Methods of treating cancers and enhancing efficacy of t cell redirecting therapeutics

Abstract

The method revealed is for treating cancer and enhancing the efficacy of T-cell redirection therapy.

Description

Technical Field

[0001] The method revealed is for treating cancer and enhancing the efficacy of T-cell redirection therapy. Prior Technology

[0002] T-cell redirection killing is the desired mode of action in many therapeutic areas. Generally, T-cell redirection molecules are engineered to have at least two antigen-binding sites, one of which binds to the surface antigen on the target cell, and the other of which binds to the T-cell surface antigen. Among the T-cell surface antigens, the human CD3 ε subunit from the TCR protein complex is most often targeted to redirect T-cell killing. Various bispecific antibody formats that mediate T-cell redirection have been demonstrated in preclinical and clinical studies (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). Within the TME, under conditions of persistent antigen and inflammation, T cells become exhausted or dysfunctional, gradually losing their effector function and proliferative capacity. Impaired function and quantity of available T cells capable of engaging mediator-mediated T cell retargeting therapies can impair the antitumor efficacy of these agents. Therefore, enhancing T cell function is necessary to optimize the efficacy of mediator-mediated T cell retargeting therapies. Summary of the Invention

[0004] This disclosure provides a method for treating cancer in an individual, comprising administering to the individual a therapeutically effective amount of an anti-CD38 antibody and a T-cell redirection therapy agent to treat the cancer.

[0005] This disclosure also provides a method for killing tumor cells in an individual, comprising administering an anti-CD38 antibody and a T-cell redirection therapy agent that binds to antigens on tumor cells for a period of time sufficient to kill the tumor cells.

[0006] This disclosure provides a method for enhancing the efficacy of T-cell redirection therapy in individuals with cancer, comprising administering an anti-CD38 antibody to the individual.

[0007] This disclosure also provides a method for treating cancer in an individual, comprising administering to the individual a therapeutically effective amount of BCMAxCD3 bispecific antibody and anti-CD38 antibody to treat cancer.

[0008] This disclosure also provides a method for treating cancer in an individual, comprising administering a therapeutically effective amount of a BCMAxCD3 bispecific antibody to the individual to treat the cancer, wherein the individual has already been treated with an anti-CD38 antibody prior to administering the BCMAxCD3 bispecific antibody.

[0009] This disclosure also provides a method for treating cancer in an individual, comprising administering a therapeutically effective amount of a BCMAxCD3 bispecific antibody to the individual to treat cancer in an individual whose cancer has relapsed or is refractory to prior anticancer treatments.

[0010] This disclosure also provides a method for treating an individual with multiple myeloma, comprising administering to the individual a therapeutically effective amount of BCMAxCD3 bispecific antibody and anti-CD38 antibody to treat multiple myeloma.

[0011] This disclosure also provides a method for treating multiple myeloma in an individual, comprising administering a therapeutically effective amount of BCMAxCD3 bispecific antibody to the individual for the treatment of multiple myeloma, wherein the individual has already been treated with anti-CD38 antibody prior to administration of the BCMAxCD3 bispecific antibody.

[0012] This disclosure also provides a method for treating an individual with multiple myeloma, comprising administering a therapeutically effective amount of a BCMAxCD3 bispecific antibody to the individual to treat multiple myeloma, wherein the individual has relapsed or is refractory to previous multiple myeloma treatments.

[0013] This disclosure also provides a pharmaceutical composition comprising a BCMAxCD3 bispecific antibody and an anti-CD38 antibody. The BCMAxCD3 bispecific antibody comprises a BCMA binding domain and a CD3 binding domain. The BCMA binding domain comprises VH of SEQ ID NO: 29 and VL of SEQ ID NO: 30. The CD3 binding domain comprises VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40. The anti-CD38 antibody comprises VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5.

[0014] This disclosure also provides a method for treating cancer in an individual, comprising administering to the individual a therapeutically effective dose of a GPRC5D-binding T-cell redirection agent and an anti-CD38 antibody to treat the cancer.

[0015] This disclosure also provides a method for treating cancer in an individual, comprising administering a therapeutically effective amount of a GPRC5DxCD3 bispecific antibody to the individual to treat cancer in an individual whose cancer has relapsed or is refractory to prior anticancer treatments.

[0016] This disclosure also provides a pharmaceutical combination comprising a GPRC5DxCD3 bispecific antibody and an anti-CD38 antibody. The GPRC5DxCD3 bispecific antibody comprises a GPRC5D binding domain and a CD3 binding domain. The GPRC5D binding domain comprises HCDR1 (SEQ ID NO: 43), HCDR2 (SEQ ID NO: 44), HCDR3 (SEQ ID NO: 45), LCDR1 (SEQ ID NO: 46), LCDR2 (SEQ ID NO: 47), and LCDR3 (SEQ ID NO: 48). The CD3 binding domain comprises HCDR1 (SEQ ID NO: 33), HCDR2 (SEQ ID NO: 34), HCDR3 (SEQ ID NO: 35), LCDR1 (SEQ ID NO: 36), LCDR2 (SEQ ID NO: 37), and LCDR3 (SEQ ID NO: 38). The anti-CD38 antibody comprises HCDR1 (SEQ ID NO: 6), HCDR2 (SEQ ID NO: 7), and LCDR3 (SEQ ID NO: 48). HCDR3 of SEQ ID NO: 9, LCDR1 of SEQ ID NO: 10, and LCDR2 of SEQ ID NO: 11.

[0017] This disclosure also provides a method for treating cancer in an individual, comprising administering to the individual a therapeutically effective dose of a CD19-binding T-cell redirection agent and an anti-CD38 antibody to treat cancer.

[0018] This disclosure also provides a method for enhancing the efficacy of CD19-binding T-cell redirection therapy in individuals with cancer, comprising administering an anti-CD38 antibody to the individual prior to administering the CD19-binding T-cell redirection therapy.

[0019] This disclosure also provides a pharmaceutical combination comprising a CD19xCD3 bispecific antibody containing blinatumomab (SEQ ID NO: 53), and an anti-CD38 antibody comprising HCDR1 (SEQ ID NO: 6), HCDR2 (SEQ ID NO: 7), HCDR3 (SEQ ID NO: 8), LCDR1 (SEQ ID NO: 9), LCDR2 (SEQ ID NO: 10), and LCDR3 (SEQ ID NO: 11).

[0020] This disclosure also provides a kit containing a pharmaceutical composition disclosed herein. Simple Explanation of the Diagram

[0021] [ [picture] [1] The lysis of the JNJ-957-mediated multiple myeloma (MM) cell line RPMI8226 was shown. Peripheral blood mononuclear cells (PB MNCs) from healthy donors were used as effector cells. [ [picture] [2] Shows the lysis of the JNJ-957-mediated multiple myeloma (MM) cell line UM9. Peripheral blood mononuclear cells (PB MNCs) from healthy donors were used as effector cells. [ [picture] [3] Shows lysis of the JNJ-957-mediated multiple myeloma (MM) cell line U226. Peripheral blood mononuclear cells (PB MNCs) from healthy donors were used as effector cells. [ [picture] [4] Shows lysis of the JNJ-957-mediated multiple myeloma (MM) cell line MM1. Peripheral blood mononuclear cells (PB MNCs) from healthy donors were used as effector cells. [ [picture] [5] In a representative case of RPMI 8226 cells cultured with healthy donor PB MNCs (n=2), JNJ-957-mediated MM cell lysis was accompanied by increased CD4+ T cell activation and degranulation as determined by the surface expression of CD25 (activation). [ [picture] [6] In a representative case of RPMI 8226 cells cultured with healthy donor PB MNCs (n=2), JNJ-957-mediated MM cell lysis was accompanied by increased CD4+ T cell activation and degranulation as determined by the surface expression of CD107a (degranulation). [ [picture] [7] In a representative example (n=2) of RPMI 8226 cells cultured with healthy donor PB MNCs, JNJ-957-mediated MM cell lysis was accompanied by CD4+ T cell activation and degranulation, as determined by the ratio of CD25 and CD107a double-positive CD4+ T cells. [ [picture] [8] In a representative case of RPMI 8226 cells cultured with healthy donor PB MNCs (n=2), JNJ-957-mediated MM cell lysis was accompanied by increased CD8+ T cell activation and degranulation as determined by the surface expression of CD25 (activation). [ [picture] [9] In a representative case of RPMI 8226 cell culture with healthy donor PB MNCs (n=2), JNJ-957-mediated MM cell lysis was accompanied by increased CD8+ T cell activation and degranulation as determined by increased surface expression of CD107a (degranulation); [ [Figure 10] shows that in a representative example (n=2) of RPMI 8226 cells cultured with healthy donor PB MNCs, JNJ-957-mediated MM cell lysis was accompanied by CD8+ T cell activation and degranulation, as determined by an increase in the proportion of CD25 and CD107a double-positive CD4+ T cells. [ [Figure 11] shows the lysis of daclatasab-mediated cytokines from newly diagnosed multiple myeloma (NDMM) and daclatasab-initial relapsed / refractory MM (RRMM) patients in vitro. Multiple myeloma cells from daclatasab-refractory RRMM patients showed resistance to daclatasab-mediated lysis. *** P<0.0001 [ [picture]

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

[13] This figure shows the dose-response relationship of plasma cell, T cell, and NK cell lysis in whole autologous bone marrow (BM) MNCs from lenalidomide-refractory patients (n=15) with multiple myeloma (MM) treated with JNJ-957. The percentage of lysis was measured at various antibody concentrations (0.0064 to 4.0 µg / mL) as shown in the figure. Circles (top line): plasma cells; squares (middle line): T cells; triangles (bottom line): NK cells. [ [picture]

[14] This figure shows the dose-response relationship of plasma cell, T cell, and NK cell lysis in whole autologous bone marrow (BM) MNCs from 11 patients (n=11) with refractory MM treated with lenalidomide and dabramab via JNJ-957. The percentage of lysis was measured at various antibody concentrations (0.0064 to 4.0 µg / mL) as shown in the figure. Circles (top line): plasma cells; squares (middle line): T cells; triangles (bottom line): NK cells. [ [picture]

[15] JNJ-957-mediated MM cell lysis was accompanied by activation of CD4+ T cells (as assessed by increased CD25 surface expression) in BM samples from patients with NDMM, daclatasab-naïve RRMM (RRMM), and daclatasab-refractory RRMM (RRMM daraR). 3930: isotype control; BC3B4: BCMAx empty bispecific antibody; 7008: empty xCD3 bispecific antibody. [ [picture]

[16] JNJ-957-mediated MM cell lysis was accompanied by degranulation of CD4+ T cells (as assessed by increased CD107a surface expression) in BM samples from patients with NDMM, daclatasab-naïve RRMM (RRMM), and daclatasab-refractory RRMM (RRMM daraR). 3930: isotype control; BC3B4: BCMAx empty bispecific antibody; 7008: empty xCD3 bispecific antibody. [ [picture]

[17] Shows the percentage of double-positive CD25+CD107a+ cells in CD4+ T cells from BM samples of patients with NDMM, daclatasab-naïve RRMM (RRMM), and daclatasab-refractory RRMM (RRMM daraR) treated with JNJ-957 at the indicated concentration. 3930: isotype control; BC3B4: BCMAx empty bispecific antibody; 7008: empty xCD3 bispecific antibody. Double-positive: CD25 and CD107a double-positive CD4+ T cells. [ [picture]

[18] JNJ-957-mediated MM cell lysis was accompanied by activation of CD8+ T cells (as assessed by increased CD25 surface expression) in BM samples from patients with NDMM, daclatasab-naïve RRMM (RRMM), and daclatasab-refractory RRMM (RRMM daraR). 3930: isotype control; BC3B4: BCMAx empty bispecific antibody; 7008: empty xCD3 bispecific antibody. [ [picture]

[19] JNJ-957-mediated MM cell lysis was accompanied by degranulation of CD8+ T cells (as assessed by increased CD107a surface expression) in BM samples from patients with NDMM, daclata-naïve RRMM (RRMM), and daclata-refractory RRMM (RRMM daraR). 3930: isotype control; BC3B4: BCMAx empty bispecific antibody; 7008: empty xCD3 bispecific antibody. [ [picture]

[20] shows the percentage of double-positive CD25+CD107a+ cells in CD8+ T cells from BM samples of patients with NDMM, daclatasab-naïve RRMM (RRMM), and daclatasab-refractory RRMM (RRMM daraR) treated with JNJ-957 at the indicated concentration. 3930: isotype control; BC3B4: BCMAx empty bispecific antibody; 7008: empty xCD3 bispecific antibody. Double-positive: CD25 and CD107a double-positive CD4+ T cells. [ [picture]

[21] BCMA expression levels (mean MFI ± SEM) on MM cells in individuals with NDMM, daclatasab-naïve RRMM, and daclatasab-refractory RRMM. P values ​​between the groups shown were calculated using the Mann-Whitney U test; * P < 0.05; ns: not significant. [ [picture]

[22] PD-L1 expression levels (mean MFI ± SEM) on MM cells in individuals with NDMM, daclatasab-naïve RRMM, and daclatasab-refractory RRMM. P values ​​between groups were calculated using the Mann-Whitney U test; * P < 0.05; ns: not significant. [ [picture]

[23] shows the baseline percentage of Tregs in BM MNCs from NDMM, daclatasab-initiated RRMM, and daclatasab-refractory RRMM. **p<0.01; ns: not significant. [ [picture]

[24] shows the baseline percentage of activated T cells (as assessed by HLA-DR positivity) in BM MNCs from NDMM, daclatasab-naïve RRMM, and daclatasab-refractory RRMM. **p<0.01; Ns: not significant. [ [picture]

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

[26] JNJ-957-mediated lysis of multiple myeloma cells from NDMM patients mediated by autologous BM MNCs. Samples were didifferentiated according to baseline Treg frequencies (low ≤ 50th percentile, high > 50th percentile). Ns: not significant. [ [picture]

[27] JNJ-957-mediated lysis of multiple myeloma cells from daclatasab-naïve RRMM patients mediated by autologous BM MNCs. Samples were didifferentiated according to baseline Treg frequency (low ≤ 50th percentile, high > 50th percentile). *p<0.05;**p<0.01;Ns: not significant. [ [picture]

[28] JNJ-957-mediated lysis of multiple myeloma cells from daclatasab-refractory RRMM patients mediated by autologous BM MNCs. Samples were didifferentiated according to baseline Treg frequency (low ≤ 50th percentile, high > 50th percentile). *p < 0.05; Ns: not significant. [ [picture]

[29] Shows MM cell lysis in JNJ-957-mediated samples from BM samples of patients with NDMM (n=9), daclatasab-naïve RRMM (n=18), and daclatasab-refractory RRMM (n=13) after 48 hours of culture. Data are presented as mean ± SEM. P values ​​were calculated using Student's t-test. ** P < 0.01 [ [picture]

[30] JNJ-957-mediated MM cell lysis was observed in bone marrow (BM) samples from patients with relapsed / refractory multiple myeloma (RRMM) (n=8) in a significantly higher proportion of MM cell lysis in samples from patients who had received daclazab (“Dara-exposed”) compared to samples from the same patients who had not received daclazab treatment (“Dara-initial”). Data are expressed as mean ± SEM; P values ​​were calculated using paired t-tests. ns: not significant; * P < 0.05, ** P < 0.01. [ [picture]

[31] shows the percentage of Tregs in sequential BM aspirates (also shown in Figure 30) from patients with RRMM who were prior to daclazat initiation (before dara) and who developed daclazat-refractory disease (dara exposure). ns: not significant. [ [picture]

[32] shows the percentage of CD4+ in sequential BM aspirates (also shown in Figure 30) from patients with RRMM who were prior to daclazat initiation (before dara) and who developed daclazat-refractory disease (dara exposure). ns: not significant. [ [picture]

[33] shows the percentage of CD8+ T cells in sequential BM aspirates from patients with RRMM who were initiating daclazat (before dara) and who developed daclazat-refractory disease (dara exposure) (also shown in Figure 30). [ [picture]

[34] The lysis of RPMI8226 multiple myeloma cells mediated by JNJ-957 using patient-derived PB MNCs as effector cells was amplified by PB MNCs from patients who had received daclatasab (“Dara-term PBMNCs”) compared to samples from the same patients before the initiation of daclatasab treatment (“Dara-initial PBMNCs”) (n=5). Data are expressed as mean ± SEM; P values ​​were calculated using paired t-tests. ns: not significant; * P<0.05. [ [picture]

[35] shows the percentage of Tregs in the sequential PB-MNC samples used as effector cells in Figure 10A from RRMM patients before the start of daclazatumab treatment (before Dara) and during daclazatumab treatment (dara). [ [picture]

[36] shows the percentage of CD4+ T cells in the sequential PB-MNC samples used as effector cells in Figure 10A from RRMM patients before (before Dara) and during (dara) daclamab treatment. ns: not significant. [ [picture]

[37] shows the percentage of CD8+ T cells in the sequential PB-MNC samples used as effector cells in Figure 10A from RRMM patients before (before Dara) and during (dara) daclamab treatment. ns: not significant. [ [picture]

[38] This shows that the addition of daclataab amplifies the lysis of MM cells mediated by JNJ-957. BM mononuclear cells (MNCs) from NDMM patients (n=8) were treated with JNJ-957 (0.032 to 0.8 µg / mL) alone or in combination with daclataab 10 µg / mL for 48 hours. The observed (obs) MM cell lysis level with JNJ-957 and daclataab was compared with the expected (exp) lysis level, which was calculated as a combination effect using the assumption of cumulative effect as described in the methods. Black bars represent group mean ± SEM. P-values ​​were calculated using the paired Student's t-test. ns: not significant. [ [picture]

[39] This shows that the addition of daclazab amplifies the MM cell lysis mediated by JNJ-957. BM MNCs in daclazab-initiated RRMM patients (n=17) were treated with JNJ-957 (0.032 to 0.8 µg / mL) alone or in combination with daclazab 10 µg / mL for 48 hours. The observed (obs) MM cell lysis level with JNJ-957 and daclazab was compared with the expected (exp) lysis level, which was calculated based on the assumption of a combined effect achieved by the cumulative effect as described in the methods. Black bars represent group means ± SEM. P-values ​​were calculated using the paired Student's t-test. ns: not significant. [ [picture]

[40] This shows the amplification of MM cell lysis mediated by JNJ-957 with the addition of daratumumab. BM MNCs in daratumumab-refractory RRMM patients (n=14) were treated with JNJ-957 (0.032 to 0.8 µg / mL) alone or in combination with daratumumab 10 µg / mL for 48 hours. The observed (O) MM cell lysis levels with JNJ-957 and daratumumab were compared with the expected (E) lysis levels, which were calculated based on the assumption of a combined effect achieved by the cumulative effect as described in the methods. Black bars represent group mean ± SEM. P-values ​​were calculated using the paired Student's t-test. JNJ-957 is represented as JNJ-7957 in the figure. Dara: daratumumab. [ [picture]

[41] Raji cell line lysis mediated by lantumomab is shown, using sequential PB samples (E:T 10:1) from 11 RRMM patients as effector cells, obtained immediately before daclatasmab treatment (black) and during daclatasmab treatment (grey); the median treatment duration was 7 months, ranging from 2 to 14 months. Cytotoxicity assays based on BLI were performed after Raji cells were cultured with lantumomab (0.01 to 10 µg / mL) in the presence of these PB-MNCs for 48 hours. Data represent mean ± SEM, and experiments were performed in duplicate. Statistical significance (P-value) between groups was calculated using nonlinear regression analysis. [ [picture]

[42] This figure shows the dose-response of plasma cell, T cell, and NK cell lysis mediated by JNJ-957 from BM-MNC cells obtained from six pPCL patients. The percentage of lysis was measured at various antibody concentrations (0.0064 to 4.0 µg / mL) as shown in the figure. Upper line: plasma cells; lower line: overlapping line of T cells and NK cells. JNJ-957 is represented as JNJ-7957 in the figure. [ [picture]

[43] Demonstrated lysis of anti-GPRC5DxCD3-mediated MM cell lines using sequential PB samples (E:T 10:1) from 11 RRMM patients, obtained immediately before (offline) and during (online) daclatasab treatment; median treatment duration was 7 months, ranging from 2 to 14 months. Cytotoxicity assays based on BLI were performed after Raji cells were cultured with lantumomab (0.01 to 10 µg / mL) in the presence of these PB-MNCs for 48 hours. Data represent mean ± SEM, and experiments were performed in duplicate. [ [picture]

[44] This shows the additive nature of MM cell lysis mediated by the addition of daratumumab against the anti-GPRC5DxCD3 bispecific antibody (JNJ-7564). BM MNCs in daratumumab-initiated RRMM patients (n=17) were treated for 48 hours alone or in combination with daratumumab 0.1 µg / mL. The observed (O) MM cell lysis levels with anti-GPRC5DxCD3 bispecific antibody and daratumumab were compared with the expected (E) lysis levels, which were calculated based on the assumption of a combined effect achieved by an additive effect as described in the methods. Black bars represent group mean ± SEM. P-values ​​were calculated using the paired Student's t-test. Ns: Not significant. Dara: Dalatumab. Implementation

[0022] The disclosed methods can be more readily understood by referring to the following detailed description in conjunction with the accompanying drawings (which form part of this disclosure). It should be understood that the disclosed methods are not limited to the specific methods described and / or shown herein, and the terminology used herein is intended merely to describe particular embodiments by way of example and is not intended to limit the claimed methods. All patents, published patent applications, and publications cited herein are incorporated by reference as if they were described in their entirety herein.

[0023] When used in this text, the singular forms "a / an" and "the" include the plural.

[0024] Various terms relating to different implementation methods are used throughout the specification and the claims. These terms are used in their original meaning in the technical field unless otherwise indicated. Other specially defined terms are interpreted in accordance with the definitions provided in this specification.

[0025] When used to refer to a range of numbers, a threshold, or a specific value, " "About" means within an acceptable range of error for a particular value, as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. Unless otherwise expressly stated elsewhere in the examples or specification in the context of a test, result, or embodiment, "about" means within one standard deviation, or at most 5%, whichever is greater, according to practice in the art.

[0026] " The term "antibody" is used broadly to refer to and include immunoglobulin molecules, including monoclonal antibodies (including murine, human, humanized, and chimeric monoclonal antibodies), antigen-binding fragments, multispecific antibodies (such as bispecific, trispecific, and tetraspecific antibodies), dimer, tetramer, or multimer antibodies, single-chain antibodies, domain antibodies, and any other modified configuration of immunoglobulin molecules containing an antigen-binding site with desired specificity. A "full-length antibody" comprises two heavy chains (HC) and two light chains (LC) linked by disulfide bonds, as well as their polymers (e.g., IgM). Each heavy chain contains a heavy chain variable region (VH) and a heavy chain constant region (containing domains CH1, hinge, CH2, and CH3). Each light chain contains a light chain variable region (VL) and a light chain constant region (CL). The VH and VL regions can be further subdivided into multiple hypervariable regions scattered throughout the framework region (FR), which are called complementarity-determining regions (CDRs). Each VH and VL lineage consists of three CDR and four FR segments, arranged in the following order from amino group to carboxyl group: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. Immunoglobulins can be classified into five major classes: IgA, IgD, IgE, IgG, and IgM, depending on the amino acid sequence of the heavy chain constant domain. The IgA and IgG lineages are further subdivided into isotypes IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. The antibody light chain of any vertebrate species can be divided into two distinct types (i.e., kappa (κ) and lambda (λ)), depending on the amino acid sequence of its constant domain.

[0027] " [antigen binding fragment] or "[antigen binding fragment]" The antigen-binding domain refers to a portion of an immunoglobulin molecule that binds to an antigen. Antigen-binding fragments can be synthetic, enzymatically obtained, or genetically engineered polypeptides, and include VH, VL, VH and VL, Fab, F(ab')2, Fd, and Fv fragments; domain antibodies (dAbs) consisting of a VH domain or a VL domain; shark variable IgNAR domains; camelified VH domains; and the smallest recognition unit composed of amino acid residues from the CDRs of analog antibodies (such as the FR3-CDR3-FR4 portion, HCDR1, HCDR2, and / or HCDR3, and LCDR1, LCDR2, and / or LCDR3). The VH and VL domains can be linked together via synthetic linkers to form various types of single-chain antibody designs, wherein the VH / VL domains can pair intramolecularly or intermolecularly when the VH and VL domains are represented by separate single-chain antibody constructs to form monovalent antigen-binding sites, such as single-chain Fv (scFv) or bivalent antibodies (diabody); as described in, for example, International Patent Publications 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 encompasses residues 1 to 54 of Q02223. Human BCMA contains... The amino acid sequence of [SEQ ID NO: 2]. [SEQ ID NO: 2] MLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPLTCQRYCNASVTNSVKGTNAILWTCLLSLIISLAVFVLMFLLRKINSEPLKDEFKNTGSGLLGMANIDLEKSRTGDEIILPRGLE YTVEECTCEDCIKSKPKVDSDHHCFPLPAMEEGATILVTTKTNDYCKSLPAALSATEIEKS ISAR

[0029] " [Bispecific] "[(bispecific)]" refers to antibodies that specifically bind to two different antigens or two different epitopes within the same antigen. Bispecific antibodies may exhibit cross-reactivity with other related antigens, such as cross-reactivity with the same antigens (homologs) from other species (such as cynomolgus macaques or chimpanzees), or they may bind to epitopes shared by two or more different antigens.

[0030] " "Cancer" refers to a broad group of various diseases characterized by the uncontrolled growth of abnormal cells in the body. Unregulated cell division and growth lead to the formation of malignant tumors that invade adjacent tissues and can also metastasize to distant parts of the body via the lymphatic system or bloodstream. "Cancer" or "cancer tissue" may include tumors.

[0031] " [CD]

[0123] "Refers to the human interleukin-3 receptor subunit α (IR3RA) having the amino acid sequence shown in SEQ ID NO: 57. The extracellular domain or CD123 spans residues 19 to 305 of SEQ ID NO: 57. CD123 (SEQ ID NO: 57) MVLLWLTLLLIALPCLLQTKEDPNPPITNLRMKAKAQQLTWDLNRNVTDIECVKDADYSMPAVNNSYCQFGAISLCEVTNYTVRVANPPFSTWILFPENSGKPWAGAENLTCWIHDVDFLSCSWAVGPGAPADVQYDLYLNVANRRQQYECLHYKTDAQGTRIGCRFDDISRLSSGSQSSHILVRGRSAAFGIPCTDKFVVFSQIEILTPPNMTAKCNKTHSFMHWKMRSHFNRKFRYELQIQKRMQPVITEQVRDRTSFQLLNPGTYTVQIRARERVYEFLSAWSTPQRFECDQEEGANTRAWRTSLLIALGTLLALVCVFVICRRYLVMQRLFPRIPHMKDPIGDSFQNDKLVVWEAGKAGLEECLVTEVQVVQKT

[0032] 「 [CD19]」 refers to human B-lymphocyte antigen CD19 having the amino acid sequence of SEQ ID NO: 58. The extracellular domain of CD19 spans residues 20 to 291 of SEQ ID NO: 58. CD19 (SEQ ID NO: 58) MPPPRLLFFLLFLTPMEVRPEEPLVVKVEEGDNAVLQCLKGTSDGPTQQLTWSRESPLKP FLKLSLGLPGLGIHMRPLAIWLFIFNVSQQMGGFYLCQPGPPSEKAWQPGWTVNVEGSGE LFRWNVSDLGGLGCGLKNRSSEGPSSPSGKLMSPKLYVWAKDRPEIWEGEPPCLPPRDSL NQSLSQDLTMAPGSTLWLSCGVPPDSVSRGPLSWTHVHPKGPKSLLSLELKDDRPARDMW VMETGLLLPRATAQDAGKYYCHRGNLTMSFHLEITARPVLWHWLLRTGGWKVSAVTLAYL IFCCSLVGILHLQRALVLRRKRKRMTDPTRRFFKVTPPPGSGPQNQYGNVLSLPTPTSG LGRAQRWAAGLGGTAPSYGNPSSDVQADGALGSRSPPGVGPEEEEGEGYEEPDSEEDSEF YENDSNLGQDQLSQDGSGYENPEDEPLGPEDEDSFSNAESYENEDEELTQPVARTMDFLS PHGSAWDPSREATSLGSQSYEDMRGILYAAPQLRSIRGQPGPNHEEDADSYENMDNPDGP DPAWGGGGRMGTWSTR

[0033] " [CD3] refers to a human antigen that is expressed on T cells as part of the multimolecular T cell receptor (TCR) complex, and is composed of homodimers or heterodimers formed by the association of two or four receptor chains (CD3ε, CD3δ, CD3ζ, and CD3γ). Human CD3ε contains The amino acid sequence of [SEQ ID NO: 3]. [SEQ ID NO: 22] shows the extracellular domain of CD3 ε. [SEQ ID NO: 3] MQSGTHWRVLGLCLLSVGVWGQDGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGS KPEDANFYLYLRARVCENCMEMDVMSVATIVIVDICITGGLLLLVYYWSKNRKAKAKPVTRGAGAGGRQRGQNKERPPPVPNPDYEPIRKGQRDLYSGLNQRRI [SEQ ID NO: 22] DGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHL SLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENCMEMD

[0034] " "[CD33]" refers to the bone marrow cell surface antigen CD33 having the amino acid sequence of SEQ ID NO: 97. The extracellular domain of CD33 spans residues 18 to 259 of SEQ ID NO: 97. CD33 (SEQ ID NO: 97) MPLLLLLPLLWAGALAMDPNFWLQVQESVTVQEGLCVLVPCTFFHPIPYYDKNSPVHGYWFREGAIISRDSPVATNKLDQEVQEETQGRFRLLGDPSRNNCSLSIVDARRRDNGSYFFRMERGSTKYSYKSPQLSVHVTDLTHRPKILIPGTLEPGHSKNLTCSVSWACEQGTPPIFSWLSA APTSLGPRTTHSSVLIITPRPQDHGTNLTCQVKFAGAGVTTERTIQLNVTYVPQNPTTGIFPGDGSGKQETRAGVVHGAIGGAGVTALLALCLCLIFFIVKTHRRKAARTAVGRNDTHPTTGSASPKHQKKSKLHGPTETSSCSGAAPTVEMDEELHYASLNFHGMNPSKDTSTEYSEVRTQ

[0035] " "[CD38]" refers to the human CD38 protein (UniProt accession number P28907) (synonyms: ADP ribocyclase 1, cADPr hydrolase 1, cyclic ADP ribocyclase 1). Human CD38 has the amino acid sequence shown in SEQ ID NO: 1. CD38 is a type II single transmembrane protein, containing amino acid residues 1 to 21 representing the cytoplasmic domain, amino acid residues 22 to 42 representing the transmembrane domain, and residues 43 to 300 representing the extracellular domain. [SEQ ID NO: 1] MANCEFSPVSGDKPCCRLSRRAQLCLGVSILVLILVVVLAVVVPRWRQQWSGPGTTKRFPETVLARCVKYTEIHPEMRHVDCQSVWDAFKGAFISKHPCNITEEDYQPLMKLGTQTVPCNKILLWSRIKDLAHQFTQVQRDMFTLEDTLL GYLADDLTWCGEFNTSKINYQSCPDWRKDCSNNPVSVFWKTVSRRFAEAACDVVHVMLNGSRSKIFDKNSTFGSVEVHNLQPEKVQTLEAWVIHGGREDSRDLCQDPTIKELESIISKRNIQFSCKNIYRPDKFLQCVKNPEDSSCTSEI

[0036] " [CH3] [Region] (CH3 region) or " [CH3] The "[structural domain] (CH3 domain)" refers to the CH3 region of an immunoglobulin. The CH3 region of the human IgG1 antibody corresponds to amino acid residues 341 to 446. However, the CH3 region can also be any other antibody isotype described herein.

[0037] " [Chimeric antigen receptor] or " "CAR" refers to an engineered T-cell receptor that specifically transplants a ligand or antigen onto a T cell (e.g., naive T cells, central memory T cells, effector memory T cells, or combinations thereof). CARs are also known as artificial T-cell receptors, chimeric T-cell receptors, or chimeric immune receptors. A CAR contains an extracellular domain, a transmembrane domain, and at least one intracellular domain capable of binding to an antigen. The intracellular domain of a CAR contains a polypeptide known to function as a signal transduction domain to cause activation or inhibition of biological processes in the cell. The transmembrane domain contains any peptide or polypeptide known to span the cell membrane and function to connect the extracellular domain and the signal transduction domain. Chimeric antigen receptors may optionally contain a hinge domain, which acts as a connector between the extracellular domain and the transmembrane domain.

[0038] " "Combination" refers to administering two or more therapeutic agents together as a mixture to an individual, either in parallel as single agents or in any order as single agents sequentially.

[0039] " The complementarity determining region (CDR) is the region of the antibody that binds to the antigen. The CDR can be defined using various descriptors, such as Kabat (Wu et al. J Exp Med 132: 211-50, 1970) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991), Chothia (Chothia et al. J Mol Biol 196: 901-17, 1987), IMGT (Lefranc et al. Dev Comp Immunol 27: 55-77, 2003), and AbM (Martin and Thornton J Bmol Biol 263: 800-15, 1996). Describe the correspondence between various depictions and variable region numbers (see, for example, Lefranc et al. Dev Comp Immunol 27: 55-77, 2003; Honegger and Pluckthun, J Mol Biol 309:657-70, 2001; International ImMunoGeneTics (IMGT) database; online resources, http: / / www_imgt_org). Available programs (such as abYsis for UCL Business PLC) can be used to depict CDRs. The terms "CDR," "HCDR1," "HCDR2," "HCDR3," "LCDR1," "LCDR2," and "LCDR3" as used herein include CDRs defined by any of the methods described above, such as Kabat, Chothia, IMGT, or AbM, unless otherwise expressly stated in the specification.

[0040] " The word "comprising" is intended to include instances covered by the terms "consisting essentially of" and "consisting of"; similarly, the term "consisting essentially of" is intended to include instances covered by the term "consisting of". Unless the context clearly requires otherwise, the use of the words "comprise / comprising" and similar terms throughout the specification and the claims should be interpreted in an inclusive sense, as opposed to an exclusive or exhaustive sense; that is, in the sense of "including, but not limited to".

[0041] " [Enhance] or " "Enhanced" refers to an enhancement of one or more functions of the tested molecules compared to the control molecules, or an enhancement of one or more functions of a combination of tested molecules compared to one or more control molecules. Measurable exemplary functions include tumor cell killing, T cell activation, relative or absolute T cell count, Fc-mediated effector functions (e.g., ADCC, CDC, and / or ADCP), or binding to the Fcγ receptor (FcγR) or FcRn. "Enhanced" can be an enhancement of approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more, or a statistically significant enhancement.

[0042] " [Fcγ] [Receptor](Fc gamma receptor)」( [FcγR] refers to the well-known FcγRI, FcγRIIa, FcγRIIb, or FcγRIII. Activation of Fc [γR] includes FcγRI, FcγRIIa and FcγRIII.

[0043] " "[GPRC5D]" refers to a member of the human G protein-coupled receptor C family group 5D with the amino acid sequence shown in SEQ ID NO: 98. GPRC5D (SEQ ID NO: 98) MYKDCIESTGDYFLLCDAEGPWGIILESLAILGIVVTILLLLAFLFLMRKIQDCSQWNVL PTQLLFLLSVLGLFGLAFAFIIELNQQTAPVRYFLFGVLFALCFSCLLAHASNLVKLVRG CVSFSWTTILCIAIGCSLLQIIIATEYVTLIMTRGMMFVNMTPCQLNVDFVVLLVYVLFL MALTFFVSKATFCGPCENWKQHGRLIFITVLFSIIIWVVWISMLLRGNPQFQRQPQWDDP VVCIALVTNAWVFLLLYIVPELCILYRSCRQECPLQGNACPVTAYQHSFQVENQELSRAR DSDGAEEDVALTSYGTPIQPQTVDPTQECFIPQAKLSPQQDAGGV

[0044] 「 "Human antibody" refers to an antibody optimized to produce a minimal immune response when administered to a human individual. The variable regions of a human antibody are derived from human immunoglobulin sequences. If a human antibody contains a constant region or a portion of a constant region, that constant region is also derived from a human immunoglobulin sequence. If the variable regions of a human antibody are obtained from a system using human germline immunoglobulins or rearranged immunoglobulin genes, the human antibody contains heavy and light chain variable regions "derived from" human sequences. Such exemplary systems are those using human immunoglobulin gene libraries displayed on bacteriophages and gene transfer to non-human animals (such as mice or rats carrying human immunoglobulin gene loci). When compared to immunoglobulins expressed in humans, "human antibodies" generally contain amino acid differences due to differences between systems used to obtain human antibodies and human immunoglobulin gene loci, the introduction of somatic mutations, or the deliberate introduction of substitutions into the architecture or CDR (or both). Generally, a "human antibody" has at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity in its amino acid sequence with the amino acid sequence encoded by human germline immunoglobulin or rearranged immunoglobulin genes. In some cases, a "human antibody" may contain a common architecture sequence derived from human architecture sequence analysis, such as described in Knappik et al., (2000) J Mol Biol 296:57-86, or a synthetic HCDR3 incorporated into a human immunoglobulin gene library displayed on bacteriophages, such as described in Shi et al., (2010) J Mol Biol 397:385-96 and International Patent Publication No. WO2009 / 085462. At least one CDR line derived from a non-human species is not included in the definition of a "human antibody".

[0045] " "Humanized antibody" refers to an antibody with at least one CDR line derived from a non-human species and at least one architecture derived from a human immunoglobulin sequence. Humanized antibodies may include substitutions in their architecture, so such architectures may not be exact copies of the represented human immunoglobulin or the germline gene sequence of human immunoglobulins.

[0046] " "[isolated]" refers to a homogeneous molecular population (such as synthetic polynucleotides or proteins, such as antibodies) substantially isolated and / or purified from other components of a system (such as recombinant cells) from which the molecule has been synthesized, as well as proteins that have undergone at least one purification or isolation step. "[isolated antibody]" refers to an antibody that is substantially free of other cellular materials and / or chemicals, and includes antibodies isolated to higher purity, such as 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% purity.

[0047] " A monoclonal antibody is an antibody derived from a substantially homogeneous population of antibody molecules. That is, it includes, in addition to potentially well-known modifications, the individual antibodies within that population. These modifications include the removal of a C-terminal lysine from the antibody heavy chain or post-translational modifications such as amino acid isomerization or deamination, methionine oxidation, or aspartic acid or glutamic acid deamination. Monoclonal antibodies typically bind to one antigenic epitope. Bispecific monoclonal antibodies bind to two different antigenic epitopes. Monoclonal antibodies may exhibit heteroglycosylation within the antibody population. Monoclonal antibodies can be monospecific or multispecific (e.g., bispecific), monovalent, bivalent, or multivalent.

[0048] " "Mutation" refers to an engineered or naturally occurring change in a polypeptide or polynucleotide sequence compared to a reference sequence. The change can be a substitution, insertion, or deletion of one or more amino acids or polynucleotides.

[0049] " "[Non-fixed combination]" refers to separate pharmaceutical components of a T-cell redirection therapy agent and an anti-CD38 antibody, which are administered simultaneously, concurrently, or sequentially as separate entities without a specific time interval, thereby providing an effective level of both compounds in an individual's body.

[0050] " "Multispecific" refers to antibodies that specifically bind to at least two different antigens or at least two different epitopes within the same antigen. Multispecific antibodies can bind to, for example, two, three, four, or five different antigens or different epitopes within the same antigen.

[0051] " "Pharmaceutical composition" refers to a composition that includes an active ingredient and a pharmaceutically acceptable carrier.

[0052] " [Pharmaceutically acceptable carrier] or " "Excipient" refers to a component in a pharmaceutical composition other than the active ingredient, which is non-toxic to the system.

[0053] " The "Philadelphia chromosome" or "Ph" refers to the well-known translocation between chromosomes 9 and 22, resulting in the fusion of the oncogenic BCR-ABL gene 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, designated as t(9;22)(q34;q11), following the International System of Human Cell Genetic Nomenclature (ISCN). Depending on the precise location of the fusion, the resulting fusion protein can have a molecular weight ranging from 185 to 210 kDa. "Philadelphia chromosome" refers to all BCR-ABL fusion proteins resulting from the (9;22)(q34;q11) translocation.

[0054] " "[PSMA]" refers to a human prostate-specific membrane antigen having the amino acid sequence of SEQ ID NO: 99. The extracellular domain spans residues 44 to 750 of SEQ ID NO: 99. PSMA (SEQ ID NO: 99) MWNLLHETDSAVATARRPRWLCAGALVLAGGFFLLGFLFGWFIKSSNEATNITPKHNMKAFLDELKAENIKKFLYNFTQIPHLAGTEQNFQLAKQIQSQWKEFGLDSVELAHYDVLLSYPNKTHPNYISIINEDGNEIFNTSLFEPPPPGYENVSDIVPPFSAFSPQGMPEGDLVYVNYARTEDFFK LERDMKINCSGKIVIARYGKVFRGNKVKNAQLAGAKGVILYSDPADYFAPGVKSYPDGWNLPGGGVQRGNILNLNGAGDPLTPGYPANEYAYRRGIAEAVGLPSIPVHPIGYYDAQKLLEKMGGSAPPDSSWRGSLKVPYNVGPGFTGNFSTQKVKMHIHSTNEVTRIYNVIGTLRGAVEPDRYVILG GHRDSWVFGGIDPQSGAAVVHEIVRSFGTLKKEGWRPRRTILFASWDAEEFGLLGSTEWAEENSRLLQERGVAYINADSSIEGNYTLRVDCTPLMYSLVHNLTKELKSPDEGFEGKSLYESWTKKSPSPEFSGMPRISKLGSGNDFEVFFQRLGIASGRARYTKNWETNKFSGYPLYHSVYETYELV EKFYDPMFKYHLTVAQVRGGMVFELANSIVLPFDCRDYAVVLRKYADKIYSISMKHPQEMKTYSVSFDSLFSAVKNFTEIASKFSERLQDFDKSNPIVLRMMNDQLMFLERAFIDPLGLPDRPFYRHVIYAPSSHNKYAGESFPGIYDALFDIESKVDPSKAWGEVKRQIYVAAFTVQAAAETLSEVA

[0055] " "Recombinant" refers to the DNA, antibodies, and other proteins prepared, expressed, generated, or isolated through recombination when segments from different sources are linked to produce recombinant DNA, antibodies, or proteins.

[0056] " [Reduce] or " "Reduced" refers to a decrease in the function of one or more test molecules compared to control molecules, or a decrease in the function of one or more combinations of test molecules compared to one or more control molecules. Measurable exemplary functions include tumor cell killing, T cell activation, relative or absolute T cell count, Fc-mediated effector functions (e.g., ADCC, CDC, and / or ADCP), or binding to Fcγ receptors (FcγR) or FcRn. "Reduced" can be a reduction of approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more, or a statistically significant enhancement.

[0057] " "[rHuPh20]" refers to a recombinant human hyaluronidase having the amino acid sequence of SEQ ID NO: 105, which is a recombinant hyaluronidase (HYLENEX® recombinant), described in International Patent Publication No. WO2004 / 078140. rHuPH20 (SEQ ID NO: 105) MGVLKFKHIFFRSFVKSSGVSQIVFTFLLIPCCLTLNFRAPPVIPNVPFLWAWNAPSEFCLGKFDEPLDMSLFSFIGSPINATGQGVTIFYVDRLGYYPYIDSITGVTVNGGIPQKISLQDHLDKA KKDITFYMPVDNLGMAVIDWEEWRPTWARNWKPKDVYKNRSIELVQQQNVQLSLTEATEKAKQEFEKAGKDFLVETIKLGKLLRPNHLWGYYLFPDCYNHHYKKPGYNGSCFNVEIKRNDDLSWLWN ESTALYPSIYLNTQQSPVAATLYVRNRVREAIRVSKIPDAKSPLPVFAYTRIVFTDQVLKFLSQDELVYTFGETVALGASGIVIWGTLSIMRSMKSCLLLDNYMETILNPYIINVTLAAKMCSQVLC QEQGVCIRKNWNSSDYLHLNPDNFAIQLEKGGKFTVRGKPTLEDLEQFSEKFYCSCYSTLSCKEKADVKDTDAVDVCIADGVCIDAFLKPPMETEEPQIFYNASPSTLSATMFIVSILFLIISSVASL

[0058] " "Refractory" refers to cancers that are not suitable for surgical intervention and do not respond to initial treatment.

[0059] " "Relapsed" refers to cancer that responds to treatment but then relapses.

[0060] " "[Subject]" includes any human or non-human animal. "Non-human animal" includes all vertebrates, such as mammals and non-mammals, including non-human primates, sheep, dogs, cats, horses, cattle, chickens, amphibians, reptiles, etc. Unless otherwise stated, the terms "patient" and "subject" are used interchangeably.

[0061] " [T] "T cell redirecting therapeutic" refers to a molecule containing two or more binding regions, one of which specifically binds to a cell surface antigen (such as a tumor-associated antigen) on a target cell or tissue, and a second binding region of the molecule specifically binds to a T cell antigen (such as CD3). This dual / multi-target binding capability recruits T cells to the target cell or tissue, leading to the eradication of the target cell or tissue.

[0062] " "[TMEFF2]" refers to a human transmembrane protein containing EGF-like and two follicle-inhibitory-like domains, also known as tomoregulin 2. The full-length amino acid sequence of human TMEFF2 is shown below. [SEQ ID NO: 101]. The extracellular domain of TMEFF2 spans residues 40 to 374 of SEQ ID NO: 101. [TMEFF2 (SEQ ID NO: 101)] MVLWESPRQCSSWTLCEGFCWLLLLLPVMLLIVARPVKLAAFPTSLSDCQTPTGWNCSGYDDRENDLFLCDTNTCKFDGECLRIGDTVTCVCQFKCNNDYVPVCGSNGESYQNECYLRQAACKQQSEILVVSEGSCATDAGSGSGDGVHEGSGETSQKETSTCDICQFGAECDEDAEDVWCVCNIDCS QTNFNPLCASDGKSYDNACQIKEASCQKQEKIEVMSLGRCQDNTTTTTKSEDGHYARTDYAENANKLEESAREHHIPCPEHYNGFCMHGKCEHSINMQEPSCRCDAGYTGQHCEKKDYSVLYVVPGPVRFQYVLIAAVIGTIQIAVICVVVLCITRKCPRSNRIHRQKQNTGHYSSDNTTRASTRLI

[0063] Therapeutic effective amount refers to the dosage and time period required to effectively achieve the desired therapeutic outcome. Therapeutic effective amount can vary depending on various factors, such as an individual's disease state, age, sex, weight, and the ability of the treatment agent or combination of treatment agents to induce the desired response in the individual. Indicative indicators of an effective treatment agent or combination of treatment agents include, for example, improved patient well-being.

[0064] " "Treatment" refers to both therapeutic procedures and preventative or therapeutic measures, with the goal of preventing or mitigating undesirable physiological changes or symptoms. Beneficial or desired clinical outcomes include symptom relief, reduction of disease severity, stabilization of the disease (i.e., no worsening), slowing or decelerating disease progression, improving or alleviating disease conditions, and remission (whether partial or complete), whether detectable or undetectable. "Treatment" can also mean prolonged survival compared to the expected survival of an untreated individual. Those in need of treatment include those who already have a condition or symptom, those who are susceptible to a condition or symptom, or those who need to prevent or treat a condition or symptom.

[0065] " "Tumor cell" or "cancer cell" refers to cancerous, pre-cancerous, or transformed cells that exhibit spontaneous or induced phenotypic changes in vivo, ex vivo, or tissue culture. These changes do not necessarily involve the uptake of new genetic material. Although transformation can result from infection by transforming viruses and the incorporation 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. Examples of transformation / cancer include: morphological changes in vitro, in vivo, and ex vivo; cell immortalization; abnormal growth control; lesion formation; proliferation; malignancy; regulation of tumor-specific marker levels; invasiveness; tumor growth in suitable animal hosts such as nude mice, etc.

[0066] Throughout this specification, the amino acid residues in the antibody constant region are numbered according to the EU index as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991), unless otherwise explicitly stated. Antibody constant chain numbers can be found, for example, in the IMGT Scientific charts within the IMGT Web resource on the ImMunoGeneTics website.

[0067] Substitution systems in the CH3 region are characterized by multiple modified positions in the first CH3 domain of the first heavy chain and multiple modified positions in the second CH3 domain of the second heavy chain. For example, F405L / K409R refers to the F405L mutation in the first CH3 region and the K09R mutation in the second CH3 region. L351Y_F405A_Y407V / T394W refers to the L351Y, F40FA, and Y407V mutations in the first CH3 region and the T394W mutation in the second CH3 region. D399FHKRQ / K409AGRH refers to a mutation in which D399 can be substituted by F, H, K, R, or Q, and K409 can be substituted by A, G, R, or H.

[0068] The commonly used one-letter and three-letter amino acid codes are used in this paper and are shown in Table 1. [surface] [1.] amino acids Three-letter code One-letter code alanine Ala A Arginine Arg R aspartic acid Asn N Aspartic acid Asp D Cysteine Cys C glutamic acid Gln E glutamic acid Glu Q Glycine Gly G histidine His H Isoleucine Ile I Leucine Leu L lysine Lys K Methionine Met M Phenylan Phe F proline Pro P serine Ser S threonine Thr T tryptophan Trp W Tyrosine Tyr Y Valine Val V [anti] [CD38] [Antibodies and] [T] [Combinations of Cell Redirecting Therapeutic Agents and Their Uses]

[0069] This invention is at least in part based on the discovery that the therapeutic agent JNJ-957 and the GPRC5DxCD3 antibody and the anti-CD38 antibody DARZALEX® (daclamab) (which, when they bind to their target on the same cells, mediate the killing of multiple myeloma cells) do not antagonize each other in terms of competitive binding or interactive downregulation of their mechanisms of action or targets on MM cells, and are therefore suitable for use as a combination therapy. This invention is also at least in part based on the discovery that prior treatment with DARZALEX® (daclamab) amplifies the killing of JNJ-957-mediated multiple myeloma cells obtained from heavily treated relapsed / refractory multiple myeloma individuals. This invention is also at least in part based on the discovery that DARZALEX® (daclamab) amplifies the killing of tumor cells other than multiple myeloma cells by T-cell redirection therapeutic agents targeting non-multiple myeloma tumor cells. Therefore, the combination of anti-CD38 antibodies with T-cell redirection therapies and / or pretreatment with anti-CD38 antibodies before administration of T-cell redirection therapies can enhance the anti-tumor efficacy of monotherapy. Furthermore, given that cancer is generally a heterogeneous disease, with some cancerous cells exhibiting sufficient performance of one target compared to another, combination therapy can contribute to a more thorough eradication of the disease.

[0070] CD38 is a multifunctional protein that plays a role in receptor-mediated adhesion and signaling, and mediates calcium mobilization via its extracellular enzymatic activity, catalyzing the formation of cyclic ADP-ribose (cADPR) and ADPR. CD38 mediates intercytokine secretion and lymphocyte activation and proliferation (Funaro et al., J Immunol 145:2390-6, 1990; Terhorst et al., Cell 771-80, 1981; Guse et al., Nature 398:70-3, 1999). CD38 also regulates extracellular NAD+ levels through its NAD glycolytic activity, and these NAD+ levels are involved in the regulation of T cell compartments (Adriouch et al., Microbes infect 14:1284-92, 2012; Chiarugi et al., Nature Reviews 12:741-52, 2012). In addition to Ca2+ signaling, CD38 signaling occurs via cross-talk with antigen-receptor complexes or other types of receptor complexes (e.g., MHC molecules) on T and B cells. These receptor complexes are involved in several cellular responses, including IgG1 conversion and secretion. In this paper, the anti-CD38 antibody DARZALEX™ (darazumab) has been identified as enhancing the antitumor effects of T-cell retargeting therapies. While not wishing to be bound by any particular theory, it can be hypothesized that DARZALEX® (darazumab), through its immunomodulatory activity in human individuals (i.e., reducing the number of immunosuppressive Tregs, MDSCs, and Bregs, increasing the number of CD8+ T cells and the CD8+ to Treg ratio, promoting the formation of CD8+ central memory cells, and increasing T-cell homogeneity), can lead to, and even enhance, the immune response in individuals, and thus promote T-cell binding to T-cell retargeting therapies.

[0071] This disclosure provides a method for treating cancer in an individual, comprising administering to the individual a therapeutically effective amount of an anti-CD38 antibody and a T-cell redirection therapy agent to treat the cancer.

[0072] This disclosure also provides a method for killing tumor cells in an individual, comprising administering an anti-CD38 antibody and a T-cell redirection therapy agent that binds to antigens on tumor cells for a period of time sufficient to kill the tumor cells.

[0073] This disclosure also provides a method for enhancing the efficacy of T-cell redirection therapy in individuals with cancer, comprising administering an anti-CD38 antibody to the individual.

[0074] In some embodiments, the anti-CD38 anti-system is administered prior to the administration of the T-cell redirection therapy.

[0075] T-cell redirection therapy can be administered one, two, three, one month, five, six, seven weeks, two months, three months, four months, five months, six months, or longer before the administration of anti-CD38 antibodies.

[0076] In some embodiments, T-cell redirection therapeutic agents bind to antigens on tumor cells.

[0077] In some embodiments, the antigens on tumor cells include BCMA, GPRC5D, CD33, CD123, CD19, PSMA, TMEFF2, CD20, CD10, CD21, CD22, CD25, CD30, CD34, CD37, CD44v6, CD45, CD52, CD133, ROR1, B7-H6, B7-H3, HM1.24, SLAMF7, Fms-like tyrosine kinase 3 (FLT-3, CD135), chondroitin sulfate proteoglycan 4 (CSPG4, melanoma-associated chondroitin sulfate proteoglycan), epidermal growth factor receptor (EGFR), Her2, Her3, IGFR, IL3R, fibroblast activation protein (FAP), CDCP1, Derlin1, Tenascin, frizzled protein 1 to 10, and vascular antigen VEGFR2. (KDR / FLK1), VEGFR3 (FLT4, CD309), PDGFR-α (CD140a), PDGFR-β (CD140b), endothelial glycoprotein (Endoglin), CLEC14, Tem1-8, and Tie2. Further examples may include A33, CAMPATH-1 (CDw52), carcinoembryonic antigen (CEA), carbonic anhydrase IX (MN / CA IX), de2-7, EGFR, EGFRvIII, EpCAM, Ep-CAM, folate-binding protein, G250, Fms-like tyrosine kinase 3 (FLT-3, CD135), c-Kit (CD117), CSF1R (CD115), HLA-DR, IGFR, IL-2 receptor, IL3R, MCSP (chondroitin sulfate proteoglycan for melanoma-associated cell surface), Muc-1, prostate stem cell antigen (PSCA), prostate-specific antigen (PSA), hK2, TAG-72, or neotumor cell antigens.

[0078] In some embodiments, the T-cell redirection therapy agent is combined with BCMA, GPRC5D, CD33, CD123, CD19, PSMA, TMEFF2, CD20, CD22, CD25, CD52, ROR1, HM1.24, CD38, or SLAMF7.

[0079] In some embodiments, the T-cell redirection therapy agent binds to CD3ε.

[0080] In some embodiments, the T-cell redirection therapy agent binds to CD3.

[0081] In some embodiments, the T-cell redirection therapeutic agent binds to CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, BTNL8, PD-1, CD195, or NKG2C. CD8+ T cells are more specific to these antigens than CD3 (see, for example, WO2018187215).

[0082] In some embodiments, the T-cell redirection therapeutic agent includes a CD3-binding domain, the CD3-binding domain comprising... SEQ ID NO: 33 heavy chain complementarity determination region 1 (HCDR1), SEQ ID NO: 34 HCDR2, SEQ ID NO: 35 HCDR3, SEQ ID NO: 36 light chain complementarity determination region 1 (LCDR1), SEQ ID NO: 37 LCDR2 and SEQ ID NO: 38 LCDR3; The heavy chain variable region (VH) of SEQ ID NO: 39 and the light chain variable region (VL) of SEQ ID NO: 40; SEQ ID NO: 74 HCDR1, SEQ ID NO: 75 HCDR2, SEQ ID NO: 76 HCDR3, SEQ ID NO: 77 LCDR1, SEQ ID NO: 78 LCDR2 and SEQ ID NO: 79 LCDR3; VH of SEQ ID NO: 80 and VL of SEQ ID NO: 81; SEQ ID NO: 53, CD3 binding domains HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3; or VH and VL of the CD3 binding domain of SEQ ID NO: 53.

[0083] In some embodiments, the T-cell redirection therapy agent is combined with BCMA.

[0084] In some embodiments, the T-cell redirection therapeutic agent comprises The BCMA binding domain and the CD3 binding domain, wherein the BCMA binding domain includes HCDR1 of SEQ ID NO: 23, HCDR2 of SEQ ID NO: 24, HCDR3 of SEQ ID NO: 25, LCDR1 of SEQ ID NO: 26, LCDR2 of SEQ ID NO: 27, and LCDR3 of SEQ ID NO: 28, and the CD3 binding domain includes 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 The BCMA binding domain includes VH of SEQ ID NO: 29 and VL of SEQ ID NO: 30, and the CD3 binding domain includes VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40.

[0085] In some embodiments, the T-cell retargeting therapeutic agent bound to BCMA comprises the first heavy chain (HC1) of SEQ ID NO: 31, the first light chain (LC1) of SEQ ID NO: 32, the second heavy chain (HC2) of SEQ ID NO: 41, and the second light chain (LC2) of SEQ ID NO: 42.

[0086] In some embodiments, T-cell redirection therapies conjugated with BCMA include Seattle Genetics' ACTR cancer therapy, AFM-26, ALLO-715, CRISPR Therapeutics' anti-BCMA allogeneic CAR-T cell therapy, Sorrento Therapeutics' anti-BCMA CAR-T therapy, Hrain Biotechnology's anti-CD19 / BCMA CAR-T cell therapy, Chineo Med (Beijing)'s BCMA CAR-T therapy, Triumvira Immunologics' BCMA TAC-T cell therapy, and Shanghai Unicar-Therapy Biomed's BCMA-CAR. T-cell therapy, Regeneron's BCMA / CD3 antibody, NantKwest's CAR-NK cell therapy, CC-93629, CMD-505, CTX-4419, CYAD-211, HDP-101, HPN-217, P-BCMA-ALLO1, TNB-383B, bb-2121, AUTO-2, Pregene's BCMA chimeric antigen receptor therapy, Shanghai Bioray Laboratory's BCMA-CAR T-cell therapy, CARsgen Therapeutics' BCMA-CAR-T cell therapy, Shenzhen BinDeBio's CAR-T / TCR-T cell immunotherapy, ET-140, P-BCMA-101, REGN-5458, AMG-701, Cellular Biomedicine Group's anti-BCMA therapy. CAR-T cell therapy, bb-21217, BI-836909, CC-93269, Descartes-08, IM-21, JNJ-64007957, MEDI-2228 or PF-06863135.

[0087] In some embodiments, the T-cell redirection therapeutic agent comprises any of the BCMA binding domains described in WO2017031104A1.

[0088] In some embodiments, the T-cell redirection therapy agent is combined with GPRC5D.

[0089] In some embodiments, the T-cell redirection therapeutic agent comprises The GPRC5D binding domain includes HCDR1 (SEQ ID NO: 43), HCDR2 (SEQ ID NO: 44), HCDR3 (SEQ ID NO: 45), LCDR1 (SEQ ID NO: 46), LCDR2 (SEQ ID NO: 47), and LCDR3 (SEQ ID NO: 48); the CD3 binding domain includes HCDR1 (SEQ ID NO: 33), HCDR2 (SEQ ID NO: 34), HCDR3 (SEQ ID NO: 35), LCDR1 (SEQ ID NO: 36), LCDR2 (SEQ ID NO: 37), and LCDR3 (SEQ ID NO: 38); and / or The GPRC5D binding domain includes VH of SEQ ID NO: 49 and VL of SEQ ID NO: 50, and the CD3 binding domain includes VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40.

[0090] In some embodiments, the T-cell redirection 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.

[0091] In some embodiments, the T-cell redirection therapy includes Eureka Therapeutics' GPRC5D antibody.

[0092] In some embodiments, the T-cell redirection therapeutic agent comprises any of the GPRC5D binding domains described in WO20180037651A1.

[0093] In some embodiments, the T-cell redirection therapy agent binds to CD33.

[0094] In some embodiments, the T-cell redirection therapeutic agent comprises a CD33-binding domain and a CD3-binding domain, wherein the CD33-binding domain comprises HCDR1 of SEQ ID NO: 84, HCDR2 of SEQ ID NO: 85, HCDR3 of SEQ ID NO: 86, LCDR1 of SEQ ID NO: 87, LCDR2 of SEQ ID NO: 88, and LCDR3 of SEQ ID NO: 89, and the CD3-binding domain comprises HCDR1 of SEQ ID NO: 74, HCDR2 of SEQ ID NO: 75, HCDR3 or SEQ ID NO: 76, LCDR1 or SEQ ID NO: 77, LCDR2 or SEQ ID NO: 78, and LCDR3 of SEQ ID NO: 79; and / or The CD33 binding domain includes VH of SEQ ID NO: 90 and VL of SEQ ID NO: 91, and the CD3 binding domain includes VH of SEQ ID NO: 80 and VL of SEQ ID NO: 81.

[0095] In some embodiments, the CD33-binding T-cell redirection therapy 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.

[0096] In some embodiments, CD33-binding T-cell redirection therapies include Shenzhen BinDeBio's CAR-T / TCR-T cell immunotherapy, AMG-330, AMV-564, JNJ-67571244, ICG-144, AMG-673, Ziopharm's CD33 CAR-T therapy INXN 3004, huCD33-BsAb, VOR-33, HMBD-004A, GEM-333, TGB-3550, or CD33.taNK.

[0097] In some embodiments, the T-cell redirection therapy agent binds to CD123.

[0098] In some embodiments, the T-cell redirection therapeutic agent comprises The CD123 binding domain includes HCDR1 (SEQ ID NO: 94), HCDR2 (SEQ ID NO: 95), HCDR3 (SEQ ID NO: 96), LCDR1 (SEQ ID NO: 9), LCDR2 (SEQ ID NO: 10), and LCDR3 (SEQ ID NO: 59); the CD3 binding domain includes HCDR1 (SEQ ID NO: 33), HCDR2 (SEQ ID NO: 34), HCDR3 (SEQ ID NO: 35), LCDR1 (SEQ ID NO: 36), LCDR2 (SEQ ID NO: 37), and LCDR3 (SEQ ID NO: 38); and / or The CD123 binding domain includes VH of SEQ ID NO: 100 and VL of SEQ ID NO: 61, and the CD3 binding domain includes VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40.

[0099] In some embodiments, the T-cell redirection therapy 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.

[0100] In some embodiments, CD123-binding T-cell redirection therapies include TheraVectys' acute myeloid leukemia therapy, APVO-437, Nanjing Legend Biotech's anti-CD123 CAR-T cell therapy, APVO-436, Hebei Senlang Biotechnology's CD123 CAR-T cell therapy, flotetuzumab, IM-23, JNJ-63709178, Mustang Bio's MB-102, UCART-123, XmAb-14045, or Sanofi's CD3-CD123 bispecific T-cell binder.

[0101] In some embodiments, the T-cell redirection therapeutic agent comprises any of the CD123 binding domains described in WO2016036937A1.

[0102] In some embodiments, the T-cell redirection therapy agent is combined with CD19.

[0103] In some embodiments, the T-cell redirection therapeutic agent comprises The CD19 binding domain and the CD3 binding domain, wherein the CD19 binding domain includes HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of the CD19 binding domain of SEQ ID NO: 53, and the CD3 binding domain includes HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of the CD3 binding domain of SEQ ID NO: 53; and / or The amino acid sequence of SEQ ID NO: 53.

[0104] In some embodiments, CD19-binding T-cell retargeting agents include axicabtagene ciloleucel, blinatumomab, tisagenlecleucel-t, AMG-562, AUTO-1, Cellular Biomedicine Group's CAR-T CD19, Ziopharm's CD19 chimeric antigen receptor T-cell therapy, ioceltech Therapeutics' CD19-CAR-T cell therapy, Marino Biotechnology's CD19-CAR-T cell therapy, Guangdong Zhaotai InVivo's CD19-CAR-T2 cell therapy, Juno Therapeutics' CD19 / 4-1BBL armored CAR T-cell therapy, CSG-CD19, DI-B4, ET-190, GC-007F, GC-022, HRAIN Biotechnology's human CD19 T-cell therapy, Kite Pharma's humanized anti-CD19 control CAR (3rd Gen), and Immune Cell. Therapy's ICAR-19 CAR-T cells, ICTCAR-003, Marino Biotechnology's iPD1 CD19 eCAR T cells, JWCAR029, PTG-01, PZ01, Senl_1904A, Senl_1904B, UCART-19, UWC-19, AUTO-3, BinD-19, Shanghai Unicar-Therapy Biomed's CAR-T cell therapy, Shenzhen BinDeBio's CAR-T / TCR-T cell immunotherapy, Miltenyi Biotec's CD-19 CAR-T cell therapy, Shanghai Unicar-Therapy Biomed's CD19 CAR-T cells, Takara Bio's CD19-CAR T cell therapy, Shanghai Bioray Laboratory's CD19-CAR, Sinobioway's CD19-targeted chimeric antigen receptor T cells, and Shanghai Longyao Biotechnology's CD19 / CD20... CAR-T cell therapy, CIK-CAR.CD19, ICTCAR-011, IM-19, JCAR-014, loncastuximab tesirine, MB-CART2019.1. OXS-1550, PBCAR-0191, PCAR-019, PCAR-119, Senl-001, TI-1007, XmAb-5871, inebilizumab, lisocabtagene maraleucel, XmAb-5574, Eden BioCell's 3rd generation CD19-CAR-T cells + mbIL15, A-329, ALLO-501, Beijing Doing Biomedical Co's anti-CD19 and anti-CD20 bispecific CAR-redirected autologous T cells, Allife Medical Science's anti-CD19 CAR NK cell therapy, Hrain Biotechnology's anti-CD19 / BCMA CAR-T cell therapy, ATA-2431, ATA-3219, AVA-008, Celularity's CD19 CAR-T cell therapy, Ziopharm's third-generation CD19 chimeric antigen receptor T-cell therapy, Inovio's CD19 dBiTE, Bellicum's CD19 TCR-cell therapy, Wilex's CD19-ATAC, Chineo Med (Beijing)'s CD19 / 20 CAR-T therapy, Eureka Therapeutics' CD19 / CD22 dual-targeting therapy, Helix BioPharma's chimeric antigen receptor T-cell (CAR-T) therapy, CMD-502, CTX-110, CYAD-04, CYAD-221, ET-019002, FT-596, FT-819, TC Biopharm's γ-δ CAR-T therapy, ICTCAR-014, iDD-002, KITE-037, NI-2201, RB-1916, Senl_002, TAC01-CD19, TC-110, TC-310, TCB-003, or TI-7007.

[0105] In some embodiments, the T-cell redirection therapy agent is combined with PSMA.

[0106] In some embodiments, the T-cell redirection therapeutic agent comprises The PSMA binding domain includes HCDR1 and HCDR2 of SEQ ID NO: 54, or HCDR3 of SEQ ID NO: 55, or LCDR1 of SEQ ID NO: 56, or LCDR2 of SEQ ID NO: 9, or LCDR2 of SEQ ID NO: 10, and LCDR3 of SEQ ID NO: 59; the CD3 binding domain includes 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 The PSMA binding domain includes VH of SEQ ID NO: 60 and VL of SEQ ID NO: 61, and the CD3 binding domain includes VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40.

[0107] In some embodiments, the T-cell redirection therapeutic agent bound 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.

[0108] In some embodiments, the T-cell redirection therapy agent is combined with TMEFF2.

[0109] In some embodiments, the T-cell redirection therapeutic agent comprises The TMEFF2 binding domain includes HCDR1 (SEQ ID NO: 64), HCDR2 (SEQ ID NO: 65), HCDR3 (SEQ ID NO: 66), LCDR1 (SEQ ID NO: 67), LCDR2 (SEQ ID NO: 68), and LCDR3 (SEQ ID NO: 69). The CD3 binding domain includes HCDR1 (SEQ ID NO: 74), HCDR2 (SEQ ID NO: 75), HCDR3 (SEQ ID NO: 75), or LCDR1 (SEQ ID NO: 76), or LCDR2 (SEQ ID NO: 77), or LCDR3 (SEQ ID NO: 78), and LCDR3 (SEQ ID NO: 79); and / or The TMEFF2 binding domain contains VH of SEQ ID NO: 70 and VL of SEQ ID NO: 71, and the CD3 binding domain contains VH of SEQ ID NO: 80 and VL of SEQ ID NO: 81.

[0110] In some embodiments, the T-cell redirection 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.

[0111] In some embodiments, the T-cell redirection therapy agent is combined with CD20.

[0112] In some embodiments, the T-cell redirection therapy agent binds to CD22.

[0113] In some embodiments, the T-cell redirection therapy agent binds to CD25.

[0114] In some embodiments, the T-cell redirection therapy agent binds to CD52.

[0115] In some embodiments, the T-cell redirection therapy agent is combined with ROR1.

[0116] In some embodiments, the T-cell redirection therapy agent is combined with HM1.24.

[0117] In some embodiments, the T-cell redirection therapy agent is combined with SLAMF7.

[0118] In some embodiments, the T-cell redirection therapeutic agent is a multispecific antibody, a chimeric antigen receptor (CAR), or a T cell containing the CAR.

[0119] In some embodiments, the T-cell redirection therapy agent is a CAR.

[0120] In some embodiments, the T-cell redirection therapy is a T-cell expression of CAR.

[0121] In some embodiments, the T-cell redirection therapeutic agent is a multispecific antibody.

[0122] In some embodiments, the multispecific antibody system consists of IgG1, IgG2, IgG3, or IgG4 isotypes.

[0123] In some embodiments, the multispecific antibody system is IgG1 isotype.

[0124] In some embodiments, the multispecific antibody system is IgG2 isotype.

[0125] In some embodiments, the multispecific antibody system is IgG3 isotype.

[0126] In some embodiments, the multispecific antibody system is IgG4 isotype.

[0127] Multispecific antibodies can be of any allotype. It is expected that allotypes will not affect the properties of multispecific antibodies, such as binding or Fc-mediated effector functions. The immunogenicity of therapeutic antibodies is associated with an increased risk of infusion reaction and a reduced duration of therapeutic response (Baert et al., (2003) N Engl J Med 348:602-08). The extent to which a therapeutic antibody induces an immune response in the host can be partly determined by the antibody's allotype (Stickler et al., (2011) Genes and Immunity 12:213-21). Antibody allotypes are associated with amino acid sequence variations at specific locations within the antibody's constant region sequence. [surface] [2] Displays the selected IgG1, IgG2, and IgG4 isotypes. [surface] [2.] Allogeneic Amino acid residues in diverse locations (residue number: EU index) IgG2 IgG4 IgG1 189 282 309 422 214 356 358 431 G2m(n) T M G2m(n-) P V G2m(n) / (n-) T V nG4m(a) L R G1m(17) K E M A G1m(17,1) K D L A

[0128] 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). Substitutions that reduce the binding of the multispecific antibody to the FcγR reduce Fc effector functions such as ADCC, ADCP, and / or CDC of the multispecific antibody. Specific substitutions may be manufactured by comparing wild-type IgG1 of SEQ ID NO: 103 or wild-type IgG4 of SEQ ID NO: 104.

[0129] In some embodiments, one or more Fc substitution lines are selected from F234A / L235A on IgG4, L234A / L235A on IgG1, V234A / G237A / P238S / H268A / V309L / A330S / P331S on IgG2, F234A / L235A on IgG4, S228P / F234A / L235A on IgG4, N297A on all Ig isotypes, V234A / G237A on IgG2, and K214T / E233P / on IgG1. The group consisting of L234V / L235A / G236-deletion / A327G / P331A / D365E / L358M, H268Q / V309L / A330S / P331S on IgG2, S267E / L328F on IgG1, L234F / L235E / D265A on IgG1, L234A / L235A / G237A / P238S / H268A / A330S / P331S on IgG1, S228P / F234A / L235A / G237A / P238S on IgG4, and S228P / F234A / L235A / G236-deletion / G237A / P238S on IgG4, wherein the residue numbers are based on the EU index.

[0130] In some embodiments, one or more Fc substitutes for F234A / L235A on IgG4.

[0131] In some embodiments, one or more Fc substitutes for L234A / L235A on IgG1.

[0132] In some embodiments, one or more Fc substitutions are made on V234A / G237A / P238S / H268A / V309L / A330S / P331S of the IgG2 line.

[0133] In some embodiments, one or more Fc substitutes for F234A / L235A on IgG4.

[0134] In some embodiments, one or more Fc substitutions are made on S228P / F234A / L235A of IgG4.

[0135] In some embodiments, one or more Fcs replace N297A on all Ig isotypes.

[0136] In some embodiments, one or more Fc substitutes V234A / G237A on IgG2.

[0137] In some embodiments, one or more Fc substitutions are made on IgG1 containing K214T / E233P / L234V / L235A / G236- deletion / A327G / P331A / D365E / L358M.

[0138] In some embodiments, one or more Fc substitutions are made on H268Q / V309L / A330S / P331S of the IgG2 line.

[0139] In some embodiments, one or more Fc substitutes for S267E / L328F on IgG1. In some embodiments, one or more Fc substitutes for L234F / L235E / D265A on IgG1.

[0140] In some embodiments, one or more Fc substitutes L234A / L235A / G237A / P238S / H268A / A330S / P331S on IgG1.

[0141] In some embodiments, one or more Fc substitutions are used for S228P / F234A / L235A / G237A / P238S on IgG4 and S228P / F234A / L235A / G236-deletion / G237A / P238S on IgG4.

[0142] In some embodiments, the multispecific antibody further comprises an S228P substitution.

[0143] In some embodiments, the multispecific antibody contains one or more asymmetric substitutions in the first CH3 domain, the second CH3 domain, or both the first CH3 domain and the second CH3 domain.

[0144] In some embodiments, one or more asymmetric substitution lines are selected from F450L / K409R, wild-type / F409L_R409K, T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S, and T366W / T366S_L368A_Y407V, L351Y_F405A_Y407V / T394W The group consisting of T366I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F, and T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W.

[0145] In some embodiments, one or more asymmetric substitution systems F450L / K409R.

[0146] In some embodiments, one or more asymmetric substitution lines are wild-type / F409L_R409K.

[0147] In some embodiments, one or more asymmetric substitution systems T366Y / F405A.

[0148] In some embodiments, one or more asymmetric substitution systems T366W / F405W.

[0149] In some embodiments, one or more asymmetric substitution systems F405W / Y407A.

[0150] In some embodiments, one or more asymmetric substitution systems T394W / Y407T.

[0151] In some embodiments, one or more asymmetric substitution systems T394S / Y407A.

[0152] In some embodiments, one or more asymmetric substitution systems T366W / T394S.

[0153] In some embodiments, one or more asymmetric substitution systems F405W / T394S.

[0154] In some embodiments, one or more asymmetric substitution systems T366W / T366S_L368A_Y407V.

[0155] In some embodiments, one or more asymmetric substitution systems L351Y_F405A_Y407V / T394W.

[0156] In some embodiments, one or more asymmetric substitution systems T366I_K392M_T394W / F405A_Y407V.

[0157] In some embodiments, one or more asymmetric substitution systems T366L_K392M_T394W / F405A_Y407V.

[0158] In some embodiments, one or more asymmetric substitution systems L351Y_Y407A / T366A_K409F.

[0159] In some embodiments, one or more asymmetric substitution systems L351Y_Y407A / T366V_K409F.

[0160] In some embodiments, one or more asymmetric substitution systems Y407A / T366A_K409F.

[0161] In some embodiments, one or more asymmetric substitution systems T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W.

[0162] In some embodiments, cancer is a hematologic malignancy or a solid tumor.

[0163] In some embodiments, hematological malignancies include multiple myeloma, smoldering multiple myeloma, monoclonal gammopathy of undetermined significance (MGUS), acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma (BL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and Waldenstrom's macroglobulinemia. Macroglobulinema, plasma cell leukemia, light chain amyloidosis (AL), precursor B-cell lymphoblastic leukemia, acute myeloid leukemia (AML), myelomectomy syndrome (MDS), chronic lymphocytic leukemia (CLL), B-cell malignancy, chronic myeloid leukemia (CML), hair-like cell leukemia (HCL), blastic plasmacytoid dendritic cell tumor, Hodgkin's lymphoma, non-Hodgkin's lymphoma, marginal zone B-cell lymphoma (MZL), mucosa-associated lymphoid tissue lymphoma (MALT), plasma cell leukemia, degenerative large cell lymphoma (ALCL), leukemia or lymphoma.

[0164] In some embodiments, the hematologic malignancy is multiple myeloma.

[0165] In some embodiments, multiple myeloma refers to newly diagnosed multiple myeloma.

[0166] In some embodiments, multiple myeloma refers to relapsed or refractory multiple myeloma.

[0167] In some embodiments, multiple myeloma is high-risk multiple myeloma. Individuals with high-risk multiple myeloma are known for early relapse and poor prognosis and outcomes. Individuals classified as having high-risk multiple myeloma 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.

[0168] In some embodiments, an individual at high risk of multiple myeloma has one or more chromosomal abnormalities, including: t(4;14)(p16; q32); t(14;16)(q32; q23); del17p; 1qAmp; t(4;14)(p16;q32) and t(14;16)(q32;q23); t(4;14)(p16;q32) and del17p; t(14;16)(q32;q23) and del17p; or t(4;14)(p16; q32), t(14;16)(q32;q23), and del17p, or any combination thereof.

[0169] Various qualitative and / or quantitative methods can be used to determine the relapse or refractory nature of a disease. Possible related symptoms include, for example, a decline or stagnation in the patient's health, the recurrence or worsening of various symptoms associated with solid tumors, and / or the spread of cancer cells from one location to other organs, tissues, or cells in the body.

[0170] Cytogenetic abnormalities can be detected by methods such as fluorescence in situ hybridization (FISH). In chromosomal translocations, oncogenes are translocated to the IgH region on chromosome 14q32, leading to dysregulation of these genes. t(4;14)(p16;q32) involves translocations of fibroblast growth factor receptor 3 (FGFR3) and a protein containing the multiple myeloma SET domain (MMSET) (also known as WHSC1 / NSD2), while t(14;16)(q32;q23) involves a translocation of the MAF transcription factor C-MAF. Deletion of 17p (del17p) involves loss of the p53 locus.

[0171] In some embodiments, treatment with anti-CD38 antibodies, lenalinomide, bortezomib, pomalidomide, carfilzomib, elotozumab, ixazomib, melphalan, or thalidomide, or any combination thereof, results in relapse or refractory multiple myeloma.

[0172] In some embodiments, hematologic malignancies are classified as AML.

[0173] In some embodiments, AML is AML with at least one genetic abnormality, multilineage dysplasia, treatment-associated AML, undifferentiated AML, minimal maturation AML, maturation AML, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroid leukemia, acute megakaryoblastic leukemia, acute basophilic leukemia, acute panmyelosis with fibrosis, or myeloid sarcoma.

[0174] In some embodiments, at least one gene abnormality is a translocation between chromosomes 8 and 21, a translocation or inversion in chromosome 16, a translocation between chromosomes 15 and 17, a change in chromosome 11, or a mutation in fms-associated tyrosine kinase 3 (FLT3), nucleolar phosphatase 1 (NPM1), isocitrate dehydrogenase 1 (IDH1), isocitrate dehydrogenase 2 (IDH2), DNA (cytosine-5)-methyltransferase 3 (DNMT3A), CCAAT / enhancer-binding protein α (CEBPA), U2 small nuclear RNA cofactor 1 (U2AF1), enhancer of the second unit of the zeste 2 polycomb repressor complex (EZH2), chromosome structure maintenance protein 1A (SMC1A), or chromosome structure maintenance protein 3 (SMC3).

[0175] In some embodiments, at least one gene abnormality is present in the following translocations: t(8; 21)(q22; q22), inversion inv(16)(p13; q22), translocation t(16; 16)(p13; q22), translocation t(15; 17)(q22; q12), mutation FLT3-ITD, mutation R132H or R100Q / R104V / F108L / R119Q / I130V in IDH1, or mutation R140Q or R172 in IDH2.

[0176] In some embodiments, hematologic malignancies are ALL.

[0177] In some embodiments, ALL can be B-cell ALL, T-cell ALL, adult ALL, or pediatric ALL.

[0178] In some embodiments, individuals with ALL have the Philadelphia chromosome or are resistant to BCR-ABL kinase inhibitor treatment or have acquired resistance.

[0179] The Ph chromosome is present in approximately 20% of adults with ALL and a small percentage of children with ALL, and is associated with poor prognosis. At relapse, patients with Ph+ positive ALL may have received tyrosine kinase inhibitor (TKI) regimens and may therefore become resistant to TKIs. Therefore, anti-CD38 antibodies can be administered to individuals who have become resistant to selective or partially selective BCR-ABL inhibitors. Examples of BCR-ABL inhibitors include imatinib, dasatinib, nilotinib, bosutinib, ponatinib, bafetinib, saracatinib, tozasertib, or danusertib.

[0180] Other chromosomal rearrangement lineages identified in B-cell ALL patients include 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.

[0181] In some embodiments, an individual has ALL, which has 11q23)(MLL rearrangement), t(1; 19)(q23; p13.3); TCF3-PBX1 (E2A-PBX1), t(12; 21)(p13; q22); ETV6-RUNX1 (TEL-AML1) or t(5; 14)(q31; q32); IL3-IGH chromosome rearrangement.

[0182] Chromosomal rearrangements can be identified using known methods, such as fluorescence in situ hybridization, karyotype analysis, pulsed-field colloidal electrophoresis, or sequencing.

[0183] In some embodiments, the hematologic malignancy is smoldering multiple myeloma.

[0184] In some embodiments, hematologic malignancies are classified as MGUS.

[0185] In some embodiments, hematologic malignancies are ALL.

[0186] In some embodiments, hematologic malignancies are DLBLC.

[0187] In some embodiments, hematologic malignancies are classified as BL.

[0188] In some embodiments, hematologic malignancies are classified as FL.

[0189] In some embodiments, hematologic malignancies are classified as MCL.

[0190] In some embodiments, hematologic malignancies are Waldenström macroglobulinemia.

[0191] In some embodiments, hematologic malignancies are plasma cell leukemia.

[0192] In some embodiments, hematologic malignancies are classified as AL.

[0193] In some embodiments, hematologic malignancies are precursor B-cell lymphoblastic leukemia.

[0194] In some embodiments, hematologic malignancies are precursor B-cell lymphoblastic leukemia.

[0195] In some embodiments, hematologic malignancies are myelomectomy syndrome (MDS).

[0196] In some embodiments, hematologic malignancies are classified as CLL.

[0197] In some embodiments, hematologic malignancies are B-cell malignancies.

[0198] In some embodiments, hematologic malignancies are CML.

[0199] In some embodiments, hematologic malignancies are HCL.

[0200] In some embodiments, hematologic malignancies are blastic plasmacytoid dendritic cell tumors.

[0201] In some embodiments, the hematologic malignancy is Hodgkin's lymphoma.

[0202] In some embodiments, the hematologic malignancy is non-Hodgkin's lymphoma.

[0203] In some embodiments, hematologic malignancies are classified as MZL.

[0204] In some embodiments, hematologic malignancies are associated with MALT.

[0205] In some embodiments, hematologic malignancies are plasma cell leukemia.

[0206] In some embodiments, the hematologic malignancy is ALCL.

[0207] In some embodiments, the hematologic malignancy is leukemia.

[0208] In some embodiments, hematologic malignancies are lymphomas.

[0209] In some embodiments, solid tumors include prostate cancer, lung cancer, non-small cell lung cancer (NSCLC), liver cancer, cervical cancer, colon cancer, breast cancer, ovarian cancer, endometrial cancer, pancreatic cancer, melanoma, esophageal cancer, gastric cancer, stomach cancer, kidney cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, urothelial carcinoma, head and neck cancer, glioma, glioblastoma, colorectal cancer, thyroid cancer, epithelial carcinoma, adenocarcinoma, or advanced solid tumors.

[0210] In some embodiments, the solid tumor is prostate cancer.

[0211] In some embodiments, the solid tumor is lung cancer.

[0212] In some embodiments, the solid tumor is non-small cell lung cancer (NSCLC).

[0213] In some embodiments, the solid tumor is liver cancer.

[0214] In some embodiments, the solid tumor is cervical cancer.

[0215] In some embodiments, the solid tumor is colon cancer.

[0216] In some embodiments, the solid tumor is breast cancer.

[0217] In some embodiments, the solid tumor is ovarian cancer.

[0218] In some embodiments, the solid tumor is endometrial cancer.

[0219] In some embodiments, the solid tumor is pancreatic cancer.

[0220] In some embodiments, the solid tumor is melanoma.

[0221] In some embodiments, the solid tumor is esophageal cancer.

[0222] In some embodiments, a solid tumor is gastric cancer.

[0223] In some embodiments, the solid tumor is gastric cancer.

[0224] In some embodiments, the solid tumor is renal cell carcinoma.

[0225] In some embodiments, the solid tumor is bladder cancer.

[0226] In some embodiments, the solid tumor is hepatocellular carcinoma.

[0227] In some embodiments, the solid tumor is renal cell carcinoma.

[0228] In some embodiments, the solid tumor is a urothelial carcinoma.

[0229] In some embodiments, the solid tumor is head and neck cancer.

[0230] In some embodiments, the solid tumor is a glioma.

[0231] In some embodiments, the solid tumor is a glioblastoma.

[0232] In some embodiments, the solid tumor is colorectal cancer.

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

[0234] In some embodiments, the tumor is a solid tumor-type epithelial carcinoma.

[0235] In some embodiments, the tumor is adenocarcinoma.

[0236] In some embodiments, the solid tumor is a late-stage solid tumor.

[0237] In some embodiments, prostate cancer refers to recurrent, refractory, malignant, or castration-resistant prostate cancer, or any combination thereof.

[0238] 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.

[0239] In some embodiments, the CD38 antibody comprises VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5.

[0240] In some embodiments, the anti-CD38 anti-system belongs to the IgG1 isotype.

[0241] In some embodiments, the anti-CD38 antibody comprises HC of SEQ ID NO: 12 and LC of SEQ ID NO: 13.

[0242] The anti-CD38 antibody used in the method of this invention may be a known antibody, such as mAb003, which contains the VH and VL sequences of SEQ ID NO: 14 and 15, respectively, and is described in U.S. Patent No. 7,829,673. The VH and VL of mAb003 may be represented by IgG1 / κ; mAb024, which contains the VH and VL sequences of SEQ ID NO: 16 and 17, respectively, and is described in U.S. Patent No. 7,829,673. The VH and VL of mAb024 may be represented by IgG1 / κ; MOR-202 (MOR-03087), which contains the VH and VL sequences of SEQ ID NO: 18 and 19, respectively, and is described in U.S. Patent No. 8,088,896. The VH and VL of MOR-202 can be represented by IgG1 / κ; or isatuximab, which contains the VH and VL sequences of SEQ ID NO: 20 and 21, respectively, and is described in U.S. Patent No. 8,153,765. The VH and VL of isatuximab can be represented by IgG1 / κ. [SEQ ID NO: 4](Dalamab VH) EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQAPGKGLEWVSAISGSGGGTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCAKDKILWFGEPVFDYWGQGTLVTVSS [SEQ ID NO: 5] (Dalamab VL) EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPTFGQGTKVEIK [SEQ ID NO: 6](Dalamumab HCDR1) SFAMS [SEQ ID NO: 7](Dalamab HCDR2) AISGSGGGTYYADSVKG [SEQ ID NO: 8](Dalamab HCDR3) DKILWFGEPVFDY [SEQ ID NO: 9](Dalamab LCDR1) RASQSVSSYLA [SEQ ID NO: 10](Dalamab LCDR2) DASNRAT [SEQ ID NO: 11](Dalamab LCDR3) QQRSNWPPTF [SEQ ID NO: 12](Dalamumab HC) EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQAPGKGLEWVSAISGSGGGTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCAKDKILWFGEPVFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK [SEQ ID NO: 13](Daratumumab LC) EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC [SEQ ID NO: 14] QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAFSWVRQAPGQGLEWMGRVIPFLGIANSAQKFQGRVTITADKSTSTAYMDLSSLRSEDTAVYYCARDDIAALGPFDYWGQGTLVTVSSAS [SEQ ID NO: 15] DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQKPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPRTFGQGTKVEIK [SEQ ID NO: 16] EVQLVQSGAEVKKPGESLKISCKGSGYSFSNYWIGWVRQMPGKGLEWMGIIYPHDSDARYSPSFQGQVTFSADKSISTAYLQWSSLKASDTAMYYCARHVGWGSRYWYFDLWGRGTLVTVSS [SEQ ID NO: 17] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPGLLIYDASNRASGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK [SEQ ID NO: 18] QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMNWVRQAPGKGLEWVSGISGDPSNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDLPLVYTGFAYWGQGTLVTVSS [SEQ ID NO: 19] DIELTQPPSVSVAPGQTARISCSGDNLRHYYVYWYQQKPGQAPVLVIYGDSKRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQTYTGGASLVFGGGTKLTVLGQ [SEQ ID NO 20:] QVQLVQSGAEVAKPGTSVKLSCKASGYTFTDYWMQWVKQRPGQGLEWIGT IYPGDGDTGYAQKFQGKATLTADKSSKTVYMHLSSLASEDSAVYYCARGD YYGSNSLDYWGQGTSVTVSS [SEQ ID NO: 21:] DIVMTQSHLSMSTSLGDPVSITCKASQDVSTVVAWYQQKPGQSPRRLIYS ASYRYIGVPDRFTGSGAGTDFTFTISSVQAEDLAVYYCQQHYSPPYTFGG GTKLEIK

[0243] In some embodiments, the anti-CD38 antibody comprises: VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15; VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17; VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19; or VH of SEQ ID NO: 20 and VL of SEQ ID NO: 21.

[0244] In some embodiments, the anti-CD38 anti-system belongs to the IgG1 isotype.

[0245] In some embodiments, the T-cell redirection therapeutic agent is BCMAxCD3 bispecific antibody, GPRC5DxCD3 bispecific antibody, CD33xCD3 bispecific antibody, CD19xCD3 bispecific antibody, CD123xCD3 bispecific antibody, PSMAxCD3 bispecific antibody, or TMEFF2xCD3 bispecific antibody.

[0246] In some embodiments, the T-cell redirection therapy agent is a BCMAxCD3 bispecific antibody.

[0247] In some embodiments, the T-cell redirection therapy agent is a GPRC5DxCD3 bispecific antibody.

[0248] In some embodiments, the T-cell redirection therapy agent is a CD33xCD3 bispecific antibody.

[0249] In some embodiments, the T-cell redirection therapy agent is a CD19xCD3 bispecific antibody.

[0250] In some embodiments, the T-cell redirection therapy agent is a CD123xCD3 bispecific antibody.

[0251] In some embodiments, the T-cell redirection therapy agent is a PSMAxCD3 bispecific antibody.

[0252] In some embodiments, the T-cell redirection therapy agent is a TMEFF2xCD3 bispecific antibody.

[0253] In some embodiments, the method further includes administering one or more anticancer therapies to the individual.

[0254] 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.

[0255] In some embodiments, one or more anticancer therapies are selected from lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, erlotuzumab, ixazomib, melphalan, dexamethasone, vincristine, cyclophosphamide, hydroxydaunorubicin, prednisone, rituximab, imatinib, dasatinib, nilotinib, bosutinib, ponatinib, bafetinib, saracatinib, and tozasert. The group consisting of ib) or danusertib, cytarabine, daunorubicin, idarubicin, mitoxantrone, hydroxyurea, decitabine, cladribine, fludarabine, topotecan, etoposide, 6-thioguanine, corticosteroids, methotrexate, 6-mercaptopurine, azacitidine, arsenic trioxide and all-trans retinoic acid, or any combination thereof.

[0256] In some embodiments, the anti-CD38 system is administered at a dose between about 8 mg / kg and about 16 mg / kg.

[0257] In some embodiments, the anti-CD38 system is administered or provided as a pharmaceutical composition comprising an anti-CD38 antibody at a concentration of about 20 mg / mL to about 120 mg / mL in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mM mannitol, and about 0.04% w / v polysorbate-20 (PS-20); pH is about 5.5.

[0258] In some embodiments, the anti-CD38 anti-system is administered or provided as a pharmaceutical composition comprising about 1,800 mg of anti-CD38 antibody and about 30,000 U of rHuPH20.

[0259] In some embodiments, the anti-CD38 anti-system is administered or provided as a pharmaceutical composition comprising approximately 120 mg / mL of anti-CD38 antibody and approximately 2,000 U / mL of rHuPH20.

[0260] In some embodiments, the CD38 anti-system is administered or provided as a pharmaceutical composition for administration, the pharmaceutical composition comprising... Histidine between approximately 5 mM and approximately 15 mM; Sorbitol is between approximately 100 mM and approximately 300 mM; PS-20, ranging from approximately 0.01% w / v to approximately 0.04% w / v; and Methionine is present in concentrations between approximately 1 mg / mL and approximately 2 mg / mL, with a pH of approximately 5.5 to 5.6.

[0261] In some embodiments, the anti-CD38 anti-system is administered or provided as a pharmaceutical composition for administration, the pharmaceutical composition comprising... Approximately 1,800 mg of this anti-CD38 antibody; Approximately 30,000 U of rHuPH20; Approximately 10 mM histidine; Approximately 300 mM sorbitol; Approximately 0.04% (w / v) PS-20; and Approximately 1 mg / mL of methionine, with a pH of approximately 5.6.

[0262] In some embodiments, the anti-CD38 anti-system is administered or provided as a pharmaceutical composition for administration, the pharmaceutical composition comprising... The anti-CD38 antibody is present at a concentration of approximately 120 mg / mL. rHuPH20 at approximately 2,000 U / mL; Approximately 10 mM histidine; Approximately 300 mM sorbitol; Approximately 0.04% (w / v) PS-20; and Approximately 1 mg / mL of methionine, with a pH of approximately 5.6. [anti] [CD38] [Antibodies and] [BCMAxCD3] [Combination of bispecific antibodies]

[0263] This disclosure also provides a method for treating cancer in an individual, comprising administering to the individual a therapeutically effective amount of BCMAxCD3 bispecific antibody and anti-CD38 antibody to treat cancer.

[0264] This disclosure also provides a method for treating cancer in an individual, comprising administering a therapeutically effective amount of a BCMAxCD3 bispecific antibody to the individual to treat the cancer, wherein the individual has already been treated with an anti-CD38 antibody prior to administering the BCMAxCD3 bispecific antibody.

[0265] This disclosure also provides a method for treating cancer in an individual, comprising administering a therapeutically effective amount of a BCMAxCD3 bispecific antibody to the individual to treat cancer in an individual whose cancer has relapsed or is refractory to prior anticancer treatments.

[0266] T-cell retargeting agents, such as BCMAxCD3 bispecific antibodies like JNJ-957, redirect T cells to BCMA-positive tumor cells, such as multiple myeloma cells, subsequently releasing perforin / granule-dissolving enzymes or activating the FASL / FAS pathway, ultimately leading to the death of BCMA-positive tumor cells. Therefore, the efficacy of T-cell retargeting agents such as BCMAxCD3 bispecific antibodies can be influenced by the availability and activity of recruited T cells, as well as the potential regulatory expression of tumor-associated antigens such as BCMA on tumor cells.

[0267] In some embodiments, the cancer is a BCMA-presenting cancer.

[0268] B-cell maturation antigen (BCMA) is a member of the cell membrane-bound tumor necrosis factor receptor family involved in the differentiation of B cells into plasma cells. BCMA expression is limited to the B-cell lineage, primarily manifested in the interfollicular region of the germinal center and on differentiated plasma cells and plasmablasts. BCMA is almost entirely absent from naive and memory B cells (Tai and Anderson, Immunotherapy 7: 1187-99, 2015).

[0269] In some embodiments, cancer is a blood malignancy.

[0270] In some embodiments, the cancer is multiple myeloma, smoldering myeloma, monoglobulinosis of unknown clinical significance (MGUS), B-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, mantle cell lymphoma, Waldenström macroglobulinemia, plasma cell leukemia, light chain amyloidosis, or non-Hodgkin's lymphoma. The diagnosis of cancer is made by an experienced physician.

[0271] In some embodiments, treatment with an individual using an anti-CD38 antibody or lenalidomide or a combination thereof results in relapse or refractory disease.

[0272] In some embodiments, an individual has experienced a relapse or refractory response to previous anticancer treatments, such as those used to treat multiple myeloma or other hematologic malignancies.

[0273] In some embodiments, an individual is refractory to or has relapsed from treatment with THALOMID®, REVLIMID®, POMALYST®, VELCADE®, NINLARO, KYPROLIS®, FARADYK®, ARDIA®, ZOMETA®, DARZALEX®, erlotuzumab, or melphalan.

[0274] In some embodiments, an individual’s response to DARZALEX® (darazumab) treatment results in a relapse.

[0275] In some embodiments, the BCMAxCD3 bispecific antibody and the anti-CD38 antibody system antigen-binding fragments. Exemplary antigen-binding fragments are Fab, F(ab')2, Fd, and Fv fragments.

[0276] In some embodiments, the BCMAxCD3 bispecific antibody system is chimeric, humanized, or human.

[0277] In some embodiments, the BCMAxCD3 bispecific antibody system contains IgG1, IgG2, IgG3, or IgG4 isotypes.

[0278] In some embodiments, the BCMAxCD3 bispecific antibody system is IgG4 isotype.

[0279] In some embodiments, the BCMAxCD3 bispecific antibody comprises a BCMA binding domain and a CD3 binding domain. The BCMA binding domain comprises HCDR1 of SEQ ID NO: 23, HCDR2 of SEQ ID NO: 24, HCDR3 of SEQ ID NO: 25, LCDR1 of SEQ ID NO: 26, LCDR2 of SEQ ID NO: 27, and LCDR3 of SEQ ID NO: 28. The CD3 binding domain comprises HCDR1 of SEQ ID NO: 33, HCDR2 of SEQ ID NO: 34, HCDR3 of SEQ ID NO: 35, LCDR1 of SEQ ID NO: 36, LCDR2 of SEQ ID NO: 37, and LCDR3 of SEQ ID NO: 38.

[0280] In some embodiments, the BCMA binding domain includes VH of SEQ ID NO: 29 and VL of SEQ ID NO: 30, and the CD3 binding domain includes VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40.

[0281] In some embodiments, the BCMAxCD3 bispecific antibody system IgG4 isotype comprises phenylalanine at position 405 and arginine at position 409 in the first heavy chain (HC1), and leucine at position 405 and lysine at position 409 in the second heavy chain (HC2), wherein the residue numbers are based on the EU index.

[0282] 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.

[0283] In some embodiments, the BCMAxCD3 bispecific antibody comprises HC1 of SEQ ID NO: 31, the first light chain (LC1) of SEQ ID NO: 32, HC2 of SEQ ID NO: 41, and the second light chain (LC2) of SEQ ID NO: 42.

[0284] In some embodiments, the BCMAxCD3 bispecific antibody system BI 836909, PF-06863135, AMG-701 or CC-93269.

[0285] 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.

[0286] In some embodiments, the anti-CD38 antibody comprises VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5.

[0287] In some embodiments, the anti-CD38 antibody comprises the heavy chain (HC) of SEQ ID NO: 12 and the light chain (LC) of SEQ ID NO: 13.

[0288] In some embodiments, the anti-CD38 anti-system DARZALEX® (darazumab) is used.

[0289] In some embodiments, the anti-CD38 antibody comprises: VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15; VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17; VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19; or VH of SEQ ID NO: 20 and VL of SEQ ID NO: 21.

[0290] In some embodiments, the anti-CD38 anti-system is chimeric, humanized, or human.

[0291] In some embodiments, the anti-CD38 anti-system consists of IgG1, IgG2, IgG3, or IgG4 isotypes.

[0292] In some embodiments, the anti-CD38 anti-system belongs to the IgG1 isotype.

[0293] In some embodiments, the anti-CD38 system is administered at a dose between about 8 mg / kg and about 16 mg / kg.

[0294] In some embodiments, the BCMAxCD3 bispecific antibody and the anti-CD38 anti-system are administered via intravenous injection.

[0295] In some embodiments, the BCMAxCD3 bispecific anti-system is administered via intravenous injection and the anti-CD38 anti-system antigen-binding fragment is administered via subcutaneous injection.

[0296] In some embodiments, the BCMAxCD3 bispecific antibody and the anti-CD38 anti-system are administered via subcutaneous injection.

[0297] In some embodiments, the method further includes administering one or more anticancer therapies to the individual.

[0298] 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.

[0299] In some embodiments, one or more anticancer therapies are selected from the group consisting of lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, erlotuzumab, ixazomib, melphalan, prednisone or dexamethasone, or any combination thereof.

[0300] In some embodiments, the anti-CD38 system is administered or provided as a pharmaceutical composition comprising an anti-CD38 antibody at a concentration of about 20 mg / mL to about 120 mg / mL in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mM mannitol, and about 0.04% w / v polysorbate-20 (PS-20); pH is about 5.5.

[0301] In some embodiments, the anti-CD38 anti-system is administered or provided as a pharmaceutical composition comprising about 1,800 mg of anti-CD38 antibody and about 30,000 U of rHuPH20.

[0302] In some embodiments, the anti-CD38 anti-system is administered or provided as a pharmaceutical composition comprising approximately 120 mg / mL of anti-CD38 antibody and approximately 2,000 U / mL of rHuPH20.

[0303] In some embodiments, the anti-CD38 anti-system is administered or provided as a pharmaceutical composition for administration, the pharmaceutical composition comprising... Histidine between approximately 5 mM and approximately 15 mM; Sorbitol is between approximately 100 mM and approximately 300 mM; PS-20, ranging from approximately 0.01% w / v to approximately 0.04% w / v; and Methionine is present in concentrations between approximately 1 mg / mL and approximately 2 mg / mL, with a pH of approximately 5.5 to 5.6.

[0304] In some embodiments, the anti-CD38 anti-system is administered or provided as a pharmaceutical composition for administration, the pharmaceutical composition comprising... Approximately 1,800 mg of this anti-CD38 antibody; Approximately 30,000 U of rHuPH20; Approximately 10 mM histidine; Approximately 300 mM sorbitol; Approximately 0.04% (w / v) PS-20; and Approximately 1 mg / mL of methionine, with a pH of approximately 5.6.

[0305] In some embodiments, the anti-CD38 anti-system is administered or provided as a pharmaceutical composition for administration, the pharmaceutical composition comprising... The anti-CD38 antibody is present at a concentration of approximately 120 mg / mL. rHuPH20 at approximately 2,000 U / mL; Approximately 10 mM histidine; Approximately 300 mM sorbitol; Approximately 0.04% (w / v) PS-20; and Approximately 1 mg / mL of methionine, with a pH of approximately 5.6.

[0306] The dose of BCMAxCD3 bispecific antibody and anti-CD38 antibody administered to an individual with cancer (such as multiple myeloma) is sufficient to alleviate or at least partially discontinue the disease to be treated ("therapeutic effective dose") and includes antibodies from about 0.005 mg to about 100 mg / kg, for example, about 0.05 mg to about 30 mg / kg, or about 5 mg to about 25 mg / kg, or about 4 mg / kg, about 8 mg / kg, about 16 mg / kg, or about 24 mg / kg. Suitable doses include, for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 40, 50, 60, 70, 80, 90, or 100 mg / kg.

[0307] A fixed unit dose of BCMAxCD3 bispecific antibody and / or anti-CD38 antibody may also be administered, such as 50, 100, 200, 500, or 1000 mg, or the dose may be based on the patient's surface area, such as 500, 400, 300, 250, 200, or 100 mg / m². Treatment of cancers (such as multiple myeloma) is usually administered in doses between 1 and 8 (e.g., 1, 2, 3, 4, 5, 6, 7, or 8), but 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more doses may be given.

[0308] BCMAxCD3 bispecific antibody and / or anti-CD38 antibody administration can be repeated after one, two, three, four, five, six, one week, two weeks, three weeks, one month, five weeks, six weeks, seven weeks, two months, three months, four months, five months, six months, or longer. Repeated treatment is also possible, if it is a chronic administration. Repeated administration can be at the same dose or at different doses. For example, BCMAxCD3 bispecific antibody and anti-CD38 antibody can be administered intravenously at weekly intervals of 8 mg / kg or 16 mg / kg for 8 weeks, followed by an additional 16 weeks of administration at 8 mg / kg or 16 mg / kg every two weeks, followed by administration at 8 mg / kg or 16 mg / kg every four weeks.

[0309] BCMAxCD3 bispecific antibodies and anti-CD38 antibodies can be administered via maintenance therapy, such as once a week for 6 months or longer. For example, BCMAxCD3 bispecific antibody and anti-CD38 antibody may be administered at least one day during 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, or alternatively at least one week during weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 after the start of treatment, or any combination thereof, in a single or separate dose, or any combination thereof, every 24, 12, 8, 6, 4, or 2 hours, at a dose of about 0.1 mg / kg to about 100 mg / kg. Daily doses of mg / kg, such as 0.5, 0.9, 1.0, 1.1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90, or 100 mg / kg per day.

[0310] BCMAxCD3 bispecific antibodies and anti-CD38 antibodies can also be administered prophylactically to reduce the risk of developing cancer (such as multiple myeloma), delay the onset of cancer progression events, and / or reduce the risk of relapse when cancer is in remission.

[0311] In some embodiments, the BCMAxCD3 bispecific antibody system is administered to the individual after the individual has been given an anti-CD38 antibody. The BCMAxCD3 bispecific antibody may be administered one week, two weeks, three weeks, one month, five weeks, six weeks, seven weeks, two months, three months, four months, five months, six months, or longer after the anti-CD38 antibody administration. In some embodiments, the individual who has been given the BCMAxCD3 antibody is resistant to and / or refractory to anti-CD38 antibody treatment.

[0312] The present invention also provides a pharmaceutical composition comprising a BCMAxCD3 bispecific antibody and an anti-CD38 antibody. The BCMAxCD3 bispecific antibody comprises a BCMA binding domain and a CD3 binding domain. The BCMA binding domain comprises VH of SEQ ID NO: 29 and VL of SEQ ID NO: 30. The CD3 binding domain comprises VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40. The anti-CD38 antibody comprises VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5.

[0313] In some embodiments, the pharmaceutical composition comprises a BCMAxCD3 bispecific antibody and an anti-CD38 antibody. 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. The anti-CD38 antibody comprises HC of SEQ ID NO: 12 and LC of SEQ ID NO: 13.

[0314] In some embodiments, the pharmaceutical components are not a fixed combination.

[0315] In some embodiments, the pharmaceutical composition comprises about 20 mg / mL to about 120 mg / mL of anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mM mannitol and about 0.04% w / v polysorbate-20 (PS-20); pH is about 5.5.

[0316] BCMAxCD3 bispecific antibodies can be formulated into pharmaceutical compositions comprising approximately 20 mg / mL to approximately 120 mg / mL of antibody, acetic acid, histidine, sodium chloride, mannitol, and / or polysorbate-20.

[0317] In some embodiments, the pharmaceutical composition comprises about 1,800 mg of anti-CD38 antibody and about 30,000 U of rHuPH20.

[0318] In some embodiments, the pharmaceutical composition comprises about 120 mg / mL of anti-CD38 antibody and about 2,000 U / mL of rHuPH20.

[0319] In some embodiments, the pharmaceutical composition further comprises one or more excipients.

[0320] In some embodiments, one or more excipients are histidine, methionine, sorbitol or polysorbate-20 (PS-20), or any combination thereof.

[0321] In some embodiments, the pharmaceutical composition includes Anti-CD38 antibodies at concentrations between approximately 100 mg / mL and 120 mg / mL, formulated in histidine at concentrations between approximately 5 mM and 15 mM; Sorbitol is between approximately 100 mM and approximately 300 mM; PS-20, ranging from approximately 0.01% w / v to approximately 0.04% w / v; and Methionine is present in concentrations between approximately 1 mg / mL and approximately 2 mg / mL, with a pH of approximately 5.5 to 5.6.

[0322] In some embodiments, the pharmaceutical composition comprises about 10 mM histidine.

[0323] In some embodiments, the pharmaceutical composition comprises about 300 mM sorbitol.

[0324] In some embodiments, the pharmaceutical composition comprises about 0.04% (w / v) PS-20.

[0325] In some embodiments, the pharmaceutical composition contains about 1 mg / mL of methionine.

[0326] In some embodiments, the pharmaceutical composition includes Approximately 1,800 mg of this anti-CD38 antibody; Approximately 30,000 U of rHuPH20; Approximately 10 mM histidine; Approximately 300 mM sorbitol; Approximately 0.04% (w / v) PS-20; and Approximately 1 mg / mL of methionine, with a pH of approximately 5.6.

[0327] In some embodiments, the pharmaceutical composition includes The anti-CD38 antibody is present at a concentration of approximately 120 mg / mL. rHuPH20 at approximately 2,000 U / mL; Approximately 10 mM histidine; Approximately 300 mM sorbitol; Approximately 0.04% (w / v) PS-20; and Approximately 1 mg / mL of methionine, with a pH of approximately 5.6.

[0328] This disclosure also provides kits containing pharmaceutical components, which include a BCMAxCD3 bispecific antibody and an anti-CD38 antibody. [In individuals with relapsed or refractory disease] [BCMAxCD3] [Treatment with bispecific antibodies]

[0329] This disclosure also provides a method for treating cancer in an individual, comprising administering a therapeutically effective amount of a BCMAxCD3 bispecific antibody to the individual to treat cancer in an individual whose cancer has relapsed or is refractory to prior anticancer treatments.

[0330] In some embodiments, the BCMAxCD3 bispecific antibody comprises a BCMA binding domain and a CD3 binding domain. The BCMA binding domain comprises HCDR1 of SEQ ID NO: 23, HCDR2 of SEQ ID NO: 24, HCDR3 of SEQ ID NO: 25, LCDR1 of SEQ ID NO: 26, LCDR2 of SEQ ID NO: 27, and LCDR3 of SEQ ID NO: 28. The CD3 binding domain comprises HCDR1 of SEQ ID NO: 33, HCDR2 of SEQ ID NO: 34, HCDR3 of SEQ ID NO: 35, LCDR1 of SEQ ID NO: 36, LCDR2 of SEQ ID NO: 37, and LCDR3 of SEQ ID NO: 38.

[0331] In some embodiments, the BCMA binding domain includes VH of SEQ ID NO: 29 and VL of SEQ ID NO: 30, and the CD3 binding domain includes VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40.

[0332] In some embodiments, the BCMAxCD3 bispecific antibody system is IgG4 isotype and includes phenylalanine at position 405 and arginine at position 409 in HC1, and leucine at position 405 and lysine at position 409 in HC2, wherein the residue numbering is based on the EU index.

[0333] 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.

[0334] In some embodiments, the BCMAxCD3 bispecific antibody comprises HC1 of SEQ ID NO: 31, LC1 of SEQ ID NO: 32, HC2 of SEQ ID NO: 41, and LC2 of SEQ ID NO: 42.

[0335] In some embodiments, cancer is a blood malignancy.

[0336] In some embodiments, the hematologic malignancy is multiple myeloma.

[0337] In some embodiments, multiple myeloma is a high-risk multiple myeloma.

[0338] In some embodiments, an individual at high risk of multiple myeloma has one or more chromosomal abnormalities, including: t(4;14)(p16;q32); t(14;16)(q32;q23); del17p; 1qAmp; t(4;14)(p16;q32) and t(14;16)(q32;q23); t(4;14)(p16;q32) and del17p; t(14;16)(q32;q23) and del17p; or t(4;14)(p16;q32), t(14;16)(q32;q23), and del17p, or any combination thereof.

[0339] In some embodiments, the individual has relapsed or is refractory to treatment with anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, erlotuzumab, ixazomib, melphalan or thalidomide, or any combination thereof.

[0340] In some embodiments, treatment with an individual anti-CD38 antibody results in relapse.

[0341] 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.

[0342] In some embodiments, the anti-CD38 antibody comprises VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5.

[0343] In some embodiments, the anti-CD38 anti-system belongs to the IgG1 isotype.

[0344] In some embodiments, the anti-CD38 antibody comprises HC of SEQ ID NO: 12 and LC of SEQ ID NO: 13.

[0345] In some embodiments, the anti-CD38 antibody comprises: VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15; VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17; VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19; or VH of SEQ ID NO: 20 and VL of SEQ ID NO: 21.

[0346] In some embodiments, the anti-CD38 anti-system belongs to the IgG1 isotype.

[0347] In some embodiments, the individual is a human being.

[0348] In some embodiments, the method further includes administering one or more anticancer therapies to the individual.

[0349] 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.

[0350] In some embodiments, one or more anticancer therapies are selected from the group consisting of lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, erlotuzumab, ixazomib, melphalan, prednisone or dexamethasone, or any combination thereof. [and] [GPRC5D] [Combined] [T] [Cell redirection therapy and anti-] [CD38] [Antibody Combination Therapy]

[0351] This disclosure also provides a method for treating cancer in an individual, comprising administering to the individual a therapeutically effective dose of a GPRC5D-binding T-cell redirection agent and an anti-CD38 antibody to treat the cancer.

[0352] In some embodiments, the anti-CD38 anti-system is administered to the individual prior to the administration of the GPRC5D-binding T-cell redirection therapy.

[0353] In some embodiments, an individual has experienced a relapse or refractory response to previous anticancer treatments.

[0354] In some embodiments, the cancer is a GPRC5D phenotypic cancer.

[0355] In some embodiments, GPRC5D phenotypic cancer is a hematologic malignancy or a solid tumor.

[0356] In some embodiments, hematologic malignancies are leukemia, lymphoma, or multiple myeloma.

[0357] In some embodiments, solid tumors are ovarian cancer, lung cancer, gastric cancer, prostate cancer, kidney cancer, liver cancer, pancreatic cancer, colon cancer, esophageal cancer, bladder cancer, cervical cancer, or malignant melanoma.

[0358] GPRC5D has been shown to manifest in these tumors, see, for example, WO2018147245A1.

[0359] In some embodiments, the individual has relapsed or is refractory to treatment with anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, erlotuzumab, ixazomib, melphalan or thalidomide, or any combination thereof.

[0360] In some embodiments, treatment with an individual against CD38 antibodies is for relapsed or refractory disease.

[0361] In some embodiments, multiple myeloma refers to newly diagnosed multiple myeloma.

[0362] In some embodiments, multiple myeloma refers to relapsed or refractory multiple myeloma.

[0363] In some embodiments, multiple myeloma is a high-risk multiple myeloma.

[0364] In some embodiments, an individual at high risk of multiple myeloma has one or more chromosomal abnormalities, including: t(4;14)(p16;q32); t(14;16)(q32;q23); del17p; 1qAmp; t(4;14)(p16;q32) and t(14;16)(q32;q23); t(4;14)(p16;q32) and del17p; t(14;16)(q32;q23) and del17p; or t(4;14)(p16;q32), t(14;16)(q32;q23), and del17p, or any combination thereof.

[0365] In some embodiments, the T-cell redirection therapy agent is combined with CD3, CD3ε, CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, BTNL8, PD-1, CD195, or NKG2C.

[0366] In some embodiments, the T-cell redirection therapeutic agent comprises a GPRC5D binding domain and a CD3 binding domain, wherein the GPRC5D binding domain comprises HCDR1 of SEQ ID NO: 43, HCDR2 of SEQ ID NO: 44, HCDR3 of SEQ ID NO: 45, LCDR1 of SEQ ID NO: 46, LCDR2 of SEQ ID NO: 47, and LCDR3 of SEQ ID NO: 48, and the CD3 binding domain comprises HCDR1 of SEQ ID NO: 33, HCDR2 of SEQ ID NO: 34, HCDR3 of SEQ ID NO: 35, LCDR1 of SEQ ID NO: 36, LCDR2 of SEQ ID NO: 37, and LCDR3 of SEQ ID NO: 38.

[0367] In some embodiments, the GPRC5D binding domain includes VH of SEQ ID NO: 49 and VL of SEQ ID NO: 50, and the CD3 binding domain includes VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40.

[0368] In some embodiments, the T-cell retargeting agent that binds to GPRC5D is a multispecific antibody, a CAR, or T cells expressing a CAR.

[0369] In some embodiments, the multispecific antibody system consists of IgG1, IgG2, IgG3, or IgG4 isotypes.

[0370] 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).

[0371] In some embodiments, one or more Fc substitution lines are selected from F234A / L235A on IgG4, L234A / L235A on IgG1, V234A / G237A / P238S / H268A / V309L / A330S / P331S on IgG2, F234A / L235A on IgG4, S228P / F234A / L235A on IgG4, N297A on all Ig isotypes, V234A / G237A on IgG2, and K214T / E233P / on IgG1. The group consisting of L234V / L235A / G236-deletion / A327G / P331A / D365E / L358M, H268Q / V309L / A330S / P331S on IgG2, S267E / L328F on IgG1, L234F / L235E / D265A on IgG1, L234A / L235A / G237A / P238S / H268A / A330S / P331S on IgG1, S228P / F234A / L235A / G237A / P238S on IgG4, and S228P / F234A / L235A / G236-deletion / G237A / P238S on IgG4, wherein the residue numbers are based on the EU index.

[0372] In some embodiments, the multispecific antibody further comprises an S228P substitution.

[0373] In some embodiments, the multispecific antibody contains one or more asymmetric substitutions in the first CH3 domain, the second CH3 domain, or both the first CH3 domain and the second CH3 domain.

[0374] In some embodiments, one or more asymmetric substitution lines are selected from F450L / K409R, wild-type / F409L_R409K, T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S, and T366W / T366S_L368A_Y407V, L351Y_F405A_Y407V / T394W The group consisting of T366I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F, and T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W.

[0375] 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.

[0376] 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.

[0377] In some embodiments, the anti-CD38 antibody comprises VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5.

[0378] In some embodiments, the anti-CD38 anti-system belongs to the IgG1 isotype.

[0379] In some embodiments, the anti-CD38 antibody comprises HC of SEQ ID NO: 12 and LC of SEQ ID NO: 13.

[0380] In some embodiments, the anti-CD38 antibody comprises: VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15; VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17; VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19; or VH of SEQ ID NO: 20 and VL of SEQ ID NO: 21.

[0381] In some embodiments, the anti-CD38 anti-system belongs to the IgG1 isotype.

[0382] In some embodiments, the anti-CD38 system is administered at a dose between about 8 mg / kg and about 16 mg / kg.

[0383] In some embodiments, the T-cell redirection therapy agent and the anti-CD38 anti-system bound to GPRC5D are administered via intravenous injection.

[0384] In some embodiments, the T-cell redirection therapy agent bound to GPRC5D is administered intravenously and the anti-CD38 anti-system is administered subcutaneously.

[0385] In some embodiments, the T-cell redirection therapy agent and anti-CD38 anti-system bound to GPRC5D are administered via subcutaneous injection.

[0386] In some embodiments, the individual is a human being.

[0387] In some embodiments, the T-cell redirection therapy agent that binds to GPRC5D is a GPRC5DxCD3 bispecific antibody.

[0388] In some embodiments, the method further includes administering one or more anticancer therapies to the individual.

[0389] 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.

[0390] In some embodiments, one or more anticancer therapies are selected from the group consisting of lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, erlotuzumab, ixazomib, melphalan, dexamethasone, or prednisone.

[0391] In some embodiments, the anti-CD38 system is administered or provided as a pharmaceutical composition comprising an anti-CD38 antibody at a concentration of about 20 mg / mL to about 120 mg / mL in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mM mannitol, and about 0.04% w / v polysorbate-20 (PS-20); pH is about 5.5.

[0392] In some embodiments, the anti-CD38 anti-system is administered or provided as a pharmaceutical composition comprising about 1,800 mg of anti-CD38 antibody and about 30,000 U of rHuPH20.

[0393] In some embodiments, the anti-CD38 anti-system is administered or provided as a pharmaceutical composition comprising approximately 120 mg / mL of anti-CD38 antibody and approximately 2,000 U / mL of rHuPH20.

[0394] In some embodiments, the anti-CD38 anti-system is administered or provided as a pharmaceutical composition for administration, the pharmaceutical composition comprising... This anti-CD38 antibody has a concentration between approximately 100 mg / mL and approximately 120 mg / mL. Histidine between approximately 5 mM and approximately 15 mM; Sorbitol is between approximately 100 mM and approximately 300 mM; PS-20, ranging from approximately 0.01% w / v to approximately 0.04% w / v; and Methionine is present in concentrations between approximately 1 mg / mL and approximately 2 mg / mL, with a pH of approximately 5.5 to 5.6.

[0395] In some embodiments, the anti-CD38 anti-system is administered or provided as a pharmaceutical composition for administration, the pharmaceutical composition comprising... Approximately 1,800 mg of this anti-CD38 antibody; Approximately 30,000 U of rHuPH20; Approximately 10 mM histidine; Approximately 300 mM sorbitol; Approximately 0.04% (w / v) PS-20; and Approximately 1 mg / mL of methionine, with a pH of approximately 5.6.

[0396] In some embodiments, the anti-CD38 anti-system is administered or provided as a pharmaceutical composition for administration, the pharmaceutical composition comprising... The anti-CD38 antibody is present at a concentration of approximately 120 mg / mL. rHuPH20 at approximately 2,000 U / mL; Approximately 10 mM histidine; Approximately 300 mM sorbitol; Approximately 0.04% (w / v) PS-20; and Approximately 1 mg / mL of methionine, with a pH of approximately 5.6.

[0397] This disclosure also provides a pharmaceutical combination comprising a GPRC5DxCD3 bispecific antibody and an anti-CD38 antibody. The GPRC5DxCD3 bispecific antibody comprises a GPRC5D binding domain and a CD3 binding domain. The GPRC5D binding domain comprises HCDR1 (SEQ ID NO: 43), HCDR2 (SEQ ID NO: 44), HCDR3 (SEQ ID NO: 45), LCDR1 (SEQ ID NO: 46), LCDR2 (SEQ ID NO: 47), and LCDR3 (SEQ ID NO: 48). The CD3 binding domain comprises HCDR1 (SEQ ID NO: 33), HCDR2 (SEQ ID NO: 34), HCDR3 (SEQ ID NO: 35), LCDR1 (SEQ ID NO: 36), LCDR2 (SEQ ID NO: 37), and LCDR3 (SEQ ID NO: 38). The anti-CD38 antibody comprises HCDR1 (SEQ ID NO: 6), HCDR2 (SEQ ID NO: 7), and LCDR3 (SEQ ID NO: 48). HCDR3 of SEQ ID NO: 9, LCDR1 of SEQ ID NO: 10, and LCDR2 of SEQ ID NO: 11.

[0398] In some embodiments, the GPRC5D binding domain includes VH of SEQ ID NO: 49 and VL of SEQ ID NO: 50, and the CD3 binding domain includes VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40, and the anti-CD38 antibody includes VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5.

[0399] 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.

[0400] In some embodiments, the drug combination is not a fixed combination.

[0401] In some embodiments, the pharmaceutical combination comprises about 20 mg / mL to about 120 mg / mL of anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mM mannitol and about 0.04% w / v polysorbate-20 (PS-20); pH is about 5.5.

[0402] In some embodiments, the drug combination comprises about 1,800 mg of anti-CD38 antibody and about 30,000 U of rHuPH20.

[0403] In some embodiments, the drug combination comprises about 120 mg / mL of anti-CD38 antibody and about 2,000 U / mL of rHuPH20.

[0404] In some embodiments, the pharmaceutical combination further comprises one or more excipients.

[0405] In some embodiments, one or more excipients are histidine, methionine, sorbitol or polysorbate-20 (PS-20), or any combination thereof.

[0406] In some embodiments, the pharmaceutical composition includes This anti-CD38 antibody has a concentration between approximately 100 mg / mL and approximately 120 mg / mL. Histidine between approximately 5 mM and approximately 15 mM; Sorbitol is between approximately 100 mM and approximately 300 mM; PS-20, ranging from approximately 0.01% w / v to approximately 0.04% w / v; and Methionine is present in concentrations between approximately 1 mg / mL and approximately 2 mg / mL, with a pH of approximately 5.5 to 5.6.

[0407] In some embodiments, the pharmaceutical combination comprises about 10 mM histidine.

[0408] In some embodiments, the pharmaceutical combination comprises about 300 mM sorbitol.

[0409] In some embodiments, the pharmaceutical combination comprises about 0.04% (w / v) PS-20.

[0410] In some embodiments, the pharmaceutical combination contains about 1 mg / mL of methionine.

[0411] In some embodiments, the pharmaceutical combination includes Approximately 1,800 mg of this anti-CD38 antibody; Approximately 30,000 U of rHuPH20; Approximately 10 mM histidine; Approximately 300 mM sorbitol; Approximately 0.04% (w / v) PS-20; and Approximately 1 mg / mL of methionine, with a pH of approximately 5.6.

[0412] In some embodiments, the pharmaceutical combination includes The anti-CD38 antibody is present at a concentration of approximately 120 mg / mL. rHuPH20 at approximately 2,000 U / mL; Approximately 10 mM histidine; Approximately 300 mM sorbitol; Approximately 0.04% (w / v) PS-20; and Approximately 1 mg / mL of methionine, with a pH of approximately 5.6.

[0413] This disclosure also provides a pharmaceutical combination comprising a T-cell redirection therapy agent that binds to GPRC5D and an anti-CD38 antibody. [In individuals with relapsed or refractory disease] [GPRC5DxCD3] [Treatment with bispecific antibodies]

[0414] This disclosure also provides a method for treating cancer in an individual, comprising administering a therapeutically effective amount of a GPRC5DxCD3 bispecific antibody to the individual to treat cancer in an individual whose cancer has relapsed or is refractory to prior anticancer treatments.

[0415] In some embodiments, the GPRC5DxCD3 bispecific antibody comprises a GPRC5D binding domain and a CD3 binding domain. The GPRC5D binding domain comprises HCDR1 of SEQ ID NO: 43, HCDR2 of SEQ ID NO: 44, HCDR3 of SEQ ID NO: 45, LCDR1 of SEQ ID NO: 46, LCDR2 of SEQ ID NO: 47, and LCDR3 of SEQ ID NO: 48. The CD3 binding domain comprises HCDR1 of SEQ ID NO: 33, HCDR2 of SEQ ID NO: 34, HCDR3 of SEQ ID NO: 35, LCDR1 of SEQ ID NO: 36, LCDR2 of SEQ ID NO: 37, and LCDR3 of SEQ ID NO: 38.

[0416] In some embodiments, the GPRC5D binding domain includes VH of SEQ ID NO: 49 and VL of SEQ ID NO: 50, and the CD3 binding domain includes VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40.

[0417] In some embodiments, the GPRC5DxCD3 bispecific antibody system isotype IgG4 and includes phenylalanine at position 405 and arginine at position 409 in HC1, and leucine at position 405 and lysine at position 409 in HC2, wherein the residue numbering is based on the EU index.

[0418] 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.

[0419] 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.

[0420] In some embodiments, cancer is a hematologic malignancy or a solid tumor.

[0421] In some embodiments, cancer refers to multiple myeloma, lymphoma, melanoma, breast cancer, endometrial cancer, ovarian cancer, lung cancer, stomach cancer, prostate cancer, kidney cancer, liver cancer, pancreatic cancer, colon cancer, esophageal cancer, bladder cancer, or cervical cancer.

[0422] In some embodiments, multiple myeloma is a high-risk multiple myeloma.

[0423] In some embodiments, an individual at high risk of multiple myeloma has one or more chromosomal abnormalities, including: t(4;14)(p16;q32); t(14;16)(q32;q23); del17p; 1qAmp; t(4;14)(p16;q32) and t(14;16)(q32;q23); t(4;14)(p16;q32) and del17p; t(14;16)(q32;q23) and del17p; or t(4;14)(p16;q32), t(14;16)(q32;q23), and del17p, or any combination thereof.

[0424] In some embodiments, the individual is refractory to or has relapsed from treatment with anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, erlotuzumab, ixazomib, melphalan, or thalidomide, or any combination thereof.

[0425] In some embodiments, treatment with an individual against CD38 antibodies is for relapsed or refractory disease.

[0426] 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.

[0427] In some embodiments, the anti-CD38 antibody comprises VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5.

[0428] In some embodiments, the anti-CD38 anti-system belongs to the IgG1 isotype.

[0429] In some embodiments, the anti-CD38 antibody comprises HC of SEQ ID NO: 12 and LC of SEQ ID NO: 13.

[0430] In some embodiments, the anti-CD38 antibody comprises: VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15; VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17; VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19; or VH of SEQ ID NO: 20 and VL of SEQ ID NO: 21.

[0431] In some embodiments, the anti-CD38 anti-system belongs to the IgG1 isotype.

[0432] In some embodiments, the individual is a human being.

[0433] In some embodiments, the method further includes administering one or more anticancer therapies to the individual.

[0434] 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.

[0435] In some embodiments, one or more anticancer therapies are selected from lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, erlotuzumab, ixazomib, melphalan, dexamethasone, vincristine, cyclophosphamide, hydroxydanomycin, prednisone, rituximab, imatinib, dasatinib, nilotinib, bosutinib, ponatinib, bafetinib, saracatinib, tozasertib, or danuserti. b) The group consisting of cytarabine, daunorubicin, idarubicin, mitoxantrone, hydroxyurea, decitabine, cladribine, fludarabine, topotecan, etoposide, 6-thioguanine, corticosteroids, methotrexate, 6-mercaptopurine, azacitidine, arsenic trioxide, and all-trans retinoic acid, or any combination thereof. [and] [CD19] [Combined] [T] [Cell redirection therapy and anti-] [CD38] [Antibody Combination Therapy]

[0436] This disclosure also provides a method for treating cancer in an individual, comprising administering to the individual a therapeutically effective dose of a CD19-binding T-cell redirection agent and an anti-CD38 antibody to treat cancer.

[0437] In some embodiments, the individual has been treated with an anti-CD38 antibody prior to administration of a T-cell redirection agent that binds to CD19.

[0438] This disclosure also provides a method for enhancing the efficacy of CD19-binding T-cell redirection therapy in individuals with cancer, comprising administering an anti-CD38 antibody to the individual prior to administering the CD19-binding T-cell redirection therapy.

[0439] In some embodiments, an individual has experienced a relapse or refractory response to previous anticancer treatments.

[0440] In some embodiments, cancer is a hematologic malignancy or a solid tumor.

[0441] In some embodiments, hematologic malignancies include lymphoma, B-cell malignancy, Hodgkin's lymphoma, non-Hodgkin's lymphoma, DLBLC, FL, MCL, marginal zone B-cell lymphoma (MZL), mucosa-associated lymphoid tissue lymphoma (MALT), CLL, ALL, AML, Waldenström macroglobulinemia, or T-cell lymphoma.

[0442] In some embodiments, solid tumors include lung cancer, liver cancer, cervical cancer, colon cancer, breast cancer, ovarian cancer, pancreatic cancer, melanoma, glioblastoma, prostate cancer, esophageal cancer, or gastric cancer. WO2019057124A1 discloses cancers suitable for treatment with CD19-binding T-cell redirection therapies.

[0443] In some embodiments, the T-cell redirection therapy agent is combined with CD3ε, CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, BTNL8, PD-1, CD195, or NKG2C.

[0444] In some embodiments, CD19-binding T-cell redirection agents include blinatumomab, axicabtagene ciloleucel, tisagenlecleucel-t, inebilizumab, lisocabtagene maraleucel, XmAb-5574, CIK-CAR.CD19, ICTCAR-011, IM-19, JCAR-014, loncastuximab, and tesslin. tesirine), MB-CART2019.1, OXS-1550, PBCAR-0191, PCAR-019, PCAR-119, Senl-001, TI-1007, XmAb-5871, PTG-01, PZ01, Senl_1904A, Senl_1904B, UCART-19, CSG-CD19, DI-B4, ET-190, GC-007F or GC-022 CD19 binding domain.

[0445] In some embodiments, CD19-binding T-cell redirection agents include blinatumomab, axicabtagene ciloleucel, tisagenlecleucel-t, inebilizumab, lisocabtagene maraleucel, XmAb-5574, CIK-CAR.CD19, ICTCAR-011, IM-19, JCAR-014, loncastuximab, and tesslin. tesirine), MB-CART2019.1, OXS-1550, PBCAR-0191, PCAR-019, PCAR-119, Senl-001, TI-1007, XmAb- 5871, PTG-01, PZ01, Senl_1904A, Senl_1904B, UCART-19, CSG-CD19, DI-B4, ET-190, GC-007F or GC-022.

[0446] In some embodiments, the CD19-binding T-cell redirection therapy is a multispecific antibody, a CAR, or T cells expressing a CAR.

[0447] 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.

[0448] In some embodiments, the anti-CD38 antibody comprises VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5.

[0449] In some embodiments, the anti-CD38 anti-system belongs to the IgG1 isotype.

[0450] In some embodiments, the anti-CD38 antibody comprises HC of SEQ ID NO: 12 and LC of SEQ ID NO: 13.

[0451] In some embodiments, the anti-CD38 antibody comprises: VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15; VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17; VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19; or VH of SEQ ID NO: 20 and VL of SEQ ID NO: 21.

[0452] In some embodiments, the anti-CD38 anti-system belongs to the IgG1 isotype.

[0453] In some embodiments, the anti-CD38 system is administered at a dose between about 8 mg / kg and about 16 mg / kg.

[0454] In some embodiments, the CD19-binding T-cell redirection therapy and the anti-CD38 anti-system are administered via intravenous injection.

[0455] In some embodiments, the CD19-binding T-cell redirection therapy is administered intravenously and the anti-CD38 anti-system is administered subcutaneously.

[0456] In some embodiments, the CD19-binding T-cell redirection therapy and the anti-CD38 anti-system are administered via subcutaneous injection.

[0457] In some embodiments, the individual is a human being.

[0458] In some embodiments, the T-cell redirection therapy agent that binds to CD19 is a CD19xCD3 bispecific antibody.

[0459] In some embodiments, the method further includes administering one or more anticancer therapies to the individual.

[0460] 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.

[0461] This disclosure also provides a pharmaceutical combination comprising a CD19xCD3 bispecific antibody containing lantomosum (SEQ ID NO: 53), and an anti-CD38 antibody comprising HCDR1 (SEQ ID NO: 6), HCDR2 (SEQ ID NO: 7), HCDR3 (SEQ ID NO: 8), LCDR1 (SEQ ID NO: 9), LCDR2 (SEQ ID NO: 10), and LCDR3 (SEQ ID NO: 11).

[0462] In some embodiments, the anti-CD38 antibody comprises VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5.

[0463] In some embodiments, the anti-CD38 antibody comprises HC of SEQ ID NO: 12 and LC of SEQ ID NO: 13.

[0464] In some embodiments, the drug combination is not a fixed combination.

[0465] In some embodiments, the pharmaceutical combination comprises about 20 mg / mL to about 120 mg / mL of anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mM mannitol and about 0.04% w / v polysorbate-20 (PS-20); pH is about 5.5.

[0466] In some embodiments, the drug combination comprises about 1,800 mg of anti-CD38 antibody and about 30,000 U of rHuPH20.

[0467] In some embodiments, the drug combination comprises about 120 mg / mL of anti-CD38 antibody and about 2,000 U / mL of rHuPH20.

[0468] In some embodiments, the pharmaceutical combination further comprises one or more excipients.

[0469] In some embodiments, one or more excipients are histidine, methionine, sorbitol or polysorbate-20 (PS-20), or any combination thereof.

[0470] In some embodiments, the pharmaceutical combination includes

[0471] This anti-CD38 antibody has a concentration between approximately 100 mg / mL and approximately 120 mg / mL. Histidine between approximately 5 mM and approximately 15 mM; Sorbitol is between approximately 100 mM and approximately 300 mM; PS-20, ranging from approximately 0.01% w / v to approximately 0.04% w / v; and Methionine is present in concentrations between approximately 1 mg / mL and approximately 2 mg / mL, with a pH of approximately 5.5 to 5.6.

[0472] In some embodiments, the pharmaceutical combination includes Approximately 10 mM histidine.

[0473] In some embodiments, the pharmaceutical combination comprises about 300 mM sorbitol.

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

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

[0476] In some embodiments, the pharmaceutical combination includes Approximately 1,800 mg of this anti-CD38 antibody; Approximately 30,000 U of rHuPH20; Approximately 10 mM histidine; Approximately 300 mM sorbitol; Approximately 0.04% (w / v) PS-20; and Approximately 1 mg / mL of methionine, with a pH of approximately 5.6.

[0477] In some embodiments, the pharmaceutical combination includes The anti-CD38 antibody is present at a concentration of approximately 120 mg / mL. rHuPH20 at approximately 2,000 U / mL; Approximately 10 mM histidine; Approximately 300 mM sorbitol; Approximately 0.04% (w / v) PS-20; and Approximately 1 mg / mL of methionine, with a pH of approximately 5.6.

[0478] In some embodiments, the drug combination comprises 35 mcg of lantomosumab, lysine salt (23.23 mg), polysorbate 80 (0.64 mg), trehalose dihydrate (95.5 mg), and sodium hydroxide to adjust the pH to 7.0.

[0479] In some embodiments, lantumomab is reconstituted with 3 mL of sterile water for injection (USP) without preservatives.

[0480] A kit comprising a combination of drugs, the combination of drugs comprising lantumomab (SEQ ID NO: 53) and anti-CD38 antibodies comprising HCDR1 (SEQ ID NO: 6), HCDR2 (SEQ ID NO: 7), HCDR3 (SEQ ID NO: 8), LCDR1 (SEQ ID NO: 9), LCDR2 (SEQ ID NO: 10), and LCDR3 (SEQ ID NO: 11). [T] [Cell redirection therapy] [Multispecific antibody]

[0481] T-cell redirection therapies can be multispecific molecules such as bispecific antibodies. Various multispecific and / or bispecific formats include those described herein and recombinant IgG dual-targeting molecules, wherein each flank contains Fab fragments of at least two different antibodies or portions of those Fab fragments; IgG fusion molecules, wherein a full-length IgG antibody system is fused to an additional Fab fragment or a portion of that Fab fragment; Fc fusion molecules, wherein a single-chain Fv molecule or a stabilized bivalent antibody system is fused to a heavy chain constant domain, Fc region, or a portion thereof; Fab fusion molecules, wherein different Fab fragments are fused together; ScFv-based antibodies and bivalent antibody-based antibodies and heavy chain antibodies (e.g., domain antibodies, nanoantibodies), wherein different single-chain Fv molecules or different bivalent antibodies or different heavy chain antibodies (e.g., domain antibodies, nanoantibodies) are fused to each other or to another protein or carrier molecule, or multispecific antibodies produced via arm exchange. Exemplary multispecific and / or bispecific formats include dual-targeting molecules, such as dual-targeting (DT)-Ig (GSK / Domantis), dual-antibody combination (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 dual-Fab (Genentech), Dock-and-Lock (DNL) (ImmunoMedics), bivalent bispecific (Biotecnol) and Fab-Fv (UCB-Celltech), Bispecific T-cell conjugate (BITE) (Micromet), Tandem Diabody (Tandab) (Affimed), Dual-Affinity Retargeting Technology (DART) (MacroGenics), Single-Chain Dimeric Antibody (Academic), TCR-like Antibody (AIT, ReceptorLogics), Human Serum Albumin ScFv Fusion (Merrimack) and COMBODY (Epigen Biotech), Dual-Targeting Nanoantibody (Ablynx), Dual-Targeting Heavy-Chain Domain-Only Antibody.Bispecific antibodies in various formats have been described, for example, in Chames and Baty (2009) Curr Opin Drug Disc Dev 12: 276 and Nunez-Prado et al., (2015) Drug Discovery Today 20(5):588-594. [Method for producing antibodies used in the method of the present invention]

[0482] The antibodies used in the method of the present invention that bind to a specific antigen can be re-selected, for example, from a phage presentation library, wherein the phage system is engineered to represent human immunoglobulins or portions thereof, such as Fab, single-chain antibodies (scFv), or unpaired or paired antibody variable regions (Knappik et al., J Mol Biol 296:57-86, 2000; Krebs et al., J Immunol Meth 254:67-84, 2001; Vaughan et al., Nature Biotechnology 14:309-14, 1996; Sheets et al., PITAS (USA) 95:6157-62, 1998; Hoogenboom and Winter, J Mol Biol 227:381, 1991; Marks et al., J Mol Biol 222:581, 1991). The phage presentation library displays antibody heavy and light chain variable regions as fusion proteins with the phage pIX coat protein, as described in Shi et al. (2010) J. Mol. Biol. 397:385-96 and International Patent Publication No. WO2009 / 085462. Positive strains obtained by screening antibody libraries for binding to desired antigens (such as BCMA, CD3, CD38, CD123, CD19, CD33, PSMA, or TMEFF2 extracellular domains) can be further characterized and isolated from the strain lysate, subsequently selected for full-length antibody colony. This phage presentation method for isolating human antibodies has been established in the art. See, for example: U.S. Patent No. 5,223,409; U.S. Patent No. 5,403,484; U.S. Patent No. 5,571,698; 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.

[0483] T-cell redirected bispecific antibodies can be generated in vitro in a cell-free environment by introducing asymmetric mutations into the CH3 region of two monospecific homodimer antibodies and forming the bispecific heterodimer antibody from the two parent monospecific homodimer antibodies under reducing conditions (to allow disulfide isomerization), according to the method described in International Patent Publication No. WO2011 / 131746. In this method, two monospecific bivalent antibody systems are engineered to have certain substitutions in the CH3 region that promote heterodimer stability; these antibody systems are co-cultured under reducing conditions sufficient to allow disulfide isomerization of cysteine ​​in the hinge region; thereby generating the bispecific antibody by Fab arm exchange. The culture conditions can be optimally restored to non-reducing conditions. Examples of identifiable reducing agents include 2-mercaptoethylamine (2-MEA), dithiothreitol (DTT), dithioerythritol (DTE), glutathione, TCEP (2-carboxyethylphosphine), L-cysteine, and β-mercaptoethanol. The reducing agent is preferably selected from the group consisting of 2-mercaptoethylamine, dithiothreitol, and TCEP. For example, it can be used to incubate at a temperature of at least 20°C in the presence of at least 25 mM 2-MEA or at the presence of at least 0.5 mM dithiothreitol at a pH of 5 to 8 (e.g., at pH 7.0 or 7.4) for at least 90 min.

[0484] Exemplary CH3 mutant lines K409R and / or F405L that can be used in the first heavy chain and the second heavy chain of this bispecific antibody.

[0485] Additional CH3 mutations that can be used include techniques such as the Duobody® mutation (Genmab), the Knob-in-Hole mutation (Genentech), the electrostatic attraction mutation (Chugai, Amgen, NovoNordisk, Oncomed), the strand exchange engineered domain ontology (SEEDbody) (EMD Serono), and other asymmetric mutations (e.g., Zymeworks).

[0486] Duobody® mutations (Genmab) are disclosed in, for example, US9150663 and US2014 / 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.

[0487] Button mutations are disclosed, for example, in WO1996 / 027011, and include mutations at the interface of the CH3 region, in which an amino acid (pore) with a small side chain is introduced into the first CH3 region and an amino acid (button) with a large side chain is introduced into the second CH3 region, resulting in preferential interaction between the first and second CH3 regions. Exemplary CH3 region mutations forming buttons and pores are T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S, and T366W / T366S_L368A_Y407V.

[0488] Heavy chain heterodimer formation can be promoted by using electrostatic interactions involving the substitution of positively charged residues in the first CH3 region and negatively charged residues in the second CH3 region, as described in US2010 / 0015133, US2009 / 0182127, US2010 / 028637 or US2011 / 0123532.

[0489] Other asymmetric mutants that can be used to promote heavy chain heterodimerization include L351Y_F405A_Y407V / T394W, T366I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, and L351Y_Y407A / T366A_K409. F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F, or T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W, as described in US2012 / 0149876 or US2013 / 0195849.

[0490] SEEDbody mutations involve replacing selected IgG residues with IgA residues to promote heavy chain heterodimerization, as described in US20070287170.

[0491] Other exemplary mutant lines that can 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, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, K392D / D399K, K392D / E356K, K253E_D282K_K322D / D239K_E240K_K292D, K392D_K409D / D356K_D399K, as described in WO2007 / 147901, WO 2011 / 143545, WO2013157954, WO2013096291 and US2018 / 0118849.

[0492] Additional bispecific or multispecific structures that can be used as T-cell redirection therapeutic agents include dual variable domain immunoglobulins (DVD) (International Patent Publication No. WO2009 / 134776; DVD is a full-length antibody containing a heavy chain with the structure VH1-linker-VH2-CH and a light chain with the structure VL1-linker-VL2-CL; the linker is optional), structures including various dimerizing domains to connect two antibody arms with different specificities, such as leucine zippers or collagen dimerizing domains (International Patent Publication No. WO2012 / 022811, US Patent No. 5,932,448; US Patent No. 6,833,441), antibodies (dAbs) with two or more domains conjoined, bivalent antibodies, heavy chain-only antibodies such as camel antibodies and engineered camel antibodies, dual-targeting (DT)-Ig (GSK / Domantis), dual-antibody combination (Genentech), cross-linked Mab (Karmanos Cancer Center), mAb2 (F-Star) and CovX-integral (CovX / Pfizer), IgG-like bispecific (InnClone / Eli Lilly), Ts2Ab (MedImmune / AZ) and BsAb (Zymogenetics), HERCULES (Biogen Idec) and TvAb (Roche), ScFv / Fc fusion (Academic Institution), SCORPION (Emergent BioSolutions / Trubion, Zymogenetics / BMS), dual-affinity retargeting technology (Fc-DART) (MacroGenics) and dual (ScFv) 2-Fab (National Research Center for Antibody Medicine--China), dual-action or dual-Fab (Genentech), Dock-and-Lock (DNL) (ImmunoMedics), bivalent bispecific (Biotecnol) and Fab-Fv (UCB-Celltech).ScFv-based antibodies, bivalent antibody-based antibodies, and domain antibodies include, but are not limited to, Bispecific T Cell Engager (BiTE) (Micromet), Tandem Diabody (Tandab) (Affimed), Dual Affinity Retargeting Technology (DART) (MacroGenics), Single-chain Diabody (Academic), TCR-like Antibodies (AIT, ReceptorLogics), Human Serum Albumin ScFv Fusion (Merrimack) and COMBODY (Epigen Biotech), dual-targeting nanoantibodies (Ablynx), and dual-targeting heavy chain only domain antibodies. [Antibodies] [Fc] [Engineering Renovation]

[0493] T-cell redirection therapies, such as bispecific or multispecific antibodies or anti-CD38 antibodies, may have their Fc regions containing at least one substitution that reduces the binding of the T-cell redirection therapies to the activating 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)).

[0494] The Fc positions that can be substituted to reduce the binding of Fc to activating FcγR and subsequently decrease its effector function are as follows: 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 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-deletion / G237A / P238S on IgG4.

[0495] It can be used to reduce the K322A substitution of the Fc substitution system in CDC.

[0496] It is widely known that S228P substitution can be further used in IgG4 antibodies to enhance IgG4 stability.

[0497] An illustrative wild-type IgG1 contains the amino acid sequence of SEQ ID NO: 103. [SEQ ID NO: 103:] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPCSCDKTHTCPPCPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLPGK

[0498] Exemplary wild type IgG4 contains SEQ ID NO: 104 [SEQ ID NO: 104:] ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCSPSPPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0499] " Antibody-dependent cellular cytotoxicity (ADCC), also known as antibody-dependent cell-mediated cytotoxicity, is a mechanism that induces cell death through the interaction between antibody-coated target cells and lytic effector cells (such as natural killer cells (NK cells), monocytes, macrophages, and neutrophils) via Fcγ receptors (FcγR) expressed on the effector cells. For example, NK cells express FcγRIIIa, while monocytes express FcγRI, FcγRII, and FcγRIIIa. The ADCC activity of an antibody can be assessed in vitro using cells expressing the protein bound to the antibody as target cells and NK cells as effector cells. Cell lysis can be detected by the release of markers (such as radioactive matrix, fluorescent dyes, or native intracellular proteins) from lysed cells. In one indicative assay, target cells were used at a ratio of 1 target cell to 4 effector cells. Target cells were pre-labeled with BATDA and combined with effector cells and test antibodies. Samples were cultured for 2 hours, and cell lysis was measured by measuring the amount of BATDA released into the supernatant. Data were normalized relative to the maximum cytotoxicity using 0.67% Triton X-100 (Sigma Aldrich) and the minimum control value determined by spontaneous release of BATDA from target cells in the absence of any antibody.

[0500] " Antibody-dependent phagocytosis (ADCP) refers to a mechanism by which antibody-coated target cells are eliminated through internalization by phagocytes (such as macrophages or dendritic cells). ADCP can be evaluated using macrophages derived from mononuclear globules as effector cells and cells expressing the antibody-bound protein as target cells, which are also engineered to express GFP or another marker molecule. In an indicative assay, the effector cell:target cell ratio may be, for example, 4:1. Effector cells and target cells can be co-cultured for 4 hours with or without the antibody of the present invention. After culture, the cells are separated using accutase. Macrophages can be identified using fluorescently labeled anti-CD11b and anti-CD14 antibodies, and the percentage of phagocytosis can be determined using standard methods based on the percentage of GFP fluorescence in these CD11+CD14+ macrophages.

[0501] " Complement-dependent cytotoxicity (CDC) refers to a mechanism that induces cell death in which the Fc effector domain of an antibody binding to the target cell binds to and activates the complement component C1q, which in turn activates the complement cascade, leading to the death of the target cell. Complement activation can also cause complement components to deposit on the surface of the target cell, promoting CDC by binding to complement receptors on leukocytes (e.g., CR3). Cellular CDC can be measured by, for example, the following steps: seeding Daudi cells at 1 × 10⁵ cells / well (50 µL / well) in RPMI-B (RPMI supplemented with 1% BSA), adding 50 µL of test antibody to the well to achieve a final concentration between 0 and 100 µg / mL, incubating the reaction at room temperature for 15 min, adding 11 µL of pooled human serum to the well, and incubating the reaction at 37°C for 45 min. The percentage of lysed cells (%) can be detected using standard methods as the percentage of cells stained with propidium iodide in FACS assays.

[0502] The binding of antibodies to FcγR or FcRn can be assessed using flow cytometry on cells engineered to represent the respective receptors. In one indicative binding assay, 2 × 10⁵ cells per well were seeded in 96-well plates and blocked at 4°C in BSA staining buffer (BD Biosciences, San Jose, USA) for 30 min. Cells and test antibodies were then incubated on ice at 4°C for 1.5 h. 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 min. Cells were washed twice with staining buffer and then resuspended in 150 µL of staining buffer containing 1:200 dilution of DRAQ7 live / dead staining agent (Cell Signaling Technology, Danvers, USA). PE and DRAQ7 signals of stained cells were detected using the B2 and B4 channels, respectively, on a Miltenyi MACSQuant flow cytometer (Miltenyi Biotec, Auburn, USA). DRAQ7 was used to exclude viable cells, and the geometric mean fluorescence signal of at least 10,000 viable events was determined. FlowJo software (Tree Star) was used for analysis. The data were plotted as a log-log average fluorescence signal of antibody concentration. Nonlinear regression analysis was performed. [Chimeric antigen receptor] [(CAR)]

[0503] Chimeric antigen receptors (CARs) are genetically engineered receptors. These engineered receptors can be easily inserted into immune cells, including T cells, using techniques known in the field. Using CARs, a single receptor can be programmed to recognize a specific antigen, and upon binding to the antigen, activates immune cells to attack and destroy cells carrying that antigen. When these antigens are present on tumor cells, CAR-expressing immune cells can target and kill the tumor cells.

[0504] CARs generally include an extracellular domain that binds to an antigen (e.g., prostate neoantigen), an optional linker, a transmembrane domain, and a cytoplasmic domain that includes a co-stimulatory domain and / or a signaling domain.

[0505] The extracellular domain of a CAR can contain any polypeptide that binds to the desired antigen (e.g., prostate neoantigen). The extracellular domain can contain scFv, a portion of an antibody, or a replacement scaffold. CARs can also be engineered to bind to two or more desired antigens; they can be tandemly configured and separated by linker sequences. For example, one or more domain antibodies, scFv, vicuña VHH antibodies, or other VH-only antibody fragments can be tandemly organized via linkers to provide bispecificity or multispecificity to the CAR.

[0506] The transmembrane domain of CARs can be derived from the transmembrane domain of CD8, the α, β or ζ chains of T cell receptors, CD28, CD3ε, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, KIRDS2, OX40, CD2, CD27, LFA-1 (CD11a, CD18), ICOS (CD278), 4-1 BB (CD137), 4-1 BBL, GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRFI), CD160, CD19, IL2R β, IL2R γ, 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, NKp46, NKG2D, and / or NKG2C.

[0507] The intracellular co-stimulatory domains of CARs 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, which provide the second signal required for the effective activation and action of T lymphocytes when they bind to antigens. Indicative co-stimulatory domains that can be used in CARs include 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.

[0508] The intracellular signaling domain of a CAR can be derived from signaling domains such as O3ζ, CD3ε, CD22, CD79a, CD66d, or CD39. The "intracellular signaling domain" refers to the CAR polypeptide portion involved in transducing the message of binding of the effective CAR to the target antigen into immune effector cells to induce effector cell function. This effector cell function includes activation, intercytokine production, proliferation, and cytotoxic activity, including the release of cytotoxic factors to the CAR-bound target cell, or other cellular responses induced after the antigen binds to the extracellular CAR domain.

[0509] The linker for the CAR located between the extracellular domain and the transmembrane domain can be a polypeptide of approximately 2 to 100 amino acids in length. The linker may include or consist of flexible residues such as glycine and serine, allowing adjacent protein domains to move freely relative to each other. Longer linkers can be used when it is desirable to ensure that two adjacent domains do not interfere with each other spatially. The linker can 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 or a portion of the hinge region of any immunoglobulin.

[0510] Examples of CARs that can be used include CARs containing an extracellular domain that binds to the prostate neoantigen of the present invention, a CD8 transmembrane domain, and a CD3ζ signaling domain. Other exemplary CARs contain an extracellular domain that binds to the prostate neoantigen of the present invention, a CD8 or CD28 transmembrane domain, a CD28, 41BB, or OX40 co-stimulatory domain, and a CD3ζ signaling domain.

[0511] CARs are produced using standard molecular biology techniques. The extracellular domain that binds to the desired antigen can be derived from antibodies or antigen-binding fragments produced using the techniques described herein.

[0512] Although the invention has been described in general terms, embodiments of the invention will be further disclosed in the following examples, and should not be construed as limiting the scope of the patent application. [Further Embodiments of the Invention]

[0513] The following presents certain further embodiments of the invention as disclosed elsewhere herein. Features described in relation to the invention disclosed herein from the embodiments of the invention presented above are also relevant to each of these further numbered embodiments.

[0514] Example 1. A combination of an anti-CD38 antibody and a T-cell redirection therapy for treating individuals with cancer.

[0515] Example 2. An anti-CD38 antibody for enhancing the efficacy of T-cell redirection therapy in individuals with cancer.

[0516] Example 3. Use of an antiCD38 antibody in combination with a T-cell redirection therapeutic agent for preparing a pharmaceutical or medical composition for treating cancer patients.

[0517] Example 4. Use of a combination of an anti-CD38 antibody and a T-cell redirection therapeutic agent, characterized in that it is a combination prepared for the treatment of individuals with cancer in patients in need of treatment.

[0518] Example 5. The anti-CD38 antibody used according to any one of Examples 1 to 4, wherein the anti-CD38 antibody system is administered before the T-cell redirection therapy is administered.

[0519] Example 6. An anti-CD38 antibody used according to any one of Examples 1 to 5, wherein the T-cell redirection therapeutic agent binds to BCMA, GPRC5D, CD33, CD123, CD19, PSMA, TMEFF2, or CD20.

[0520] Example 7. An anti-CD38 antibody used according to any one of Examples 1 to 6, wherein the T-cell redirection therapeutic agent binds to CD3, CD3ε, CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, BTNL8, PD-1, CD195, or NKG2C.

[0521] Example 8. An anti-CD38 antibody used according to any one of Examples 1 to 7, wherein the T-cell redirection therapeutic agent comprises a CD3 binding domain, the CD3 binding domain comprising SEQ ID NO: 33 heavy chain complementarity determination region 1 (HCDR1), SEQ ID NO: 34 HCDR2, SEQ ID NO: 35 HCDR3, SEQ ID NO: 36 light chain complementarity determination region 1 (LCDR1), SEQ ID NO: 37 LCDR2 and SEQ ID NO: 38 LCDR3; The heavy chain variable region (VH) of SEQ ID NO: 39 and the light chain variable region (VL) of SEQ ID NO: 40; SEQ ID NO: 74 HCDR1, SEQ ID NO: 75 HCDR2, SEQ ID NO: 76 HCDR3, SEQ ID NO: 77 LCDR1, SEQ ID NO: 78 LCDR2 and SEQ ID NO: 79 LCDR3; VH of SEQ ID NO: 80 and VL of SEQ ID NO: 81; SEQ ID NO: 53, CD3 binding domains HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3; or VH and VL of the CD3 binding domain of SEQ ID NO: 53.

[0522] Example 9. The anti-CD38 antibody used according to any one of Examples 1 to 8, wherein the T-cell redirection therapeutic agent comprises The BCMA binding domain and the CD3 binding domain, wherein the BCMA binding domain includes HCDR1 of SEQ ID NO: 23, HCDR2 of SEQ ID NO: 24, HCDR3 of SEQ ID NO: 25, LCDR1 of SEQ ID NO: 26, LCDR2 of SEQ ID NO: 27, and LCDR3 of SEQ ID NO: 28, and the CD3 binding domain includes 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 The BCMA binding domain includes VH of SEQ ID NO: 29 and VL of SEQ ID NO: 30, and the CD3 binding domain includes VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40.

[0523] Example 10. The anti-CD38 antibody used according to any one of Examples 1 to 9, wherein the T-cell redirection therapeutic agent comprises the first heavy chain (HC1) of SEQ ID NO: 31, the first light chain (LC1) of SEQ ID NO: 32, the second heavy chain (HC2) of SEQ ID NO: 41, and the second light chain (LC2) of SEQ ID NO: 42.

[0524] Example 11. The anti-CD38 antibody used according to any one of Examples 1 to 10, wherein the T-cell redirection therapeutic agent comprises The GPRC5D binding domain includes HCDR1 (SEQ ID NO: 43), HCDR2 (SEQ ID NO: 44), HCDR3 (SEQ ID NO: 45), LCDR1 (SEQ ID NO: 46), LCDR2 (SEQ ID NO: 47), and LCDR3 (SEQ ID NO: 48); the CD3 binding domain includes HCDR1 (SEQ ID NO: 33), HCDR2 (SEQ ID NO: 34), HCDR3 (SEQ ID NO: 35), LCDR1 (SEQ ID NO: 36), LCDR2 (SEQ ID NO: 37), and LCDR3 (SEQ ID NO: 38); and / or The GPRC5D binding domain includes VH of SEQ ID NO: 49 and VL of SEQ ID NO: 50, and the CD3 binding domain includes VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40.

[0525] Example 12. The anti-CD38 antibody used according to any one of Example 111, wherein the T-cell redirection therapeutic agent comprises HC1 of SEQ ID NO: 51, LC1 of SEQ ID NO: 52, HC2 of SEQ ID NO: 41, and LC2 of SEQ ID NO: 42.

[0526] Example 13. The anti-CD38 antibody used according to any one of Examples 1 to 12, wherein the T-cell redirection therapeutic agent comprises The CD33 binding domain includes 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; the CD3 binding domain includes HCDR1 of SEQ ID NO: 74, HCDR2 and HCDR3 of SEQ ID NO: 75 or LCDR1 of SEQ ID NO: 76 or LCDR2 of SEQ ID NO: 77 or LCDR2 of SEQ ID NO: 78 and LCDR3 of SEQ ID NO: 79; and / or The CD33 binding domain includes VH of SEQ ID NO: 90 and VL of SEQ ID NO: 91, and the CD3 binding domain includes VH of SEQ ID NO: 80 and VL of SEQ ID NO: 81.

[0527] Example 14. The anti-CD38 antibody used according to any one of Examples 1 to 13, wherein the T-cell redirection 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.

[0528] Example 15. The anti-CD38 antibody used according to any one of Examples 1 to 14, wherein the T-cell redirection therapeutic agent comprises The CD123 binding domain includes HCDR1 (SEQ ID NO: 94), HCDR2 (SEQ ID NO: 95), HCDR3 (SEQ ID NO: 96), LCDR1 (SEQ ID NO: 9), LCDR2 (SEQ ID NO: 10), and LCDR3 (SEQ ID NO: 59); the CD3 binding domain includes HCDR1 (SEQ ID NO: 33), HCDR2 (SEQ ID NO: 34), HCDR3 (SEQ ID NO: 35), LCDR1 (SEQ ID NO: 36), LCDR2 (SEQ ID NO: 37), and LCDR3 (SEQ ID NO: 38); and / or The CD123 binding domain includes VH of SEQ ID NO: 100 and VL of SEQ ID NO: 61, and the CD3 binding domain includes VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40.

[0529] Example 16. The anti-CD38 antibody used according to any one of Examples 1 to 15, wherein the T-cell redirection 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.

[0530] Example 17. The anti-CD38 antibody used according to any one of Examples 1 to 16, wherein the T-cell redirection therapeutic agent comprises The CD19 binding domain and the CD3 binding domain, wherein the CD19 binding domain includes HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of the CD19 binding domain of SEQ ID NO: 53, and the CD3 binding domain includes HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of the CD3 binding domain of SEQ ID NO: 53; and / or The amino acid sequence of SEQ ID NO: 53.

[0531] Example 18. The anti-CD38 antibody used according to any one of Examples 1 to 17, wherein the T-cell redirection therapeutic agent comprises The PSMA binding domain includes HCDR1 and HCDR2 of SEQ ID NO: 54, or HCDR3 of SEQ ID NO: 55, or LCDR1 of SEQ ID NO: 56, or LCDR2 of SEQ ID NO: 9, or LCDR2 of SEQ ID NO: 10, and LCDR3 of SEQ ID NO: 59; the CD3 binding domain includes 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 The PSMA binding domain includes VH of SEQ ID NO: 60 and VL of SEQ ID NO: 61, and the CD3 binding domain includes VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40.

[0532] Example 19. The anti-CD38 antibody used according to any one of Examples 1 to 18, wherein the T-cell redirection 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.

[0533] Example 20. The anti-CD38 antibody used according to any one of Examples 1 to 19, wherein the T-cell redirection therapeutic agent comprises The TMEFF2 binding domain includes HCDR1 (SEQ ID NO: 64), HCDR2 (SEQ ID NO: 65), HCDR3 (SEQ ID NO: 66), LCDR1 (SEQ ID NO: 67), LCDR2 (SEQ ID NO: 68), and LCDR3 (SEQ ID NO: 69). The CD3 binding domain includes HCDR1 (SEQ ID NO: 74), HCDR2 (SEQ ID NO: 75), HCDR3 (SEQ ID NO: 75), or LCDR1 (SEQ ID NO: 76), or LCDR2 (SEQ ID NO: 77), or LCDR3 (SEQ ID NO: 78), and LCDR3 (SEQ ID NO: 79); and / or The TMEFF2 binding domain contains VH of SEQ ID NO: 70 and VL of SEQ ID NO: 71, and the CD3 binding domain contains VH of SEQ ID NO: 80 and VL of SEQ ID NO: 81.

[0534] Example 21. The anti-CD38 antibody used according to any one of Examples 1 to 20, wherein the T-cell redirection therapeutic agent comprises HC1 of SEQ ID NO: 72, LC1 of SEQ ID NO: 73, HC2 of SEQ ID NO: 82 and LC2 of SEQ ID NO: 83.

[0535] Example 22. The anti-CD38 antibody used according to any one of Examples 1 to 21, wherein the T cell redirection therapeutic agent is a multispecific antibody, a chimeric antigen receptor (CAR), or a T cell containing the CAR.

[0536] Example 23. The anti-CD38 antibody used in Example 22, wherein the multispecific antibody system is isotyped IgG1, IgG2, IgG3 or IgG4.

[0537] Example 24. The anti-CD38 antibody used according to Example 22 or 23, wherein the multispecific antibody comprises one or more Fc substitutions that reduce the binding of the multispecific antibody to the Fcγ receptor (FcγR).

[0538] Example 25. The anti-CD38 antibody used according to any one of Examples 22 to 24, wherein the one or more Fc substitution systems are selected from F234A / L235A on IgG4, L234A / L235A on IgG1, V234A / G237A / P238S / H268A / V309L / A330S / P331S on IgG2, F234A / L235A on IgG4, S228P / F234A / L235A on IgG4, N297A on all Ig isotypes, V234A / G237A on IgG2, and K214T / E233P / on IgG1. The group consisting of L234V / L235A / G236-deletion / A327G / P331A / D365E / L358M, H268Q / V309L / A330S / P331S on IgG2, S267E / L328F on IgG1, L234F / L235E / D265A on IgG1, L234A / L235A / G237A / P238S / H268A / A330S / P331S on IgG1, S228P / F234A / L235A / G237A / P238S on IgG4, and S228P / F234A / L235A / G236-deletion / G237A / P238S on IgG4, wherein the residue numbers are based on the EU index.

[0539] Example 26. The anti-CD38 antibody used in Example 25, wherein the multispecific antibody further comprises an S228P substitution.

[0540] Example 27. The anti-CD38 antibody used according to any one of Examples 22 to 26, wherein the multispecific antibody contains 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.

[0541] Example 28. The anti-CD38 antibody used in Example 27, wherein the one or more asymmetric substitution lines are selected from F450L / K409R, wild-type / F409L_R409K, T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S, and T366W / T366S_L368A_Y407V, L351Y_F405A_Y407 The group consisting of V / T394W, T366I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F, and T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W.

[0542] Example 29. The anti-CD38 antibody used according to any one of Examples 1 to 28, wherein the individual has a newly diagnosed cancer.

[0543] Example 30. The anti-CD38 antibody used according to any one of Examples 1 to 29, wherein the individual has relapsed or is refractory to previous anticancer therapy.

[0544] Example 31. The anti-CD38 antibody used according to any one of Examples 1 to 30, wherein the cancer is a hematologic malignancy or a solid tumor.

[0545] Example 32. The anti-CD38 antibody used according to any one of Examples 1 to 31, wherein the hematological malignancy is multiple myeloma, smoldering multiple myeloma, or monooclonal gammopathy of undetermined significance. MGUS), Acute lymphoblastic leukemia (ALL), Diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma (BL), Follicular lymphoma (FL), Mantle cell lymphoma (MCL), Waldenström macroglobulinemia, Plasma cell leukemia, Light chain amyloidosis (AL), Precursor B-cell lymphoblastic leukemia, Acute myeloid leukemia (AML), Myelomectomy syndrome (MDS), Chronic lymphocytic leukemia (CLL), B-cell malignancy, Chronic myeloid leukemia (CML), Hair-like cell leukemia (HCL), blastic plasmacytoid dendritic cell tumor, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, Marginal zone B-cell lymphoma (MZL) or mucosa-associated lymphoid tissue lymphoma (MALT), Plasma cell leukemia, Degenerative large cell lymphoma (ALCL), Leukemia or lymphoma.

[0546] Example 33. The anti-CD38 antibody used according to any one of Examples 1 to 32, wherein the multiple myeloma is a newly diagnosed multiple myeloma.

[0547] Example 34. The anti-CD38 antibody used in any one of Examples 1 to 32, wherein the multiple myeloma is a relapsed or refractory multiple myeloma.

[0548] Example 35. The anti-CD38 antibody used according to any one of Examples 1 to 34, wherein the multiple myeloma is a high-risk multiple myeloma.

[0549] Example 36. The anti-CD38 antibody used in Example 35, wherein an individual with this 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.

[0550] Example 37. The anti-CD38 antibody used according to any one of Examples 1 to 36, wherein the multiple myeloma has relapsed or is refractory to treatment with the anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, erlotuzumab, ixazomib, melphalan or thalidomide, or any combination thereof.

[0551] Example 38. The anti-CD38 antibody used according to any one of Examples 1 to 37, wherein the solid tumor is prostate cancer, lung cancer, liver cancer, cervical cancer, colon cancer, breast cancer, ovarian cancer, endometrial cancer, pancreatic cancer, melanoma, glioblastoma, esophageal cancer, gastric cancer, stomach cancer, kidney cancer, colon cancer, bladder cancer, cervical carcinoma, melanoma, hepatocellular carcinoma, renal cell carcinoma, urothelial carcinoma, head and neck cancer, glioma, or glioblastoma.

[0552] Example 39. The anti-CD38 antibody used in Example 38, wherein the prostate cancer is recurrent, refractory, malignant, or castration-resistant prostate cancer, or any combination thereof.

[0553] Example 40. The anti-CD38 antibody used in Example 32, wherein the AML lineage has at least one genetic abnormality, AML with multilineage dysplasia, treatment-associated AML, undifferentiated AML, minimal maturation AML, maturation AML, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroid leukemia, acute megakaryoblastic leukemia, acute basophilic leukemia, acute panmyelosis with fibrosis, or myeloid sarcoma.

[0554] Example 41. The anti-CD38 antibody used in Example 40, wherein the at least one gene abnormality is a translocation between chromosomes 8 and 21, a translocation or inversion in chromosome 16, a translocation between chromosomes 15 and 17, a change in chromosome 11, or a mutation in fms-associated tyrosine kinase 3 (FLT3), nucleolar phosphatase 1 (NPM1), isocitrate dehydrogenase 1 (IDH1), isocitrate dehydrogenase 2 (IDH2), DNA (cytosine-5)-methyltransferase 3 (DNMT3A), CCAAT / enhancer-binding protein α (CEBPA), U2 small nuclear RNA cofactor 1 (U2AF1), enhancer of the second unit of the zeste 2 polycomb repressor complex (EZH2), chromosome structure maintenance protein 1A (SMC1A), or chromosome structure maintenance protein 3 (SMC3).

[0555] Example 42. The anti-CD38 antibody used in Example 41, wherein the at least one gene 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.

[0556] Example 43. The anti-CD38 antibody used in Example 32, wherein the ALL lineage is B cell line ALL, T cell line ALL, adult ALL or pediatric ALL.

[0557] Example 44. The anti-CD38 antibody used in Example 43, wherein the individual with ALL has the Philadelphia chromosome or is resistant to treatment with BCR-ABL kinase inhibitors or has acquired resistance.

[0558] Example 45. An anti-CD38 antibody used according to any one of Examples 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.

[0559] Example 46. The anti-CD38 antibody used according to any one of Examples 1 to 45, wherein the anti-CD38 antibody comprises VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5.

[0560] Example 47. The anti-CD38 antibody used according to any one of Examples 1 to 46, wherein the anti-CD38 anti-system is IgG1 isotype.

[0561] Example 48. The anti-CD38 antibody used according to any one of Examples 1 to 47, wherein the anti-CD38 antibody comprises HC of SEQ ID NO: 12 and LC of SEQ ID NO: 13.

[0562] Example 49. The anti-CD38 antibody used according to any one of Examples 1 to 44, wherein the anti-CD38 antibody comprises VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15; VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17; VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19; or VH of SEQ ID NO: 20 and VL of SEQ ID NO: 21.

[0563] Example 50. The anti-CD38 antibody used in Example 49, wherein the anti-CD38 antibody system is IgG1 isotype.

[0564] Example 51. The anti-CD38 antibody used according to any one of Examples 1 to 50, wherein the T-cell redirection 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.

[0565] Example 52. The anti-CD38 antibody used according to any one of Examples 1 to 51 further comprises administering one or more anticancer therapies to the individual.

[0566] Example 53. The anti-CD38 antibody used according to any one of Examples 1 to 52, wherein the 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.

[0567] Example 54. An anti-CD38 antibody used according to any one of Examples 1 to 53, wherein the one or more anticancer therapies are selected from lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, erlotuzumab, ixazomib, melphalan, dexamethasone, vincristine, cyclophosphamide, hydroxydanomycin, prednisone, rituximab, imatinib, dasatinib, nilotinib, bosutinib, ponatinib, bafetinib, sercatinib, tozaserti. b) or the group consisting of danusertib, cytarabine, daunorubicin, idarubicin, mitoxantrone, hydroxyurea, decitabine, cladribine, fludarabine, topotecan, etoposide, 6-thioguanine, corticosteroids, methotrexate, 6-mercaptopurine, azacitidine, arsenic trioxide, and all-trans retinoic acid, or any combination thereof.

[0568] Example 55. The anti-CD38 antibody used according to any one of Examples 1 to 54, wherein the anti-CD38 antibody system is administered at a dose between about 8 mg / kg and about 16 mg / kg.

[0569] Example 56. The anti-CD38 antibody used according to any one of Examples 1 to 55, wherein the anti-CD38 antibody system is administered or provided as a pharmaceutical composition comprising the anti-CD38 antibody at a concentration of about 20 mg / mL to about 120 mg / mL in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mM mannitol and about 0.04% w / v polysorbate-20 (PS-20); pH is about 5.5.

[0570] Example 57. The anti-CD38 antibody used according to any one of Examples 1 to 53, wherein the anti-CD38 antibody system is administered or provided as a pharmaceutical composition for administration, the pharmaceutical composition comprising about 1,800 mg of the anti-CD38 antibody and about 30,000 U of rHuPH20.

[0571] Example 58. The anti-CD38 antibody used according to Example 57, wherein the anti-CD38 antibody system is administered or provided as a pharmaceutical composition for administration, the pharmaceutical composition comprising about 120 mg / mL of the anti-CD38 antibody and about 2,000 U / mL of rHuPH20.

[0572] Example 59. The anti-CD38 antibody used according to any one of Examples 57 to 58, wherein the anti-CD38 antibody system is administered or provided as a pharmaceutical composition for administration, the pharmaceutical composition comprising Histidine between approximately 5 mM and approximately 15 mM; Sorbitol is between approximately 100 mM and approximately 300 mM; PS-20, ranging from approximately 0.01% w / v to approximately 0.04% w / v; and Methionine is present in concentrations between approximately 1 mg / mL and approximately 2 mg / mL, with a pH of approximately 5.5 to 5.6.

[0573] Example 60. The anti-CD38 antibody used according to any one of Examples 57 to 59, wherein the anti-CD38 antibody system is administered or provided as a pharmaceutical composition for administration, the pharmaceutical composition comprising Approximately 1,800 mg of this anti-CD38 antibody; Approximately 30,000 U of rHuPH20; Approximately 10 mM histidine; Approximately 300 mM sorbitol; Approximately 0.04% (w / v) PS-20; and Approximately 1 mg / mL of methionine, with a pH of approximately 5.6.

[0574] Example 61. The anti-CD38 antibody used according to any one of Examples 57 to 60, wherein the anti-CD38 antibody system is administered or provided as a pharmaceutical composition for administration, the pharmaceutical composition comprising The anti-CD38 antibody is present at a concentration of approximately 120 mg / mL. rHuPH20 at approximately 2,000 U / mL; Approximately 10 mM histidine; Approximately 300 mM sorbitol; Approximately 0.04% (w / v) PS-20; and Approximately 1 mg / mL of methionine, with a pH of approximately 5.6.

[0575] Example 62. A combination of a BCMAxCD3 bispecific antibody and an anti-CD38 antibody for treating individuals with cancer.

[0576] Example 63. The BCMAxCD3 bispecific antibody used in Example 62, wherein the individual had been treated with anti-CD38 antibody prior to administration of the BCMAxCD3 bispecific antibody.

[0577] Example 64. The BCMAxCD3 bispecific antibody used according to Example 62 or 63, wherein the BCMAxCD3 bispecific antibody comprises a BCMA binding domain and a CD3 binding domain, the BCMA binding domain comprising HCDR1 of SEQ ID NO: 23, HCDR2 of SEQ ID NO: 24, HCDR3 of SEQ ID NO: 25, LCDR1 of SEQ ID NO: 26, LCDR2 of SEQ ID NO: 27, and LCDR3 of SEQ ID NO: 28, and the CD3 binding domain comprising HCDR1 of SEQ ID NO: 33, HCDR2 of SEQ ID NO: 34, HCDR3 of SEQ ID NO: 35, LCDR1 of SEQ ID NO: 36, LCDR2 of SEQ ID NO: 37, and LCDR3 of SEQ ID NO: 38.

[0578] Example 65. The BCMAxCD3 bispecific antibody used according to any one of Examples 62 to 64, wherein the BCMA binding domain comprises VH of SEQ ID NO: 29 and VL of SEQ ID NO: 30, and the CD3 binding domain comprises VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40.

[0579] Example 66. The BCMAxCD3 bispecific antibody used according to any one of Examples 62 to 65, wherein the BCMAxCD3 bispecific antibody system is IgG4 isotype and contains phenylalanine at position 405 and arginine at position 409 in HC1, and leucine at position 405 and lysine at position 409 in HC2, wherein the residue numbers are based on the EU index.

[0580] Example 67. The BCMAxCD3 bispecific antibody used according to any one of Examples 62 to 66, 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.

[0581] Example 68. The BCMAxCD3 bispecific antibody used according to any one of Examples 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.

[0582] Example 69. The BCMAxCD3 bispecific antibody used according to any one of Examples 62 to 68, wherein the cancer is a BCMA-presenting cancer.

[0583] Example 70. The BCMAxCD3 bispecific antibody used according to any one of Examples 62 to 69, wherein the cancer is a hematologic malignancy.

[0584] Example 71. The BCMAxCD3 bispecific antibody used in any of Examples 62 to 70, wherein the individual has relapsed or is refractory to treatment with the anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, erlotuzumab, ixazomib, melphalan or thalidomide, or any combination thereof.

[0585] Example 72. The BCMAxCD3 bispecific antibody used in any of Examples 62 to 71, wherein the individual’s treatment with the anti-CD38 antibody is relapsed or refractory.

[0586] Example 73. The BCMAxCD3 bispecific antibody used in any of Examples 62 to 72, wherein the hematologic malignancy is multiple myeloma, myeloma, DLBLC, CLL, Waldenstrom's hypergammaglobulinaemia, or non-Hodgkin's lymphoma.

[0587] Example 74. The BCMAxCD3 bispecific antibody used in Example 73, wherein the multiple myeloma is a newly diagnosed multiple myeloma.

[0588] Example 75. The BCMAxCD3 bispecific antibody used in Example 74, wherein the multiple myeloma is a relapsed or refractory multiple myeloma.

[0589] Example 76. The BCMAxCD3 bispecific antibody used in Example 74, wherein the multiple myeloma is a high-risk multiple myeloma.

[0590] Example 77. The BCMAxCD3 bispecific antibody used in Example 76, wherein an individual with this 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.

[0591] Example 78. The BCMAxCD3 bispecific antibody used according to any one of Examples 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.

[0592] Example 79. The BCMAxCD3 bispecific antibody used according to any one of Examples 62 to 78, wherein the anti-CD38 antibody comprises VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5.

[0593] Example 80. The BCMAxCD3 bispecific antibody used in any of Examples 62 to 79, wherein the anti-CD38 anti-system is IgG1 isotype.

[0594] Example 81. The BCMAxCD3 bispecific antibody used according to any one of Examples 62 to 80, wherein the anti-CD38 antibody comprises HC of SEQ ID NO: 12 and LC of SEQ ID NO: 13.

[0595] Example 82. The BCMAxCD3 bispecific antibody used according to any one of Examples 62 to 77, wherein the anti-CD38 antibody comprises VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15; VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17; VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19; or VH of SEQ ID NO: 20 and VL of SEQ ID NO: 21.

[0596] Example 83. The BCMAxCD3 bispecific antibody used in Example 82, wherein the anti-CD38 anti-system is IgG1 isotype.

[0597] Example 84. The BCMAxCD3 bispecific antibody used according to any one of Examples 62 to 83, wherein the anti-CD38 anti-system is administered at a dose between about 8 mg / kg and about 16 mg / kg.

[0598] Example 85. The BCMAxCD3 bispecific antibody used according to any one of Examples 62 to 84, wherein the BCMAxCD3 bispecific antibody and the anti-CD38 anti-system are administered by intravenous injection.

[0599] Example 86. The BCMAxCD3 bispecific antibody used according to any one of Examples 62 to 84, wherein the BCMAxCD3 bispecific antibody system is administered by intravenous injection and the anti-CD38 antibody system is administered by subcutaneous injection.

[0600] Example 87. The BCMAxCD3 bispecific antibody used according to any one of Examples 62 to 86, wherein the system is human.

[0601] Example 88. The BCMAxCD3 bispecific antibody used in any of Examples 62 to 87 further comprises administering one or more anticancer therapies to the individual.

[0602] Example 89. The BCMAxCD3 bispecific antibody used in Example 88, wherein the 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.

[0603] Example 90. The BCMAxCD3 bispecific antibody used according to any one of Examples 88 to 89, wherein the one or more anticancer therapies are selected from the group consisting of lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, erlotuzumab, ixazomib, melphalan, prednisone or dexamethasone, or any combination thereof.

[0604] Example 91. The BCMAxCD3 bispecific antibody used according to any one of Examples 62 to 90, wherein the anti-CD38 anti-system is administered or provided as a pharmaceutical composition comprising the anti-CD38 antibody at a concentration of about 20 mg / mL to about 120 mg / mL in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mM mannitol and about 0.04% w / v polysorbate-20 (PS-20); pH is about 5.5.

[0605] Example 92. The BCMAxCD3 bispecific antibody used according to any one of Examples 62 to 90, wherein the anti-CD38 anti-system is administered or provided as a pharmaceutical composition comprising about 1,800 mg of the anti-CD38 antibody and about 30,000 U of rHuPH20.

[0606] Example 93. The BCMAxCD3 bispecific antibody used in Example 92, wherein the anti-CD38 anti-system is administered or provided as a pharmaceutical composition comprising approximately 120 mg / mL of the anti-CD38 antibody and approximately 2,000 U / mL of rHuPH20.

[0607] Example 94. The BCMAxCD3 bispecific antibody used according to any one of Examples 92 to 93, wherein the anti-CD38 anti-system is administered as a pharmaceutical composition or provided for administration as a pharmaceutical composition, the pharmaceutical composition comprising Histidine between approximately 5 mM and approximately 15 mM; Sorbitol is between approximately 100 mM and approximately 300 mM; PS-20, ranging from approximately 0.01% w / v to approximately 0.04% w / v; and Methionine is present in concentrations between approximately 1 mg / mL and approximately 2 mg / mL, with a pH of approximately 5.5 to 5.6.

[0608] Example 95. The BCMAxCD3 bispecific antibody used according to any one of Examples 92 to 94, wherein the anti-CD38 anti-system is administered as a pharmaceutical composition or provided for administration as a pharmaceutical composition, the pharmaceutical composition comprising Approximately 1,800 mg of this anti-CD38 antibody; Approximately 30,000 U of rHuPH20; Approximately 10 mM histidine; Approximately 300 mM sorbitol; Approximately 0.04% (w / v) PS-20; and Approximately 1 mg / mL of methionine, with a pH of approximately 5.6.

[0609] Example 96. The BCMAxCD3 bispecific antibody used according to any one of Examples 92 to 95, wherein the anti-CD38 anti-system is administered as a pharmaceutical composition or provided for administration as a pharmaceutical composition, the pharmaceutical composition comprising The anti-CD38 antibody is present at a concentration of approximately 120 mg / mL. rHuPH20 at approximately 2,000 U / mL; Approximately 10 mM histidine; Approximately 300 mM sorbitol; Approximately 0.04% (w / v) PS-20; and Approximately 1 mg / mL of methionine, with a pH of approximately 5.6.

[0610] Example 97. A BCMAxCD3 bispecific antibody for treating an individual with cancer who has relapsed or is refractory to prior anticancer treatment.

[0611] Example 98. The BCMAxCD3 bispecific antibody used in Example 97, wherein the BCMAxCD3 bispecific antibody comprises a BCMA binding domain and a CD3 binding domain, the BCMA binding domain comprising HCDR1 of SEQ ID NO: 23, HCDR2 of SEQ ID NO: 24, HCDR3 of SEQ ID NO: 25, LCDR1 of SEQ ID NO: 26, LCDR2 of SEQ ID NO: 27, and LCDR3 of SEQ ID NO: 28, and the CD3 binding domain comprising HCDR1 of SEQ ID NO: 33, HCDR2 of SEQ ID NO: 34, HCDR3 of SEQ ID NO: 35, LCDR1 of SEQ ID NO: 36, LCDR2 of SEQ ID NO: 37, and LCDR3 of SEQ ID NO: 38.

[0612] Example 99. The BCMAxCD3 bispecific antibody used according to Example 97 or 98, wherein the BCMA binding domain comprises VH of SEQ ID NO: 29 and VL of SEQ ID NO: 30, and the CD3 binding domain comprises VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40.

[0613] Example 100. The BCMAxCD3 bispecific antibody used according to any one of Examples 97 to 99, wherein the BCMAxCD3 bispecific antibody system is IgG4 isotype and contains phenylalanine at position 405 and arginine at position 409 in HC1, and leucine at position 405 and lysine at position 409 in HC2, wherein the residue numbers are based on the EU index.

[0614] Example 101. The BCMAxCD3 bispecific antibody used in Example 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.

[0615] Example 102. The BCMAxCD3 bispecific antibody used according to any one of Examples 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.

[0616] Example 103. The BCMAxCD3 bispecific antibody used according to any one of Examples 97 to 102, wherein the cancer is a hematologic malignancy.

[0617] Example 104. The BCMAxCD3 bispecific antibody used in Example 103, wherein the hematologic malignancy is multiple myeloma.

[0618] Example 105. The BCMAxCD3 bispecific antibody used in Example 104, wherein the multiple myeloma is a high-risk multiple myeloma.

[0619] Example 106. The BCMAxCD3 bispecific antibody used in Example 105, wherein an individual with this 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.

[0620] Example 107. The BCMAxCD3 bispecific antibody used in any of Examples 97 to 106, wherein the individual is refractory or relapsed to treatment with the anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, erlotuzumab, ixazomib, melphalan or thalidomide, or any combination thereof.

[0621] Example 108. The BCMAxCD3 bispecific antibody used according to any one of Examples 97 to 107, wherein the individual's treatment with the anti-CD38 antibody resulted in a relapse.

[0622] Example 109. The BCMAxCD3 bispecific antibody used according to any one of Examples 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.

[0623] Example 110. The BCMAxCD3 bispecific antibody used according to any one of Examples 97 to 109, wherein the anti-CD38 antibody comprises VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5.

[0624] Example 111. The BCMAxCD3 bispecific antibody used according to any one of Examples 97 to 110, wherein the anti-CD38 anti-system is IgG1 isotype.

[0625] Example 112. The BCMAxCD3 bispecific antibody used according to any one of Examples 97 to 111, wherein the anti-CD38 antibody comprises HC of SEQ ID NO: 12 and LC of SEQ ID NO: 13.

[0626] Example 113. The BCMAxCD3 bispecific antibody used according to any one of Examples 97 to 108, wherein the anti-CD38 antibody comprises VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15; VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17; VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19; or VH of SEQ ID NO: 20 and VL of SEQ ID NO: 21.

[0627] Example 114. The BCMAxCD3 bispecific antibody used in Example 113, wherein the anti-CD38 anti-system is IgG1 isotype.

[0628] Example 115. The BCMAxCD3 bispecific antibody used according to any one of Examples 97 to 114, wherein the system is human.

[0629] Example 116. The BCMAxCD3 bispecific antibody used in any of Examples 97 to 115 further comprises administering one or more anticancer therapies to the individual.

[0630] Example 117. The BCMAxCD3 bispecific antibody used in Example 116, wherein the 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.

[0631] Example 118. The BCMAxCD3 bispecific antibody used in Example 116, wherein the one or more anticancer therapies are selected from the group consisting of lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, erlotuzumab, ixazomib, melphalan, prednisone or dexamethasone, or any combination thereof.

[0632] Example 119. A pharmaceutical composition comprising a BCMAxCD3 bispecific antibody and an anti-CD38 antibody, wherein the BCMAxCD3 bispecific antibody comprises a BCMA binding domain and a CD3 binding domain, the BCMA binding domain comprising VH of SEQ ID NO: 29 and VL of SEQ ID NO: 30, the CD3 binding domain comprising VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40, and the anti-CD38 antibody comprising VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5.

[0633] Example 120. The pharmaceutical composition of Example 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.

[0634] Example 121. The pharmaceutical composition of Examples 119 or 120 is not a fixed combination.

[0635] Example 122. A pharmaceutical composition as in Example 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 mM mannitol and about 0.04% w / v polysorbate-20 (PS-20); pH is about 5.5.

[0636] Example 123. A pharmaceutical composition as in Example 121, comprising about 1,800 mg of the anti-CD38 antibody and about 30,000 U of rHuPH20.

[0637] Example 124. A pharmaceutical composition as in Example 123, comprising approximately 120 mg / mL of the anti-CD38 antibody and approximately 2,000 U / mL of rHuPH20.

[0638] Example 125. A pharmaceutical composition as described in Example 124, further comprising one or more excipients.

[0639] Example 126. A pharmaceutical composition as in Example 125, wherein the one or more excipients are histidine, methionine, sorbitol or polysorbate-20 (PS-20), or any combination thereof.

[0640] Example 127. A pharmaceutical composition as described in Example 126, wherein the pharmaceutical composition comprises This anti-CD38 antibody has a concentration between approximately 100 mg / mL and approximately 120 mg / mL. Histidine between approximately 5 mM and approximately 15 mM; Sorbitol is between approximately 100 mM and approximately 300 mM; PS-20, ranging from approximately 0.01% w / v to approximately 0.04% w / v; and Methionine is present in concentrations between approximately 1 mg / mL and approximately 2 mg / mL, with a pH of approximately 5.5 to 5.6.

[0641] Example 128. A pharmaceutical composition as in Example 127, comprising about 10 mM histidine.

[0642] Example 129. A pharmaceutical composition as in Example 127 or 128, comprising about 300 mM sorbitol.

[0643] Example 130. A pharmaceutical composition as described in any of Examples 127 to 129, comprising about 0.04% (w / v) PS-20.

[0644] Example 131. A pharmaceutical composition as described in any of Examples 127 to 130, comprising about 1 mg / mL of methionine.

[0645] Example 132. A pharmaceutical composition as described in any of Examples 127 to 131, comprising... Approximately 1,800 mg of this anti-CD38 antibody; Approximately 30,000 U of rHuPH20; Approximately 10 mM histidine; Approximately 300 mM sorbitol; Approximately 0.04% (w / v) PS-20; and Approximately 1 mg / mL of methionine, with a pH of approximately 5.6.

[0646] Example 133. A pharmaceutical composition as described in any of Examples 127 to 132, comprising... The anti-CD38 antibody is present at a concentration of approximately 120 mg / mL. rHuPH20 at approximately 2,000 U / mL; Approximately 10 mM histidine; Approximately 300 mM sorbitol; Approximately 0.04% (w / v) PS-20; and Approximately 1 mg / mL of methionine, with a pH of approximately 5.6.

[0647] Example 134. A kit comprising a pharmaceutical composition as described in any one of Examples 119 to 133.

[0648] Example 135. A combination of a GPRC5D-binding T-cell redirection therapy and an anti-CD38 antibody for treating individuals with cancer.

[0649] Example 136. The T-cell retargeting agent that binds to GPRC5D used in Example 135, wherein the anti-CD38 antibody is administered to the individual prior to administration of the T-cell retargeting agent that binds to GPRC5D.

[0650] Example 137. A T-cell redirection therapy agent that binds to GPRC5D, used according to Example 135 or 136, wherein the individual has relapsed or is refractory to previous anticancer therapy.

[0651] Example 138. A T-cell redirection therapy agent that binds to GPRC5D used according to any one of Examples 135 to 137, wherein the cancer is a GPRC5D-expressing cancer.

[0652] Example 139. A T-cell redirection therapy agent that binds to GPRC5D used according to any one of Examples 135 to 138, wherein the GPRC5D-expressing cancer is a hematologic malignancy or a solid tumor.

[0653] Example 140. The T-cell redirection therapy agent that binds to GPRC5D used in Example 139, wherein the hematologic malignancy is leukemia, lymphoma, or multiple myeloma.

[0654] Example 141. The T-cell redirection therapy agent that binds to GPRC5D used in Example 139, wherein the solid tumor is ovarian cancer, lung cancer, gastric cancer, prostate cancer, kidney cancer, liver cancer, pancreatic cancer, colon cancer, esophageal cancer, bladder cancer, cervical cancer or malignant melanoma.

[0655] Example 142. A T-cell redirection therapy that binds to GPRC5D used according to any one of Examples 135 to 141, wherein the individual has relapsed or is refractory to treatment with the anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, erlotuzumab, ixazomib, melphalan or thalidomide, or any combination thereof.

[0656] Example 143. A T-cell redirection therapy agent that binds to GPRC5D used according to any one of Examples 135 to 142, wherein the individual has relapsed or is refractory to treatment with the anti-CD38 antibody.

[0657] Example 144. A T-cell redirection therapy agent that binds to GPRC5D used according to any one of Examples 140 to 143, wherein the multiple myeloma is a newly diagnosed multiple myeloma.

[0658] Example 145. A T-cell redirection therapy agent that binds to GPRC5D used according to any one of Examples 140 to 143, wherein the multiple myeloma is a relapsed or refractory multiple myeloma.

[0659] Example 146. A T-cell redirection therapy agent that binds to GPRC5D used according to any one of Examples 140 to 145, wherein the multiple myeloma is a high-risk multiple myeloma.

[0660] Example 147. A T-cell redirection therapy agent that binds to GPRC5D, used according to Example 146, wherein an individual with this 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.

[0661] Example 148. A T-cell redirection therapy agent that binds to GPRC5D according to any one of Examples 135 to 147, wherein the T-cell redirection therapy agent binds to CD3, CD3ε, CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, BTNL8, PD-1, CD195, or NKG2C.

[0662] Example 149. A T-cell retargeting agent that binds to GPRC5D used according to any one of Examples 135 to 148, wherein the T-cell retargeting agent comprises a GPRC5D binding domain and a CD3 binding domain, the GPRC5D binding domain comprising HCDR1 of SEQ ID NO: 43, HCDR2 of SEQ ID NO: 44, HCDR3 of SEQ ID NO: 45, LCDR1 of SEQ ID NO: 46, LCDR2 of SEQ ID NO: 47, and LCDR3 of SEQ ID NO: 48, and the CD3 binding domain 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.

[0663] Example 150. A T-cell retargeting agent that binds to GPRC5D according to any one of Examples 135 to 149, wherein the GPRC5D binding domain comprises VH of SEQ ID NO: 49 and VL of SEQ ID NO: 50, and the CD3 binding domain comprises VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40.

[0664] Example 151. A T-cell retargeting agent that binds to GPRC5D used according to any one of Examples 135 to 150, wherein the T-cell retargeting agent that binds to GPRC5C is a multispecific antibody, a CAR, or T cells expressing the CAR.

[0665] Example 152. A T-cell redirection therapy agent that binds to GPRC5D according to Example 151, wherein the multispecific anti-inflammatory system is of IgG1, IgG2, IgG3 or IgG4 isotype.

[0666] Example 153. A T-cell retargeting therapeutic agent that binds to GPRC5D used according to any one of Examples 151 to 152, wherein the multispecific antibody comprises one or more Fc substitutions that reduce the binding of the multispecific antibody to the Fcγ receptor (FcγR).

[0667] Example 154. A T-cell retargeting agent that binds to GPRC5D used according to any one of Examples 151 to 153, wherein the one or more Fc substitutions are selected from F234A / L235A on IgG4, L234A / L235A on IgG1, V234A / G237A / P238S / H268A / V309L / A330S / P331S on IgG2, F234A / L235A on IgG4, S228P / F234A / L235A on IgG4, N297A on all Ig isotypes, V234A / G237A on IgG2, and K214T / E233P / on IgG1. The group consisting of L234V / L235A / G236-deletion / A327G / P331A / D365E / L358M, H268Q / V309L / A330S / P331S on IgG2, S267E / L328F on IgG1, L234F / L235E / D265A on IgG1, L234A / L235A / G237A / P238S / H268A / A330S / P331S on IgG1, S228P / F234A / L235A / G237A / P238S on IgG4, and S228P / F234A / L235A / G236-deletion / G237A / P238S on IgG4, wherein the residue numbers are based on the EU index.

[0668] Example 155. The T-cell retargeting therapeutic agent that binds to GPRC5D used in Example 154, wherein the multispecific antibody further comprises an S228P substitution.

[0669] Example 156. A T-cell retargeting therapeutic agent that binds to GPRC5D used according to any one of Examples 151 to 155, wherein the multispecific antibody contains one or more asymmetric substitutions in the first CH3 domain or the second CH3 domain, or in both the first CH3 domain and the second CH3 domain.

[0670] Example 157. A T-cell retargeting therapeutic agent bound to GPRC5D used according to Example 156, wherein the one or more asymmetric substitution lines are selected from F450L / K409R, wild-type / F409L_R409K, T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S, and T366W / T366S_L368A_Y407V, L351Y_F40 The group consisting of 5A_Y407V / T394W, T366I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F, and T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W.

[0671] Example 158. A T-cell retargeting therapeutic agent that binds to GPRC5D according to any one of Examples 151 to 157, wherein the multispecific antibody comprises HC1 of SEQ ID NO: 51, LC1 of SEQ ID NO: 52, HC2 of SEQ ID NO: 41 and LC2 of SEQ ID NO: 42.

[0672] Example 159. A T-cell redirection therapy agent that binds to GPRC5D according to any one of Examples 135 to 158, wherein the anti-CD38 antibody comprises HCDR1 of SEQ ID NO: 6, HCDR2 of SEQ ID NO: 7, HCDR3 of SEQ ID NO: 8, LCDR1 of SEQ ID NO: 9, LCDR2 of SEQ ID NO: 10, and LCDR3 of SEQ ID NO: 11.

[0673] Example 160. A T-cell retargeting therapeutic agent that binds to GPRC5D used according to any one of Examples 135 to 159, wherein the anti-CD38 antibody comprises VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5.

[0674] Example 161. A T-cell redirection therapy agent that binds to GPRC5D used according to any one of Examples 135 to 160, wherein the anti-CD38 anti-system IgG1 isotype.

[0675] Example 162. A T-cell retargeting therapeutic agent that binds to GPRC5D used according to any one of Examples 135 to 161, wherein the anti-CD38 antibody comprises HC of SEQ ID NO: 12 and LC of SEQ ID NO: 13.

[0676] Example 163. A T-cell retargeting therapeutic agent binding to GPRC5D used according to any one of Examples 135 to 158, wherein the anti-CD38 antibody comprises VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15; VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17; VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19; or VH of SEQ ID NO: 20 and VL of SEQ ID NO: 21.

[0677] Example 164. The T-cell redirection therapy agent that binds to GPRC5D used in Example 163, wherein the anti-CD38 anti-system IgG1 isotype.

[0678] Example 165. A T-cell redirection therapy agent bound to GPRC5D used according to any one of Examples 135 to 164, wherein the anti-CD38 anti-system is administered at a dose between about 8 mg / kg and about 16 mg / kg.

[0679] Example 166. A GPRC5D-binding T-cell redirection therapy agent used according to any one of Examples 135 to 165, wherein the GPRC5D-binding T-cell redirection therapy agent and the anti-CD38 anti-system are administered by intravenous injection.

[0680] Example 167. A GPRC5D-binding T-cell redirection therapy agent used according to any one of Examples 135 to 165, wherein the GPRC5D-binding T-cell redirection therapy agent is administered by intravenous injection and the anti-CD38 anti-system is administered by subcutaneous injection.

[0681] Example 168. A T-cell retargeting agent bound to GPRC5D used according to any one of Examples 135 to 167, wherein the system is human.

[0682] Example 169. A T-cell retargeting agent that binds to GPRC5D used according to any one of Examples 135 to 168, wherein the T-cell retargeting agent that binds to GPRC5D is a GPRC5DxCD3 bispecific antibody.

[0683] Example 170. The T-cell redirection therapy agent that binds to GPRC5D used according to any one of Examples 135 to 170 further comprises administering one or more anticancer therapies to the individual.

[0684] Example 171. The T-cell redirection therapy agent that binds to GPRC5D according to Example 170, wherein the 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.

[0685] Example 172. The T-cell redirection therapy agent that binds to GPRC5D used according to Example 170, wherein the one or more anticancer therapies are selected from lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, erlotuzumab, ixazomib, melphalan, dexamethasone, or prednisone.

[0686] Example 173. A T-cell redirection therapy agent bound to GPRC5D used according to any one of Examples 135 to 172, wherein the anti-CD38 anti-system is administered or provided as a pharmaceutical composition comprising the anti-CD38 antibody at a concentration of about 20 mg / mL to about 120 mg / mL in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mM mannitol, and about 0.04% w / v polysorbate-20 (PS-20); pH is about 5.5.

[0687] Example 174. A T-cell redirection therapy agent that binds to GPRC5D according to any one of Examples 135 to 172, wherein the anti-CD38 anti-system is administered or provided as a pharmaceutical composition comprising about 1,800 mg of the anti-CD38 antibody and about 30,000 U of rHuPH20.

[0688] Example 175. The T-cell redirection therapy agent bound to GPRC5D used according to Example 174, wherein the anti-CD38 anti-system is administered or provided as a pharmaceutical composition comprising about 120 mg / mL of the anti-CD38 antibody and about 2,000 U / mL of rHuPH20.

[0689] Example 176. A T-cell redirection therapy agent bound to GPRC5D used according to Example 174 or 175, wherein the anti-CD38 anti-system is administered or provided as a pharmaceutical composition for administration, the pharmaceutical composition comprising This anti-CD38 antibody has a concentration between approximately 100 mg / mL and approximately 120 mg / mL. Histidine between approximately 5 mM and approximately 15 mM; Sorbitol is between approximately 100 mM and approximately 300 mM; PS-20, ranging from approximately 0.01% w / v to approximately 0.04% w / v; and Methionine is present in concentrations between approximately 1 mg / mL and approximately 2 mg / mL, with a pH of approximately 5.5 to 5.6.

[0690] Example 177. A T-cell redirection therapy agent binding to GPRC5D used according to any one of Examples 174 to 176, wherein the anti-CD38 anti-system is administered or provided as a pharmaceutical composition for administration, the pharmaceutical composition comprising Approximately 1,800 mg of this anti-CD38 antibody; Approximately 30,000 U of rHuPH20; Approximately 10 mM histidine; Approximately 300 mM sorbitol; Approximately 0.04% (w / v) PS-20; and Approximately 1 mg / mL of methionine, with a pH of approximately 5.6.

[0691] Example 178. A T-cell redirection therapy agent binding to GPRC5D used according to any one of Examples 174 to 177, wherein the anti-CD38 anti-system is administered or provided as a pharmaceutical composition for administration, the pharmaceutical composition comprising The anti-CD38 antibody is present at a concentration of approximately 120 mg / mL. rHuPH20 at approximately 2,000 U / mL; Approximately 10 mM histidine; Approximately 300 mM sorbitol; Approximately 0.04% (w / v) PS-20; and Approximately 1 mg / mL of methionine, with a pH of approximately 5.6.

[0692] Example 179. A GPRC5DxCD3 bispecific antibody for treating an individual with cancer who has relapsed or is refractory to prior anticancer treatment.

[0693] Example 180. The GPRC5DxCD3 bispecific antibody used in Example 179, wherein the GPRC5DxCD3 bispecific antibody comprises a GPRC5D binding domain and a CD3 binding domain, the GPRC5D binding domain comprising HCDR1 of SEQ ID NO: 43, HCDR2 of SEQ ID NO: 44, HCDR3 of SEQ ID NO: 45, LCDR1 of SEQ ID NO: 46, LCDR2 of SEQ ID NO: 47, and LCDR3 of SEQ ID NO: 48, and the CD3 binding domain comprising HCDR1 of SEQ ID NO: 33, HCDR2 of SEQ ID NO: 34, HCDR3 of SEQ ID NO: 35, LCDR1 of SEQ ID NO: 36, LCDR2 of SEQ ID NO: 37, and LCDR3 of SEQ ID NO: 38.

[0694] Example 181. The GPRC5DxCD3 bispecific antibody used in Example 179 or 180, wherein the GPRC5D binding domain comprises VH of SEQ ID NO: 49 and VL of SEQ ID NO: 50, and the CD3 binding domain comprises VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40.

[0695] Example 182. The GPRC5DxCD3 bispecific antibody used according to any one of Examples 179 to 181, wherein the GPRC5DxCD3 bispecific antibody system is IgG4 isotype and contains phenylalanine at position 405 and arginine at position 409 in HC1, and leucine at position 405 and lysine at position 409 in HC2, wherein the residue numbers are based on the EU index.

[0696] Example 183. The GPRC5DxCD3 bispecific antibody used in Example 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.

[0697] Example 184. The GPRC5DxCD3 bispecific antibody used according to any one of Examples 179 to 183, wherein 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.

[0698] Example 185. The GPRC5DxCD3 bispecific antibody used according to any one of Examples 179 to 184, wherein the cancer is a hematologic malignancy or a solid tumor.

[0699] Example 186. The GPRC5DxCD3 bispecific antibody used in Example 185, wherein the cancer is multiple myeloma, lymphoma, melanoma, breast cancer, endometrial cancer, ovarian cancer, lung cancer, gastric cancer, prostate cancer, kidney cancer, liver cancer, pancreatic cancer, colon cancer, esophageal cancer, bladder cancer, or cervical cancer.

[0700] Example 187. The GPRC5DxCD3 bispecific antibody used in Example 186, wherein the multiple myeloma is a high-risk multiple myeloma.

[0701] Example 188. The GPRC5DxCD3 bispecific antibody used in Example 187, wherein an individual with this 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.

[0702] Example 189. The GPRC5DxCD3 bispecific antibody used in any of Examples 179 to 188, wherein the individual is refractory or relapsed to treatment with the anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, erlotuzumab, ixazomib, melphalan or thalidomide, or any combination thereof.

[0703] Example 190. The GPRC5DxCD3 bispecific antibody used according to any one of Examples 179 to 189, wherein the individual has relapsed or is refractory to treatment with the anti-CD38 antibody.

[0704] Example 191. The GPRC5DxCD3 bispecific antibody used according to any one of Examples 179 to 190, wherein the anti-CD38 antibody comprises HCDR1 of SEQ ID NO: 6, HCDR2 of SEQ ID NO: 7, HCDR3 of SEQ ID NO: 8, LCDR1 of SEQ ID NO: 9, LCDR2 of SEQ ID NO: 10 and LCDR3 of SEQ ID NO: 11.

[0705] Example 192. The GPRC5DxCD3 bispecific antibody used according to any one of Examples 179 to 191, wherein the anti-CD38 antibody comprises VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5.

[0706] Example 193. The GPRC5DxCD3 bispecific antibody used in any of Examples 179 to 192, wherein the anti-CD38 anti-system is IgG1 isotype.

[0707] Example 194. The GPRC5DxCD3 bispecific antibody used according to any one of Examples 179 to 193, wherein the anti-CD38 antibody comprises HC of SEQ ID NO: 12 and LC of SEQ ID NO: 13.

[0708] Example 195. The GPRC5DxCD3 bispecific antibody used according to any one of Examples 179 to 190, wherein the anti-CD38 antibody comprises VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15; VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17; VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19; or VH of SEQ ID NO: 20 and VL of SEQ ID NO: 21.

[0709] Example 196. The GPRC5DxCD3 bispecific antibody used in Example 195, wherein the anti-CD38 anti-system is IgG1 isotype.

[0710] Example 197. The GPRC5DxCD3 bispecific antibody used according to any one of Examples 179 to 196, wherein the system is human.

[0711] Example 198. The GPRC5DxCD3 bispecific antibody used in any of Examples 179 to 197 further comprises administering one or more anticancer therapies to the individual.

[0712] Example 199. The GPRC5DxCD3 bispecific antibody used in Example 198, wherein the 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.

[0713] Example 200. The GPRC5DxCD3 bispecific antibody used in Example 198, wherein the one or more anticancer therapies are selected from lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, erlotuzumab, ixazomib, melphalan, dexamethasone, vincristine, cyclophosphamide, hydroxydanomycin, prednisone, rituximab, imatinib, dasatinib, nilotinib, bosutinib, ponatinib, bafetinib, saracatinib, and tozaser. The group consisting of tib or danusertib, cytarabine, daunorubicin, idarubicin, mitoxantrone, hydroxyurea, decitabine, cladribine, fludarabine, topotecan, etoposide, 6-thioguanine, corticosteroids, methotrexate, 6-mercaptopurine, azacitidine, arsenic trioxide and all-trans retinoic acid, or any combination thereof.

[0714] Example 201. A pharmaceutical combination comprising a GPRC5DxCD3 bispecific antibody and an anti-CD38 antibody, wherein the GPRC5DxCD3 bispecific antibody comprises a GPRC5D binding domain and a CD3 binding domain, the GPRC5D binding domain comprising HCDR1 of SEQ ID NO: 43, HCDR2 of SEQ ID NO: 44, HCDR3 of SEQ ID NO: 45, LCDR1 of SEQ ID NO: 46, LCDR2 of SEQ ID NO: 47, and LCDR3 of SEQ ID NO: 48, and the CD3 binding domain comprising HCDR1 of SEQ ID NO: 33, HCDR2 of SEQ ID NO: 34, HCDR3 of SEQ ID NO: 35, LCDR1 of SEQ ID NO: 36, LCDR2 of SEQ ID NO: 37, and LCDR3 of SEQ ID NO: 38, and the anti-CD38 antibody comprising HCDR1 of SEQ ID NO: 6, HCDR2 of SEQ ID NO: 7, and LCDR3 of SEQ ID NO: 8. HCDR3 of SEQ ID NO: 9, LCDR1 of SEQ ID NO: 10, and LCDR2 of SEQ ID NO: 11.

[0715] Example 202. The drug combination as in Example 201, wherein the GPRC5D binding domain comprises VH of SEQ ID NO: 49 and VL of SEQ ID NO: 50, and the CD3 binding domain comprises VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40, and the anti-CD38 antibody comprises VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5.

[0716] Example 203. The drug combination as in Example 201 or 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.

[0717] Example 204. The combination of drugs as described in any of Examples 201 to 203 is not a fixed combination.

[0718] Example 205. The pharmaceutical combination as in Example 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 mM mannitol and about 0.04% w / v polysorbate-20 (PS-20); pH is about 5.5.

[0719] Example 206. The pharmaceutical combination as in Example 204, comprising about 1,800 mg of the anti-CD38 antibody and about 30,000 U of rHuPH20.

[0720] Example 207. A pharmaceutical composition as in Example 206, comprising approximately 120 mg / mL of the anti-CD38 antibody and approximately 2,000 U / mL of rHuPH20.

[0721] Example 208. The pharmaceutical combination of Example 207 further comprises one or more excipients.

[0722] Example 209. A pharmaceutical combination as in Example 208, wherein the one or more excipients are histidine, methionine, sorbitol or polysorbate-20 (PS-20), or any combination thereof.

[0723] Example 210. A pharmaceutical composition as described in Example 209, wherein the pharmaceutical composition comprises This anti-CD38 antibody has a concentration between approximately 100 mg / mL and approximately 120 mg / mL. Histidine between approximately 5 mM and approximately 15 mM; Sorbitol is between approximately 100 mM and approximately 300 mM; PS-20, ranging from approximately 0.01% w / v to approximately 0.04% w / v; and Methionine is present in concentrations between approximately 1 mg / mL and approximately 2 mg / mL, with a pH of approximately 5.5 to 5.6.

[0724] Example 211. A pharmaceutical combination as in Example 209 or 210, comprising about 10 mM histidine.

[0725] Example 212. A pharmaceutical combination as described in any of Examples 209 to 211, comprising about 300 mM sorbitol.

[0726] Example 213. A pharmaceutical combination of any one of Examples 209 to 212, comprising about 0.04% (w / v) PS-20.

[0727] Example 214. A pharmaceutical combination as described in any of Examples 209 to 213, comprising about 1 mg / mL of methionine.

[0728] Example 215. A pharmaceutical combination as described in any one of Examples 209 to 214, comprising... Approximately 1,800 mg of this anti-CD38 antibody; Approximately 30,000 U of rHuPH20; Approximately 10 mM histidine; Approximately 300 mM sorbitol; Approximately 0.04% (w / v) PS-20; and Approximately 1 mg / mL of methionine, with a pH of approximately 5.6.

[0729] Example 216. A pharmaceutical combination as described in any of Examples 209 to 215, comprising... The anti-CD38 antibody is present at a concentration of approximately 120 mg / mL. rHuPH20 at approximately 2,000 U / mL; Approximately 10 mM histidine; Approximately 300 mM sorbitol; Approximately 0.04% (w / v) PS-20; and Approximately 1 mg / mL of methionine, with a pH of approximately 5.6.

[0730] Example 217. A kit comprising a combination of pharmaceuticals as described in any one of Examples 201 to 215.

[0731] Example 218. A combination of a CD19-binding T-cell redirection therapy and an anti-CD38 antibody for treating individuals with cancer.

[0732] Example 219. An anti-CD38 antibody for enhancing the efficacy of a CD19-binding T-cell redirection therapy in an individual with cancer, wherein the individual has been treated with the anti-CD38 antibody prior to administration of the CD19-binding T-cell redirection therapy.

[0733] Example 220. The T-cell redirection therapy or anti-CD38 antibody used according to Example 218 or 219, wherein the individual is refractory or relapsed to previous anticancer therapy.

[0734] Example 221. The T-cell redirection therapy or anti-CD38 antibody used according to any one of Examples 218 to 221, wherein the cancer is a hematologic malignancy or a solid tumor.

[0735] Example 222. The T-cell redirection therapy or anti-CD38 antibody used in Example 221, wherein the hematologic malignancy is lymphoma, B-cell malignancy, Hodgkin's lymphoma, non-Hodgkin's lymphoma, DLBLC, FL, MCL, marginal zone B-cell lymphoma (MZL), mucosa-associated lymphoid tissue lymphoma (MALT), CLL, ALL, AML, Waldenström macroglobulinemia, or T-cell lymphoma.

[0736] Example 223. The T-cell redirection therapy agent or anti-CD38 antibody used in Example 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.

[0737] Example 224. A T-cell redirection therapy or anti-CD38 antibody used according to any one of Examples 218 to 223, wherein the T-cell redirection therapy binds to CD3ε, CD8, KI2L4, NKG2E, NKG2D, NKG2F, BTNL3, CD186, BTNL8, PD-1, CD195, or NKG2C.

[0738] Example 225. A T-cell redirection therapy or anti-CD38 antibody used according to any one of Examples 218 to 224, wherein the CD19-binding T-cell redirection therapy comprises blinatumomab, axicabtagene ciloleucel, tisagenlecleucel-t, inebilizumab, lisocabtagene maraleucel, XmAb-5574, CIK-CAR.CD19, ICTCAR-011, IM-19, JCAR-014, loncastuximab, or loncastuximab. tesirine), MB-CART2019.1, OXS-1550, PBCAR-0191, PCAR-019, PCAR-119, Senl-001, TI-1007, XmAb-5871, PTG-01, PZ01, Senl_1904A, Senl_1904B, UCART-19, CSG-CD19, DI-B4, ET-190, GC-007F or GC-022 CD19 binding domain.

[0739] Example 226. A T-cell redirection therapy or anti-CD38 antibody used according to any one of Examples 218 to 225, wherein the CD19-binding T-cell redirection therapy comprises blinatumomab, axicabtagene ciloleucel, tisagenlecleucel-t, inebilizumab, lisocabtagene maraleucel, XmAb-5574, CIK-CAR.CD19, ICTCAR-011, IM-19, JCAR-014, loncastuximab, or loncastuximab. tesirine), MB-CART2019.1, OXS-1550, PBCAR-0191, PCAR-019, PCAR-119, Senl-001, TI-1007, XmAb- 5871, PTG-01, PZ01, Senl_1904A, Senl_1904B, UCART-19, CSG-CD19, DI-B4, ET-190, GC-007F or GC-022.

[0740] Example 227. The T-cell redirection therapy or anti-CD38 antibody used according to any one of Examples 218 to 226, wherein the CD19-binding T-cell redirection therapy is a multispecific antibody, a CAR, or T cells expressing the CAR.

[0741] Example 228. The T-cell redirection therapeutic agent or anti-CD38 antibody used according to any one of Examples 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.

[0742] Example 229. A T-cell redirection therapeutic agent or anti-CD38 antibody used according to any one of Examples 218 to 228, wherein the anti-CD38 antibody comprises VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5.

[0743] Example 230. The T-cell redirection therapy agent or anti-CD38 antibody used according to any one of Examples 218 to 229, wherein the anti-CD38 anti-system is IgG1 isotype.

[0744] Example 231. A T-cell redirection therapeutic agent or anti-CD38 antibody used according to any one of Examples 218 to 230, wherein the anti-CD38 antibody comprises HC of SEQ ID NO: 12 and LC of SEQ ID NO: 13.

[0745] Example 232. The T-cell redirection therapeutic agent or anti-CD38 antibody used according to any one of Examples 218 to 227, wherein the anti-CD38 antibody comprises VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15; VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17; VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19; or VH of SEQ ID NO: 20 and VL of SEQ ID NO: 21.

[0746] Example 233. The T-cell redirection therapy agent or anti-CD38 antibody used in Example 232, wherein the anti-CD38 anti-system is IgG1 isotype.

[0747] Example 234. The T-cell redirection therapy agent or anti-CD38 antibody used according to any one of Examples 218 to 233, wherein the anti-CD38 antibody system is administered at a dose between about 8 mg / kg and about 16 mg / kg.

[0748] Example 235. The T-cell redirection therapy or anti-CD38 antibody used according to any one of Examples 218 to 234, wherein the CD19-binding T-cell redirection therapy and the anti-CD38 antibody system are administered by intravenous injection.

[0749] Example 236. The T-cell redirection therapy or anti-CD38 antibody used according to any one of Examples 218 to 234, wherein the CD19-binding T-cell redirection therapy is administered by intravenous injection and the anti-CD38 antibody is administered by subcutaneous injection.

[0750] Example 237. The T-cell redirection therapeutic agent or anti-CD38 antibody used according to any one of Examples 218 to 236, wherein the system is human.

[0751] Example 238. The T-cell redirection therapy agent or anti-CD38 antibody used according to any one of Examples 218 to 237, wherein the T-cell redirection therapy agent that binds to CD19 is a CD19xCD3 bispecific antibody.

[0752] Example 239. The T-cell redirection therapy agent or anti-CD38 antibody used according to any one of Examples 218 to 238 further comprises administering one or more anticancer therapies to the individual.

[0753] Example 240. The T-cell redirection therapy or anti-CD38 antibody used according to Example 238, wherein the one or more anticancer therapies are selected from the group consisting of autologous stem cell transplantation (ASCT), radiation, surgery, chemotherapy, immunomodulators and targeted cancer therapies.

[0754] Example 241. A pharmaceutical combination comprising a CD19xCD3 bispecific antibody containing lantomosum (SEQ ID NO: 53), and an anti-CD38 antibody comprising HCDR1 (SEQ ID NO: 6), HCDR2 (SEQ ID NO: 7), HCDR3 (SEQ ID NO: 8), LCDR1 (SEQ ID NO: 9), LCDR2 (SEQ ID NO: 10), and LCDR3 (SEQ ID NO: 11).

[0755] Example 242. The drug combination as in Example 241, wherein the anti-CD38 antibody comprises VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5.

[0756] Example 243. A pharmaceutical combination as in Example 241 or 242, wherein the anti-CD38 antibody comprises HC of SEQ ID NO: 12 and LC of SEQ ID NO: 13.

[0757] Example 244. The combination of medicines as described in any of Examples 241 to 243 is not a fixed combination.

[0758] Example 245. A pharmaceutical combination as described in any of Examples 241 to 244, 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 mM mannitol and about 0.04% w / v polysorbate-20 (PS-20); pH is about 5.5.

[0759] Example 246. A pharmaceutical combination as described in any of Examples 241 to 243, comprising about 1,800 mg of the anti-CD38 antibody and about 30,000 U of rHuPH20.

[0760] Example 247. The pharmaceutical combination as in Example 246, comprising approximately 120 mg / mL of the anti-CD38 antibody and approximately 2,000 U / mL of rHuPH20.

[0761] Example 248. The pharmaceutical combination of Example 246 or 257 further comprises one or more excipients.

[0762] Example 249. A pharmaceutical combination as described in any of Examples 246 to 248, wherein the one or more excipients are histidine, methionine, sorbitol or polysorbate-20 (PS-20), or any combination thereof.

[0763] Example 250. A pharmaceutical combination as described in any one of Examples 246 to 249, wherein the pharmaceutical combination comprises This anti-CD38 antibody has a concentration between approximately 100 mg / mL and approximately 120 mg / mL. Histidine between approximately 5 mM and approximately 15 mM; Sorbitol is between approximately 100 mM and approximately 300 mM; PS-20, ranging from approximately 0.01% w / v to approximately 0.04% w / v; and Methionine is present in concentrations between approximately 1 mg / mL and approximately 2 mg / mL, with a pH of approximately 5.5 to 5.6.

[0764] Example 251. A pharmaceutical combination as described in any of Examples 246 to 250, comprising about 10 mM histidine.

[0765] Example 252. A pharmaceutical combination of any one of Examples 246 to 251, comprising about 300 mM sorbitol.

[0766] Example 253. A pharmaceutical combination of any of Examples 246 to 252, comprising about 0.04% (w / v) PS-20.

[0767] Example 254. A pharmaceutical combination of any one of Examples 246 to 253, comprising about 1 mg / mL methionine.

[0768] Example 255. A pharmaceutical combination as described in any of Examples 246 to 254, comprising... Approximately 1,800 mg of this anti-CD38 antibody; Approximately 30,000 U of rHuPH20; Approximately 10 mM histidine; Approximately 300 mM sorbitol; Approximately 0.04% (w / v) PS-20; and Approximately 1 mg / mL of methionine, with a pH of approximately 5.6.

[0769] Example 256. A pharmaceutical composition as described in any of Examples 246 to 255, comprising... The anti-CD38 antibody is present at a concentration of approximately 120 mg / mL. rHuPH20 at approximately 2,000 U / mL; Approximately 10 mM histidine; Approximately 300 mM sorbitol; Approximately 0.04% (w / v) PS-20; and Approximately 1 mg / mL of methionine, with a pH of approximately 5.6.

[0770] Example 257. A kit comprising a pharmaceutical composition as described in any one of Examples 241 to 256. [Example]

[0771] The following examples are provided to further describe some of the embodiments disclosed herein. These examples are intended to illustrate, and not limit, the disclosed embodiments. [General Materials and Methods] [Antibodies and Reagents]

[0772] The anti-BCMA / anti-CD3 antibody JNJ-957 (described in WO2017031104A1) and daclatasab were manufactured by Janssen Pharmaceuticals. CNTO7008 (CD3x empty), BC3B4 (BCMAx empty), and 3930 (IgG isotype control) were all manufactured by Janssen Pharmaceuticals and were used as control antibodies. JNJ-957 is also known as JNJ-7957.

[0773] JNJ-957 contains the BCMA-binding arm BCMB69 and the CD3-binding arm CD3B219, whose amino acid sequences are shown in […]. [surface] [3] [and table] [4] [surface] [3.] area Sequence SEQ ID NO: BCMB69 HCDR1 SGSYFWG 23 HCDR2 SIYYSGITYYNPSLKS 24 [[ID=1,8]] HCDR3 HDGAVAGLFDY 25 LCDR1 GGNNIGSKSVH 26 LCDR2 DDSDRPS 27 LCDR3 QVWDSSSDHVV 28 VH QLQLQESGPGLVKPSETLSLTCTVSGGSISSGSYFWGWIRQPPGKGLEWIGSIYYSGITYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARHDGAVAGLFDYWGQGTLVTVSS 29 VL SYVLTQPPSVSVAPGQTARITCGGNNIGSKSVHWYQQPPGQAPVVVVYDDSDRPSGIPERFSGSNSGNTATLTISRVEAGDEAVYYCQVWDSSSDHVVFGGGTKLTVLGQP 30 HC QLQLQESGPGLVKPSETLSLTCTVSGGSISSGSYFWGWIRQPPGKGLEWIGSIYYSGITYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARHDGAVAGLFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK 31 LC SYVLTQPPSVSVAPGQTARITCGGNNIGSKSVHWYQQPPGQAPVVVVYDDSDRPSGIPERFSGSNSGNTATLTISRVEAGDEAVYYCQVWDSSSDHVVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKGDSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 32 [Table] [4.] Region Sequence SEQ ID NO: CD3B219 HCDR1 TYAMN 33 HCDR2 RIRSKYNNYATYYAASVKG 34 HCDR3 HGNFGNSYVSWFAY 35 LCDR1 RSSTGAVTTSNYAN 36 LCDR2 GTNKRAP 37 LCDR3 ALWYSNLWV 38 VH EVQLVESGGGLVQPGGSLRLSCAASGFTFNTYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAASVKGRFTISRDDSKNSLYLQMNSLKTEDTAVYYCARHGNFGNSYVSWFAYWGQGTLVTVSS 39 VL QTVVTQEPSLTVSPGGTVTLTCRSSTGAVTTSNYANWVQQKPGQAPRGLIGGTNKRAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCALWYSNLWVFGGGTKLTVLGQP 40 HC EVQLVESGGGLVQPGGSLRLSCAASGFTFNTYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAASVKGRFTISRDDSKNSLYLQMNSLKTEDTAVYYCARHGNFGNSYVSWFA YWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESK YGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEK TISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK 41 LC QTVVTQEPSLTVSPGGTVTLTCRSSTGAVTTSNYANWVQQKPGQAPRGLIGGTNKRAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCALWYSNLWVFGGGTKLT VLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 42 [Bone marrow and peripheral blood mononuclear cells]

[0774] Peripheral blood mononuclear cells (PBMCs) from healthy donors and MM patients, and bone marrow mononuclear cells (BM-MNCs) from BM aspirates from MM patients were isolated by Ficoll-Hypaque density gradient centrifugation. [Cell lines and cultures]

[0775] Luciferase (LUC)-transduced multiple myeloma cell lines UM9, RPMI8226, U266, and MM1.S, as well as non-transduced multiple myeloma cell lines NCI-H929 and RPMI8226, were cultured in RPMI 1640 (Invitrogen) supplemented with 10% fetal bovine serum (FBS; Lonza) and antibiotics (100 units / mL penicillin and 100 µg / mL streptomycin; both from Life Technologies). [From] [MM] [Flow cytometric analysis of patient bone marrow and blood samples]

[0776] BM localized MM cell lines were identified and analyzed for cell surface marker expression levels by staining with HuMax-003 (CD38) FITC (this antibody binds to a different epitope than daclatas (Janssen Pharmaceuticals)), CD138 PE, CD56 PC7, CD45 Krome Orange (all from Beckman Coulter), CD269 (BCMA) APC (Biolegend), CD274 (PD-L1) BV421, and CD19 APC-H7 (both from Becton Dickinson) at 1.0 x 10⁶ cells / mL. BM or PB immune cell subsets were identified and analyzed for cell surface marker expression levels using staining at 1.0 x 10⁶ cells / mL with CD45 Krome Orange, CD56 PC7 (both from Beckman Coulter), CD14 APC-H7, CD19 APC-H7, CD3 V450, CD4 APC-H7 or PE, CD8 FITC, CD45-RA APC, CD127 PE.Cy7, CD62L PE, CD274 (PD-1) BV421, CD16 APC, HLA-DR APC-H7 (all from Becton Dickinson), and CD25 PE (Dako). All BM samples were analyzed within 24 hours of collection.

[0777] Flow cytometry was performed using a 7-laser LSFORTESSA (Becton Dickinson). The performance of the flow cytometry system was monitored and validated daily using fluorescent indicator beads (CS&T beads, Becton Dickinson). [Optical path and fluid flow] (stream flow) [。] This procedure provides controlled, standardized results and allows for the assessment of long-term drift and incidental changes within the flow cell analyzer. No changes that could affect the results were observed. [Using compensation beads to determine spectral overlap, using...] [Diva] [Software automatically calculates compensation.] Flow cytometry data were analyzed using FACS Diva software. [Based on flow cytometry] [BM-MNC] [Extracorporeal] [( , ex vivo , ) ] [Pyrolysis Detection]

[0778] BM-MNCs derived from MM patients containing tumor cells were used in the lysis assay, but autologous effector cells were also used. Sample viability in culture exceeded 98%, as assessed using 7-AAD (Becton Dickinson). For the lysis assay, BM-MNCs were cultured with a control antibody or JNJ-957 (0.0064 to 4.0 µg / mL) and / or daclatasab (10 µg / mL) in 96-well U-plates in RPMI + 10% fetal bovine serum for 48 hours. The survival of primary CD138+ MM cells in BM-MNCs was determined by flow cytometry as previously described (van der Veers et al., Haematologica. 2011;96(2):284-290; van der Veer MS et al., Blood Cancer J. 2011;1(10):e41; Nijhof IS et al., Leukemia2015;29(10):2039-2049; Nijhof IS, et al., Blood2016;128(7):959-970.). In both assays, the absolute number of surviving MM cells was determined by single-platform flow cytometry analysis of CD138+ cells in the presence of a flow counting fluorescent ball (Beckman Coulter) and a LIVE / DEAD-fixable dead cell staining near-infrared fluorescent reactive dye (Invitrogen). The percentage of lysis induced by JNJ-957 was then calculated using the following formula: MM cell lysis% = 1 - (absolute number of CD138+ cells surviving in the presence of JNJ-957 / absolute number of CD138+ cells surviving in untreated wells) × 100%.

[0779] JNJ-957-induced activation and degranulation of CD4+ and CD8+ T cells were analyzed by flow cytometry to detect the surface expression of CD25 and CD107a cells, respectively. [Based on flow cytometry] [PB MNC] [As effector cells] [MM] [Cell line lysis test]

[0780] BCMA-positive MM cell lines were co-cultured with PB MNCs from healthy donors or MM patients at an effector-to-target ratio of 9:1 in 96-well U-plates for 48 hours in the presence of control antibody or JNJ-957 (0.00256 to 4.0 µg / mL). MM cell viability was determined by flow cytometry as described above. [Based on bioluminescent imaging] [(BLI)] [Usage] [LUC] [Transduced] [MM] [Cell line lysis assay]

[0781] LUC-transduced MM cell lines were cultured for 16 hours in the presence or absence of pooled BM stromal cells (BMSCs) from newly diagnosed MM patients (n=12). They were then cultured for 48 hours in 96-well Greiner-Bio-One plates with effector cells (freshly isolated PBMCs from healthy donors) at an effector-to-target ratio of 9:1 and serially diluted JNJ-957 (0.00256 to 4.0 µg / mL) or control antibody. LUC+-MM cell viability was then determined by BLI 10 minutes after the addition of promega-957 (150 µg / mL). MM cell lysis was determined using the following formula: Lysis% = 1 - (mean BLI signal in effector cells and JNJ-957 / mean BLI signal in effector cells in untreated wells) × 100%.

[0782] To evaluate the effect of pretreatment of PB MNCs with daclazab monotherapy on the efficacy of JNJ-957 in vivo, LUC-transduced MM cell line 4 was co-cultured with PB MNCs obtained from MM patients before the initiation of daclazab monotherapy and at the time of best response to daclazab monotherapy (effectant to target ratio 9:1). BLI assays were performed as previously described. [Cytogenetic Analysis]

[0783] Cytogenetic abnormalities were assessed in purified MM cells using fluorescence in situ hybridization (FISH) and single nucleotide polymorphism (SNP) arrays. High-risk diseases were defined by the presence of del(17p), del(1p), ampl(1q), t(4;14), or t(14;16) 2. [Soluble] [BCMA] [Verification]

[0784] Soluble BCMA (sBCMA) was measured in cell culture supernatant using an MSD GOLD™ 96-well small spot streptavidin SECTOR plate (Meso Scale Diagnostics) according to the manufacturer's recommended procedure. [Granule-dissolving enzyme] [B] [Verification]

[0785] Granulase B was measured in cell culture supernatant using the MSD R-Plex Granulase B Assay Plate (Meso Scale Diagnostics) according to the manufacturer's specifications. [Multi-cytokine assay]

[0786] Interleukins [interferon-γ (IFN-γ), interleukin (IL)-2, IL-6, IL-8, IL-10, and tumor necrosis factor-α (TNF-α)] in cell culture supernatant were analyzed using V-Plex Pro-inflammatory Plate 1 Human Kit (Meso Scale Diagnostics) according to the manufacturer's specifications. [statistics]

[0787] If the data do not follow a normal distribution, comparisons between variables are performed using a two-tailed (paired) Student's t-test, Mann-Whitney U test, or Wilcoxon paired sign rank test. The Spearman rank correlation coefficient is used to determine the correlation between variables. A p-value below 0.05 is considered significant. Taking the combination therapy of JNJ-957 and daclamab as an example, the expected cleavage value is calculated using the following formula to test the null hypothesis that there is only an additive effect between JNJ-957 and daclamab: Expected cleavage % = (Cleavage % of JNJ-957 + Cleavage % of daclamab) - (Cleavage % of JNJ-957 x Cleavage % of daclamab), as described previously in 20, 23, 24. If the observed value is significantly higher than the expected value (P < 0.05), the null hypothesis of an "additive effect" is rejected. [Example] [1] [anti] [BCMA / ] [anti] [CD3] [Antibody] [JNJ-957] [The medium] [BCMA, + , ] [Multiple myeloma cell line lysis] [T] [Cell activation and degranulation]

[0788] JNJ-957 for media RPMI8226 ( [picture] [1]), UM9 [picture] [2]), U226 [picture] [3]) and MM1.S( [picture] [4]) The effector effect of multiple myeloma cell line lysis was assessed using peripheral blood mononuclear cells from healthy donors (HD) as effector cells at JNJ-957 concentrations ranging from 0.00128 to 4.0 µg / mL. Depending on the cell lines seen in Figures 1, 2, 3, and 4, JNJ-957 mediated the lysis of all tested cell lines in a dose-dependent manner and achieved near 100% maximum efficacy at an antibody concentration of approximately 0.1 µg / mL.

[0789] Previous studies have shown that BMSCs protect MM cells against various anti-MM agents, including daclatasab and MM-reactive T cells. Therefore, the potential impact of BMSC-MM cell interactions on the efficacy of JNJ-957 was assessed. The activity of JNJ-957 against 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 moderately inhibited by BMSCs in MM1.S cells at lower concentrations (P < 0.0001), this effect was completely eliminated with increasing JNJ-7957 dosage.

[0790] T cell activation was assessed in the RPMI 8226 cell line. Treatment with JNJ-957 resulted in activation and degranulation of both CD4+ and CD8+ T cells in a dose-dependent manner, as evidenced by increased cell surface expression of CD25 and CD107a, or the proportion of double-positive CD25 and CD107a cells. [picture] [5] Shows the percentage of CD25+ CD4 T cells increased by JNJ-957 mediator. [picture] [6] Shows the percentage of CD107a+ CD4 T cells increased by JNJ-957 mediator. [picture] [7] Shows the percentage of double-positive CD25+CD107+CD4 T cells increased by JNJ-957 mediator. [picture] [8] shows the percentage of CD25+ CD8 T cells increased by JNJ-957 mediator. [picture] [9] shows the percentage of CD107a+ CD8 T cells increased by JNJ-957 mediator. [picture]

[10] showed that JNJ-957 mediators increased the percentage of double-positive CD25+CD107+CD8 T cells. [Example] [2] [Dalamumab Improvement] [T] [Efficacy of Cell Redirecting Antibodies] [patient]

[0791] BCMA performance levels, immune cell subset composition, and ex vivo efficacy of JNJ-957 were assessed in 55 peripheral blood aspirates obtained from 11 newly diagnosed MM patients, 21 daclamab-initial relapsed / refractory MM patients, and 17 daclamab-refractory / refractory MM patients (daclamab-relapsed / refractory patients were enrolled in the Phase 1 and Phase 2 studies of the combination of daclamab and all-trans retinoic acid (ATRA); clinical trial identifier NCT02751255) and primary plasma cell leukemia (pPCL; n=6). Sequential BM samples were obtained from 8 patients treated in the DARA / ATRA study before immediate initiation of daclamab monotherapy and at the time of disease progression during daclamab treatment. In the same study, we obtained sequential peripheral blood samples from 10 patients before immediate initiation of daclamab monotherapy and at the time of achieving maximum daclamab response.

[0792] In the DARA / ATRA study (NCT02751255), patients with MM required systemic therapy and were relapsed or refractory to ≥2 prior lines of therapy. Patients were ≥18 years old, had a life expectancy of ≥3 months, a WHO performance status ≤2, and measurable disease.

[0793] During the first phase of the study, daclamab was administered according to the recommended dosage and schedule (16 mg / kg weekly for 8 weeks, followed by 2 weeks for 16 weeks, and then every 4 weeks until PD). The procedures were approved by the research center's ethics committee or human trial review committee, and were conducted in accordance with the principles of the Declaration of Helsinki, the International Council for the Coordination of Pharmaceutical Regulatory Affairs (ICCRA), and the Good Clinical Practice (GCP) guidelines. Written informed consent was given to all patients.

[0794] Baseline characteristics of patients enrolled in the Phase 1 and Phase 2 studies NCT02751255 are shown in Tables 5 and 6. RRMM patients had received an average of 5 prior lines of therapy (range 1 to 9) and RRMM dara R patients had received an average of 6 prior lines of therapy (range 3 to 12). [surface] [7] Shows an updated summary of baseline characteristics of patients enrolled in the Phase 1 and Phase 2 studies. [surface] [5.] [NDMM] [n=11] [RRMM] [n=19] [RRMM dara R] [n=15] Age, median (scope) 66 (31-80) 66 (46-77) 68 (48-80) Gender, Male n (%) 5 (46) 11 (58) 9 (60) M protein, n (%) - IgG - IgA - FLC only 5 (46) 0 6 (55) 13 (68) 0 6 (32) 11 (73) 2 (13) 2 (13) NDMM: Newly diagnosed multiple myeloma RRMM: Relapsed / Refractory Multiple Myeloma RRMM:daraR Daclazab-refractory multiple myeloma [surface] [6.] RRMM n=19 RRMM dara R n=15 Frontline n (range) 5 (1 - 9) 6 (3 - 12) Exposure n (%) Refractory n (%) Exposure n (%) Refractory n (%) Lenalidomide 16 (84) 16 (84) 15 (100) 15 (100) Bortezomib 14 (74) 14 (74) 14 (93) 9 (60) pomalidomide 12 (63) 12 (63) 10 (67) 10 (67) Carfilzomi 5 (21) 4 (21) 4 (26) 4 (26) Dalamab 0 0 15 (100) 15 (100) [surface] [7.] [parameter] [NDMM] n=11 [RRMM] [patient,] [dara-] [initial] n = 21 [RRMM] [patient,] [dara-] [Treatment refractory] n=17 [pPCL] n=6 Median age, in years (range) 66 (31 - 80) 66 (46 - 77) 68 (48 - 80) 65 (57-98) Gender, Male, n (%) 5 (45) 11 (52) 9 (53) 2 (33) [M] [Protein Type] - IgG, n (%) - IgA, n (%) - FLC,n (%) only - Unknown 5 (45) 0 6 (55) 0 15 (71) 1 (5) 5 (24) 0 13 (76) 2 (12) 2 (12) 0 2 (33) 0 3 (50) 1 (17) [Cytogenetics] [n (%) - High risk* - Standard Risk - Unrated 5 (45) 5 (45) 1 (9) 12 (57) 7 (33) 2 (10) 9 (53) 5 (29) 3 (18) 3 (50) 1 (17) 2 (33) Previous line therapy, n (range) 0 3 (1 - 9) 6 (3 - 12) 0 [Recent Treatment] - No treatment - Based on PI - Based on IMiD - PI + IMiD - Dalamumab 11 (100) 0 0 0 0 0 2 (10) 15 (71) 4 (19) 0 0 0 1 (6)# 1 (6)# 15 (88) 6 (100) 0 0 0 0 Lenalidomide - Exposure, n (%) - Refractory**, n (%) na 19 (90)§ 18 (86) 17 (100) 17 (100) na Bortezomib - Exposure, n (%) - Refractory**, n (%) na 17 (81)† 10 (48) 16 (94)‡ 11 (65) na Pomalidomide refractory**, n (%) na 13 (62) 10 (59) na Carfilzomib refractory**, n (%) na 4 (19) 4 (24) na Dalamab refractory**, n (%) na 0 17 (100) na Erotozumab refractory**, n (%) na 2 (10) 1 (6) na Ixazomib refractory **, n (%) na 1 (5) 1 (6) na [*] High-risk diseases are defined by the presence of del(17p), del(1p), ampl(1q), t(4;14), or t(14;16). [**]According to the internationally unified response criteria for multiple myeloma, refractory disease is defined as progressive disease during the treatment period, no response (less than PR), or progressive disease within 60 days of stopping treatment. #BM aspirates were obtained immediately upon the onset of progressive disease during daclazat monotherapy (n=15), however, two BM samples were obtained 22 and 48 months after progression during daclazat monotherapy, and after 3 and 5 other lines of therapy, respectively. §Additionally, one of the 19 patients was lenalidomide intolerant; †Additionally, 4 of the 17 patients were intolerant to bortezomib; ‡Additionally, 3 of the 16 patients were intolerant to bortezomib; Abbreviations: MM, Multiple myeloma; NDMM, Newly diagnosed MM; RRMM, Relapsed / Refractory MM; Dara, Dalatumab; pPCL, Primary plasma cell leukemia; n, Quantity; IgG, Immunoglobulin G; IgA, Immunoglobulin A; FLC, Free Light Chain; del, Deletion; amp, Amplification; t, Translocation; PI, Proteasome Inhibitor; IMiD, Immunomodulatory Drug; [result]

[0795] Dalamumab mediates the effective lysis of MM cells from newly diagnosed (NDMM) and relapsed / refractory dalamumab-initialized patients; however, cells from RRMM dalamumab-refractory patients are resistant to lysis. [picture]

[11] ).

[0796] In newly diagnosed (ND) MM patient samples (n=8), JNJ-957 4.0 µg / mL resulted in a mean lysis rate of 79% for MM cells (range: 66 to 92%). [picture]

[12] ). Similar MM cleavage (but with greater variability) was achieved in lenalidomide (LEN) refractory patient samples (n=15; mean cleavage at 4.0 µg / mL: 69%; range: 24 to 98%). [picture]

[13] ), they were also refractory to bortezomib (73%), pomalidomide (82%) and carfilzomib (9%). JNJ-957 was also effective in samples from daclatasab (DARA) refractory MM patients (n=11; mean cleavage at 4.0 µg / mL: 83%; range: 52 to 99%). [picture]

[14] ). NK and T cell frequencies were unaffected in any test sample.

[0797] The CD3x empty and BCMAx empty control antibodies showed significantly reduced activity compared to JNJ-957 in different patient samples, indicating the need for MM cell and effector T cell crosslinking and the absence of a direct effect of BCMA blockade.

[0798] JNJ-957-mediated lysis of primary MM cells was associated with a dose-dependent increase in the percentage of activated CD4+ and CD8+ T cells, as assessed by the expression of the CD25 activation antigen. JNJ-957 treatment also led to degranulation of CD4+ and CD8+ T cells, as determined by the expression of CD107a on the cell surface. There were no differences in the degree of T cell activation and degranulation among patients with NDMM, daclatasab-naïve RRMM, and daclatasab-refractory RRMM. [picture]

[15] shows that JNJ-957 mediators increase the percentage of CD25+ CD4 T cells. [picture]

[16] shows the percentage of CD107a+ CD4 T cells increased by JNJ-957 mediator. [picture]

[17] showed that JNJ-957 mediators increased the percentage of double-positive CD25+CD107+CD4 T cells. [picture]

[18] shows that JNJ-957 mediators increase the percentage of CD25+ CD8 T cells. [picture]

[19] shows the percentage of CD107a+ CD8 T cells increased by JNJ-957 mediator. [picture]

[20] showed that JNJ-957 mediators increased the percentage of double-positive CD25+CD107+CD8 T cells.

[0799] The levels of granilase B and various cytokines in the supernatant of BM-MNC from daclazat-naïve and daclazat-refractory RRMM patients treated with JNJ-957 were also evaluated. JNJ-957-mediated T cell activation led to a dose-dependent increase in granilase B, IFN-γ, IL-2, IL-6, IL-8, IL-10, and TNF-α levels (data not shown).

[0800] The efficacy of JNJ-957 in killing MM cells was not associated with tumor characteristics (BCMA or PD-L1 expression, presence of standard or high-risk cytogenetic abnormalities) or patient characteristics such as the effector cell:target ratio, T cell system composition, or PD-1 / HLA-DR expression on T cells. However, when analyzed separately for patient categories, BCMA ( [picture]

[21] ) and PD-L1 ( [picture]

[22] The expression level of JNJ-957 was significantly higher in RRMM patients (compared to NDMM patients), regardless of daclazat exposure. Although the number of patients was small, the activity of JNJ-957 was inversely correlated with the PD-L1 expression level in daclazat-naïve RRMM patients (P=0.045).

[0801] The composition of immune cells in NDMM, daclatasab-naïve RRMM, and daclatasab-naïve RRMM BM aspirate samples was evaluated to understand the differential effect of JNJ-957 in samples obtained from three patient subgroups. In the combined patient cohort, high T cell frequency (P=0.034) and high E:T ratio (P=0.029) were associated with enhanced JNJ-7957-mediated MM cell lysis. Other immune parameters (number of T cells, Tregs, PD-1+ T cells, HLA-DR+ T cells, or naïve T cells) did not affect JNJ-7957-mediated MM cell lysis.

[0802] In subgroup analysis, RRMM patients had a significantly higher frequency of Tregs compared to NDMM patients. [picture]

[23] ) and activated T cells (defined by HLA-DR expression) [picture]

[24] ), and a reduced frequency of naïve T cells. Furthermore, daclatasab-refractory patient samples contained significantly more TEMRA T cells than daclatasab-naïve samples. [picture]

[25] However, in this subgroup analysis, the frequency of activated, naive, central memory (CM), effector memory (EM), or TEMRA T cells was not correlated with the response to JNJ-7957. A high baseline percentage of Tregs indicated a negative impact on JNJ-957-mediated MM cell lysis in RRMM patient samples, which was overcome by optimal administration. NDMM mediated by autologous effector cells ( [picture]

[26] ), dalatumab initial RRMM ( [picture]

[27] ) and dabrasumab-refractory RRMM ( [picture]

[28] JNJ-597-mediated lysis in patient samples was assessed as autologous effector cells didifferentiating according to the baseline percentage of Tregs. Samples were categorized as "low" or "high" using the 50th percentile: NDMM: Low: ≤7.34%, High: >7.34%. Dalamumab-naïve RRMM: Low ≤15.57%, High >15.57%. Dalamumab-refractory RRMM: Low ≤11.24%, High >11.24%. Higher Treg concentrations reduced JNJ-957-mediated MM cell lysis in both dalamumab-naïve and dalamumab-refractory RRMM samples. The Treg effect was eliminated at higher JNJ-957 concentrations.

[0803] The proportion of PD-1+ T cells and the E:T ratio were similar across the three patient cohorts. Only in patients with NDMM did low-frequency T cells (P=0.010) and high-frequency PD-1+ T cells (P=0.048) impair JNJ-957-mediated MM cell lysis (data not shown).

[0804] The efficacy of daclatamab treatment against JNJ-957 was assessed by evaluating the lysis of JNJ-957-mediated tumor cells after 48 hours of culture in BM samples from patients with NDMM (n=9), daclatamab-naïve RRMM (n=18), and daclatamab-refractory RRMM (n=13). At relatively low concentrations of JNJ-957 (0.0064 to 0.032 µg / mL), tumor cell lysis was significantly better in daclatamab-exposed patients compared to both daclatamab-naïve RRMM and NDMM patients. [picture]

[29] Percentage of lysis in the patient population is shown. Data are presented as mean ± SEM, and p-values ​​were calculated using the Student's t-test.

[0805] Since improved tumor reduction may be aided by the recently discovered immunostimulatory effects of DARA, sequential BM aspirates from MM patients before and after DARA treatment were analyzed (n=5). Here we observed comparable BCMA performance in samples obtained after disease progression during DARA compared to samples obtained before DARA initiation, but with improved JNJ-957 MM cell lysis (mean lysis at 4.0 µg / mL: 93% vs. 74%). [picture]

[30] ). In these BM aspirates, Treg( [picture]

[31] ) and CD4+ cells ( [picture]

[32] ) The percentage of CD8+ cells decreased slightly, however [picture]

[33] ) The percentage of patients initially treated with daclazatumab was increased compared to those initially exposed to daclazatumab. In this study, the sample consisted of patients whose median duration of daclazatumab monotherapy was 3 (1 to 7) months. In a follow-up study of 8 RRMM patients, the percentage of CD38+Treg and Breg was significantly reduced in dara-refractory patients compared to those initially treated with daclazatumab (data not shown).

[0806] The JNJ-957-mediated RPMI 8226 multiple myeloma cell line lysis assay used sequential PB MNC samples from RRMM patients before and during daclazab treatment as effector cells. Dara-exposed PB MNCs were patients who achieved a good response (partial response, very good partial response, or complete response) during daclazab treatment, with a median daclazab treatment duration of 11 months (range 7 to 14 months). [picture]

[34] showed that RPMI 8226 lysis of JNJ-957 mediators was enhanced using PB MNCs from dara-exposed patients. In PB-MNC samples, Treg( [picture]

[35] ) and CD4+ cells ( [picture]

[36] ) The percentage of CD8+ cells decreased slightly, however [picture]

[37] ) The percentage of patients initially treated with daclazat was higher than that of patients initially treated with daclazat. In this study, the sample consisted of patients whose median duration of daclazat treatment was 3 (1 to 7) months.

[0807] The efficacy of combining JNJ-957 with dabranumab in killing MM cells from NDMM or RRMM dara patients was also tested. [picture]

[38] Percentage of blast-mediated mitotic resorption (BM) cells in newly diagnosed non-tumor mitotic resorption (NDMM) (n=8) patients lysed after 48 hours of treatment with JNJ-957 (0.032 to 0.8 µg / mL) alone or in combination with daclatasab 10 µg / mL. Observed (obs) MM cell lysis levels with JNJ-957 and daclatasab were compared with expected (exp) lysis levels, which were calculated based on the assumption of a combined effect achieved by an additive effect as described in the methods. Black bars represent group mean ± SEM. P-values ​​were calculated using the paired Student's t-test. [picture]

[39] shows the percentage of BM MNC lysis in patients with initial RRNN dara. [picture]

[40] shows the percentage of BM MNC lysis in RRMM dabramumab refractory patients.

[0808] Therefore, studies have shown that JNJ-957 is effective in newly diagnosed and heavily pretreated MM patients. High percentage or modulating T cells negatively impact the efficacy of JNJ-957 at low doses; however, these negative effects are overcome by increasing the dose of JNJ-957. In vivo daclatasab pretreatment enhances the efficacy of JNJ-957 against MM cells.

[0809] The in vitro combination of JNJ-957 and daclazab showed additive efficacy; in addition, in vitro pretreatment of daclazab amplified the in vitro efficacy of BCMAxCD3. [Example] [3] [Dalamumab treatment enhances the in vitro efficacy of lantumab]

[0810] To assess whether daclazat therapy also benefits other T-cell redirection therapies, CD19+ Raji cell lines were treated with lantumuzumab (FDA-approved CD19xCD3 BiTE for the treatment of acute lymphoblastic leukemia) using paired daclazat-naïve and daclazat-exposed PB-MNCs from 11 MM patients. Similar to observations in JNJ-957, lantumuzumab activity was significantly enhanced by co-culturing with daclazat-exposed PB-MNCs compared to daclazat-naïve PB-MNCs (P<0.0001). [picture]

[41] ). Lantomosumab contains The amino acid sequence of [SEQ ID NO: 53]. [SEQ ID NO: 53] DIQLTQSPASLAVSLGQRATISCKASQSVDYDGDSYLNWYQQIPGQPPKL LIYDASNLVSGIPPRFSGSGSGTDFTLNIHPVEKVDAATYHCQQSTEDPW TFGGGTKLEIKGGGGGSGGGGSGGGGSQVQLQQSGAELVRPGSSVKISCKA SGYAFSSYWMNWVKQRPGQGLEWIGQIWPGDGDTNYNGKFKGKATLTADE SSSTAYMQLSSLASEDSAVYFCARRETTTVGRYYYAMDYWGQGTTVTVSS GGGGSDIKLQQSGAELARPGASVKMSCKTSGYTFTRYTMHWVKQRPGQGL EWIGYINPSRGYTNYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYY CARYYDDHYCLDYWGQGTTLTVSSVEGGSGGSGGSGGSGGVDDIQLTQSP AIMSASPGEKVTMTCRASSSVSYMNWYQQKSGTSPKRWIYDTSKVASGVP YRFSGSGSGTSYSLTISSMEAEDAATYYCQQWSSNPLTFGAGTKLELKHH HHHH [Example] [4 JNJ-957] [Effectively kills primary infections] [pPCL] [cell]

[0811] The in vitro activity of JNJ-957 was assessed in tumor cell lysis (BM) samples from 6 newly diagnosed pPCL patients (characterized by aggressive clinical behavior). In these pPCL samples, JNJ-957-mediated tumor cell lysis was similar to that observed in NDMM and daclatasab-naïve RRMM samples, but less than that observed in daclatasab-refractory RRMM patient samples (P=0.0014). [picture]

[42] ) Although the median E:T ratio in pPCL samples was approximately 8-fold lower than that in NDMM, pPCL showed better activation of both CD4+ (P=0.0040) and CD8+ T cells (P<0.0001), as well as better degranulation of CD8+ T cells (P=0.0141). Degranulation of CD4+ T cells was similar to that observed in NDMM.

[0812] BM-MNCs were obtained from six pPCL patients and cultured for 48 hours with JNJ-957 (0.0064 to 4.0 µg / mL) or control antibodies 3930, BC3B4, and 7008 (4.0 µg / mL). Flow cytometry was then used to analyze and identify surviving CD138+ tumor cells, as well as T cells and NK cells. Data are presented as mean cell lysis % ± SEM. All experiments were performed in duplicate. [Example] [5 GPRC5DxCD3] [Combination of bispecific antibody and daclatab]

[0813] To further evaluate whether daclazab treatment is also beneficial for other T-cell retargeting therapies, RPMI MM cell lines were treated with a GPRC5DxCD3 bispecific antibody using paired daclazab-naïve and daclazab-exposed PB-MNCs from 11 MM patients (samples were obtained from the same patients as described above). As controls, antibodies whose CD3 or GPRC5D binding VH / VL domains were replaced with zero (empty) domains binding to an unrelated antigen (gp120) were used (control mAb 3930 empty x empty, control mAb 7008 empty x CD3, control mAb GPRC5D x empty). Antibodies were tested at concentrations ranging from 0.00064 to 4.0 µg / ml. The GPRC5DxCD3 bispecific antibody mediated MM cell lysis in both daclazab-naïve and daclazab-refractory samples with similar potency. [picture]

[43] ).

[0814] The efficacy of the combination of GPRC5DxCD3 bispecific antibody and dabramab in killing MM cells obtained from NDMM or RRMM dara initial patients was also tested. [picture]

[44] The percentage of lysis of primary MM cells mediated by GPRC5DxCD3 bispecific antibody (0.0128 to 0.8 µg / mL) alone or in combination with daclatasab 0.1 µg / mL for 48 hours is shown. The observed (O) MM cell lysis level with GPRC5DxCD3 bispecific antibody and daclatasab was compared with the expected (E) lysis level, which was calculated based on the assumption of a combined effect achieved by an additive effect as described in the method. Black bars represent group mean ± SEM. P values ​​were calculated using the paired Student's t-test. Co-culture with daclatasab additively enhances MM cell lysis mediated by GPRC5DxCD3 bispecific antibody.

[0815] The GPRC5DxCD3 bispecific antibody comprises the GPRC5D binding arm GC5B596 and the CD3 binding arm CD3B219. The amino acid sequence of GC5B596 is shown below. [surface] [8]. The amino acid sequence of CD3B219 is shown in... [surface] [4]

[0816] The GPRC5DxCD3 bispecific antibody system used in the experiment is described in WO20180037651A1 and contains the following sequence: The GPRC5D binding domain includes HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 as specified in SEQ ID NOs 43, 44, 45, 446, 47, and 48, respectively; and the CD3 binding domain includes HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 as specified in SEQ ID NOs 33, 34, 35, 36, 37, and 38, respectively. The GPRC5D binding domain includes VH of SEQ ID NO: 49 and VL of SEQ ID NO: 50; and the CD3 binding domain includes VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40; and The first heavy chain (HC1) of SEQ ID NO: 51, the first light chain (LC1) of SEQ ID NO: 52, the second heavy chain (HC2) of SEQ ID NO: 41, and the second light chain (LC2) of SEQ ID NO: 42.

[0817] GPRC5DxCD3 bispecific antibody system IgG4 isotype.

[0818] HC1 includes S228P, F234A and L235A substitutions.

[0819] HC2 includes S228P, F234A, L235A, F405L and R409K as substitutes. [surface] [8.] PS3B27 area sequence SEQ ID NO: GC5B596 HCDR1 GYTMN 43 HCDR2 LINPYNSDTNYAQKLQG 44 HCDR3 VALRVALDY 45 LCDR1 KASQNVATHVG 46 LCDR2 SASYRYS 47 LCDR3 QQYNRYPYT 48 VH QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYTMNWVRQAPGQGLEWMGLINPYNSDTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARVALRVALDYWGQGTLVTVSS 49 VL DIQMTQSPSSLSASVGDRVTITCKASQNVATHVGWYQQKPGKAPKRLIYSASYRYSGVPSRFSGSGSGTEFTLTISNLQPEDFATYYCQQYNRYPYTFGQGTKLEIK 50 HC QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYTMNWVRQAPGQGLEWMGLINPYNSDTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARVALRVALDYWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK 51 LC DIQMTQSPSSSLSASVGDRVTITCKASQNVATHVGWYQQKPGKAPKRLIYSASYRYSGVPSRFSGSGSGTEFTLTISNLQPEDFATYYCQQYNRYPYTFGQGTKLE IKKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKGDSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 52 [Example] [6 T] [Cell Redirecting Therapy and Anti-] [CD38] [Antibody Combinations]

[0820] The effects of combining additional T-cell redirection therapy with anti-CD38 antibodies were assessed similarly to those described in Examples 1 through 5. The additive or synergistic effect of the combined T-cell redirection therapy on the killing of tumor cells targeted by the T-cell redirection therapy (i.e., tumor cells exhibiting antigens bound by the T-cell redirection therapy) was tested. The effect of anti-CD38 antibody pretreatment on the efficacy of T-cell redirection therapy was assessed as described in the examples herein.

[0821] T-cell redirection therapies tested in combination with anti-CD38 antibodies include PSMAxCD3, TMEFF2xCD3, CD123xCD3, and CD33xCD3 bispecific antibodies.

[0822] An illustrative PSMAxCD3 bispecific antibody system, PS3B27, comprises a PSMA binding domain PSMB127 and a CD3 binding domain CD3B219. [surface] [9] The amino acid sequence of PS3B27 is shown. The amino acid sequence of CD3B219 is shown in Table 4.

[0823] The exemplary PSMAxCD3 bispecific antibody used in the experiment contains the following sequence: The PSMA binding domain includes HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 54, 55, 56, 9, 10, and 59, respectively; and the CD3 binding domain includes HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 33, 34, 35, 36, 37, and 38, respectively. The PSMA binding domain includes VH of SEQ ID NO: 60 and VL of SEQ ID NO: 61; and the CD3 binding domain includes VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40; and The first heavy chain (HC1) of SEQ ID NO: 62, the first light chain (LC1) of SEQ ID NO: 63, the second heavy chain (HC2) of SEQ ID NO: 41, and the second light chain (LC2) of SEQ ID NO: 42.

[0824] Anti-PSMAxCD3 bispecific anti-IgG4 isotype.

[0825] HC1 includes S228P, F234A and L235A substitutions.

[0826] HC2 includes S228P, F234A, L235A, F405L and R409K as substitutes. [surface] [9.] area sequence SEQ ID NO: PSMB127 HCDR1 SDAMH 54 HCDR2 EISGSGGYTNYADSVKG 55 HCDR3 DSYDSSLYVGDYFDY 56 LCDR1 RASQSVSSYLA 9 LCDR2 DASNRAT 10 LCDR3 QQRSNWPLT 59 VH EVQLLESGGGLVQPGGSLRLSCAASGFTFKSDAMHWVRQAPGKGLEWVSEISGSGGYTNYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDSYDSSLYVGDYFDYWGQGTLVTVSS 60 VL EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGQGTKVEIK 61 HC EVQLLESGGGLVQPGGSLRLSCAASGFTFKSDAMHWVRQAPGKGLEWVSEISGSGGYTNYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDSYDSSLYVGDYFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK 62 LC EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 63

[0827] An illustrative example is the TMEFF2xCD3 bispecific antibody system TMCB150, which comprises the TMEFF2 binding arm TMEB762 and the CD3 binding arm CD3B376. [surface]

[10] Shows the amino acid sequence of TMEB762. [surface]

[11] Shows the amino acid sequence of CD3B376.

[0828] The exemplary TMEFF2xCD3 bispecific antibody system TMCB150 used in the experiment contains the following sequences: The TMEFF2 binding domain includes HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 as specified in SEQ ID NOs: 64, 65, 66, 67, 68, and 69, respectively; and the CD3 binding domain includes HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 as specified in SEQ ID NOs: 74, 75, 76, 77, 78, and 79, respectively. The TMEFF2 binding domain includes VH of SEQ ID NO: 70 and VL of SEQ ID NO: 71; and the CD3 binding domain includes VH of SEQ ID NO: 80 and VL of SEQ ID NO: 81; and The first heavy chain (HC1) of SEQ ID NO: 72, the first light chain (LC1) of SEQ ID NO: 73, the second heavy chain (HC2) of SEQ ID NO: 82, and the second light chain (LC2) of SEQ ID NO: 83.

[0829] Anti-TMEFF2xCD3 bispecific anti-IgG4 isotype system.

[0830] HC1 contains S228P, F234A, and L235A substitutions.

[0831] HC2 contains S228P, F234A, L235A, F405L, and R409K substitutions. [Table] [10.] Region Sequence SEQ ID NO: TMEB762 HCDR1 SYSMS 64 HCDR2 VISGSGGFTDYADSVKG 65 HCDR3 MPLNSPHDY 66 LCDR1 RASQGIRNDLG 67 LCDR2 AASSLQS 68 LCDR3 LQDYNYPLT​​​​​​​​​​​​​​​​ vqllesggglvqpggslrlscaasgftfssysmswvrqapgkglewvsvisgsggftdyadsvkgrftisrdnskntlylqmnslraedtavyycarmplnsphdywgqgtlvtvssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapeaaggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgk 72 LC diqmtqspsslsasvgdrvtitcrasqgirndlgwyqqkpgkapklliyaasslqsgvpsrfsgsgsgtdftltisslqpedfatyyclqdynypltfgggtkveikrtvaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec 73 [Table] [11.] <A Region Sequence SEQ ID NO: CD3B396 HCDR1 NNNAAWS 74 HCDR2 RTYYRSKWLYDYAVSVKS 75 HCDR3 GYSSSFDY 76 LCDR1 tgtssnigtykfvs 77 LCDR2 evskrps 78 LCDR3 Vsyagsgtll 79 VH QVQLQQSGPRLVRPSQTLSLTCAISGDSVFNNNAAWSWIRQSPSRGLEWLGRTYYRSKWLYDYAVSVKSRITVNPDTSRNQFTLQLNSVTPEDTALYYCARGYSSSFDYWGQGTLVTVSS 80 VL qsaltqpasvsgspgqsitisctgtssnigtykfvswyqqhpdkapkvllyevskrpsgvssrfsgsksgntasltisglqaedqadyhcVsyagsgtllfgggtkltvl 81 HC QVQLQQSGPRLVRPSQTLSLTCAISGDSVFNNNAAWSWIRQSPSRGLEWLGRTYYRSKWLYDYAVSVKSRITVNPDTSRNQFTLQLNSVTPEDTALYYCARGYSSSFDYWG QGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYG PPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKT ISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK 82 LC QSALTQPASVSGSPGQSITISCTGTSSNIGTYKFVSWYQQHPDKAPKVLLYEVSKRPSGVSSRFSGSKSGNTASLTISGLQAEDQADYHCVSYAGSGTLLFGGGTKLT VLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 83

[0832] An illustrative CD33xCD3 bispecific antibody system, C3CB189, comprises a CD33-binding arm, C33B904, and a CD3-binding arm, CD3B376. [surface]

[12] The amino acid sequence of C33B904 is shown. The amino acid sequence of CD3B376 is shown in... [surface]

[11]

[0833] The exemplary CD33xCD3 bispecific antibody system C3CB189 used in the experiment contains the following sequences: The CD33 binding domain includes HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 84, 85, 86, 87, 88, and 89, respectively; and the CD3 binding domain includes HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 74, 75, 76, 77, 78, and 79, respectively; The CD33 binding domain includes VH of SEQ ID NO: 90 and VL of SEQ ID NO: 91; and the CD3 binding domain includes VH of SEQ ID NO: 80 and VL of SEQ ID NO: 81; and The first heavy chain (HC1) of SEQ ID NO: 92, the first light chain (LC1) of SEQ ID NO: 93, the second heavy chain (HC2) of SEQ ID NO: 82, and the second light chain (LC2) of SEQ ID NO: 83.

[0834] Anti-CD33xCD3 bispecific anti-IgG4 isotype.

[0835] HC1 includes S228P, F234A and L235A substitutions.

[0836] HC2 includes S228P, F234A, L235A, F405L and R409K as substitutes. [surface] [12.] area sequence SEQ ID NO: C33B904 HCDR1 DYAMH 84 HCDR2 GIGWSGGSIVYADSVKG 85 HCDR3 DSPYGDFFDY 86 LCDR1 KSSQTVFYSSNNKNYLA 87 LCDR2 WASTRKS 88 LCDR3 QHYYSTPYT 89 VH EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGIGWSGGSIVYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKDSPYGDFFDYWGQGTLVTVSS 90 VL DIVMTQSPDSLAVSLGERATINCKSSQTVFYSSNNKNYLAWYQQKPGQPPKLLISWASTRKSGVPDRFSGSGSGTDFTLTVSSLQAEDVAVYYCQHYYSTPYTFGQGTKLEIK 91 HC EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGIGWSGGSIVYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKDSPYGDFFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK 92 LC DIVMTQSPDSLAVSLGERATINCKSSQTVFYSSNNKNYLAWYQQKPGQPPKLLISWASTRKSGVPDRFSGSGSGTDFTLTVSSLQAEDVAVYYCQHYYSTPYTFGQGT KLEIKKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKGDSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 93

[0837] An illustrative CD123xCD3 bispecific antibody system 8747 comprises a CD123 binding arm I3RB218 and a CD3 binding arm CD3B219. 8747 is described in WO2016036937A1. [surface]

[13] The amino acid sequence of I3RB218 is shown. The amino acid sequence of CD3B219 is shown in... [surface] [4]

[0838] The exemplary CD123xCD3 bispecific antibody system 8747 used in the experiment contains the following sequences: The CD123 binding domain includes HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 94, 95, 96, 9, 10, and 59, respectively; and the CD3 binding domain includes HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 33, 34, 35, 36, 37, and 38, respectively. The CD123 binding domain includes VH of SEQ ID NO: 100 and VL of SEQ ID NO: 61; and the CD3 binding domain includes VH of SEQ ID NO: 39 and VL of SEQ ID NO: 40; and The first heavy chain (HC1) of SEQ ID NO: 102, the first light chain (LC1) of SEQ ID NO: 63, the second heavy chain (HC2) of SEQ ID NO: 41, and the second light chain (LC2) of SEQ ID NO: 42.

[0839] Anti-CD123xCD3 bispecific anti-IgG4 isotype.

[0840] HC1 includes S228P, F234A and L235A substitutions.

[0841] HC2 includes S228P, F234A, L235A, F405L and R409K as substitutes. [surface] [13.] area sequence SEQ ID NO: I3RB218 HCDR1 GYWMH 94 HCDR2 AIRSDGSSKYYADSVKG 95 HCDR3 DGVIEDTFDY 96 LCDR1 RASQSVSSYLA 9 LCDR2 DASNRAT 10 LCDR3 QQRSNWPLT 59 VH EVQLLESGGGLVQPGGSLRLSCAASGFTFSGYWMHWVRQAPGKGLEWVSAIRSDGSSKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDGVIEDTFDYWGQGTLVTVSS 100 VL EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGQGTKVEIK 61 HC EVQLLESGGGLVQPGGSLRLSCAASGFTFSGYWMHWVRQAPGKGLEWVSAIRSDGSSKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDGVIEDTFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK 102 LC EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 63

[0842] To evaluate the effect of anti-CD38 antibody pretreatment on the tumor-killing efficacy of T-cell redirection therapy, tumor cells were isolated from individuals with tumors exhibiting antigens (such as CD123, CD33, PSMA, TMEFF2, and analogues) that bind to the T-cell redirection therapy, or from established tumor cell lines. Tumor cell killing was assessed in vitro by co-culturing tumor cells with PB-MNCs obtained from individuals initially exposed to or induced by anti-CD38 antibodies, as described in the examples, and the percentage of tumor cell lysis was assessed in each group. In separate examples, the T-cell redirection therapy and the anti-CD38 antibody system were cultured together or separately with target and effector cells, and the combination was evaluated against tumor cell killing mediated by the individual therapy.

[0843] The effect of anti-CD38 antibodies on the killing of CD123xCD3 bispecific antibody-mediated tumor cells is assessed using CD123-positive tumor cells such as AML tumors, or cell lines such as AML cell lines KG1a, HL60, or MOLM13 as target cells.

[0844] The effect of anti-CD38 antibodies on killing CD33xCD3 bispecific antibody-mediated tumor cells is assessed using CD33-positive tumor cells such as AML tumors, or cell lines such as AML cell lines KG1a, HL60, or MOLM13 as target cells.

[0845] The effect of anti-CD38 antibody on tumor cell killing mediated by TMEFF2xCD3 bispecific antibody was assessed using TMEFF2-positive tumor cells, such as LnCP cells, as target cells.

[0846] The effect of anti-CD38 antibody on tumor cell killing mediated by PSMAxCD3 bispecific antibody was assessed using TMEFF2-positive tumor cells, such as LnCP cells, as target cells.

[0847] Individual PBMCs or BM-MNCs isolated from individuals who have received anti-CD38 antibody or anti-CD38 antibody therapy as initial recipients are used as effector cells.

[0848] Those skilled in the art will recognize that many variations and modifications can be made to the preferred embodiments of the present invention without departing from the spirit of the invention. Therefore, the appended claims are intended to encompass all such equivalent variations, which fall within the true spirit and scope of the invention.

[0849] All patents, patent applications, and publications cited or described in this document are incorporated herein by reference in their entirety.

[0850]

[0851]

[0852]

[0853]

[0854]

[0855]

[0856]

[0857]

[0858]

[0859]

[0860]

[0861]

[0862]

[0863]

[0864]

[0865]

[0866]

[0867]

[0868]

[0869]

[0870]

[0871]

[0872]

[0873]

[0874]

[0875]

[0876]

[0877]

[0878]

[0879]

[0880]

[0881]

[0882]

[0883]

[0884]

[0885]

[0886]

[0887]

[0888]

[0889]

[0890]

[0891]

[0892]

[0893]

[0894]

[0895]

[0896]

[0897]

[0898]

[0899]

[0900]

[0901]

[0902]

[0903]

[0904]

[0905]

[0906]

[0907]

[0908]

[0909]

[0910]

[0911]

[0912]

[0913]

[0914]

[0915]

[0916]

[0917]

[0918]

[0919]

[0920]

[0921]

[0922]

[0923]

[0924]

[0925]

[0926]

[0927]

[0928]

[0929]

[0930]

[0931]

[0932]

[0933]

[0934]

[0935]

[0936]

[0937]

Claims

1. The use of a GPRC5DxCD3 bispecific antibody in the preparation of a medicament for treating cancer in an individual who has relapsed or is refractory to prior anticancer therapy, wherein the GPRC5DxCD3 bispecific antibody comprises a GPRC5D binding domain and a CD3 binding domain, the GPRC5D binding domain comprising HCDR1 of SEQ ID NO: 43, HCDR2 of SEQ ID NO: 44, HCDR3 of SEQ ID NO: 45, LCDR1 of SEQ ID NO: 46, LCDR2 of SEQ ID NO: 47, and LCDR3 of SEQ ID NO: 48, and the CD3 binding domain comprising HCDR1 of SEQ ID NO: 33, HCDR2 of SEQ ID NO: 34, HCDR3 of SEQ ID NO: 35, LCDR1 of SEQ ID NO: 36, LCDR2 of SEQ ID NO: 37, and LCDR3 of SEQ ID NO: 38, and wherein the cancer is multiple myeloma.

2. The use as described in claim 1, wherein the GPRC5DxCD3 bispecific antibody comprises VH of SEQ ID NO: 49 and VL of SEQ ID NO:

50.

3. The use as described in claim 1, wherein: The GPRC5D binding domain includes VH of SEQ ID NO: 49 and VL of SEQ ID NO: 50, and the CD3 binding domain includes VH of SEQ ID NO: 39 and VL of SEQ ID NO:

40.

4. The use as described in claim 1, wherein the GPRC5D binding field includes SEQ ID NO: 49, 50, 39 and 40.

5. The use as described in claim 1, wherein: The GPRC5DxCD3 bispecific antibody system is IgG4 isotype and contains phenylalanine at position 405 and arginine at position 409 in the first heavy chain (HC1), and leucine at position 405 and lysine at position 409 in the second heavy chain (HC2), wherein the residue numbers are based on the EU index.

6. The use as described in claim 5, 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.

7. The use as described in claim 1, wherein the GPRC5DxCD3 bispecific antibody comprises HC2 of SEQ ID NO: 41 and LC2 of SEQ ID NO:

42.

8. The use as described in claim 1, wherein 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.

9. The use as described in claim 1, wherein the multiple myeloma is a high-risk multiple myeloma.

10. The use as described in claim 9, wherein an individual with the 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.

11. The use as described in claim 1, wherein the individual is refractory or relapsed to treatment with anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, erlotuzumab, ixazomib, melphalan or thalidomide, or any combination thereof.

12. The use as described in claim 1, wherein the individual’s treatment with the anti-CD38 antibody is relapsed or refractory.

13. The use as described in claim 12, 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.

14. The use as described in claim 12, wherein the anti-CD38 antibody comprises VH of SEQ ID NO: 4 and VL of SEQ ID NO:

5.

15. The use as described in claim 12, wherein the anti-CD38 anti-system isotype IgG1.

16. The use as described in claim 12, wherein the anti-CD38 antibody comprises HC of SEQ ID NO: 12 and LC of SEQ ID NO:

13.

17. The use as described in claim 12, wherein the anti-CD38 antibody comprises: a) VH of SEQ ID NO: 14 and VL of SEQ ID NO: 15; b) VH of SEQ ID NO: 16 and VL of SEQ ID NO: 17; c) VH of SEQ ID NO: 18 and VL of SEQ ID NO: 19; or d) VH of SEQ ID NO: 20 and VL of SEQ ID NO:

21.

18. The use as described in claim 17, wherein the anti-CD38 anti-system isotype IgG1.

19. The use as described in any of claims 1-3, 13-16 or 17, wherein the system is human.

20. The use as described in any one of claims 1-3, 13-16 or 17 further comprises administering one or more anticancer therapies to the individual.

21. The use as described in claim 20, wherein: i) The 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; and / or ii) The one or more anticancer therapies are selected from lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, erlotuzumab, ixazomib, melphalan, dexamethasone, vincristine, cyclophosphamide, hydroxydaunorubicin, prednisone, rituximab, imatinib, dasatinib, nilotinib, bosutinib, ponatinib, bafetinib, saracatinib, tozasertib, or danusertib. The group consisting of ib), cytarabine, daunorubicin, idarubicin, mitoxantrone, hydroxyurea, decitabine, cladribine, fludarabine, topotecan, etoposide, 6-thioguanine, corticosteroids, methotrexate, 6-mercaptopurine, azacitidine, arsenic trioxide, and all-trans retinoic acid, or any combination thereof.

Images