comprises VH of SEQ ID NO. 49 and VL of SEQ ID NO. 50, and the CD3 binding domain comprises VH of SEQ ID NO. 39 and VL of SEQ ID NO. 40.

[1047] Embodiment 151. In any one of Embodiments 135 to 150, the T-cell re-induction therapeutic agent binding to GPRC5C is a multispecific antibody, a CAR, or a T cell expressing said CAR, and is a T-cell re-induction therapeutic agent binding to GPRC5D for said use.

[1048] Embodiment 152. The T-cell re-induction therapeutic agent for use in Embodiment 151, wherein the multispecific antibody is an IgG1, IgG2, IgG3, or IgG4 allotype, which binds to GPRC5D.

[1049] Embodiment 153. A T-cell re-induction therapeutic agent for use that binds to GPRC5D, wherein the multispecific antibody of Embodiment 151 or Embodiment 152 comprises one or more Fc substitutions that reduce the binding of the multispecific antibody to the Fcγ receptor (FcγR).

[1050] Embodiment 154. In any one of Embodiments 151 to 153, the one or more Fc substitutions are F234A / L235A on IgG4, L234A / L235A on IgG1, V234A / G237A / P238S / H268A / V309L / A330S / P331S on IgG2, F234A / L235A on IgG4, S228P / F234A / L235A on IgG4, N297A on all Ig isotypes, V234A / G237A on IgG2, K214T / E233P / L234V / L235A / G236-deletion / A327G / P331A / D365E / L358M on IgG1, and on IgG2 A T-cell re-induction therapeutic agent binding to GPRC5D for the above use, selected from the group consisting of H268Q / V309L / A330S / P331S, S267E / L328F on IgG1, L234F / L235E / D265A on IgG1, L234A / L235A / G237A / P238S / H268A / A330S / P331S on IgG1, S228P / F234A / L235A / G237A / P238S on IgG4, and S228P / F234A / L235A / G236-deleted / G237A / P238S on IgG4, wherein residue numbering follows the EU index.

[1051] Embodiment 155. A T-cell re-induction therapeutic agent for use in Embodiment 154, wherein the multispecific antibody further comprises an S228P substitution.

[1052] Embodiment 156. A T-cell re-induction therapeutic agent for said use that binds to GPRC5D, wherein in any one of Embodiments 151 to 155, the multispecific antibody comprises one or more asymmetric substitutions in a first CH3 domain or in a second CH3 domain, or in both the first CH3 domain and the second CH3 domain.

[1053] Embodiment 157. In Embodiment 156, the one or more asymmetric substitutions are F450L / K409R, wild type / F409L_R409K, T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S and T366W / T366S_L368A_Y407V, L351Y_F405A_Y407V / T394W, T366I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, A T-cell re-induction therapeutic agent that binds to GPRC5D for said use, selected from the group consisting of L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F and T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W.

[1054] Embodiment 158. A T-cell re-induction therapeutic agent for use that binds to GPRC5D, wherein in any one of Embodiments 151 to 157, the multispecific antibody comprises HC1 of SEQ ID NO. 51, LC1 of SEQ ID NO. 52, HC2 of SEQ ID NO. 41, and LC2 of SEQ ID NO. 42.

[1055] Embodiment 159. A T-cell re-induction therapeutic agent for use that binds to GPRC5D, wherein in any one of Embodiments 135 to 158, the anti-CD38 antibody comprises HCDR1 of SEQ ID NO. 6, HCDR2 of SEQ ID NO. 7, HCDR3 of SEQ ID NO. 8, LCDR1 of SEQ ID NO. 9, LCDR2 of SEQ ID NO. 10, and LCDR3 of SEQ ID NO. 11.

[1056] Embodiment 160. A T-cell re-induction therapeutic agent for use that binds to GPRC5D, wherein in any one of Embodiments 135 to 159, the anti-CD38 antibody comprises VH of SEQ ID NO. 4 and VL of SEQ ID NO. 5.

[1057] Embodiment 161. In any one of Embodiments 135 to 160, the anti-CD38 antibody is an IgG1 allotype, a T-cell re-induction therapeutic agent for use that binds to GPRC5D.

[1058] Embodiment 162. A T-cell re-induction therapeutic agent for use that binds to GPRC5D, wherein in any one of Embodiments 135 to 161, the anti-CD38 antibody comprises HC of SEQ ID NO. 12 and LC of SEQ ID NO. 13.

[1059] Embodiment 163. In any one of Embodiments 135 to 158, the anti-CD38 antibody

[1060] VH of sequence number 14 and VL of sequence number 15;

[1061] VH of sequence number 16 and VL of sequence number 17;

[1062] VH of SEQ ID NO. 18 and VL of SEQ ID NO. 19; or

[1063] A T-cell re-induction therapeutic agent that binds to GPRC5D for the above use, comprising VH of SEQ ID NO. 20 and VL of SEQ ID NO. 21.

[1064] Embodiment 164. In Embodiment 163, the anti-CD38 antibody is an IgG1 allotype and is a T-cell re-induction therapeutic agent that binds to GPRC5D for use.

[1065] Embodiment 165. A T-cell re-induction therapeutic agent binding to GPRC5D for use, wherein in any one of Embodiments 135 to 164, the anti-CD38 antibody is administered at a dose of about 8 mg / kg to about 16 mg / kg.

[1066] Embodiment 166. In any one of Embodiments 135 to 165, the T-cell re-induction therapeutic agent binding to GPRC5D and the anti-CD38 antibody are administered by intravenous injection, the T-cell re-induction therapeutic agent binding to GPRC5D for said use.

[1067] Embodiment 167. A T-cell re-induction therapeutic agent that binds to GPRC5D for use, wherein in any one of Embodiments 135 to 165, the T-cell re-induction therapeutic agent that binds to GPRC5D is administered by intravenous injection and the anti-CD38 antibody is administered by subcutaneous injection.

[1068] Embodiment 168. A T-cell re-induction therapeutic agent that binds to GPRC5D for use, wherein the subject is a human in any one of Embodiments 135 to 167.

[1069] Embodiment 169. A T-cell re-induction therapeutic agent for use that binds to GPRC5D, wherein in any one of Embodiments 135 to 168, the T-cell re-induction therapeutic agent that binds to GPRC5D is a GPRC5DxCD3 bispecific antibody.

[1070] Embodiment 170. A T-cell re-induction therapeutic agent that binds to GPRC5D for said use, wherein, in any one of Embodiments 135 to 170, the step of administering one or more anticancer therapies to said subject is further included.

[1071] Embodiment 171. The T-cell re-induction therapeutic agent that binds to GPRC5D for said use, wherein one or more anticancer therapies are selected from the group consisting of autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapy agents, immunomodulators, and targeted cancer therapies.

[1072] Embodiment 172. In Embodiment 170, the one or more anticancer therapies are T-cell re-induction therapeutic agents that bind to GPRC5D for said use, selected from the group consisting of lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, erlotozumab, ixazomib, melphalan, dexamethasone, or prednisone.

[1073] Embodiment 173. A T-cell re-induction therapeutic agent binding to GPRC5D for said use, wherein in any one of Embodiments 135 to 172, the anti-CD38 antibody is administered into a pharmaceutical composition having a pH of about 5.5 comprising about 20 mg / mL to about 120 mg / mL of the anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mg / mL mannitol, and about 0.04% w / v polysorbate-20 (PS-20), or provided for administration into said pharmaceutical composition.

[1074] Embodiment 174. A T-cell re-induction therapeutic agent binding to GPRC5D for said use, wherein in any one of Embodiments 135 to 172, the anti-CD38 antibody is administered as a pharmaceutical composition comprising about 1,800 mg of the anti-CD38 antibody and about 30,000 U of rHuPH20, or provided for administration to said pharmaceutical composition.

[1075] Embodiment 175. A T-cell re-induction therapeutic agent that binds to GPRC5D for use, wherein the anti-CD38 antibody in Embodiment 174 is administered as a pharmaceutical composition comprising about 120 mg / mL of the anti-CD38 antibody and about 2,000 U / mL of rHuPH20, or provided for administration to said pharmaceutical composition.

[1076] Embodiment 176. In Embodiment 174 or Embodiment 175, the anti-CD38 antibody is

[1077] About 100 mg / mL to about 120 mg / mL of the above anti-CD38 antibody;

[1078] About 5 mM to about 15 mM histidine;

[1079] About 100 mM to about 300 mM sorbitol;

[1080] About 0.01% w / v to about 0.04% w / v PS-20; and

[1081] A T-cell re-induction therapeutic agent that binds to GPRC5D for said use, administered as a pharmaceutical composition having a pH of about 5.5 to 5.6 containing about 1 mg / mL to about 2 mg / mL of methionine, or provided for administration as said pharmaceutical composition.

[1082] Embodiment 177. In any one of Embodiments 174 to 176, the anti-CD38 antibody

[1083] Approximately 1,800 mg of the above anti-CD38 antibody;

[1084] Approximately 30,000 U of rHuPH20;

[1085] Approximately 10 mM histidine;

[1086] Approximately 300 mM sorbitol;

[1087] Approximately 0.04% (w / v) PS-20; and

[1088] A T-cell re-induction therapeutic agent that binds to GPRC5D for said use, administered as a pharmaceutical composition having a pH of about 5.6 containing about 1 mg / mL of methionine or provided for administration as said pharmaceutical composition.

[1089] Embodiment 178. In any one of Embodiments 174 to 177, the anti-CD38 antibody

[1090] Approximately 120 mg / mL of the above anti-CD38 antibody;

[1091] Approximately 2,000 U / mL of rHuPH20;

[1092] Approximately 10 mM histidine;

[1093] Approximately 300 mM sorbitol;

[1094] Approximately 0.04% (w / v) PS-20; and

[1095] A T-cell re-induction therapeutic agent that binds to GPRC5D for said use, administered as a pharmaceutical composition having a pH of about 5.6 containing about 1 mg / mL of methionine or provided for administration as said pharmaceutical composition.

[1096] Embodiment 179. A GPRC5DxCD3 bispecific antibody for use in treating a subject having cancer, wherein the subject is relapsed or refractory to treatment with a previous anticancer agent.

[1097] Embodiment 180. The GPRC5DxCD3 bispecific antibody for use according to Embodiment 179, 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.

[1098] Embodiment 181. A GPRC5DxCD3 bispecific antibody for use, wherein, in Embodiment 179 or Embodiment 180, the GPRC5D binding domain comprises VH of SEQ ID NO. 49 and VL of SEQ ID NO. 50, and the CD3 binding domain comprises VH of SEQ ID NO. 39 and VL of SEQ ID NO. 40.

[1099] Embodiment 182. An Embodiment 182 of any one of Embodiments 179 to 181, wherein the GPRC5DxCD3 bispecific antibody is IgG4 homotype and comprises phenylalanine at position 405 and arginine at position 409 in HC1 and leucine at position 405 and lysine at position 409 in HC2, and the residue numbering follows the EU index, an GPRC5DxCD3 bispecific antibody for said use.

[1100] Embodiment 183. The GPRC5DxCD3 bispecific antibody for use in Embodiment 182, wherein the GPRC5DxCD3 bispecific antibody further comprises proline at position 228, alanine at position 234, and alanine at position 235 in both HC1 and HC2.

[1101] Embodiment 184. Any one of Embodiments 179 to 183, wherein the GPRC5DxCD3 bispecific antibody for use comprises HC1 of SEQ ID NO. 51, LC1 of SEQ ID NO. 52, HC2 of SEQ ID NO. 41, and LC2 of SEQ ID NO. 42.

[1102] Embodiment 185. A GPRC5DxCD3 bispecific antibody for use, wherein in any one of Embodiments 179 to 184, the cancer is a hematological malignant tumor or a solid tumor.

[1103] Embodiment 186. A GPRC5DxCD3 bispecific antibody for use in Embodiment 185, wherein the cancer is multiple myeloma, lymphoma, melanoma, breast cancer, endometrial cancer, ovarian cancer, lung cancer, gastric adenocarcinoma, prostate cancer, renal carcinoma, liver cancer, pancreatic cancer, colon cancer, esophageal cancer, bladder cancer, or cervical cancer.

[1104] Embodiment 187. The GPRC5DxCD3 bispecific antibody for use in Embodiment 186, wherein the multiple myeloma is a high-risk multiple myeloma.

[1105] Embodiment 188. The GPRC5DxCD3 bispecific antibody for use in Embodiment 187, wherein the subject having high-risk multiple myeloma has one or more chromosomal abnormalities comprising the following:

[1106] t(4;14)(p16;q32);

[1107] t(14;16)(q32;q23);

[1108] del17p;

[1109] 1qAmp;

[1110] t(4;14)(p16;q32) and t(14;16)(q32;q23);

[1111] t(4;14)(p16;q32) and del17p;

[1112] t(14;16)(q32;q23) and del17p; or

[1113] t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p, or any combination thereof.

[1114] Embodiment 189. Any one of Embodiments 179 to 188, wherein the subject is a GPRC5DxCD3 bispecific antibody for said use that is refractory or relapsed to treatment with the anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, erlotozumab, ixazomib, melphalan, or thalidomide, or any combination thereof.

[1115] Embodiment 190. Any one of Embodiments 179 to 189, wherein the subject is relapsed or refractory to treatment with the anti-CD38 antibody, the GPRC5DxCD3 bispecific antibody for said use.

[1116] Embodiment 191. A GPRC5DxCD3 bispecific antibody for use, wherein in any one of Embodiments 179 to 190, the anti-CD38 antibody comprises HCDR1 of SEQ ID NO. 6, HCDR2 of SEQ ID NO. 7, HCDR3 of SEQ ID NO. 8, LCDR1 of SEQ ID NO. 9, LCDR2 of SEQ ID NO. 10, and LCDR3 of SEQ ID NO. 11.

[1117] Embodiment 192. In any one of Embodiments 179 to 191, the anti-CD38 antibody comprises VH of SEQ ID NO. 4 and VL of SEQ ID NO. 5, a GPRC5DxCD3 bispecific antibody for said use.

[1118] Embodiment 193. In any one of Embodiments 179 to 192, the anti-CD38 antibody is an IgG1 homotype, a GPRC5DxCD3 bispecific antibody for said use.

[1119] Embodiment 194. In any one of Embodiments 179 to 193, the anti-CD38 antibody comprises the HC of SEQ ID NO. 12 and the LC of SEQ ID NO. 13, a GPRC5DxCD3 bispecific antibody for said use.

[1120] Embodiment 195. In any one of Embodiments 179 to 190, the anti-CD38 antibody

[1121] VH of sequence number 14 and VL of sequence number 15;

[1122] VH of sequence number 16 and VL of sequence number 17;

[1123] VH of SEQ ID NO. 18 and VL of SEQ ID NO. 19; or

[1124] A GPRC5DxCD3 bispecific antibody for the above use comprising VH of SEQ ID NO. 20 and VL of SEQ ID NO. 21.

[1125] Embodiment 196. In Embodiment 195, the anti-CD38 antibody is an IgG1 isotype, a GPRC5DxCD3 bispecific antibody for the above use.

[1126] Embodiment 197. Any one of Embodiments 179 to 196, wherein the subject is a human, a GPRC5DxCD3 bispecific antibody for said use.

[1127] Embodiment 198. A GPRC5DxCD3 bispecific antibody for said use, wherein in any one of Embodiments 179 to 197, the step of administering one or more anticancer therapies to said subject is further included.

[1128] Embodiment 199. The GPRC5DxCD3 bispecific antibody for use in Embodiment 198, wherein one or more anticancer therapies are selected from the group consisting of autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapy agents, immunomodulators, and targeted cancer therapies.

[1129] Embodiment 200. In Embodiment 198, the one or more anticancer therapies are lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, erlotozumab, ixazomib, melphalan, dexamethasone, vincristine, cyclophosphamide, hydroxyidaunorubicin, prednisone, rituximab, imatinib, dasatinib, nilotinib, bosutinib, ponatinib, bafetinib, saracatinib, tozasertip or danucertip, cytarabine, daunorubicin, idarubicin, mitoxantrone, hydroxyurea, decitabine, cladribine, fludarabine, topotecan, etoposide, 6-thioguanine, corticosteroid, methotrexate, 6-mercaptopurine, A GPRC5DxCD3 bispecific antibody for said use, selected from the group consisting of azacitidine, arsenic trioxide and all-trans retinoic acid, or any combination thereof.

[1130] Embodiment 201. A pharmaceutical combination comprising 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, and an anti-CD38 antibody comprising HCDR1 of SEQ ID NO. 6, HCDR2 of SEQ ID NO. 7, HCDR3 of SEQ ID NO. 8, LCDR1 of SEQ ID NO. 9, LCDR2 of SEQ ID NO. 10, and LCDR3 of SEQ ID NO. 11.

[1131] Embodiment 202. A pharmaceutical combination according to Embodiment 201, wherein the GPRC5D binding domain comprises VH of SEQ ID NO. 49 and VL of SEQ ID NO. 50, the CD3 binding domain comprises VH of SEQ ID NO. 39 and VL of SEQ ID NO. 40, and the anti-CD38 antibody comprises VH of SEQ ID NO. 4 and VL of SEQ ID NO. 5.

[1132] Embodiment 203. A pharmaceutical combination according to Embodiment 201 or Embodiment 202, wherein the GPRC5CxCD3 bispecific antibody comprises HC1 of SEQ ID NO. 51, LC1 of SEQ ID NO. 52, HC2 of SEQ ID NO. 41, and LC2 of SEQ ID NO. 42, and the anti-CD38 antibody comprises HC of SEQ ID NO. 12 and LC of SEQ ID NO. 13.

[1133] Embodiment 204. A pharmaceutical combination that is a non-fixed combination in any one of Embodiments 201 to 203.

[1134] Embodiment 205. A pharmaceutical combination according to Embodiment 204, comprising about 20 mg / mL to about 120 mg / mL of the anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mg mannitol, and about 0.04% w / v polysorbate-20 (PS-20), wherein the pH is about 5.5.

[1135] Embodiment 206. A pharmaceutical combination of Embodiment 204, comprising about 1,800 mg of the anti-CD38 antibody and about 30,000 U of rHuPH20.

[1136] Embodiment 207. A pharmaceutical composition comprising about 120 mg / mL of the anti-CD38 antibody and about 2,000 U / mL of rHuPH20 in Embodiment 206.

[1137] Embodiment 208. A pharmaceutical combination according to Embodiment 207, further comprising one or more excipients.

[1138] Embodiment 209. A pharmaceutical combination according to Embodiment 208, wherein one or more excipients are histidine, methionine, sorbitol or polysorbate-20 (PS-20), or any combination thereof.

[1139] Embodiment 210. In Embodiment 209, the pharmaceutical composition is

[1140] About 100 mg / mL to about 120 mg / mL of the above anti-CD38 antibody;

[1141] About 5 mM to about 15 mM histidine;

[1142] About 100 mM to about 300 mM sorbitol;

[1143] About 0.01% w / v to about 0.04% w / v PS-20; and

[1144] A pharmaceutical combination containing about 1 mg / mL to about 2 mg / mL of methionine and having a pH of about 5.5 to 5.6.

[1145] Embodiment 211. A pharmaceutical combination according to Embodiment 209 or Embodiment 210, comprising about 10 mM histidine.

[1146] Embodiment 212. A pharmaceutical combination comprising about 300 mM sorbitol in any one of Embodiments 209 to 211.

[1147] Embodiment 213. A pharmaceutical combination comprising about 0.04% (w / v) PS-20 in any one of Embodiments 209 to 212.

[1148] Embodiment 214. A pharmaceutical combination comprising about 1 mg / mL of methionine in any one of Embodiments 209 to 213.

[1149] Embodiment 215. In any one of Embodiments 209 to 214,

[1150] Approximately 1,800 mg of the above anti-CD38 antibody;

[1151] Approximately 30,000 U of rHuPH20;

[1152] Approximately 10 mM histidine;

[1153] Approximately 300 mM sorbitol;

[1154] Approximately 0.04% (w / v) PS-20; and

[1155] A pharmaceutical combination containing about 1 mg / mL of methionine and having a pH of about 5.6.

[1156] Embodiment 216. In any one of Embodiments 209 to 215,

[1157] Approximately 120 mg / mL of the above anti-CD38 antibody;

[1158] Approximately 2,000 U / mL of rHuPH20;

[1159] Approximately 10 mM histidine;

[1160] Approximately 300 mM sorbitol;

[1161] Approximately 0.04% (w / v) PS-20; and

[1162] A pharmaceutical combination containing about 1 mg / mL of methionine and having a pH of about 5.6.

[1163] Embodiment 217. A kit comprising any one of Embodiments 201 to 215, a pharmaceutical combination.

[1164] Embodiment 218. A CD19-binding T-cell re-induction therapeutic agent for use in combination with an anti-CD38 antibody to treat a subject with cancer.

[1165] Embodiment 219. An anti-CD38 antibody for use in enhancing the efficacy of a CD19-binding T-cell re-induction therapeutic agent in a subject having cancer, wherein the subject has been treated with the anti-CD38 antibody prior to administration of the CD19-binding T-cell re-induction therapeutic agent.

[1166] Embodiment 220. In Embodiment 218 or Embodiment 219, the subject is a T-cell re-induction therapeutic agent or an anti-CD38 antibody for said use, which is refractory or relapsed to treatment with a previous anticancer therapeutic agent.

[1167] Embodiment 221. A T-cell re-induction therapeutic agent or anti-CD38 antibody for use in any one of Embodiments 218 to 221, wherein the cancer is a hematological malignant tumor or a solid tumor.

[1168] Embodiment 222. A T-cell re-induction therapeutic agent or anti-CD38 antibody for use in Embodiment 221, wherein the hematological malignancy is lymphoma, B-cell malignancy, Hodgkin lymphoma, non-Hodgkin lymphoma, DLBLC, FL, MCL, marginal zone B-cell lymphoma (MZL), mucosa-associated lymphoid tissue lymphoma (MALT), CLL, ALL, AML, Waldenström macroglobulinemia, or T-cell lymphoma.

[1169] Embodiment 223. A T-cell re-induction therapeutic agent or anti-CD38 antibody for use in Embodiment 221, wherein the solid tumor is lung cancer, liver cancer, cervical cancer, colon cancer, breast cancer, ovarian cancer, pancreatic cancer, melanoma, glioblastoma, prostate cancer, esophageal cancer, or gastric cancer.

[1170] Embodiment 224. In any one of Embodiments 218 to 223, the T-cell re-induction therapeutic agent is a T-cell re-induction therapeutic agent or an anti-CD38 antibody for said use that binds to CD3 epsilon (CD3ε), CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, BTNL8, PD-1, CD195, or NKG2C.

[1171] Embodiment 225. In any one of Embodiments 218 to 224, the T-cell re-induction therapeutic agent binding to CD19 is blinatumomab, axicarbatagen ciloleucel, tisagen recleucel-t, inebilizumab, lysocarbatagen marareucel, XmAb-5574, CIK-CAR.CD19, ICTCAR-011, IM-19, JCAR-014, loncastuximab tesirin, MB-CART2019.1, OXS-1550, PBCAR-0191, PCAR-019, PCAR-119, Senl-001, TI-1007, XmAb-5871, PTG-01, PZ01, Senl_1904A, Senl_1904B, UCART-19, CSG-CD19, A T-cell re-induction therapeutic or anti-CD38 antibody for the above use, comprising the CD19 binding domain of DI-B4, ET-190, GC-007F, or GC-022.

[1172] Embodiment 226. In any one of Embodiments 218 to 225, the T-cell re-induction therapeutic agent binding to CD19 is blinatumomab, axicarbatagen ciloleucel, tisagen recleucel-t, inebilizumab, lysocarbatagen marareucel, XmAb-5574, CIK-CAR.CD19, ICTCAR-011, IM-19, JCAR-014, loncastuximab tesirin, MB-CART2019.1, OXS-1550, PBCAR-0191, PCAR-019, PCAR-119, Senl-001, TI-1007, XmAb-5871, PTG-01, PZ01, Senl_1904A, Senl_1904B, UCART-19, CSG-CD19, A T-cell re-induction therapeutic or anti-CD38 antibody for the above use, comprising DI-B4, ET-190, GC-007F, or GC-022.

[1173] Embodiment 227. In any one of Embodiments 218 to 226, the T-cell re-induction therapeutic agent binding to CD19 is a multispecific antibody, a CAR, or a T cell expressing said CAR, for said use, a T-cell re-induction therapeutic agent or an anti-CD38 antibody.

[1174] Embodiment 228. A T-cell re-induction therapeutic agent or anti-CD38 antibody for use in any one of Embodiments 218 to 227, wherein the anti-CD38 antibody comprises HCDR1 of SEQ ID NO. 6, HCDR2 of SEQ ID NO. 7, HCDR3 of SEQ ID NO. 8, LCDR1 of SEQ ID NO. 9, LCDR2 of SEQ ID NO. 10, and LCDR3 of SEQ ID NO. 11.

[1175] Embodiment 229. A T-cell re-induction therapeutic agent or anti-CD38 antibody for use in any one of Embodiments 218 to 228, wherein the anti-CD38 antibody comprises VH of SEQ ID NO. 4 and VL of SEQ ID NO. 5.

[1176] Embodiment 230. In any one of Embodiments 218 to 229, the anti-CD38 antibody is an IgG1 allotype, a T-cell re-induction therapeutic agent or an anti-CD38 antibody for said use.

[1177] Embodiment 231. A T-cell re-induction therapeutic agent or an anti-CD38 antibody for use in any one of Embodiments 218 to 230, wherein the anti-CD38 antibody comprises the HC of SEQ ID NO. 12 and the LC of SEQ ID NO. 13.

[1178] Embodiment 232. In any one of Embodiments 218 to 227, the anti-CD38 antibody

[1179] VH of sequence number 14 and VL of sequence number 15;

[1180] VH of sequence number 16 and VL of sequence number 17;

[1181] VH of SEQ ID NO. 18 and VL of SEQ ID NO. 19; or

[1182] A T-cell re-induction therapeutic agent or anti-CD38 antibody for the above use, comprising VH of SEQ ID NO. 20 and VL of SEQ ID NO. 21.

[1183] Embodiment 233. In Embodiment 232, the anti-CD38 antibody is an IgG1 allotype, a T-cell re-induction therapeutic agent or an anti-CD38 antibody for said use.

[1184] Embodiment 234. A T-cell re-induction therapeutic agent or anti-CD38 antibody for use, wherein in any one of Embodiments 218 to 233, the anti-CD38 antibody is administered at a dose of about 8 mg / kg to about 16 mg / kg.

[1185] Embodiment 235. In any one of Embodiments 218 to 234, the T-cell re-induction therapeutic agent binding to CD19 and the anti-CD38 antibody for said use are administered by intravenous injection.

[1186] Embodiment 236. A T-cell re-induction therapeutic agent or an anti-CD38 antibody for use, wherein in any one of Embodiments 218 to 234, the T-cell re-induction therapeutic agent binding to CD19 is administered by intravenous injection and the anti-CD38 antibody is administered by subcutaneous injection.

[1187] Embodiment 237. In any one of Embodiments 218 to 236, the subject is a human, and the T-cell re-induction therapeutic agent or anti-CD38 antibody for said use.

[1188] Embodiment 238. In any one of Embodiments 218 to 237, the T-cell re-induction therapeutic agent that binds to CD19 is a CD19xCD3 bispecific antibody, a T-cell re-induction therapeutic agent or an anti-CD38 antibody for said use.

[1189] Embodiment 239. A T-cell re-induction therapeutic agent or anti-CD38 antibody for said use, wherein in any one of Embodiments 218 to 238, the step of administering one or more anticancer therapies to said subject is further included.

[1190] Embodiment 240. In Embodiment 238, the one or more anticancer therapies for said use are selected from the group consisting of autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapy agents, immunomodulators, and targeted cancer therapies, and are T-cell re-induction therapies or anti-CD38 antibodies.

[1191] Embodiment 241. A pharmaceutical combination comprising a CD19xCD3 bispecific antibody comprising blinatumomab of SEQ ID NO. 53, and anti-CD38 antibodies comprising HCDR1 of SEQ ID NO. 6, HCDR2 of SEQ ID NO. 7, HCDR3 of SEQ ID NO. 8, LCDR1 of SEQ ID NO. 9, LCDR2 of SEQ ID NO. 10, and LCDR3 of SEQ ID NO. 11.

[1192] Embodiment 242. A pharmaceutical combination according to Embodiment 241, wherein the anti-CD38 antibody comprises VH of SEQ ID NO. 4 and VL of SEQ ID NO. 5.

[1193] Embodiment 243. A pharmaceutical combination according to Embodiment 241 or Embodiment 242, wherein the anti-CD38 antibody comprises HC of SEQ ID NO. 12 and LC of SEQ ID NO. 13.

[1194] Embodiment 244. A pharmaceutical combination that is a non-fixed combination in any one of Embodiments 241 to 243.

[1195] Embodiment 245. A pharmaceutical combination comprising, in any one of Embodiments 241 to 244, about 20 mg / mL to about 120 mg / mL of the anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mg mannitol, and about 0.04% w / v polysorbate-20 (PS-20), and having a pH of about 5.5.

[1196] Embodiment 246. A pharmaceutical combination comprising about 1,800 mg of the anti-CD38 antibody and about 30,000 U of rHuPH20 in any one of Embodiments 241 to 243.

[1197] Embodiment 247. A pharmaceutical combination according to Embodiment 246, comprising about 120 mg / mL of the anti-CD38 antibody and about 2,000 U / mL of rHuPH20.

[1198] Embodiment 248. A pharmaceutical combination according to Embodiment 246 or Embodiment 257, further comprising one or more excipients.

[1199] Embodiment 249. A pharmaceutical combination in any one of Embodiments 246 to 248, wherein one or more excipients are histidine, methionine, sorbitol or polysorbate-20 (PS-20), or any combination thereof.

[1200] Embodiment 250. In any one of Embodiments 246 to 249,

[1201] About 100 mg / mL to about 120 mg / mL of the above anti-CD38 antibody;

[1202] About 5 mM to about 15 mM histidine;

[1203] About 100 mM to about 300 mM sorbitol;

[1204] About 0.01% w / v to about 0.04% w / v PS-20; and

[1205] A pharmaceutical combination containing about 1 mg / mL to about 2 mg / mL of methionine and having a pH of about 5.5 to 5.6.

[1206] Embodiment 251. A pharmaceutical combination comprising about 10 mM histidine in any one of Embodiments 246 to 250.

[1207] Embodiment 252. A pharmaceutical combination comprising about 300 mM sorbitol in any one of Embodiments 246 to 251.

[1208] Embodiment 253. A pharmaceutical combination comprising about 0.04% (w / v) PS-20 in any one of Embodiments 246 to 252.

[1209] Embodiment 254. A pharmaceutical combination comprising about 1 mg / mL of methionine in any one of Embodiments 246 to 253.

[1210] Embodiment 255. In any one of Embodiments 246 to 254,

[1211] Approximately 1,800 mg of the above anti-CD38 antibody;

[1212] Approximately 30,000 U of rHuPH20;

[1213] Approximately 10 mM histidine;

[1214] Approximately 300 mM sorbitol;

[1215] Approximately 0.04% (w / v) PS-20; and

[1216] A pharmaceutical combination containing about 1 mg / mL of methionine and having a pH of about 5.6.

[1217] Embodiment 256. In any one of Embodiments 246 to 255,

[1218] Approximately 120 mg / mL of the above anti-CD38 antibody;

[1219] Approximately 2,000 U / mL of rHuPH20;

[1220] Approximately 10 mM histidine;

[1221] Approximately 300 mM sorbitol;

[1222] Approximately 0.04% (w / v) PS-20; and

[1223] A pharmaceutical composition containing about 1 mg / mL of methionine and having a pH of about 5.6.

[1224] Embodiment 257. A kit comprising a pharmaceutical composition of any one of Embodiments 241 to 256.

[1225] Examples

[1226] The following examples are provided to further explain some of the embodiments disclosed herein. The examples are intended to illustrate the disclosed embodiments and are not intended to limit them.

[1227] General materials and methods

[1228] Antibodies and reagents

[1229] The anti-BCMA / anti-CD3 antibody JNJ-957 (described in International Patent Application Publication WO2017031104A1) and daratumumab were manufactured by Janssen Pharmaceuticals. CNTO7008 (CD3 x null), BC3B4 (BCMA x null), and 3930 (IgG allotype control), all manufactured by Janssen Pharmaceuticals, were used as control antibodies. JNJ-957 is also named JNJ-7957.

[1230] JNJ-957 includes the BCMA-binding arm BCMB69 and the CD3-binding arm CD3B219, and their amino acid sequences are respectively Tables 3 and 4 It is presented in.

[1231] [Table 3]

[1232]

[1233] [Table 4]

[1234]

[1235] Bone marrow and peripheral blood mononuclear cells

[1236] Peripheral blood mononuclear cells (PBMCs) from healthy donors and MM patients, and bone marrow mononuclear cells (BM-MNCs) from MM patient BM aspirates were isolated by Ficoll-Hypaque density-gradient centrifugation.

[1237] Cell lines and cultures

[1238] Luciferase (LUC)-transduced multiple myeloma cell lines UM9, RPMI8226, U266, and MM1.S, as well as untransduced multiple myeloma cell lines NCI-H929 and RPMI8226, were cultured in RPMI 1640 (Invitrogen) supplemented with 10% fetal bovine serum (FBS; Lonza) and antibiotics (100 units / mL penicillin, 100 µg / ml streptomycin; both Life Technologies).

[1239] Flow cytometry analysis of bone marrow and blood samples from MM patients

[1240] HuMax-003 (CD38) FITC (this antibody binds to an epitope distinct from the epitope bound by daratumumab, Janssen Pharmaceuticals), CD138 PE, CD56 PC7, CD45 Krome Orange (all Beckman Coulter), CD269 (BCMA) APC (Biolegend), CD274 (PD-L1) BV421, and CD19 APC-H7 (both Becton Dickinson) at 1.0 × 10⁶ 6BM-localized MM cells were identified by staining cells / mL, and the expression levels of cell surface markers were analyzed. 1.0 × 10⁶ were identified using CD45 Chrome Orange, CD56 PC7 (both Beckman Coulter), CD14 APC-H7, CD19 APC-H7, CD3 V450, CD4 APC-H7 or PE, CD8 FITC, CD45-RA APC, CD127 PE.Cy7, CD62L PE, CD274(PD-1) BV421, CD16 APC, HLA-DR APC-H7 (all Becton Dickinson), and CD25 PE (Dako). 6 By staining cells / mL, BM or PB immune cell subsets were identified and cell surface marker expression levels were analyzed. All BM samples were analyzed within 24 hours of collection.

[1241] Flow cytometry was performed using a 7-laser LSRFORTESSA (Becton Dickinson). Fluorescently labeled beads (CS&T Beads, Becton Dickinson) were used daily to monitor the performance of the flow cytometer and verify the optical path and stream flow. This procedure enables controlled and standardized results and allows for the determination of long-term drift and incidental changes within the flow cytometer. No changes that could affect the results were observed. Spectral overlap was determined using compensation beads, and compensation was automatically calculated using Diva software. Flow cytometry data were analyzed using FACS Diva software.

[1242] Flow cytometry-based in vitro lysis assay in BM-MNC

[1243] BM-MNCs derived from MM patients containing tumor cells as well as autoeffector cells were used in the lysis assay. Sample viability at incubation was greater than 98% when evaluated using 7-AAD (Becton Dickinson). For the lysis assay, BM-MNCs were incubated for 48 hours in RPMI + 10% fetal bovine serum in 96-well U-bottom plates with a control antibody or JNJ-957 (0.0064 to 4.0 µg / mL) and / or daratumumab (10 µg / mL). Primary CD138 within BM-MNCs + The viability of MM cells was determined by flow cytometry as previously described (reference [van der Veers et al., Haematologica . 2011;96(2):284-290]; van der Veer MS et al., Blood Cancer J . 2011;1(10):e41]; literature[Nijhof IS et al., Leukemia 2015;29(10):2039-2049]; literature[Nijhof IS, et al., Blood [2016;128(7):959-970]). In both assays, CD138 in the presence of a flow-count fluorosphere (Beckman Coulter) and a live / dead fixable dead cell stain near-IR fluorescent dye (Invitrogen). + The absolute number of viable MM cells was determined by counting surviving MM cells using single-platform flow cytometry analysis. Subsequently, the percentage of lysis induced by JNJ-957 was calculated using the following formula: % lysis of MM cells = 1 - (surviving CD138 cells in the presence of JNJ-957) + Absolute number of cells / Surviving CD138 in untreated wells + Absolute number of cells) × 100%.

[1244] CD4 + and CD8 + JNJ-957-induced activation and degranulation of T-cells were analyzed by flow cytometry detection of CD25 and CD107a cell surface expression, respectively.

[1245] Flow cytometry-based lysis assay in MM cell lines containing PB MNCs as effector cells.

[1246] BCMA-positive MM cell lines were co-cultured with PB NMCs from healthy donors or MM patients in 96-well U-bottom plates for 48 hours in the presence of a control antibody or JNJ-957 (0.00256 to 4.0 µg / mL) at an effector-to-target ratio of 9:1. The viability of MM cells was determined by flow cytometry as described above.

[1247] Bioluminescence Imaging (BLI)-Based Lysis Scheme Using LUC-Transgenic MM Cell Lines

[1248] LUC-transduced MM cell lines were obtained from newly diagnosed MM patients (n=12) and cultured for 16 hours in the presence or absence of pooled BM stromal cells (BMSCs). Subsequently, they were incubated with effector cells (PBMCs freshly isolated from healthy donors) at an effector-to-target ratio of 9:1, and serial dilutions of JNJ-957 (0.00256 to 4.0 µg / mL) or control antibody were performed in 96-well flat-bottom plates (Greiner-Bio-One) for 48 hours. Then, 10 minutes after the addition of substrate luciferin (150 µg / mL; Promega), LUC was introduced by BLI. + - The viability of MM cells was determined. The lysis of MM cells was determined using the following formula: % lysis = 1 - (Average BLI signal in the presence of effector cells and JNJ-957 / Average BLI signal in the presence of effector cells in untreated wells) × 100%.

[1249] To evaluate the effect of in vivo pretreatment of PB MNCs with daratumumab monotherapy on the efficacy of JNJ-957, LUC-transduced MM cell line 4 was also co-cultured with PB MNCs obtained from MM patients before the initiation of daratumumab monotherapy and at the time of the best response to daratumumab monotherapy (effector-to-target ratio = 9:1). The BLI assay was performed as described above.

[1250] Cytogenetic analysis

[1251] Cytogenetic abnormalities in purified MM cells were evaluated by fluorescence in situ hybridization (FISH) and single nucleotide polymorphism (SNP) arrays. High-risk diseases were identified as del(17p), del(1p), ampl(1q), t(4;14), or t(14;16). 2 It was defined by the existence of.

[1252] Availability BCMA test

[1253] Soluble BCMA (sBCMA) in the cell culture supernatant was measured using an MSD GOLD™ 96-well Small Spot Streptavidin SECTOR plate (Meso Scale Diagnostics) according to the manufacturer's recommended protocol.

[1254] Granzyme B test

[1255] Granzyme B was measured in the cell culture supernatant using the MSD R-Plex Granzyme B assay plate (Meso Scale Diagnostics) according to the manufacturer's protocol.

[1256] Multiplex Cytokine Test

[1257] Cytokines [interferon-gamma (IFN-γ), interleukin (IL)-2, IL-6, IL-8, IL-10, and tumor necrosis factor-alpha (TNF-α)] in the cell culture supernatant were analyzed using the V-Flex Pro-inflammatory Panel 1 Human Kit (Meso Scale Diagnostics) according to the manufacturer's protocol.

[1258] statistics

[1259] When the data does not follow a normal distribution, two-sided (paired) Student t -Black(two-tailed (paired) Student's t -test), or Mann-Whitney U Comparisons between variables were performed using the test or the Wilcoxon matched-pairs signed-rank test. The correlations between variables were assessed using Spearman's rank correlation coefficient. Less than 0.05 P The -value was considered significant. In the case of combination therapy with JNJ-957 and daratumumab, to test the null hypothesis that there is only an additive effect between JNJ-957 and daratumumab, as previously described 20,23,24 , the expected dissolution value was calculated using the following formula: Expected % dissolution = (% dissolution by JNJ-957 + % dissolution by daratumumab) - (% dissolution by JNJ-957 × % dissolution by daratumumab). If the observed value was significantly higher than the expected value ( P <0.05), the null hypothesis of the "additive effect" was rejected.

[1260] Example 1 BCMA + JNJ-957-mediated lysis of multiple myeloma cell lines using the anti-BCMA / anti-CD3 antibody is achieved by T-cell activation and degranulation.

[1261] RPMI8226( Fig. 1 ), UM9( Fig. 2), U226( Fig. 3 ) and MM1.S( Fig. 4 The effect of JNJ-957 on mediating the lysis of ) was evaluated using healthy donor (HD) peripheral blood mononuclear cells as effector cells across a constant concentration range of JNJ-957 (0.00128 to 4.0 μg / mL). JNJ-957 mediated the lysis of all tested cell lines in a dose-dependent manner, and, as can be seen in Figures 1, 2, 3, and 4, nearly 100% maximum efficacy was achieved at an antibody concentration of about 0.1 μg / ml depending on the cell line.

[1262] It has been previously revealed that BMSCs protect MM cells against various anti-MM agonists, including daratumumab and MM-reactive T-cells. Therefore, we evaluated the potential impact of BMSC-MM cell interactions on the efficacy of JNJ-957. The activity of JNJ-957 on MM cell lines RPMI-8226, UM9, and U266 was not affected by the presence of BMSCs (data not shown). Although JNJ-957-mediated MM cell lysis was slightly inhibited by BMSCs in MM1.S cells at lower concentrations ( P <0.0001), these effects were completely eliminated by increasing the dose of JNJ-7957.

[1263] T cell activation was evaluated in the RPMI 8226 cell line. Treatment with JNJ-957 CD4 in a dose-dependent manner + and CD8 + It resulted in the activation and degranulation of both T cells, as evidenced by the increased cell surface expression of CD25 and CD107a, respectively, or by the ratio of double-positive CD25 and CD107a cells. Fig. 5 is CD25 + It indicates a JNJ-957-mediated increase in the percentage of CD4 T cells. Fig. 6 CD107a +It indicates a JNJ-957-mediated increase in the percentage of CD4 T cells. Fig. 7 is double-positive CD25 + CD107 + It indicates a JNJ-957-mediated increase in the percentage of CD4 T cells. Fig. 8 CD25 + It indicates a JNJ-957-mediated increase in the percentage of CD8 T cells. Fig. 9 is CD107a + It indicates a JNJ-957-mediated increase in the percentage of CD8 T cells. Fig. 10 is double-positive CD25 + CD107 + It indicates a JNJ-957-mediated increase in the percentage of CD8 T cells.

[1264] Example 2 Daratumumab improved the efficacy of T-cell re-induction antibodies.

[1265] patient

[1266] BCMA expression levels of JNJ-957, composition of immune cell subsets, and ex vivo efficacy were evaluated in 55 BM aspirates obtained from 11 newly diagnosed MM patients, 21 daratumumab-unsensitized relapsed / refractory MM patients, and 17 daratumumab-refractory relapsed / refractory MM patients (daratumumab relapsed / refractory patients were enrolled in the Phase 1 and Phase 2 studies of daratumumab in combination with all-trans retinate (ATRA); clinical trial identification number NCT02751255), and primary plasma cell leukemia (pPCL; n=6). Sequential BM samples were obtained from 8 patients treated in the DARA / ATRA study immediately prior to the initiation of daratumumab monotherapy and at the time of disease progression during daratumumab treatment. In the same study, the inventors obtained sequential peripheral blood samples from 10 patients immediately before the initiation of daratumumab monotherapy and at the time of maximum response achieved with daratumumab.

[1267] In the DARA / ATRA study (NCT02751255), patients had MM requiring systemic treatment and were relapsed from or refractory to two or more previous therapies. Patients were 18 years of age or older, had a life expectancy of at least 3 months, a WHO performance score of 2 or less, and measurable disease.

[1268] During Phase 1 of this study, daratumumab was administered according to the recommended dosage and schedule (weekly for 8 weeks, followed by every 2 weeks for 16 weeks, and 16 mg / kg every 4 weeks until PD). This protocol was approved by the study site ethics committee or the institutional review board and was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonization, and the Guidelines for Good Clinical Practice. All patients provided written informed consent.

[1269] The baseline characteristics of patients enrolled in the Phase 1 and 2 study NCT02751255 Table 5 and Table 6 This is shown in [figure]. RRMM patients have received an average of 5 (range: 1 to 9) previous therapies, and RRMM patients have received an average of 6 (range: 3 to 12) previous therapies. Table 7 represents an updated summary of baseline characteristics of patients enrolled in Phase 1 and Phase 2 studies.

[1270] [Table 5]

[1271]

[1272] [Table 6]

[1273]

[1274] [Table 7]

[1275]

[1276] Abbreviations: MM, multiple myeloma; NDMM, newly diagnosed MM; RRMM, relapsed / refractory MM; Dara: daratumumab; pPCL, primary plasma cell leukemia; n, number; IgG, immunoglobulin G; IgA, immunoglobulin A; FLC, free light chain; del, deletion; amp, amplification; t, translocation; PI, proteasome inhibitor; IMiD, immunomodulatory drug;

[1277] result

[1278] Daratumumab mediated the efficient lysis of MM cells from newly diagnosed (NDMM) patients and relapsed / refractory daratumumab-unaware patients, whereas cells from RRMM daratumumab-refractory patients exhibited resistance to lysis. Fig. 11 ).

[1279] In newly diagnosed (ND) MM patient samples (n=8), the mean lysis of MM cells by JNJ-957 4.0 µg / mL was 79% (range: 66 to 92%; Fig. 12 ). In lenalidomide (LEN) refractory patient samples, MM dissolution was achieved with similar but greater variability (n=15; mean dissolution at 4.0 μg / mL: 69%; range: 24 to 98%; Fig. 13 ), these also bortezomib (73%), Pomalidomide (82%) and carfilzomib (9%) were refractory. JNJ-957 was also effective in samples from MM patients refractory to daratumumab (DARA) (n=11; mean dissolution at 4.0 µg / mL: 83%; range: 52 to 99%; Fig. 14 ). NK- and T-cell frequencies were not affected in any of the tested samples.

[1280] The CD3x null and BCMAx null control antibodies showed significantly lower activity in different patient samples compared to JNJ-957, indicating the absence of the direct effect of BCMA blocking as well as the requirement for cross-linking between MM cells and effector T-cells.

[1281] JNJ-957-mediated lysis of primary MM cells, as evaluated by the expression of CD25 activating antigen, activated CD4 + and CD8 + It was associated with a dose-dependent increase in the percentage of T-cells. JNJ-957 treatment also, as determined by the cell surface expression of CD107a, CD4 + and CD8 + It caused T-cell degranulation. There was no difference in the degree of T-cell activation and degranulation between NDMM patients, daratumumab-irresponsive RRMM patients, and daratumumab-refractory RRMM patients. Fig. 15 is CD25 + It indicates a JNJ-957-mediated increase in the percentage of CD4 T cells. Fig. 16 CD107a + It indicates a JNJ-957-mediated increase in the percentage of CD4 T cells. Fig. 17 is double-positive CD25 + CD107 + It indicates a JNJ-957-mediated increase in the percentage of CD4 T cells. Fig. 18 CD25 + It indicates a JNJ-957-mediated increase in the percentage of CD8 T cells. Fig. 19 is CD107a + It indicates a JNJ-957-mediated increase in the percentage of CD8 T cells. Fig. 20 is double-positive CD25 + CD107 + It indicates a JNJ-957-mediated increase in the percentage of CD8 T cells.

[1282] The levels of granzyme B and various cytokines in the supernatant of JNJ-957-treated BM-MNCs from daratumumab-unsensitive patients and daratumumab-refractory RRMM patients were also evaluated. JNJ-957-mediated T-cell activation resulted in dose-dependent increases in the levels of granzyme B, IFN-γ, IL-2, IL-6, IL-8, IL-10, and TNF-α (data not shown).

[1283] The efficacy of JNJ-957 in mediating MM apoptosis was not associated with tumor characteristics (BCMA or PD-L1 expression, presence of standard or high-risk cytogenetic abnormalities) or patient characteristics, such as effector:target ratio, composition of the T-cell system, or PD-1 / HLA-DR expression on T-cells across all BM samples. However, when patient categories were analyzed individually, BCMA ( Fig. 21 ) and PD-L1( Fig. 22 ) Expression levels were significantly higher in RRMM patients compared to NDMM patients regardless of daratumumab exposure. Although the patient sample size was small, JNJ-957 activity was inversely correlated with PD-L1 expression levels in daratumumab-insensitive RRMM patients ( P =0.045).

[1284] By evaluating the composition of immune cells in BM aspirates of NDMM, daratumumab-unsensitive RRMM, and daratumumab RRMM samples, we gained an understanding of the differential effects of JNJ-957 in samples obtained from three patient subgroups. In the combined group of patients, high T-cell frequency ( P =0.034) and high E:T ratio( P =0.029) was associated with enhanced JNJ-7957-mediated lysis of MM cells. Other immune parameters (T-cells, Treg, PD-1 + T cells, HLA-DR +The number of T cells or unsensitized T cells did not affect JNJ-7957-mediated MM cell lysis.

[1285] In subgroup analysis, RRMM patients had a significantly higher Treg frequency compared to NDMM patients ( Fig. 23 ) and activated T-cell frequency (defined by HLA-DR expression) Fig. 24 ) and had a lower unsensitized T-cell frequency. In addition, daratumumab-refractory patient samples contained significantly more TEMRA T-cells than daratumumab-unsensitized samples ( Fig. 25 However, the frequency of activated, unemotional, central memory (CM), effector memory (EM), or TEMRA T-cells was not associated with the response to JNJ-7957 in these subgroup analyses. A high baseline percentage of Tregs showed a negative effect on JNJ-957-mediated MM cell lysis in RRMM patient samples, which was overcome by optimal dosing. NDMM mediated by auto-effector cells, dichotomized according to baseline percentage of Tregs ( Fig. 26 ), daratumumab irsensitization RRMM( Fig. 27 ) and daratumumab-refractory RRMM( Fig. 28 JNJ-597-mediated lysis of patient samples was evaluated. Samples were classified as "low" or "high" in terms of Treg content using the 50th percentile: NDMM: Low: ≤7.34%, High: >7.34%. Daratumumab unsensitized RRMM: Low ≤15.57%, High >15.57%. Daratumumab refractory RRMM: Low ≤11.24%, High >11.24%. Higher Treg concentrations attenuated JNJ-957-mediated lysis of MM cells in daratumumab unsensitized RRMM and daratumumab refractory RRMM samples. The Treg effect was lost at higher JNJ-957 concentrations.

[1286] PD-1 +The proportion of T-cells and the E:T ratio were similar across the three patient groups. Only in NDMM patients was the low T-cell frequency ( P =0.010) and high PD-1 + T-cell frequency ( P =0.048) impaired JNJ-957-mediated lysis of MM cells (data not shown).

[1287] The effect of daratumumab treatment on JNJ-957 efficacy was evaluated by assessing JNJ-957-mediated lysis in BM samples from NDMM (n=9), daratumumab-unsensitive RRMM (n=18), and daratumumab-refractory RRMM (n=13) patients after 48 hours of incubation. At relatively low concentrations of JNJ-957 (0.0064 to 0.032 µg / mL), tumor cell lysis was significantly superior in daratumumab-exposed patients compared to both daratumumab-unsensitive RRMM and NDMM patients. Fig. 29 represents the percentage of dissolution in the patient group. Data are presented as mean ± SEM, and P The value is student t - It is calculated using a test.

[1288] Since the improvement in tumor reduction may be supported by the recently discovered immunostimulatory effect of DARA, sequential BM aspirates from MM patients were analyzed before and after DARA treatment (n=5). Here, the inventors observed comparable BCMA expression, but observed improved MM cell lysis by JNJ-957 in samples obtained after disease progression during DARA treatment compared to samples before DARA initiation (mean lysis at 4.0 μg / mL: 93 vs. 74%; Fig. 30 In these BM aspirates, the percentage of Tregs in daratumumab-unsensitive patient samples compared to daratumumab-exposed patient samples ( Fig. 31 ) and CD4 + Percentage of cells ( Fig. 32 While ) was slightly decreased, CD8+ Percentage of cells ( Fig. 33 ) increased. In this study, samples were obtained from patients with a median duration of daratumumab monotherapy of 3 months (1 to 7 months). In a follow-up study of samples from 8 RRMM patients, CD38 + The percentages of Treg and Breg were significantly reduced in the daratumumab refractory patient sample compared to the daratumumab unasensitized patient sample (data not shown).

[1289] JNJ-957-mediated lysis of the RPMI 8226 multiple myeloma cell line was tested using sequential PB MNC samples from RRMM patients before and during daratumumab treatment as effector cells. Daratumumab-exposed PB MNCs were obtained during daratumumab treatment from patients who had an excellent response (partial response, very good partial response, or complete response) for a median duration of 11 months (range: 7 to 14 months) of daratumumab treatment. Fig. 34 This indicates that JNJ-957-mediated lysis of RPMI 8226 was enhanced using PB MNCs from daratumumab-exposed patients. In PB-MNC samples, the percentage of Tregs in daratumumab-unsensitive patient samples compared to daratumumab-exposed patient samples ( Fig. 35 ) and CD4 + Percentage of cells ( Fig. 36 While ) was slightly decreased, CD8 + Percentage of cells ( Fig. 37 ) was increased. In this study, samples were obtained from patients with a median duration of daratumumab treatment of 3 months (1 to 7 months).

[1290] The combination of JNJ-957 and daratumumab was also tested for efficacy in killing MM cells acquired from NDMM or RRMM dara-unsensitive patients. Fig. 38represents the percentage of lysis in BM MNCs of newly diagnosed MM (NDMM) patients (n=8) treated for 48 hours with JNJ-957 (0.032 to 0.8 µg / mL) alone or in combination with daratumumab 10 µg / mL. The observed (Obs) lysis levels of MM cells by JNJ-957 and daratumumab were compared to the expected (Exp) lysis levels, which were calculated under the assumption that the combination effect is achieved by an additive effect as described in Methods. Black bars represent the group mean ± SEM. P The value is pairwise student t- It is calculated using a test. Fig. 39 RRNN represents the percentage of BM MNC dissolution in patients irsensitized to daratumumab. Fig. 40 represents the percentage of BM MNC dissolution in RRMM daratumumab-refractory patients.

[1291] Therefore, this study demonstrated that JNJ-957 was effective in a sample of newly diagnosed and intensively pre-treated MM patients. A high percentage of regulatory T cells negatively affected the efficacy of JNJ-957 at low doses, but this negative effect was overcome by increasing the dose of JNJ-957. In vivo pre-treatment with daratumumab enhanced the efficacy of JNJ-957 against MM cells.

[1292] The combination of JNJ-957 and daratumumab demonstrated additive efficacy in vitro; furthermore, in vivo pretreatment with daratumumab enhanced the in vivo efficacy of BCMAxCD3.

[1293] Example 3 Daratumumab treatment improved the in vitro efficacy of blinatumomab.

[1294] To evaluate whether daratumumab treatment is also beneficial for other T-cell re-induction therapies, using paired daratumumab-unsensitized PB-MNCs and daratumumab-exposed PB-MNCs from 11 MM patients, CD19 with blinatumumab, an FDA-approved CD19xCD3 BiTE for the treatment of acute lymphoblastic leukemia + Raji cells were treated. Similar to observations for JNJ-957, the activity of blinatumomab was significantly enhanced by co-incubation with daratumomab-exposed PB-MNCs compared to daratumomab-unsensitized PB-MNCs ( P <0.0001; Fig. 41 Blinatumomab is Sequence number 53 It includes the amino acid sequence of.

[1295] Sequence number 53

[1296] DIQLTQSPASLAVSLGQRATISCKASQSVDYDGDSYLNWYQQIPGQPPKL

[1297] LIYDASNLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAATYHCQQSTEDPW

[1298] TFGGGTKLEIKGGGGSGGGGSGGGGSQVQLQQSGAELVRPGSSVKISCKA

[1299] SGYAFSSYWMNWVKQRPGQGLEWIGQIWPGDGDTNYNGKFKGKATLTADE

[1300] SSSTAYMQLSSLASEDSAVYFCARRETTTVGRYYYAMDYWGQGTTVTVSS

[1301] GGGGSDIKLQQSGAELARPGASVKMSCKTSGYTFTRYTMHWVKQRPGQGL

[1302] EWIGYINPSRGYTNYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYY

[1303] CARYYDDHYCLDYWGQGTTLTVSSVEGGSGGSGGSGGSGGVDDIQLTQSP

[1304] AIMSASPGEKVTMTCRASSSVSYMNWYQQKSGTSPKRWIYDTSKVASGVP

[1305] YRFSGSGSGTSYSLTISSMEAEDAATYYCQQWSSNPLTFGAGTKLELKHH

[1306] HHHH

[1307] Example 4 JNJ-957 effectively killed primary pPCL cells.

[1308] The in vitro activity of JNJ-957 was evaluated in BM samples from six patients with newly diagnosed pPCL characterized by aggressive clinical behavior. JNJ-957-mediated tumor cell lysis in these pPCL samples was similar to that observed in NDMM and daratumumab-unsensitized RRMM samples, but lower than that observed in daratumumab-refractory RRMM patient samples ( P =0.0014) ( Fig. 42 The median E:T ratio in the pPCL sample was approximately 8 times lower, but CD4 + ( P =0.0040) and CD8 + T-cells ( P <0.0001) not only the degree of activation of both, but also CD8 + Degree of T-cell degranulation ( P =0.0141) was superior in pPCL compared to NDMM. CD4 + The degranulation of T-cells was similar to that observed in NDMM.

[1309] BM-MNCs were obtained from 6 pPCL patients and incubated for 48 hours with JNJ-957 (0.0064 to 4.0 µg / mL) or control antibodies 3930, BC3B4, and 7008 (4.0 µg / mL), and subsequently, surviving CD138 +Tumor cells, as well as T- and NK-cells, were counted using flow cytometry. Data were expressed as mean % lysis ± SEM of cells. All experiments were performed in duplicate.

[1310] Example 5 Combination of GPRC5DxCD3 bispecific antibody and daratumumab

[1311] To further evaluate whether daratumumab treatment is also beneficial for other T-cell re-induction therapies, RPMI MM cells were treated with a GPRC5DXCD3 bispecific antibody using paired daratumumab-unsensitized PB-MNCs and daratumumab-exposed PB-MNCs from 11 MM patients (these samples were obtained from the same patients as described in the above examples). As a control, antibodies were used in which either the CD3 or GPRC5D binding VH / VL domain was replaced with a null domain binding to an unrelated antigen (gp120) (control mAb 3930 nullxnull, control mAb 7008 nullxCD3, control mAb GPRC5Dxnull). The antibodies were tested at concentrations ranging from 0.00064 to 4.0 µg / ml. The GPRC5DxCD3 bispecific antibody mediated MM cell lysis in both daratumumab-unsensitized and daratumumab-refractory samples with similar efficacy ( Fig. 43 ).

[1312] The combination of the GPRC5DxCD3 bispecific antibody and daratumumab was also tested for efficacy in killing MM cells acquired from NDMM or RRMM dara-unsensitive patients. Fig. 44represents the percentage of lysis of BM MNCs over 48 hours mediated by the GPRC5DxCD3 bispecific antibody (0.0128 to 0.8 µg / mL) alone or in combination with daratumumab 0.1 µg / mL. The observed (O) lysis levels of MM cells induced by the GPRC5DxCD3 bispecific antibody and daratumumab were compared to the predicted (E) lysis levels, where the predicted lysis levels were calculated under the assumption that the combination effect is achieved by an additive effect as shown in the methods. Black bars represent the group mean value ± SEM. P The value is pairwise student t- It was calculated using a assay. Co-incubation with daratumumab enhanced MM cell lysis by the GPRC5DxCD3 bispecific antibody in an additive manner.

[1313] The GPRC5DxCD3 bispecific antibody contains the GPRC5D binding arm GC5B596 and the CD3 binding arm CD3B219. The amino acid sequence of GC5B596 is Table 8 It is presented in. The amino acid sequence of CD3B219 is Table 4 It is presented in.

[1314] The GPRC5DxCD3 bispecific antibody used in the experiment is described in International Patent Application Publication WO20180037651A1 and comprises the following sequence:

[1315] GPRC5D binding domains comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of sequence numbers 43, 44, 45, 446, 47, and 48, respectively, and CD3 binding domains comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of sequence numbers 33, 34, 35, 36, 37, and 38, respectively;

[1316] A GPRC5D binding domain comprising VH of SEQ ID NO. 49 and VL of SEQ ID NO. 50, and a CD3 binding domain comprising VH of SEQ ID NO. 39 and VL of SEQ ID NO. 40; and

[1317] First heavy chain (HC1) of sequence number 51, first light chain (LC1) of sequence number 52, second heavy chain (HC2) of sequence number 41, and second light chain (LC2) of sequence number 42.

[1318] The GPRC5DxCD3 bispecific antibody is an IgG4 allotype.

[1319] HC1 includes S228P, F234A, and L235A substitutions.

[1320] HC2 includes S228P, F234A, L235A, F405L, and R409K substitutions.

[1321] [Table 8]

[1322]

[1323] Example 6 Combination of T-cell re-induction therapy and anti-CD38 antibody

[1324] The effect of combining additional T-cell re-induction therapy with an anti-CD38 antibody is evaluated in a manner similar to that described in Examples 1 to 5. The additive or synergistic effects of these combinations in mediating the death of tumor cells targeted by T-cell re-induction therapy (i.e., tumor cells expressing antigens bound by T-cell re-induction therapy) are tested. The effect of pre-treatment with the anti-CD38 antibody on the efficacy of T-cell re-induction therapy is evaluated as described in the examples herein.

[1325] T-cell re-induction therapies tested in combination with anti-CD38 antibodies include PSMAxCD3, TMEFF2xCD3, CD123xCD3, and CD33xCD3 bispecific antibodies.

[1326] An exemplary PSMAxCD3 bispecific antibody is PS3B27, which contains the PSMA binding domain PSMB127 and the CD3 binding domain CD3B219. Table 9 ...presents the amino acid sequence of PS3B27. The amino acid sequence of CD3B219 is Table 4 It is presented in.

[1327] An exemplary PSMAxCD3 bispecific antibody used in the experiment comprises the following sequence:

[1328] PSMA binding domains comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of sequence numbers 54, 55, 56, 9, 10, and 59, respectively, and CD3 binding domains comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of sequence numbers 33, 34, 35, 36, 37, and 38, respectively;

[1329] A PSMA binding domain comprising the VH of SEQ ID NO. 60 and the VL of SEQ ID NO. 61, and a CD3 binding domain comprising the VH of SEQ ID NO. 39 and the VL of SEQ ID NO. 40; and

[1330] The first heavy chain (HC1) of sequence number 62, the first light chain (LC1) of sequence number 63, the second heavy chain (HC2) of sequence number 41, and the second light chain (LC2) of sequence number 42.

[1331] The anti-PSMAxCD3 bispecific antibody is an IgG4 allotype.

[1332] HC1 includes S228P, F234A, and L235A substitutions.

[1333] HC2 includes S228P, F234A, L235A, F405L, and R409K substitutions.

[1334] [Table 9]

[1335]

[1336] An exemplary TMEFF2xCD3 bispecific antibody is TMCB150, which includes the TMEFF2 binding arm TMEB762 and the CD3 binding arm CD3B376. Table 10 ...presents the amino acid sequence of TMEB762. Table 11 ...presents the amino acid sequence of CD3B376.

[1337] An exemplary TMEFF2xCD3 bispecific antibody used in the experiment is TMCB150, which contains the following sequence:

[1338] TMEFF2 binding domains comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of sequence numbers 64, 65, 66, 67, 68, and 69, respectively, and CD3 binding domains comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of sequence numbers 74, 75, 76, 77, 78, and 79, respectively;

[1339] A TMEFF2 binding domain comprising VH of SEQ ID NO. 70 and VL of SEQ ID NO. 71, and a CD3 binding domain comprising VH of SEQ ID NO. 80 and VL of SEQ ID NO. 81; and

[1340] The first heavy chain (HC1) of sequence number 72, the first light chain (LC1) of sequence number 73, the second heavy chain (HC2) of sequence number 82, and the second light chain (LC2) of sequence number 83.

[1341] The anti-TMEFF2xCD3 bispecific antibody is an IgG4 allotype.

[1342] HC1 includes S228P, F234A, and L235A substitutions.

[1343] HC2 includes S228P, F234A, L235A, F405L, and R409K substitutions.

[1344] [Table 10]

[1345]

[1346] [Table 11]

[1347]

[1348] An exemplary CD33xCD3 bispecific antibody is C3CB189, which includes the CD33 binding arm C33B904 and the CD3 binding arm CD3B376. Table 12 It presents the amino acid sequence of C33B904. The amino acid sequence of CD3B376 is Table 11 It is presented in.

[1349] An exemplary CD33xCD3 bispecific antibody used in the experiment is C3CB189, which contains the following sequence:

[1350] CD33 binding domains comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of sequence numbers 84, 85, 86, 87, 88, and 89, respectively, and CD3 binding domains comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of sequence numbers 74, 75, 76, 77, 78, and 79, respectively;

[1351] A CD33 binding domain comprising VH of SEQ ID NO. 90 and VL of SEQ ID NO. 91, and a CD3 binding domain comprising VH of SEQ ID NO. 80 and VL of SEQ ID NO. 81; and

[1352] The first heavy chain (HC1) of sequence number 92, the first light chain (LC1) of sequence number 93, the second heavy chain (HC2) of sequence number 82, and the second light chain (LC2) of sequence number 83.

[1353] The anti-CD33xCD3 bispecific antibody is an IgG4 allotype.

[1354] HC1 includes S228P, F234A, and L235A substitutions.

[1355] HC2 includes S228P, F234A, L235A, F405L, and R409K substitutions.

[1356] [Table 12]

[1357]

[1358] An exemplary CD123xCD3 bispecific antibody is 8747, which comprises a CD123 binding arm I3RB218 and a CD3 binding arm CD3B219. 8747 is described in International Patent Application Publication WO2016036937A1. Table 13 ...presents the amino acid sequence of I3RB218. The amino acid sequence of CD3B219 is Table 4 It is presented in.

[1359] An exemplary CD123xCD3 bispecific antibody used in the experiment is 8747, which contains the following sequence:

[1360] CD123 binding domains comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of sequence numbers 94, 95, 96, 9, 10, and 59, respectively, and CD3 binding domains comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of sequence numbers 33, 34, 35, 36, 37, and 38, respectively;

[1361] A CD123 binding domain comprising the VH of SEQ ID NO. 100 and the VL of SEQ ID NO. 61, and a CD3 binding domain comprising the VH of SEQ ID NO. 39 and the VL of SEQ ID NO. 40; and

[1362] First heavy chain (HC1) of sequence number 102, first light chain (LC1) of sequence number 63, second heavy chain (HC2) of sequence number 41, and second light chain (LC2) of sequence number 42.

[1363] The anti-CD123xCD3 bispecific antibody is an IgG4 allotype.

[1364] HC1 includes S228P, F234A, and L235A substitutions.

[1365] HC2 includes S228P, F234A, L235A, F405L, and R409K substitutions.

[1366] [Table 13]

[1367]

[1368] To evaluate the effect of pretreatment with an anti-CD38 antibody on the efficacy of tumor death induced by a T-cell re-induction therapy, tumor cells are isolated from subjects having tumors expressing antigens to which the T-cell re-induction therapy binds, such as CD123, CD33, PSMA, TMEFF2, etc., or established tumor cell lines are used. Tumor cell death is evaluated in vitro by co-incubating tumor cells with PB-MNCs obtained from subjects exposed to the anti-CD38 antibody or subjects unsensitized to the anti-CD38 antibody, as described in the examples, and the percentage of tumor cell lysis is evaluated in each group. In individual examples, the T-cell re-induction therapy and the anti-CD38 antibody are incubated with target and effector cells together or individually, and tumor cell death mediated by the combination is evaluated relative to the individual therapy.

[1369] The effect of an anti-CD38 antibody on CD123xCD3 bispecific antibody-mediated tumor cell death is evaluated using CD123-positive tumor cells, e.g., AML tumors, or cell lines, e.g., AML cell lines KG1a, HL60, or MOLM13, as target cells.

[1370] The effect of an anti-CD38 antibody on CD33xCD3 bispecific antibody-mediated tumor cell death is evaluated using CD33-positive tumor cells, e.g., AML tumors, or cell lines, e.g., AML cell lines KG1a, HL60, or MOLM13, as target cells.

[1371] The effect of an anti-CD38 antibody on TMEFF2xCD3 bispecific antibody-mediated tumor cell death is evaluated using TMEFF2-positive tumor cells, such as LnCP cells, as target cells.

[1372] The effect of an anti-CD38 antibody on PSMAxCD3 bispecific antibody-mediated tumor cell death is evaluated using TMEFF2-positive tumor cells, such as LnCP cells, as target cells.

[1373] PBMCs or BM-MNCs isolated from subjects who have received anti-CD38 antibodies or are unaware of anti-CD38 antibody therapy are used as effector cells.

[1374] Those skilled in the art will recognize that numerous changes and variations may be made to the preferred embodiments of the present invention, and that such changes and variations may be made without departing from the spirit of the invention. Accordingly, the appended claims are intended to include all such equivalent variations within the spirit and scope of the present invention.

[1375] The disclosures of each patent, patent application, and publication cited or described in this document are incorporated herein by reference in their entirety.

Claims

Claim 1 A pharmaceutical composition for treating multiple myeloma in a subject, comprising an anti-CD38 antibody and a T-cell redirecting therapeutic, wherein the anti-CD38 antibody comprises a heavy chain (HC) of SEQ ID NO. 12 and a light chain (LC) of SEQ ID NO. 13; and the T-cell redirecting therapeutic is a BCMAxCD3 bispecific antibody comprising a first heavy chain (HC1) of SEQ ID NO. 31, a first light chain (LC1) of SEQ ID NO. 32, a second heavy chain (HC2) of SEQ ID NO. 41, and a second light chain (LC2) of SEQ ID NO.

42. Claim 2 A pharmaceutical composition for treating multiple myeloma in a subject, comprising a T-cell re-induction therapeutic agent, administered in combination with an anti-CD38 antibody, wherein the anti-CD38 antibody comprises a heavy chain (HC) of SEQ ID NO. 12 and a light chain (LC) of SEQ ID NO. 13; and wherein the T-cell re-induction therapeutic agent is a BCMAxCD3 bispecific antibody comprising a first heavy chain (HC1) of SEQ ID NO. 31, a first light chain (LC1) of SEQ ID NO. 32, a second heavy chain (HC2) of SEQ ID NO. 41, and a second light chain (LC2) of SEQ ID NO.

42. Claim 3 A pharmaceutical composition for treating multiple myeloma in a subject, comprising an anti-CD38 antibody, administered in combination with a T-cell re-induction therapeutic agent, wherein the anti-CD38 antibody comprises a heavy chain (HC) of SEQ ID NO. 12 and a light chain (LC) of SEQ ID NO. 13; and wherein the T-cell re-induction therapeutic agent is a BCMAxCD3 bispecific antibody comprising a first heavy chain (HC1) of SEQ ID NO. 31, a first light chain (LC1) of SEQ ID NO. 32, a second heavy chain (HC2) of SEQ ID NO. 41, and a second light chain (LC2) of SEQ ID NO.

42. Claim 4 A pharmaceutical composition according to any one of claims 1 to 3, wherein the anti-CD38 antibody is administered before administering the T-cell re-induction therapeutic agent. Claim 5 A pharmaceutical composition according to any one of claims 1 to 3, wherein the multiple myeloma is: a) newly diagnosed multiple myeloma; or b) relapsed or refractory multiple myeloma. Claim 6 A pharmaceutical composition according to claim 5, wherein the multiple myeloma is a high-risk multiple myeloma. Claim 7 In claim 6, the pharmaceutical composition wherein the subject having high-risk multiple myeloma has one or more chromosomal abnormalities comprising: a. t(4;14)(p16;q32); b. t(14;16)(q32;q23); c. del17p; d. 1qAmp; e. t(4;14)(p16;q32) and t(14;16)(q32;q23); f. t(4;14)(p16;q32) and del17p; g. t(14;16)(q32;q23) and del17p; or h. t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p, or any combination thereof. Claim 8 A pharmaceutical composition according to claim 5, wherein the multiple myeloma in b) above is relapsed or refractory to treatment with an anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, erlotozumab, ixazomib, melphalan, or thalidomide or any combination thereof. Claim 9 A pharmaceutical composition that is additionally administered in combination with one or more anticancer therapies in any one of claims 1 to 3. Claim 10 In claim 9, the above-mentioned anticancer therapy is a pharmaceutical composition selected from the group consisting of autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapy agents, immunomodulators, and targeted cancer therapies. Claim 11 In claim 10, the above one or more anticancer therapies are lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, erlotozumab, ixazomib, melphalan, dexamethasone, vincristine, cyclophosphamide, hydroxyidaunorubicin, prednisone, rituximab, imatinib, dasatinib, nilotinib, bosutinib, ponatinib, bafetinib, saracatinib, tozasertip or danusertib, cytarabine, daunorubicin, idarubicin, mitoxantrone, hydroxyurea, decitabine, cladribine, fludarabine, topotecan, etoposide, 6-thioguanine, corticosteroids, methotrexate, 6-mercaptopurine, azacitidine, arsenic trioxide and A pharmaceutical composition selected from the group consisting of all-trans retinoic acid or any combination thereof. Claim 12 In any one of claims 1 to 3, the anti-CD38 antibody is administered a) at a dose of 8 mg / kg to 16 mg / kg; or b) administered or provided for administration as a pharmaceutical composition having a pH of 5.5 comprising 20 mg / mL to 120 mg / mL of the anti-CD38 antibody in 25 mM acetic acid, 60 mM sodium chloride, 140 mannitol and 0.04% w / v polysorbate-20 (PS-20); or c) both of a) and b). Claim 13 A pharmaceutical composition according to any one of claims 1 to 3, wherein the anti-CD38 antibody is administered or provided for administration as a pharmaceutical composition having a pH of 5.5 to 5.6 comprising I. 5 mM to 15 mM histidine; II. 100 mM to 300 mM sorbitol; III. 0.01% w / v to 0.04% w / v PS-20; and IV. 1 mg / mL to 2 mg / mL methionine. Claim 14 A pharmaceutical composition according to any one of claims 1 to 3, wherein the multiple myeloma is a BCMA expressing multiple myeloma. Claim 15 A pharmaceutical composition according to any one of claims 1 to 3, wherein the BCMAxCD3 bispecific antibody and the anti-CD38 antibody are administered by intravenous injection, or wherein the BCMAxCD3 bispecific antibody is administered by intravenous injection and the anti-CD38 antibody is administered by subcutaneous injection. Claim 16 A pharmaceutical composition according to any one of claims 1 to 3, wherein the subject is a human. 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